My clinical focus is on diagnostic surgical pathology with emphasis on cardiopulmonary disease, head and neck pathology and gastrointestinal pathology. My research interests include cardiothoracic transplantation, vasculitis, myocarditis, interstitial lung disease and thoracic oncology.

Clinical Focus

  • Pathology and Laboratory Medicine
  • Anatomic and Clinical Pathology

Academic Appointments

Professional Education

  • Fellowship: Stanford University Pathology Fellowships (1991) CA
  • Residency: Stanford University Pathology Residency (1989) CA
  • Internship: Ottawa General Hospital (1985) Canada
  • Medical Education: University of Ottawa School of Medicine (1984) Canada
  • Board Certification: American Board of Pathology, Anatomic Pathology (1989)
  • Board Certification: Royal College of Physicians and Surgeons of Canada, Anatomic Pathology

Current Research and Scholarly Interests

Cardiopulmonary and pulmonary transplant medicine; diagnostic surgical pathology

Clinical Trials

  • Microarray Analysis of Gene Expression and Identification of Progenitor Cells in Lung Carcinoma Not Recruiting

    This study will help us understand the gene expression profiles of lung cancer. We will identify genes related to lung cancer development, their growth and metastasis to the lung. In addition, we will examine the role nicotine in the development and progression of lung tumors of smokers, ex-smokers, non-smokers on supplemental nicotine and non smokers with no exposure to nicotine.

    Stanford is currently not accepting patients for this trial. For more information, please contact Susan Jacobs, RN, 650-725-8082.

    View full details

2023-24 Courses

All Publications

  • Hepatitis B transmission/reactivation associated with Hepatitis B core antibody and Hepatitis C nucleic acid testing positive organs: A report from the Organ Procurement and Transplantation Network Disease Transmission Advisory Committee. Transplant infectious disease : an official journal of the Transplantation Society Te, H. S., Lee, D. H., Woolley, A. E., Abidi, M. Z., Fisher, C., Sellers, M. T., Taimur, S., Livelli, T., Watkins, T., Handarova, D., Berry, G. J., Graves, R., Ho, C. S., Hughart, A. L., Kittleson, M., Marboe, C. C., Miller, R. A., Sharma, T. S., Trindade, A. J., Wood, R. P., Zaffiri, L. N., Pouch, S. M., Danziger-Isakov, L. 2024: e14305


    Better access to direct-acting antiviral (DAA) therapy has broadened the utilization of hepatitis C virus (HCV) nucleic acid testing (NAT) positive organs with excellent outcomes. However, DAA therapy has been associated with hepatitis B virus (HBV) reactivation.To determine the risk of HBV transmission or reactivation with utilization of HBV core antibody positive (HBcAb+) and HCV NAT positive (HCV+) organs, which presumably required DAA therapy.The number of HBcAb+ donors with delineated HCV NAT status was obtained from the Organ Procurement and Transplantation Network (OPTN) database. The number of unexpected HBV infections from transplanted organs adjudicated as "proven" or "probable" transmission was obtained from the OPTN Ad Hoc Disease Transmission Advisory Committee database. A chart review of the donors of "proven" or "probable" cases was conducted.From January 1, 2016, to December 31, 2021, 7735 organs were procured from 3767 HBcAb+ donors and transplanted into 7469 recipients; 545 (14.5%) donors were also HCV+. HBV transmission or reactivation occurred in seven recipients. The rate is not significantly different between recipients of HCV+ (0.18%, 2/1115) and the HCV NAT negative (HCV-) organs (0.08%, 5/6354) (p = 0.28) or between recipients of HCV+ and HCV- livers as well as non-liver organs. HBV transmission or reactivation occurred within a median of 319 (range, 41-1117) days post-transplant in the setting of missing, inadequate, or truncated prophylaxis.HBV reactivation associated with DAA therapy for HBcAb+ HCV+ organs is less frequent than reported in the non-transplant population, possibly due to the common use of HBV prophylaxis in the at-risk transplant population.

    View details for DOI 10.1111/tid.14305

    View details for PubMedID 38881210

  • Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Renaud-Picard, B., Berra, G., Hwang, D., Huszti, E., Miyamoto, E., Berry, G. J., Pal, P., Juvet, S., Keshavjee, S., Martinu, T. 2024


    BACKGROUND: Long-term survival after lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types.METHODS: Peripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, as well as epithelial and vascular abnormalities.RESULTS: CLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in pathological scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p=0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes and airway fibrosis. Immunofluorescence staining demonstrated a trend towards a lower frequency of club cells in CLAD, and a higher frequency of apoptotic club cells in BOS samples (p=0.01).CONCLUSIONS: CLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathological changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD pathological assessments.

    View details for DOI 10.1016/j.healun.2024.04.002

    View details for PubMedID 38663465

  • The Histopathologic Features of Early COVID Pneumonia in a Pediatric Patient: New Insight into the Role of Macrophages INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Bulterys, P. L., Xu, G., Pinsky, B. A., Troxell, M. L., Menke, J. R., Berry, G. J., Fernandez-Pol, S., Hazard, F. K. 2024
  • Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators. Circulation. Heart failure Shah, P., Agbor-Enoh, S., Lee, S., Andargie, T. E., Sinha, S. S., Kong, H., Henry, L., Park, W., McNair, E., Tchoukina, I., Shah, K. B., Najjar, S. S., Hsu, S., Rodrigo, M. E., Jang, M. K., Marboe, C., Berry, G. J., Valantine, H. A. 2024: e011160


    Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA.The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death.We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome.Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients.URL:; Unique identifier: NCT02423070.

    View details for DOI 10.1161/CIRCHEARTFAILURE.123.011160

    View details for PubMedID 38375637

  • Higher Molecular Injury at Diagnosis of Acute Cellular Rejection Increases the Risk of Lung Allograft Failure. American journal of respiratory and critical care medicine Keller, M. B., Tian, X., Jang, M. K., Meda, R., Charya, A., Berry, G. J., Marboe, C. C., Kong, H., Ponor, I. L., Aryal, S., Orens, J. B., Shah, P., Nathan, S. D., Agbor-Enoh, S. 2024


    The association of acute cellular rejection (ACR) with chronic lung allograft dysfunction (CLAD) in lung transplant recipients has primarily been described prior to consensus recommendations incorporating restrictive phenotypes. Further, the association of the degree of molecular allograft injury during ACR with CLAD or death remains undefined.To investigate the association of ACR with the risk of CLAD or death. To further investigate if this risk depends on the degree of molecular allograft injury.This multicenter, prospective cohort study included 188 lung transplant recipients. Subjects underwent serial plasma collections for donor-derived cell-free DNA (dd-cfDNA) at prespecified time points and bronchoscopy. Multivariable Cox proportional hazards analysis analyzed the association of ACR with subsequent CLAD or death as well as the association of dd-cfDNA during ACR with risk of CLAD or death. Additional outcomes analyses were performed with episodes of ACR categorized as "high risk" (dd-cfDNA≥1%) and "low risk" (dd-cfDNA<1%).In multivariable analysis, ACR was associated with the composite outcome of CLAD or death (HR=2.07, 95% CI, 1.05-4.10, p=0.036). Elevated dd-cfDNA ≥1% at ACR diagnosis was independently associated with increased risk of CLAD or death (HR 3.32, 95% CI: 1.31 - 8.40, p=0.012). Patients with high risk ACR were at increased risk of CLAD or death (HR 3.13, 95% CI: 1.41 - 6.93, p=0.005) while patients with low-risk status ACR were not.Patients with ACR are at higher risk of CLAD or death, however, this may depend on the degree of underlying allograft injury on the molecular level.

    View details for DOI 10.1164/rccm.202305-0798OC

    View details for PubMedID 38190701

  • Organizing pneumonia is associated with molecular allograft injury and the development of antibody-mediated rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Keller, M. B., Tian, X., Jang, M. K., Meda, R., Charya, A., Ozisik, D., Berry, G. J., Marboe, C. C., Kong, H., Ponor, I. L., Aryal, S., Orens, J. B., Shah, P. D., Nathan, S. D., Agbor-Enoh, S. 2023


    The association between Organizing Pneumonia (OP) after lung transplantation with the development of acute rejection (AR) remains undefined. In addition, molecular allograft injury, as measured by donor-derived cell-free DNA (dd-cfDNA), during episodes of OP and its relationship to episodes of AR, chronic lung allograft dysfunction (CLAD) or death is unknown.This multicenter, prospective cohort study collected serial plasma samples from 188 lung transplant recipients for dd-cfDNA at the time of bronchoscopy with biopsy. Multivariable Cox regression was used to analyze the association between OP with the development of AR (antibody mediated rejection (AMR) and acute cellular rejection), CLAD and death. Multivariable models were performed to test the association of dd-cfDNA at OP with the risk of AR, CLAD or death.In multivariable analysis, OP was associated with increased risk of AMR (HR= 2.26, 95% CI 1.04-4.92, P =0.040) but not ACR (HR=1.29, 95% CI: 0.66 - 2.5, P = 0.45) or the composite outcome of CLAD or death (HR= 0.88, 95% CI, 0.47-1.65, P=0.69). Median levels of dd-cfDNA were higher in OP compared to stable controls (1.33% vs 0.43%, P = 0.0006). Multivariable analysis demonstrated that levels of dd-cfDNA at diagnosis of OP were associated with increased risk of both AMR (HR=1.29, 95% CI 1.03-1.62, P= 0.030) and death (HR=1.16, 95% CI, 1.02-1.31, P =0.026).OP is independently associated with an increased risk of AMR but not CLAD or death. The degree of molecular allograft injury at the diagnosis of OP may further predict the risk of AMR and death.

    View details for DOI 10.1016/j.healun.2023.11.008

    View details for PubMedID 37972825

  • The 2022 Banff Meeting Lung Report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Pavlisko, E. N., Adam, B. A., Berry, G. J., Calabrese, F., Cortes-Santiago, N., Glass, C. H., Goddard, M., Greenland, J. R., Kreisel, D., Levine, D. J., Martinu, T., Verleden, S. E., Sam, W. S., Roux, A. 2023


    The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference - held in Banff, Alberta - focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and impact on lung transplant outcomes were discussed. Key conclusions from discussion were 1) recognition of limitations in current standard of care assessment of lung allograft dysfunction 2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathological data, inclusive of all lesions associated with graft outcome (e.g., non-rejection pathology), and 3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

    View details for DOI 10.1016/j.ajt.2023.10.022

    View details for PubMedID 37931751

  • Neuroendocrine metastasis to the thyroid from unknown primary and extrathyroidal disease response to peptide receptor radionuclide therapy. Radiology case reports Khessib, T., Khessib, S., Berry, G., Aparici, M. 2023; 18 (11): 3945-3948


    Neuroendocrine tumor (NET) metastasis to the thyroid is rare, and its presentation as the first manifestation of primary malignancy elsewhere is even more uncommon. We present a case of a 41-year-old female who underwent biopsy of enlarging thyroid nodules with findings suspicious for medullary thyroid cancer (MTC). Subsequent thyroidectomy demonstrated NET of unknown primary in the left lower lobe. Immediate workup with 68Ga-DOTATATE-PET/CT revealed abnormal somatostatin receptor (SR) expressing lesions in the liver, right cervical nodes, thoracic paravertebral soft tissue, precoccygeal soft tissue, and right acetabulum concerning for sites of neuroendocrine malignancy. Due to disease progression while on octreotide injections, a decision was made at the multidisciplinary NET board for the patient to receive peptide receptor radionuclide therapy (PRRT) which includes 4 cycles of 77Lu-DOTATATE (Lutathera). The patient had no side effects nor toxicities during the 8 months of PRRT and achieved a partial treatment response in the early post-treatment scan at 6 weeks. This case illustrates the importance of distinguishing NET metastasis to the thyroid from MTC to ensure appropriate workup and treatment as well as predict the response of neuroendocrine malignancies to PRRT based on the visualized overexpression of SR in the SR-PET scans, despite the organ of origin.

    View details for DOI 10.1016/j.radcr.2023.07.044

    View details for PubMedID 37680654

  • Report of the 2022 Banff Heart Concurrent: Focus on Non-HLA Antibodies in Rejection and the Pathology of "Mixed" Rejection. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Fedrigo, M., Berry, G. J., Coutance, G., Reed, E. F., Lin, C. Y., Giarraputo, A., Kransdorf, E., Thaunat, O., Goddard, M., Angelini, A., Neil, D. A., Bruneval, P., Duong Van Huyen, J. P., Loupy, A., Miller, D. V. 2023

    View details for DOI 10.1016/j.ajt.2023.10.004

    View details for PubMedID 37838218

  • Stem-like CD4+ T cells in perivascular tertiary lymphoid structures sustain autoimmune vasculitis. Science translational medicine Sato, Y., Jain, A., Ohtsuki, S., Okuyama, H., Sturmlechner, I., Takashima, Y., Le, K. C., Bois, M. C., Berry, G. J., Warrington, K. J., Goronzy, J. J., Weyand, C. M. 2023; 15 (712): eadh0380


    Autoimmune vasculitis of the medium and large elastic arteries can cause blindness, stroke, aortic arch syndrome, and aortic aneurysm. The disease is often refractory to immunosuppressive therapy and progresses over decades as smoldering aortitis. How the granulomatous infiltrates in the vessel wall are maintained and how tissue-infiltrating T cells and macrophages are replenished are unknown. Single-cell and whole-tissue transcriptomic studies of immune cell populations in vasculitic arteries identified a CD4+ T cell population with stem cell-like features. CD4+ T cells supplying the tissue-infiltrating and tissue-damaging effector T cells survived in tertiary lymphoid structures around adventitial vasa vasora, expressed the transcription factor T cell factor 1 (TCF1), had high proliferative potential, and gave rise to two effector populations, Eomesodermin (EOMES)+ cytotoxic T cells and B cell lymphoma 6 (BCL6)+ T follicular helper-like cells. TCF1hiCD4+ T cells expressing the interleukin 7 receptor (IL-7R) sustained vasculitis in serial transplantation experiments. Thus, TCF1hiCD4+ T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4+ T cells instead of only effector T cells.

    View details for DOI 10.1126/scitranslmed.adh0380

    View details for PubMedID 37672564

  • Glomangiopericytoma Presenting as a Middle Ear Mass. The Laryngoscope Liu, G. S., Berry, G. J., Soltys, S. G., Blevins, N. H. 2023


    We describe an unusual case of glomangiopericytoma presenting as a mass filling the middle ear, enveloping the ossicles, and extending into the mastoid antrum without bony destruction. Management involved three surgeries and stereotactic radiosurgery, which achieved short-term local control with no evidence of disease on MRI imaging 12 months after radiation. Facial nerve function and hearing were preserved. This is the first report to our knowledge of a glomangiopericytoma presenting as a primary temporal bone lesion. Treatment with surgery and stereotactic radiosurgery for residual or recurrent disease is a reasonable approach to achieve local control and functional preservation. Laryngoscope, 2023.

    View details for DOI 10.1002/lary.30987

    View details for PubMedID 37615366

  • Tracheal stenosis and airway complications in the Coronavirus Disease-19 era. Annals of thoracic surgery short reports Krishnan, A., Guenthart, B. A., Choi, A., Trope, W., Berry, G. J., Pinezich, M. R., Vunjak-Novakovic, G., Shaller, B., Sung, C. K., Liou, D. Z., Damrose, E. J., Lui, N. S. 2023


    Severe Coronavirus Disease 2019 (COVID-19) infection is associated with prolonged intubation and its complications. Tracheal stenosis is one such complication that may require specialized surgical management. We aimed to describe the surgical management of post-COVID-19 tracheal stenosis.This case series describes consecutive patients with tracheal stenosis from intubation for severe COVID-19 infection at our single, tertiary academic medical center between January 1st, 2021, and December 31st, 2021. Patients were included if they underwent surgical management with tracheal resection and reconstruction, or bronchoscopic intervention. Operative through six-month, symptom-free survival and histopathological analysis of resected trachea were reviewed.Eight patients are included in this case series. All patients are female, and most (87.5%) are obese. Five patients (62.5%) underwent tracheal resection and reconstruction (TRR), while three patients (38.5%) underwent non-resection-based management. Among patients who underwent TRR, six-month symptom free survival is 80%; one patient (20%) required tracheostomy after TRR due to recurrent symptoms. Two of the three (66.7%) of patients who underwent non-resection-based management experienced durable relief from symptoms of tracheal stenosis with tracheal balloon dilation, and the remaining patient required laser excision of tracheal tissue prior to experiencing symptomatic relief.The incidence of tracheal stenosis may increase as patients recover from severe COVID-19 infection requiring intubation. Management of tracheal stenosis with TRR is safe and effective, with comparable rates of success to TRR for non-COVID-19 tracheal stenosis. Non-resection-based management is an option to manage tracheal stenosis in patients with less severe stenosis or in poor surgical candidates.

    View details for DOI 10.1016/j.atssr.2023.05.013

    View details for PubMedID 37360840

    View details for PubMedCentralID PMC10246306

  • ATTR Variant Amyloidosis in Patients with Dysphagia SURGERIES Ng, C., Berry, G. J., Damrose, E. J. 2023; 4 (2): 275-282
  • Severe Diarrhea and Weight Loss Due to Protein-Losing Enteropathy: Don't Pass Up the PAS Stain. Digestive diseases and sciences Yeoh, A., Kulkarni, C., Ryan, E., Berry, G., Triadafilopoulos, G. 2023

    View details for DOI 10.1007/s10620-023-07982-6

    View details for PubMedID 37231192

  • Diffuse Panbronchiolitis in a Patient With Ulcerative Colitis Treated With Ustekinumab. ACG case reports journal Marmor, M., Berry, G., Raj, R. 2023; 10 (5): e01062

    View details for DOI 10.14309/crj.0000000000001062

    View details for PubMedID 37234998

  • Deficiency of the CD155-CD96 immune checkpoint controls IL-9 production in giant cell arteritis. Cell reports. Medicine Ohtsuki, S., Wang, C., Watanabe, R., Zhang, H., Akiyama, M., Bois, M. C., Maleszewski, J. J., Warrington, K. J., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2023; 4 (4): 101012


    Loss of function of inhibitory immune checkpoints, unleashing pathogenic immune responses, is a potential risk factor for autoimmune disease. Here, we report that patients with the autoimmune vasculitis giant cell arteritis (GCA) have a defective CD155-CD96 immune checkpoint. Macrophages from patients with GCA retain the checkpoint ligand CD155 in the endoplasmic reticulum (ER) and fail to bring it to the cell surface. CD155low antigen-presenting cells induce expansion of CD4+CD96+ T cells, which become tissue invasive, accumulate in the blood vessel wall, and release the effector cytokine interleukin-9 (IL-9). In a humanized mouse model of GCA, recombinant human IL-9 causes vessel wall destruction, whereas anti-IL-9 antibodies efficiently suppress innate and adaptive immunity in the vasculitic lesions. Thus, defective surface translocation of CD155 creates antigen-presenting cells that deviate T cell differentiation toward Th9 lineage commitment and results in the expansion of vasculitogenic effector T cells.

    View details for DOI 10.1016/j.xcrm.2023.101012

    View details for PubMedID 37075705

  • Remodeling valve-sparing pulmonary root replacement repair of giant pulmonary artery aneurysm. JTCVS techniques Paulsen, M. J., Aranda-Michel, E. C., Berry, G. J., Woo, Y. J. 2023; 18: 60-62

    View details for DOI 10.1016/j.xjtc.2023.01.018

    View details for PubMedID 37096108

    View details for PubMedCentralID PMC10122152

  • OPTN required SARS-CoV-2 lower respiratory testing for lung donors: Striking the balance. Transplant infectious disease : an official journal of the Transplantation Society Booker, S. E., Jett, C., Fox, C., Anesi, J. A., Berry, G. J., Dunn, K. E., Fisher, C. E., Goldman, J. D., Ho, C., Kittleson, M., Lee, D. H., Levine, D. J., Marboe, C. C., Marklin, G., Martinez, C., Razonable, R. R., Sellers, M. T., Taimur, S., Te, H. S., Trindade, A. J., Wood, R. P., Woolley, A. E., Zaffiri, L., Klassen, D. K., Michaels, M. G., Pouch, S. M., Danziger-Isakov, L., La Hoz, R. M. 2023: e14048

    View details for DOI 10.1111/tid.14048

    View details for PubMedID 36864666

  • alphavbeta6 Integrin Positron Emission Tomography of Lung Fibrosis in Idiopathic Pulmonary Fibrosis and Long-COVID. American journal of respiratory and critical care medicine Kimura, R. H., Sharifi, H., Shen, B., Berry, G. J., Guo, H. H. 2023

    View details for DOI 10.1164/rccm.202206-1107IM

    View details for PubMedID 36693032

  • Transplant of organs from donors with positive SARS-CoV-2 nucleic acid testing: A report from the organ procurement and transplantation network ad hoc disease transmission advisory committee. Transplant infectious disease : an official journal of the Transplantation Society Goldman, J. D., Pouch, S. M., Woolley, A. E., Booker, S. E., Jett, C. T., Fox, C., Berry, G. J., Dunn, K. E., Ho, C. S., Kittleson, M., Lee, D. H., Levine, D. J., Marboe, C. C., Marklin, G., Razonable, R. R., Taimur, S., Te, H. S., Anesi, J. A., Fisher, C. E., Sellers, M. T., Trindade, A. J., Wood, R. P., Zaffiri, L., Levi, M. E., Klassen, D., Michaels, M. G., La Hoz, R. M., Danziger-Isakov, L. 2023: e14013


    Decisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test-positive (NAT+) donors must balance risk of donor-derived transmission events (DDTE) with the scarcity of available organs.Organ Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS-CoV-2 NAT+ and NAT- donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee.From May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT- donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT- donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30-day mortality, and 30-day graft loss were similar for all organ types. No SARS-CoV-2 DDTE occurred in this interval.Transplantation of SARS-CoV-2 NAT+ donor organs appears safe for short-term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes.

    View details for DOI 10.1111/tid.14013

    View details for PubMedID 36694448

  • Resection of a synovial cell sarcoma by cardiac autotransplantation: A case report. JTCVS techniques Mullis, D. M., Zhu, Y., Guenthart, B. A., Bonham, S. A., Trope, W. L., Berry, G. J., Woo, Y. J., MacArthur, J. W. 2022; 16: 123-127

    View details for DOI 10.1016/j.xjtc.2022.09.009

    View details for PubMedID 36510550

    View details for PubMedCentralID PMC9735421

  • Late-Onset Immunotherapy-Induced Myocarditis 2 Years After Checkpoint Inhibitor Initiation. JACC. CardioOncology Nguyen, A. T., Berry, G. J., Witteles, R. M., Le, D. T., Wu, S. M., Fisher, G. A., Zhu, H. 2022; 4 (5): 727-730

    View details for DOI 10.1016/j.jaccao.2022.04.007

    View details for PubMedID 36636432

    View details for PubMedCentralID PMC9830192

  • Limited Aortic Intimal Tears: CT Imaging Features and Clinical Characteristics. Radiology. Cardiothoracic imaging Madani, M. H., Turner, V. L., Hallett, R. L., Willemink, M. J., Murillo, H., Chin, A. S., Berry, G. J., Fleischmann, D. 2022; 4 (6): e220155


    Limited aortic intimal tear is an uncommon lesion of the dissection spectrum. The lesion has several imaging features that are not well known, including asymmetric aortic contour abnormalities, filling defects, and various morphologic patterns, such as linear, L-shaped, T-shaped, and stellate configurations. Hemorrhage of the aortic wall may also be present in patients with this rare entity. This imaging essay reviews the CT imaging findings and clinical characteristics of patients with limited intimal tears. Keywords: Aorta, CT © RSNA, 2022.

    View details for DOI 10.1148/ryct.220155

    View details for PubMedID 36601454

    View details for PubMedCentralID PMC9806729

  • Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Charya, A. V., Ponor, I. L., Cochrane, A., Levine, D., Philogene, M., Fu, Y. P., Jang, M. K., Kong, H., Shah, P., Bon, A. M., Krishnan, A., Mathew, J., Luikart, H., Khush, K. K., Berry, G., Marboe, C., Iacono, A., Orens, J. B., Nathan, S. D., Agbor-Enoh, S. 2022


    Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories.Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models.Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n = 96), 18.5% developed subclinical AMR (n = 62) or 58.3% were no AMR (n = 177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n = 21) or possible AMR (n = 75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR.Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure.

    View details for DOI 10.1016/j.healun.2022.09.012

    View details for PubMedID 36319530

  • De Novo Diagnosis of Lymphocytic Colitis After SARS-CoV-2 Vaccination ACG CASE REPORTS JOURNAL Lee, P., Wei, M. T., Gubatan, J., Forgo, E., Berry, G. J., Verma, R., Friedland, S. 2022; 9 (9)
  • De Novo Diagnosis of Lymphocytic Colitis After SARS-CoV-2 Vaccination. ACG case reports journal Lee, P., Wei, M. T., Gubatan, J., Forgó, E., Berry, G. J., Verma, R., Friedland, S. 2022; 9 (9): e00849


    SARS-CoV-2 mRNA vaccines are safe and effective for most patients. Gastrointestinal complications reported after vaccination have included gastroparesis and inflammatory bowel disease flares. In this study, we present a unique case of lymphocytic colitis that occurred in a healthy middle-aged man after Moderna SARS-CoV-2 mRNA vaccination. This reveals an unexpected complication of a mRNA vaccine that presented as worsening diarrhea after vaccination in a dose-dependent pattern. Caregivers should be aware of lymphocytic colitis as a possible complication of the Moderna vaccine and monitor those patients closely for symptom resolution.

    View details for DOI 10.14309/crj.0000000000000849

    View details for PubMedID 36134123

    View details for PubMedCentralID PMC9485468

  • SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19. Journal of neuropathology and experimental neurology Serrano, G. E., Walker, J. E., Tremblay, C., Piras, I. S., Huentelman, M. J., Belden, C. M., Goldfarb, D., Shprecher, D., Atri, A., Adler, C. H., Shill, H. A., Driver-Dunckley, E., Mehta, S. H., Caselli, R., Woodruff, B. K., Haarer, C. F., Ruhlen, T., Torres, M., Nguyen, S., Schmitt, D., Rapscak, S. Z., Bime, C., Peters, J. L., Alevritis, E., Arce, R. A., Glass, M. J., Vargas, D., Sue, L. I., Intorcia, A. J., Nelson, C. M., Oliver, J., Russell, A., Suszczewicz, K. E., Borja, C. I., Cline, M. P., Hemmingsen, S. J., Qiji, S., Hobgood, H. M., Mizgerd, J. P., Sahoo, M. K., Zhang, H., Solis, D., Montine, T. J., Berry, G. J., Reiman, E. M., Roltgen, K., Boyd, S. D., Pinsky, B. A., Zehnder, J. L., Talbot, P., Desforges, M., DeTure, M., Dickson, D. W., Beach, T. G. 2022


    Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

    View details for DOI 10.1093/jnen/nlac056

    View details for PubMedID 35818336

  • Lung allograft standardized histological analysis (LASHA) template: A research consensus proposal. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Calabrese, F., Roden, A. C., Pavlisko, E., Lunardi, F., Neil, D., Adam, B., Hwang, D., Goddard, M., Berry, G. J., Ivanovic, M., Thusen, J. v., Gibault, L., Lin, C., Wassilew, K., Glass, C., Westall, G., Zeevi, A., Levine, D. J., Roux, A. 2022


    BACKGROUND: Routine monitoring of lung-transplanted patients is crucial for the identification of immunological and non-immunological complications. Determining the etiology of acute allograft dysfunction, particularly in alloimmune-mediated disorders, relies heavily on the lung biopsy with histopathologic analysis. Standardization of the pathologic diagnosis of rejection (e.g., cellular and antibody-mediated) is based on consensus statements and guidelines, indicating the importance of a multidisciplinary approach to achieve a definitive etiological diagnosis. In addition to these statements and guidelines, refinements and standardizations are feasible through systematic analysis morphological, immunophenotypic and molecular alterations observed in transbronchial biopsies. This study is to identify key morphologic features to be assessed, select consistent and reproducible terminology for each histological feature, and provide standardized definitions for pathological assessment and grading.METHODS: A template was created by experts in lung transplantation including pathologists, pulmonologists, immunologists. An initial draft was circulated, followed by discussions and multiple revisions by email and conference calls.RESULTS: The "lung allograft standardized histological analysis - LASHA" template was created and structured as multiple-choice questions with number of fields to be filled in to allow for standardization of results and easy transfer into a future electronic spreadsheet.CONCLUSION: This template will help facilitate multicenter studies through a uniform protocol and correlations with new diagnostic modalities. After validation in large-scale studies, an optimized template could be included in routine clinical practice to enhance graft assessment and medical decision-making.

    View details for DOI 10.1016/j.healun.2022.06.021

    View details for PubMedID 35931644

  • Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease. Nature cardiovascular research Zhao, T. V., Hu, Z., Ohtsuki, S., Jin, K., Wu, B., Berry, G. J., Frye, R. L., Goronzy, J. J., Weyand, C. M. 2022; 1 (7): 634-648


    Pre-existent cardiovascular disease is a risk factor for weak anti-viral immunity, but underlying mechanisms remain undefined. Here, we report that patients with coronary artery disease (CAD) have macrophages (Mϕ) that actively suppress the induction of helper T cells reactive to two viral antigens: the SARS-CoV2 Spike protein and the Epstein-Barr virus (EBV) glycoprotein 350. CAD Mϕ overexpressed the methyltransferase METTL3, promoting the accumulation of N⁶-methyladenosine (m6A) in Poliovirus receptor (CD155) mRNA. m6A modifications of positions 1635 and 3103 in the 3'UTR of CD155 mRNA stabilized the transcript and enhanced CD155 surface expression. As a result, the patients' Mϕ abundantly expressed the immunoinhibitory ligand CD155 and delivered negative signals to CD4+ T cells expressing CD96 and/or TIGIT receptors. Compromised antigen-presenting function of METTL3hi CD155hi Mϕ diminished anti-viral T cell responses in vitro and in vivo. LDL and its oxidized form induced the immunosuppressive Mϕ phenotype. Undifferentiated CAD monocytes had hypermethylated CD155 mRNA, implicating post-transcriptional RNA modifications in the bone-marrow in shaping anti-viral immunity in CAD.

    View details for DOI 10.1038/s44161-022-00096-8

    View details for PubMedID 36860353

  • Circulating microRNAs in cellular and antibody-mediated heart transplant rejection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Shah, P., Agbor-Enoh, S., Bagchi, P., deFilippi, C. R., Mercado, A., Diao, G., Morales, D. J., Shah, K. B., Najjar, S. S., Feller, E., Hsu, S., Rodrigo, M. E., Lewsey, S. C., Jang, M. K., Marboe, C., Berry, G. J., Khush, K. K., Valantine, H. A., GRAfT Investigators 2022


    BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection.METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use.RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively.CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

    View details for DOI 10.1016/j.healun.2022.06.019

    View details for PubMedID 35872109

  • The transcription factor RFX5 coordinates antigen-presenting function and resistance to nutrient stress in synovial macrophages. Nature metabolism Hu, Z., Zhao, T. V., Huang, T., Ohtsuki, S., Jin, K., Goronzy, I. N., Wu, B., Abdel, M. P., Bettencourt, J. W., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2022


    Tissue macrophages (Mϕ) are essential effector cells in rheumatoid arthritis (RA), contributing to autoimmune tissue inflammation through diverse effector functions. Their arthritogenic potential depends on their proficiency to survive in the glucose-depleted environment of the inflamed joint. Here, we identify a mechanism that links metabolic adaptation to nutrient stress with the efficacy of tissue Mϕ to activate adaptive immunity by presenting antigen to tissue-invading T cells. Specifically, Mϕ populating the rheumatoid joint produce and respond to the small cytokine CCL18, which protects against cell death induced by glucose withdrawal. Mechanistically, CCL18 induces the transcription factor RFX5 that selectively upregulates glutamate dehydrogenase 1 (GLUD1), thus enabling glutamate utilization to support energy production. In parallel, RFX5 enhances surface expression of HLA-DR molecules, promoting Mϕ-dependent expansion of antigen-specific T cells. These data place CCL18 at the top of a RFX5-GLUD1 survival pathway and couple adaptability to nutrient conditions in the tissue environment to antigen-presenting function in autoimmune tissue inflammation.

    View details for DOI 10.1038/s42255-022-00585-x

    View details for PubMedID 35739396

  • Comparison of donor-derived cell-free DNA between single vs. double lung transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Keller, M. B., Meda, R., Fu, S., Yu, K., Jang, M. K., Charya, A., Berry, G. J., Marboe, C. C., Kong, H., Luikart, H., Ponor, I. L., Shah, P. D., Khush, K. K., Nathan, S. D., Agbor-Enoh, S. 2022


    Plasma donor-derived cell-free DNA (dd-cfDNA) is a sensitive biomarker for the diagnosis of acute rejection in lung transplant recipients, however, differences in dd-cfDNA levels between single and double lung transplant remains unknown. We performed an observational analysis that included 221 patients from two prospective cohort studies who had serial measurements of plasma dd-cfDNA at the time of bronchoscopy and pulmonary function testing, and compared dd-cfDNA between single and double lung transplant recipients across a range of disease states. Levels of dd-cfDNA were lower for single vs double lung transplant in stable controls (Median (IQR): 0.15% (0.07, 0.44) vs 0.46% (0.23, 0.74), p <0.01) and acute rejection (1.06% (0.75, 2.32) vs 1.78% (1.18, 5.73), p = 0.05). Doubling dd-cfDNA for single lung transplant to account for differences in lung mass eliminated this difference. The area under the receiver operating curve (AUC) for detection of acute rejection was 0.89 and 0.86 for single and double lung transplant, respectively. The optimal dd-cfDNA threshold for detection of acute rejection was 0.54% in single lung and 1.1% in double lung transplant. In conclusion, accounting for differences in dd-cfDNA in single vs double lung transplant is key for interpretation of dd-cfDNA testing in research and clinical settings.

    View details for DOI 10.1111/ajt.17039

    View details for PubMedID 35322546

  • Benign Ectopic Thyroid in the Lateral (Level II) Neck Compartment CUREUS JOURNAL OF MEDICAL SCIENCE Liu, G. S., Berry, G. J., Desai, K., Megwalu, U. C. 2022; 14 (2)
  • Ultra-Rapid Nanopore Whole Genome Genetic Diagnosis of Dilated Cardiomyopathy in an Adolescent With Cardiogenic Shock. Circulation. Genomic and precision medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Bernstein, J. A., Ceresnak, S., Chang, P., Christle, J. W., Chubb, H., Dunn, K., Garalde, D. R., Guillory, J., Ruzhnikov, M. R., Wright, C., Wusthoff, C. J., Xiong, K., Hollander, S. A., Berry, G. J., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022: CIRCGEN121003591

    View details for DOI 10.1161/CIRCGEN.121.003591

    View details for PubMedID 35133172

  • Benign Ectopic Thyroid in the Lateral (Level II) Neck Compartment. Cureus Liu, G. S., Berry, G. J., Desai, K., Megwalu, U. C. 2022; 14 (2): e22140


    Ectopic thyroid most commonly presents in the midline and is typically associated with the absence of an orthotopic thyroid. Less commonly, ectopic thyroid can present in the lateral neck, typically with a coexisting orthotopic thyroid and abnormal pathology in either the ectopic or orthotopic thyroid tissue. This paper describes a rare case of a benign, ectopic thyroid in the lateral neck (level II) associated with a normal, benign orthotopic thyroid. This report illustrates clinical pearls for the management of this unusual entity.

    View details for DOI 10.7759/cureus.22140

    View details for PubMedID 35308702

    View details for PubMedCentralID PMC8920790

  • Age as a risk factor in vasculitis. Seminars in immunopathology Gloor, A. D., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2022


    Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8+ T cell function. Accordingly, in GCA but not in TAK, CD8+ effector T cells play a negligible role and anti-inflammatory CD8+ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.

    View details for DOI 10.1007/s00281-022-00911-1

    View details for PubMedID 35141865

  • Regulatory T Cells in Autoimmune Vasculitis. Frontiers in immunology Jin, K., Parreau, S., Warrington, K. J., Koster, M. J., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2022; 13: 844300


    Blood vessels are indispensable for host survival and are protected from inappropriate inflammation by immune privilege. This protection is lost in patients with autoimmune vasculitides, a heterogeneous group of diseases causing damage to arteries, arterioles, and capillaries. Vasculitis leads to vascular wall destruction and/or luminal occlusion, resulting in hemorrhage and tissue ischemia. Failure in the quantity and quality of immunosuppressive regulatory T cells (Treg) has been implicated in the breakdown of the vascular immune privilege. Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Mechanistic studies have identified faulty CD8+ Tregs in Giant Cell Arteritis (GCA), a vasculitis of the aorta and the large aortic branch vessels. Specifically, aberrant signaling through the NOTCH4 receptor expressed on CD8+ Treg cells leads to rerouting of intracellular vesicle trafficking and failure in the release of immunosuppressive exosomes, ultimately boosting inflammatory attack to medium and large arteries. In Kawasaki's disease, a medium vessel vasculitis targeting the coronary arteries, aberrant expression of miR-155 and dysregulated STAT5 signaling have been implicated in undermining CD4+ Treg function. Explorations of mechanisms leading to insufficient immunosuppression and uncontrolled vascular inflammation hold the promise to discover novel therapeutic interventions that could potentially restore the immune privilege of blood vessels and pave the way for urgently needed innovations in vasculitis management.

    View details for DOI 10.3389/fimmu.2022.844300

    View details for PubMedID 35296082

  • Higher levels of allograft injury in black patients early after heart transplantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Doshi, A., Shah, K. B., Agbor-Enoh, S., Tushak, Z., Garcia, V., Kong, H., Jang, M. K., Hsu, S., Feller, E. D., Rodrigo, M. E., Najjar, S. S., Tunc, I., Yang, Y., Lee, S., Solomon, M. A., Berry, G., Marboe, C., Shah, P., Valantine, H. A. 1800


    Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p=0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p=0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p=0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p=0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p=0.01), which may explain the higher levels of early allograft injury.

    View details for DOI 10.1016/j.healun.2021.12.006

    View details for PubMedID 35016813

  • Correlation Between Microvascular Inflammation in Endomyocardial Biopsies and Rejection Transcripts, Donor-specific Antibodies, and Graft Dysfunction in Antibody-mediated Rejection. Transplantation Coutance, G., Zouhry, I., Racape, M., Drieux, F., Viailly, P., Rouvier, P., Francois, A., Chenard, M., Toquet, C., Rabant, M., Berry, G. J., Angelini, A., Bruneval, P., Duong Van Huyen, J. 1800


    BACKGROUND: The pathology-based diagnosis of cardiac antibody-mediated rejection (AMR) relies on the 2013 International Society for Heart and Lung Transplantation Working Formulation, in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMBs).METHODS: We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale in which MVI scores of 0, 1, 2, and 3 represented 0%, 1%-10%, 11%-50%, and >50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by microarrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pathologic AMR [pAMR]), anti-HLA donor-specific antibodies, and graft dysfunction.RESULTS: Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%), and 44 (15.1%) EMB were given MVI scores of 0, 1, 2, and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogeneous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independent of the C4d or CD68 status (P < 0.001). Both the frequency and mean fluorescence intensity of donor-specific antibodies gradually increased with the MVI score (P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 (P < 0.001).CONCLUSIONS: The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance.

    View details for DOI 10.1097/TP.0000000000004008

    View details for PubMedID 34954735

  • Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms. Circulation. Genomic and precision medicine Lindholm, M. E., Jimenez-Morales, D., Zhu, H., Seo, K., Amar, D., Zhao, C., Raja, A., Madhvani, R., Abramowitz, S., Espenel, C., Sutton, S., Caleshu, C., Berry, G. J., Motonaga, K. S., Dunn, K., Platt, J., Ashley, E. A., Wheeler, M. T. 2021: CIRCGEN121003419


    BACKGROUND: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2.METHODS: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used coimmunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.RESULTS: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing.CONCLUSIONS: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

    View details for DOI 10.1161/CIRCGEN.121.003419

    View details for PubMedID 34802252

  • RNA splicing programs define tissue compartments and cell types at single-cell resolution ELIFE Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10
  • Response by Shah et al to Letter Regarding Article, "Cell-Free DNA to Detect Heart Allograft Acute Rejection". Circulation Shah, P., Agbor-Enoh, S., Tunc, I., Hsu, S., Russell, S., Feller, E., Shah, K., Rodrigo, M. E., Najjar, S. S., Kong, H., Pirooznia, M., Fideli, U., Bikineyeva, A., Marishta, A., Bhatti, K., Yang, Y., Mutebi, C., Yu, K., Kyoo Jang, M., Marboe, C., Berry, G. J., Valantine, H. A., GRAfT (Genomic Research Alliance for Transplantation) Investigators 2021; 144 (10): e198-e199

    View details for DOI 10.1161/CIRCULATIONAHA.121.055697

    View details for PubMedID 34491771

  • ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Crespo, M. M., Lease, E. D., Sole, A., Sandorfi, N., Snyder, L. D., Berry, G. J., Pavec, J. L., Venado, A. E., Cifrian, J. M., Goldberg, H., Dilling, D. F., Gries, C., Nair, A., Willie, K., Meyer, K. C., Shah, R. J., Tokman, S., Holm, A., Patterson, C. M., McWilliams, T., Shtraichman, O., Bemiss, B., Salgado, J., Farver, C., Strah, H., Wassilew, K., Kaza, V., Howsare, M., Murray, M., Bhorade, S., Budev, M. 2021


    Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

    View details for DOI 10.1016/j.healun.2021.07.014

    View details for PubMedID 34417111

  • Mammary Lobular Carcinoma-Like Salivary Gland Carcinoma: Report of a Rare Case. Head and neck pathology Lei, L., Van Staalduinen, E., Troxell, M., Ozawa, M. G., Zeineh, M., Berry, G. 2021


    Salivary and mammary glands are both exocrine organs sharing multiple tumorigenic processes. To the best of our knowledge, salivary gland tumors mimicking invasive lobular carcinoma of the breast have not yet been described. Herein, we report a case of a 62-year-old male who presented with progressive facial paralysis. Pathologic examination revealed an ill-defined epithelial neoplasm exhibiting discohesive growth set within an extensively fibrotic stroma. Both perineural and intraneural invasion were present. E-cadherin and p120 immunostaining showed aberrant cytoplasmic expression. Targeted next-generation sequencing detected a frameshift mutation of the CTNNA1 gene as the only known pathogenic variant. The patient was treated with surgical resection, immunotherapy, and chemotherapy. Currently, he is alive with disease twenty months after disease onset.

    View details for DOI 10.1007/s12105-021-01344-2

    View details for PubMedID 34115320

  • Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Jang, M. K., Tunc, I., Berry, G. J., Marboe, C., Kong, H., Keller, M. B., Shah, P. D., Timofte, I., Brown, A. W., Ponor, I. L., Mutebi, C., Philogene, M. C., Yu, K., Iacono, A., Orens, J. B., Nathan, S. D., Agbor-Enoh, S. 2021


    BACKGROUND: Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection.METHODS: This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection.RESULTS: ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology.CONCLUSIONS: This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury.

    View details for DOI 10.1016/j.healun.2021.04.009

    View details for PubMedID 34130911

  • Cell-Free DNA to Detect Heart Allograft Acute Rejection. Circulation Agbor-Enoh, S., Shah, P., Tunc, I., Hsu, S., Russell, S., Feller, E., Shah, K., Rodrigo, M. E., Najjar, S. S., Kong, H., Pirooznia, M., Fideli, U., Bikineyeva, A., Marishta, A., Bhatti, K., Yang, Y., Mutebi, C., Yu, K., Jang, M. K., Marboe, C., Berry, G. J., Valantine, H. A., GRAfT Investigators 2021


    Background: After heart transplantation, Endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive and its conventional histologic interpretation has limitations. This is a validation study to assesses the performance of a sensitive blood biomarker- percent donor-derived cell-free DNA (%ddcfDNA) - for detection of AR in cardiac transplant recipients. Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data was collected to define AR, its two phenotypes (acute cellular rejection, ACR, and antibody-mediated rejection, AMR) and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range - IQR) for AR, AMR and ACR to controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis. Results: The study included 171 subjects with median post-transplant follow-up of 17.7 months (IQR: 12.1-23.6), with 1,392 EMBx, and 1,834 ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (0.03-0.21) by 28 days. %ddcfDNA increased again with AR compared to controls values (0.38, IQR=0.31-0.83, vs. 0.03, IQR=0.01-0.14 p<0.001). The rise was detected 0.5 and 3.2 months before histopathological diagnosis of ACR and AMR. The area-under-the- receiver-operator characteristics curve (AUROC) for AR was 0.92. A 0.25 %ddcfDNA threshold had a negative predictive value (NPV) for AR of 99% and would have safely eliminated 81% of EMBx. %ddcfDNA showed distinctive characteristics comparing AMR to ACR, included 5-fold higher levels (pAMR ≥2 1.68, IQR=0.49-2.79 vs. ACR grade ≥2R 0.34, IQR=0.28-0.72), higher AUROC (0.95 vs. 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments. Conclusions: %ddcfDNA detected AR with a high AUROC and NPV. Monitoring with ddcfDNA, demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in heart transplant patients and paves the way for a clinical utility study. Clinical Trial Registration: URL: Unique Identifier: NCT02423070.

    View details for DOI 10.1161/CIRCULATIONAHA.120.049098

    View details for PubMedID 33435695

  • Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery. Immunity Chiou, S. H., Tseng, D. n., Reuben, A. n., Mallajosyula, V. n., Molina, I. S., Conley, S. n., Wilhelmy, J. n., McSween, A. M., Yang, X. n., Nishimiya, D. n., Sinha, R. n., Nabet, B. Y., Wang, C. n., Shrager, J. B., Berry, M. F., Backhus, L. n., Lui, N. S., Wakelee, H. A., Neal, J. W., Padda, S. K., Berry, G. J., Delaidelli, A. n., Sorensen, P. H., Sotillo, E. n., Tran, P. n., Benson, J. A., Richards, R. n., Labanieh, L. n., Klysz, D. D., Louis, D. M., Feldman, S. A., Diehn, M. n., Weissman, I. L., Zhang, J. n., Wistuba, I. I., Futreal, P. A., Heymach, J. V., Garcia, K. C., Mackall, C. L., Davis, M. M. 2021; 54 (3): 586–602.e8


    To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

    View details for DOI 10.1016/j.immuni.2021.02.014

    View details for PubMedID 33691136

  • First lung and kidney multi-organ transplant following COVID-19 Infection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Guenthart, B. A., Krishnan, A., Alassar, A., Madhok, J., Kakol, M., Miller, S., Cole, S. P., Rao, V. K., Acero, N. M., Hill, C. C., Cheung, C., Jackson, E. C., Feinstein, I., Tsai, A. H., Mooney, J. J., Pham, T., Elliott, I. A., Liou, D. Z., La Francesca, S., Shudo, Y., Hiesinger, W., MacArthur, J. W., Brar, N., Berry, G. J., McCarra, M. B., Desai, T. J., Dhillon, G. S., Woo, Y. J. 2021


    As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

    View details for DOI 10.1016/j.healun.2021.02.015

    View details for PubMedID 34059432

  • Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis. Frontiers in immunology Qiu, J., Wu, B., Goodman, S. B., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2021; 12: 652771


    Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

    View details for DOI 10.3389/fimmu.2021.652771

    View details for PubMedID 33868292

  • Examination of factors associated with lymph node metastases in lung carcinoids: Results from a single institution retrospective cohort study. Lung cancer (Amsterdam, Netherlands) Pathipati, M. P., Yohannan, T. K., Tian, L. n., Hornbacker, K. n., Benson, J. A., Berry, G. J., Lui, N. S., Kunz, P. L., Padda, S. K. 2021


    Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases.We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables).87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy.We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.

    View details for DOI 10.1016/j.lungcan.2021.01.017

    View details for PubMedID 33551175

  • Deep learning model for the prediction of microsatellite instability in colorectal cancer: a diagnostic study LANCET ONCOLOGY Yamashita, R., Long, J., Longacre, T., Peng, L., Berry, G., Martin, B., Higgins, J., Rubin, D. L., Shen, J. 2021; 22 (1): 132–41
  • Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation. PloS one Baker, S. A., Kwok, S. n., Berry, G. J., Montine, T. J. 2021; 16 (2): e0247060


    Mortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010-2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40-83 years old in the ventilated cohort and 14-80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.

    View details for DOI 10.1371/journal.pone.0247060

    View details for PubMedID 33592054

  • Deep learning model for the prediction of microsatellite instability in colorectal cancer: a diagnostic study. The Lancet. Oncology Yamashita, R. n., Long, J. n., Longacre, T. n., Peng, L. n., Berry, G. n., Martin, B. n., Higgins, J. n., Rubin, D. L., Shen, J. n. 2021; 22 (1): 132–41


    Detecting microsatellite instability (MSI) in colorectal cancer is crucial for clinical decision making, as it identifies patients with differential treatment response and prognosis. Universal MSI testing is recommended, but many patients remain untested. A critical need exists for broadly accessible, cost-efficient tools to aid patient selection for testing. Here, we investigate the potential of a deep learning-based system for automated MSI prediction directly from haematoxylin and eosin (H&E)-stained whole-slide images (WSIs).Our deep learning model (MSINet) was developed using 100 H&E-stained WSIs (50 with microsatellite stability [MSS] and 50 with MSI) scanned at 40× magnification, each from a patient randomly selected in a class-balanced manner from the pool of 343 patients who underwent primary colorectal cancer resection at Stanford University Medical Center (Stanford, CA, USA; internal dataset) between Jan 1, 2015, and Dec 31, 2017. We internally validated the model on a holdout test set (15 H&E-stained WSIs from 15 patients; seven cases with MSS and eight with MSI) and externally validated the model on 484 H&E-stained WSIs (402 cases with MSS and 77 with MSI; 479 patients) from The Cancer Genome Atlas, containing WSIs scanned at 40× and 20× magnification. Performance was primarily evaluated using the sensitivity, specificity, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). We compared the model's performance with that of five gastrointestinal pathologists on a class-balanced, randomly selected subset of 40× magnification WSIs from the external dataset (20 with MSS and 20 with MSI).The MSINet model achieved an AUROC of 0·931 (95% CI 0·771-1·000) on the holdout test set from the internal dataset and 0·779 (0·720-0·838) on the external dataset. On the external dataset, using a sensitivity-weighted operating point, the model achieved an NPV of 93·7% (95% CI 90·3-96·2), sensitivity of 76·0% (64·8-85·1), and specificity of 66·6% (61·8-71·2). On the reader experiment (40 cases), the model achieved an AUROC of 0·865 (95% CI 0·735-0·995). The mean AUROC performance of the five pathologists was 0·605 (95% CI 0·453-0·757).Our deep learning model exceeded the performance of experienced gastrointestinal pathologists at predicting MSI on H&E-stained WSIs. Within the current universal MSI testing paradigm, such a model might contribute value as an automated screening tool to triage patients for confirmatory testing, potentially reducing the number of tested patients, thereby resulting in substantial test-related labour and cost savings.Stanford Cancer Institute and Stanford Departments of Pathology and Biomedical Data Science.

    View details for DOI 10.1016/S1470-2045(20)30535-0

    View details for PubMedID 33387492

  • A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature Travaglini, K. J., Nabhan, A. N., Penland, L., Sinha, R., Gillich, A., Sit, R. V., Chang, S., Conley, S. D., Mori, Y., Seita, J., Berry, G. J., Shrager, J. B., Metzger, R. J., Kuo, C. S., Neff, N., Weissman, I. L., Quake, S. R., Krasnow, M. A. 2020


    Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecularcell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.

    View details for DOI 10.1038/s41586-020-2922-4

    View details for PubMedID 33208946

  • Two Cases of Pulmonary Tumor Thrombotic Microangiopathy Associated with ROS1-Rearranged Non-Small-Cell Lung Cancer. Clinical lung cancer Shah, A. T., Bernardo, R. J., Berry, G. J., Kudelko, K., Wakelee, H. A. 2020

    View details for DOI 10.1016/j.cllc.2020.09.020

    View details for PubMedID 33153897

  • NOTCH-induced rerouting of endosomal trafficking disables regulatory T-cells in vasculitis. The Journal of clinical investigation Jin, K., Wen, Z., Wu, B., Zhang, H., Qiu, J., Wang, Y., Warrington, K. J., Berry, G., Goronzy, J. J., Weyand, C. M. 2020


    The aorta and the large conductive arteries are immunoprivileged tissues and are protected against inflammatory attack. A breakdown of the immunoprivilege leads to autoimmune vasculitis, such as giant cell arteritis (GCA), in which CD8+ T regulatory (Treg) cells fail to contain CD4+ T cells and macrophages, resulting in the formation of tissue-destructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning CD8+ Treg cells lies in aberrant NOTCH4 signaling that deviates endosomal trafficking and minimizes exosome production. By transcriptionally controlling the profile of RAB GTPases, NOTCH4 signaling restricted membrane translocation and vesicular secretion of the enzyme NADPH oxidase 2 (NOX2). Specifically, NOTCH4hiCD8+ Treg cells increased RAB5A and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and trapping of NOX2 in an intracellular, non-secretory compartment. RAB7AloCD8+ Treg cells failed in the surface translocation and the exosomal release of NOX2. NOTCH4hi RAB5Ahi RAB7Alo RAB11Ahi CD8+ Treg cells left adaptive immunity unopposed, enabling a breakdown in tissue tolerance and aggressive vessel wall inflammation. Inhibiting NOTCH4 signaling corrected the defect and protected arteries from inflammatory insult. The study implicates NOTCH4-dependent transcriptional control of RAB proteins and intracellular vesicle trafficking in autoimmune disease and in vascular inflammation.

    View details for DOI 10.1172/JCI136042

    View details for PubMedID 32960812

  • Donor Derived Hepatitis B Virus Infection: Analysis of the OPTN/UNOS Ad Hoc Disease Transmission Advisory Committee. Transplant infectious disease : an official journal of the Transplantation Society Theodoropoulos, N. M., La Hoz, R. M., Wolfe, C., Vece, G., Bag, R., Berry, G. J., Bucio, J., Danziger-Isakov, L., Florescu, D. F., Goldberg, D., Ho, C., Lilly, K., Malinis, M., Mehta, A. K., Nalesnik, M. A., Sawyer, R., Strasfeld, L., Wood, R. P., Michaels, M. G. 2020: e13458


    Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events (PDDTE) of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: 6 were not given antiviral prophylaxis, 2 developed infection after antiviral prophylaxis was discontinued, 2 developed HBV while on lamivudine prophylaxis, 1 was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.

    View details for DOI 10.1111/tid.13458

    View details for PubMedID 32894634

  • Pathogenesis of Giant Cell Arteritis and Takayasu Arteritis-Similarities and Differences. Current rheumatology reports Watanabe, R., Berry, G. J., Liang, D. H., Goronzy, J. J., Weyand, C. M. 2020; 22 (10): 68


    PURPOSE OF REVIEW: Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are auto-inflammatory and autoimmune diseases with a highly selective tissue tropism for medium and large arteries. In both diseases, CD4+ T cells and macrophages form granulomatous lesions within the arterial wall, a tissue site normally protected by immune privilege. Vascular lesions can be accompanied by an extravascular component, typically an intense hepatic acute phase response that produces well-known laboratory abnormalities, e.g., elevated ESR and CRP. It is unclear whether GCA and TAK lie on a spectrum of disease or whether they represent fundamentally different disease processes.RECENT FINDINGS: GCA and TAK share many clinical features, but there are substantial differences in genetics, epidemiology, disease mechanisms, response to treatment, and treatment complications that give rise to different disease trajectories. A significant difference lies in the composition of the wall-infiltrating immune cell compartment, which in TAK includes a significant population of CD8+ T cells as well as natural killer cells, specifying disparate disease effector pathways mediating tissue damage and vessel wall remodeling. Despite the similarities in tissue tropism and histomorphology, GCA and TAK are two distinct vasculitides that rely on separate disease mechanisms and require disease-specific approaches in diagnosis and management.

    View details for DOI 10.1007/s11926-020-00948-x

    View details for PubMedID 32845392

  • Dysphagia and Dysphonia, a Pairing of Symptoms Caused by an Unusual Pair of Diseases: Castleman's Disease and Myasthenia Gravis. The Annals of otology, rhinology, and laryngology Abdelmeguid, A., Rojansky, R., Berry, G. J., Dewan, K. 2020: 3489420949581


    OBJECTIVES: To describe a case of coincident Castleman's disease and myasthenia gravis that initially presented as rapidly progressive dysphagia and dysphonia and to review the unique pathophysiology of these two uncommon diagnoses.METHODS: Case report and literature review.RESULTS: Castleman's disease, angiofollicular or giant lymph node hyperplasia, is a rare benign lymphoid proliferation. Traditionally, the disease is classified based on histologic and clinical characteristics. Fewer than 10 cases with concurrent myasthenia gravis have been reported. Myasthenia gravis and thymic epithelial tumors are both associated with acetylcholine receptor antibody. While patients with isolated Castleman's disease are usually asymptomatic, those who have concurrent myasthenia gravis and undergo surgical treatment are at increased risk of postoperative myasthenic crisis. Both pre- and postoperative plasmapheresis are suggested to improve muscle strength and prevent severe postoperative complications.CONCLUSIONS: In the setting of multiple cranial neuropathies including velopalatal insufficiency and bilateral ptosis it is important to consider myasthenia gravis. Castleman's disease occurs rarely in conjunction with myasthenia gravis but may increase the risk of myasthenic crisis.

    View details for DOI 10.1177/0003489420949581

    View details for PubMedID 32812444

  • The XVth Banff Conference on Allograft Pathology The Banff Workshop Heart Report: Improving the Diagnostic Yield from Endomyocardial Biopsies and Quilty Effect Revisited. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Duong Van Huyen, J., Fedrigo, M., Fishbein, G. A., Leone, O., Neil, D., Marboe, C., Peyster, E., von der Thusen, J., Loupy, A., Mengel, M., Revelo, M. P., Adam, B., Bruneval, P., Angelini, A., Miller, D. V., Berry, G. J. 2020


    The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting two main topics in cardiac transplant pathology were addressed: 1 - Improvement of endomyocardial biopsy accuracy for the diagnosis of rejection and other significant injury patterns. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from H&E stain to multiplex labelling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of TCMR and AMR. 2 - The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas reviewed, possible pathogenesis proposed, based on advances in immunology to explain conflicting data. Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.

    View details for DOI 10.1111/ajt.16083

    View details for PubMedID 32476272

  • Integrating genomic features for non-invasive early lung cancer detection. Nature Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y. J., Nesselbush, M. C., Co Ting Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020; 580 (7802): 245-251


    Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

    View details for DOI 10.1038/s41586-020-2140-0

    View details for PubMedID 32269342

  • Integrating genomic features for non-invasive early lung cancer detection NATURE Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y., Nesselbush, M. C., Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020
  • Employing Bronchoscopic Lung Cryobiopsy and a Genomic Classifier in the Multidisciplinary Diagnosis of Diffuse Interstitial Lung Diseases. Chest Kheir, F. n., Alkhatib, A. n., Berry, G. J., Daroca, P. n., Diethelm, L. n., Rampolla, R. n., Saito, S. n., Smith, D. L., Weill, D. n., Bateman, M. n., Abdelghani, R. n., Lasky, J. A. 2020


    Challenges remain for establishing a specific diagnosis in cases of ILD. Bronchoscopic lung cryobiopsy (BLC) has impacted the diagnostic impression and confidence of multidisciplinary discussions (MDD) in the evaluation of ILD. Recent reports indicate that a genomic classifier (GC) can distinguish UIP from non-UIP.This study aimed to address the impact of sequentially presented data from BLC and GC on the diagnostic confidence of the MDD in ILD.and Methods: Two MDDs teams met to discuss 24 patients with ILD without a definitive UIP pattern. MDD1 sequentially reviewed clinical-radiologic findings, BLC and GC. MDD2 sequentially reviewed GC prior to BLC. At each step in the process the MDD diagnosis and confidence level were recorded.MDD1 had a significant increase in diagnostic confidence from 43 to 93% (P = 0.023) in patients with probable UIP after the addition of GC to BLC. MDD2 had an increase in diagnostic confidence from 27 to 73% (P = 0.074) after the addition of BLC to GC. The concordance coefficients and percentage agreement of categorical IPF and non-IPF diagnoses were GC versus MDD1: 0.92, 96%; GC versus MDD2: 0.83, 92%; BLC1 versus MDD1: 0.67, 83%; BLC2 versus MDD2: 0.66, 83%.GC increased the diagnostic confidence when added to BLC in patients with a probable UIP pattern, and in appropriate clinical settings can be used without BLC. In contrast, BLC had the greatest impact regarding a specific diagnosis in cases wherein the likelihood of UIP was considered low following clinical-radiographic review.

    View details for DOI 10.1016/j.chest.2020.05.532

    View details for PubMedID 32464189

  • Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A. n., Uyumazturk, B. n., Rajpurkar, P. n., Wang, A. n., Gao, R. n., Jones, E. n., Yu, Y. n., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M. n., Allard, L. S., Ylagan, L. n., Ng, A. Y., Shen, J. n. 2020; 3: 23


    Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

    View details for DOI 10.1038/s41746-020-0232-8

    View details for PubMedID 32140566

    View details for PubMedCentralID PMC7044422

  • Classifying non-small cell lung cancer types and transcriptomic subtypes using convolutional neural networks. Journal of the American Medical Informatics Association : JAMIA Yu, K. H., Wang, F. n., Berry, G. J., Ré, C. n., Altman, R. B., Snyder, M. n., Kohane, I. S. 2020; 27 (5): 757–69


    Non-small cell lung cancer is a leading cause of cancer death worldwide, and histopathological evaluation plays the primary role in its diagnosis. However, the morphological patterns associated with the molecular subtypes have not been systematically studied. To bridge this gap, we developed a quantitative histopathology analytic framework to identify the types and gene expression subtypes of non-small cell lung cancer objectively.We processed whole-slide histopathology images of lung adenocarcinoma (n = 427) and lung squamous cell carcinoma patients (n = 457) in the Cancer Genome Atlas. We built convolutional neural networks to classify histopathology images, evaluated their performance by the areas under the receiver-operating characteristic curves (AUCs), and validated the results in an independent cohort (n = 125).To establish neural networks for quantitative image analyses, we first built convolutional neural network models to identify tumor regions from adjacent dense benign tissues (AUCs > 0.935) and recapitulated expert pathologists' diagnosis (AUCs > 0.877), with the results validated in an independent cohort (AUCs = 0.726-0.864). We further demonstrated that quantitative histopathology morphology features identified the major transcriptomic subtypes of both adenocarcinoma and squamous cell carcinoma (P < .01).Our study is the first to classify the transcriptomic subtypes of non-small cell lung cancer using fully automated machine learning methods. Our approach does not rely on prior pathology knowledge and can discover novel clinically relevant histopathology patterns objectively. The developed procedure is generalizable to other tumor types or diseases.

    View details for DOI 10.1093/jamia/ocz230

    View details for PubMedID 32364237

  • Impact of a deep learning assistant on the histopathologic classification of liver cancer. NPJ digital medicine Kiani, A. n., Uyumazturk, B. n., Rajpurkar, P. n., Wang, A. n., Gao, R. n., Jones, E. n., Yu, Y. n., Langlotz, C. P., Ball, R. L., Montine, T. J., Martin, B. A., Berry, G. J., Ozawa, M. G., Hazard, F. K., Brown, R. A., Chen, S. B., Wood, M. n., Allard, L. S., Ylagan, L. n., Ng, A. Y., Shen, J. n. 2020; 3 (1): 23


    Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists (p = 0.184, OR = 1.281), it significantly improved the accuracy (p = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy (p = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy (p = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.

    View details for DOI 10.1038/s41746-020-0232-8

    View details for PubMedID 33594170

  • Cellular Signaling Pathways in Medium and Large Vessel Vasculitis. Frontiers in immunology Watanabe, R., Berry, G. J., Liang, D. H., Goronzy, J. J., Weyand, C. M. 2020; 11: 587089


    Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumen-stenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.

    View details for DOI 10.3389/fimmu.2020.587089

    View details for PubMedID 33072134

  • Radiology-pathology Correlation in Recovered COVID-19, Demonstrating Organizing Pneumonia. American journal of respiratory and critical care medicine Pogatchnik, B. P., Swenson, K. E., Sharifi, H. n., Bedi, H. n., Berry, G. J., Guo, H. H. 2020

    View details for DOI 10.1164/rccm.202004-1278IM

    View details for PubMedID 32609531

  • Targeted Treatment of Multiple Primary Lung Cancers Harboring Distinct EGFR or RET Alterations: A Case Report. Clinical lung cancer Aredo, J. V., Diehn, M. n., Berry, G. J., Wakelee, H. A. 2020

    View details for DOI 10.1016/j.cllc.2020.12.005

    View details for PubMedID 33451914

  • Innate and Adaptive Immunity in Giant Cell Arteritis. Frontiers in immunology Akiyama, M. n., Ohtsuki, S. n., Berry, G. J., Liang, D. H., Goronzy, J. J., Weyand, C. M. 2020; 11: 621098


    Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4+ T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4+ T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8+ T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.

    View details for DOI 10.3389/fimmu.2020.621098

    View details for PubMedID 33717054

    View details for PubMedCentralID PMC7947610

  • Targeted deep sequencing of cell-free DNA in serous body cavity fluids with malignant, suspicious, and benign cytology. Cancer cytopathology Yang, S., Mooney, K. L., Libiran, P., Jones, C. D., Joshi, R., Lau, H. D., Stehr, H., Berry, G. J., Zehnder, J. L., Long, S. R., Kong, C. S., Kunder, C. A. 2019


    BACKGROUND: Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored.METHODS: We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n=15), peritoneal (n=5), and pericardial (n=1) cavity were analyzed.RESULTS: The supernatants provided a median cfDNA concentration of 10.3ng/L. Notably, all effusions were sequenced successfully to a median depth >1000*, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P=.5), depth of coverage (P=.6), or allele frequency of pathogenic mutations (P=.7).CONCLUSION: cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.

    View details for DOI 10.1002/cncy.22205

    View details for PubMedID 31751001

  • GM-CSF Is a Pro-Inflammatory Cytokine in Experimental Vasculitis of Medium and Large Arteries Watanabe, R., Zhang, H., Maeda, T., Akiyama, M., Gandhi, R., Paolini, J., Berry, G., Weyand, C. WILEY. 2019
  • Loss-of-function of the DNA Repair Nuclease MRE11A Induces Mitochondrial Failure and Tissue Inflammation in Rheumatoid Arthritis Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R., Tian, L., Berry, G., Goronzy, J., Weyand, C. WILEY. 2019
  • Metabolic Signatures of Pathogenic T Cells in Medium and Large Vessel Vasculitis Akiyama, M., Zhang, H., Watanabe, R., Maeda, T., Berry, G., Goronzy, J., Weyand, C. WILEY. 2019
  • Cytokines, growth factors and proteases in medium and large vessel vasculitis CLINICAL IMMUNOLOGY Weyand, C. M., Watanabe, R., Zhang, H., Akiyama, M., Berry, G. J., Goronzy, J. J. 2019; 206: 33–41
  • NHLBI-SPONSORED PROSPECTIVE STUDY TO VALIDATE THE USE OF DONOR-DERIVED CELL-FREE DNA TO DETECT LUNG-TRANSPLANT REJECTION - INTERIM RESULTS Agbor, S., Berry, G., Marboe, C., Tunc, I., Jackson, A., Shah, P., Fideli, U., Timofte, I., Brown, A. W., Iacono, A., Nathan, S., Jang, M., Orens, J., Valantine, H. ELSEVIER SCIENCE INC. 2019: 25–26
  • The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation. Cell metabolism Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R., Tian, L., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2019


    In the autoimmune disease rheumatoid arthritis (RA), CD4+ Tcells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells' bioenergetic failure. MRE11A deficiency in RA Tcells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing Tcells in RA patients. Invivo, pharmacologic and genetic inhibition of MRE11A resulted in tissuedeposition of mtDNA, caspase-1 proteolysis, andaggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.

    View details for DOI 10.1016/j.cmet.2019.06.016

    View details for PubMedID 31327667

  • CD28 AS A POTENTIAL THERAPEUTIC TARGET FOR GIANT CELL ARTERITIS Watanabe, R., Zhang, H., Berry, G., Nadler, S., Goronzy, J., Weyand, C. BMJ PUBLISHING GROUP. 2019: 146
  • CD28 Signaling Controls Metabolic Fitness of Pathogenic T Cells in Medium and Large Vessel Vasculitis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Zhang, H., Watanabe, R., Berry, G. J., Nadler, S. G., Goronzy, J. J., Weyand, C. M. 2019; 73 (14): 1811–23


    In giant cell arteritis, vessel-wall infiltrating CD4 T cells and macrophages form tissue-destructive granulomatous infiltrates, and the artery responds with a maladaptive response to injury, leading to intramural neoangiogenesis, intimal hyperplasia, and luminal occlusion. Lesion-residing T cells receive local signals, which represent potential therapeutic targets.The authors examined how CD28 signaling affects vasculitis induction and maintenance, and which pathogenic processes rely on CD28-mediated T-cell activation.Vasculitis was induced by transferring peripheral blood mononuclear cells from giant cell arteritis patients into immunodeficient NSG mice engrafted with human arteries. Human artery-NSG chimeras were treated with anti-CD28 domain antibody or control antibody. Treatment effects and immunosuppressive mechanisms were examined in vivo and in vitro applying tissue transcriptome analysis, immunohistochemistry, flow cytometry, and immunometabolic analysis.Blocking CD28-dependent signaling markedly reduced tissue-infiltrating T cells and effectively suppressed vasculitis. Mechanistic studies implicated CD28 in activating AKT signaling, T-cell proliferation and differentiation of IFN-γ and IL-21-producing effector T cells. Blocking CD28 was immunosuppressive by disrupting T-cell metabolic fitness; specifically, the ability to utilize glucose. Expression of the glucose transporter Glut1 and of glycolytic enzymes as well as mitochondrial oxygen consumption were all highly sensitive to CD28 blockade. Also, induction and maintenance of CD4+CD103+ tissue-resident memory T cells, needed to replenish the vasculitic infiltrates, depended on CD28 signaling. CD28 blockade effectively suppressed vasculitis-associated remodeling of the vessel wall.CD28 stimulation provides a metabolic signal required for pathogenic effector functions in medium and large vessel vasculitis. Disease-associated glycolytic activity in wall-residing T-cell populations can be therapeutically targeted by blocking CD28 signaling.

    View details for PubMedID 30975299

  • Examination of Factors Associated With Lymph Node Metastases in Lung Carcinoids Pathipati, M. P., Yohannan, T. K., Tian, L., Benson, J. A., Hornbacker, K., Berry, G. J., Lui, N., Kunz, P. L., Padda, S. K. LIPPINCOTT WILLIAMS & WILKINS. 2019: 447
  • Targeted deep sequencing of cell-free DNA from body cavity fluids with malignant, suspicious, and benign cytology Yang, S., Libiran, P., Jones, C., Joshi, R., Lau, H., Stehr, H., Longacre, T., Allison, K., Zehnder, J., Long, S., Berry, G., Kunder, C. NATURE PUBLISHING GROUP. 2019
  • Targeted deep sequencing of cell-free DNA from body cavity fluids with malignant, suspicious, and benign cytology Yang, S., Libiran, P., Jones, C., Joshi, R., Lau, H., Stehr, H., Longacre, T., Allison, K., Zehnder, J., Long, S., Berry, G., Kunder, C. NATURE PUBLISHING GROUP. 2019
  • Cytokines, growth factors and proteases in medium and large vessel vasculitis. Clinical immunology (Orlando, Fla.) Weyand, C. M., Watanabe, R., Zhang, H., Akiyama, M., Berry, G. J., Goronzy, J. J. 2019


    Giant cell arteritis and Takayasu arteritis are autoimmune vasculitides that cause aneurysm formation and tissue infarction. Extravascular inflammation consists of an intense acute phase response. Deeper understanding of pathogenic events in the vessel wall has highlighted the loss of tissue protective mechanisms, the intrusion of immune cells into "forbidden territory", and the autonomy of self-renewing vasculitic infiltrates. Adventitial vasa vasora critically control vessel wall access and drive differentiation of tissue-invasive T cells. Selected T cells establish tissue residency and build autonomous, self-sufficient inflammatory lesions. Pathogenic effector T cells intrude and survive due to failed immune checkpoint inhibition. Vasculitis-sustaining T cells and macrophages provide a broad portfolio of effector functions, involving heterogeneous populations of pro-inflammatory T cells and diverse macrophage subsets that ultimately induce wall capillarization and intimal hyperplasia. Redirecting diagnostic and therapeutic strategies from control of extravascular inflammatory markers to suppression of vascular inflammation will improve disease management.

    View details for PubMedID 30772599

  • Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation. EBioMedicine Agbor-Enoh, S., Wang, Y., Tunc, I., Jang, M. K., Davis, A., De Vlaminck, I., Luikart, H., Shah, P. D., Timofte, I., Brown, A. W., Marishta, A., Bhatti, K., Gorham, S., Fideli, U., Wylie, J., Grimm, D., Goodwin, N., Yang, Y., Patel, K., Zhu, J., Iacono, A., Orens, J. B., Nathan, S. D., Marboe, C., Berry, G. J., Quake, S. R., Khush, K., Valantine, H. A. 2019


    BACKGROUND: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.METHODS: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.FINDINGS: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.INTERPRETATION: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.

    View details for PubMedID 30692045

  • Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis. Frontiers in immunology Akiyama, M. n., Zeisbrich, M. n., Ibrahim, N. n., Ohtsuki, S. n., Berry, G. J., Hwang, P. H., Goronzy, J. J., Weyand, C. M. 2019; 10: 2617


    Objective: Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA). Methods: Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies. Results: Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils (P < 0.001) and release of higher amounts of NETs (P < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients. Conclusion: Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.

    View details for DOI 10.3389/fimmu.2019.02617

    View details for PubMedID 31798577

    View details for PubMedCentralID PMC6874157

  • Combined Deceased Donor Parathyroid and Kidney Transplantation - An Underutilized Approach for ESRD Patients with Permanent Hypoparathyroidism Lee, L., Pan, J., Vasa, P., Berry, G., Lenihan, C., Busque, S. WILEY. 2019: 56
  • Spectrum of chronic lung allograft pathology in a mouse minor-mismatched orthotopic lung transplant model. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Martinu, T., Oishi, H., Juvet, S. C., Cypel, M., Liu, M., Berry, G. J., Hwang, D. M., Keshavjee, S. 2018


    Chronic lung allograft dysfunction (CLAD) is a fatal condition that limits survival after lung transplantation (LTx). The pathological hallmark of CLAD is obliterative bronchiolitis (OB). A subset of patients present with a more aggressive CLAD phenotype, called restrictive allograft syndrome (RAS), characterized by lung parenchymal fibrosis (PF). The mouse orthotopic single LTx model has proven relevant to the mechanistic study of allograft injury. The minor-alloantigen- mismatched strain combination using C57BL/10(B10) donors and C57BL/6(B6) recipients reportedly leads to OB. Recognizing that OB severity is a spectrum that may co-exist with other pathologies, including PF, we aimed to characterize and quantify pathologic features of CLAD in this model. Left LTx was performed in the following combinations: B10B6, B6B10, B6B6. Four weeks post-transplant, blinded pathologic semi-quantitative assessment showed that OB was present in 66% of B10B6 and 30% of B6B10 grafts. Most mice with OB also had PF with a pattern of pleuroparenchymal fibroelastosis, reminiscent of human RAS-related pathology. Grading of pathologic changes demonstrated variable severity of airway fibrosis, PF, acute rejection, vascular fibrosis and epithelial changes, similar to those seen in human CLAD. These assessments can make the murine LTx model a more useful tool for further mechanistic studies of CLAD pathogenesis. This article is protected by copyright. All rights reserved.

    View details for PubMedID 30378739

  • Glucose metabolism controls disease-specific signatures of macrophage effector functions. JCI insight Watanabe, R., Hilhorst, M., Zhang, H., Zeisbrich, M., Berry, G. J., Wallis, B. B., Harrison, D. G., Giacomini, J. C., Goronzy, J. J., Weyand, C. M. 2018; 3 (20)


    BACKGROUND: In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling.METHODS: To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA).RESULTS: Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1beta and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1beta and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function.CONCLUSIONS: We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment.FUNDING: Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.

    View details for PubMedID 30333306

  • Matrix Metalloprotease-9 (MMP-9)-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circulation research Watanabe, R., Maeda, T., Zhang, H., Berry, G. J., Zeisbrich, M., Brockett, R. D., Greenstein, A. E., Tian, L., Goronzy, J., Weyand, C. M. 2018


    Rationale: Giant cell arteritis (GCA), a primary vasculitis of medium and large arteries, is associated with vessel wall damage, elastic membrane fragmentation and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. Objective: The matrix metalloproteinase 9 (MMP-9), a type IV collagenase, is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. Methods and Results: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from GCA patients. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting recombinant MMP-9. Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates (p<0.001), reduced intramural neoangiogenesis (p<0.001) and prevented intimal layer hyperplasia (p<0.001). Recombinant MMP-9 amplified all domains of vasculitogenic activity, promoted assembly of T cell infiltrates (p<0.05), intensified formation of new microvessels (p<0.001) and worsened intimal thickening (p<0.001). Systemic delivery of N-acetyl-proline-glycine-proline (ac-PGP), a matrikine produced by MMP-9-mediated gelatinolysis, had limited vasculitogenic effects. Conclusions: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks and neointimal growth all require the enzymatic activity of MMP-9; identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis.

    View details for PubMedID 29970365

  • Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Jackson, A. M., Tunc, I., Berry, G. J., Cochrane, A., Grimm, D., Davis, A., Shah, P., Brown, A. W., Wang, Y., Timofte, I., Shah, P., Gorham, S., Wylie, J., Goodwin, N., Jang, M., Marishta, A., Bhatti, K., Fideli, U., Yang, Y., Luikart, H., Cao, Z., Pirooznia, M., Zhu, J., Marboe, C., Iacono, A., Nathan, S. D., Orens, J., Valantine, H. A., Khush, K. 2018; 37 (7): 925–32


    Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

    View details for PubMedID 29500138

  • Pathological antibody-mediated rejection in pediatric heart transplant recipients: Immunologic risk factors, hemodynamic significance, and outcomes. Pediatric transplantation Hollander, S. A., Peng, D. M., Mills, M., Berry, G. J., Fedrigo, M., McElhinney, D. B., Almond, C. S., Rosenthal, D. N. 2018: e13197


    Biopsy-diagnosed pAMR has been observed in over half of pediatric HT recipients within 6years of transplantation. We report the incidence and outcomes of pAMR at our center. All endomyocardial biopsies for all HT recipients transplanted between 2010 and 2015 were reviewed and classified using contemporary ISHLT guidelines. Graft dysfunction was defined as a qualitative decrement in systolic function by echocardiogram or an increase of ≥3mmHg in atrial filling pressure by direct measurement. Among 96 patients, pAMR2 occurred in 7 (7%) over a median follow-up period of 3.1years, while no cases of pAMR3 occurred. A history of CHD, DSA at transplant, and elevated filling pressures were associated with pAMR2. Five-sixths (83%) of patients developed new C1q+ DSA at the time of pAMR diagnosis. There was a trend toward reduced survival, with 43% of patients dying within 2.3years of pAMR diagnosis.

    View details for PubMedID 29729067

  • Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis CIRCULATION Zhang, H., Watanabe, R., Berry, G. J., Tian, L., Goronzy, J. J., Weyand, C. M. 2018; 137 (18): 1934–48


    Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4+ T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascular neoangiogenesis and results in lumen-occlusive intimal hyperplasia. We have examined whether persistent vessel wall inflammation is maintained by lesional T cells, including the newly identified tissue-resident memory T cells, and whether such T cells are sensitive to the cytokine-signaling inhibitor tofacitinib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1.Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant cell arteritis. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (reverse transcription polymerase chain reaction), protein expression (immunohistochemistry), and infiltrating cell populations (flow cytometry).Tofacitinib effectively suppressed innate and adaptive immunity in the vessel wall. Lesional T cells responded to tofacitinib with reduced proliferation rates (<10%) and minimal production of the effector molecules interferon-γ, interleukin-17, and interleukin-21. Tofacitinib disrupted adventitial microvascular angiogenesis, reduced outgrowth of hyperplastic intima, and minimized CD4+CD103+ tissue-resident memory T cells.Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of medium and large arteries. The JAK inhibitor tofacitinib effectively suppresses tissue-resident memory T cells and inhibits core vasculitogenic effector pathways.

    View details for PubMedID 29254929

    View details for PubMedCentralID PMC5930040

  • Primary mammary analogue secretory carcinoma of the lung: a case report HUMAN PATHOLOGY Huang, T., McHugh, J. B., Berry, G. J., Myers, J. L. 2018; 74: 109–13


    Mammary analogue secretory carcinoma (MASC) is a recently discovered salivary gland tumor described mostly in the major salivary glands and occasionally in the skin. We report a primary endobronchial tumor with histology, immunophenotype, and ETV6 rearrangement characteristic of MASC in a 62-year-old woman. The diagnosis was initially made on a transbronchial biopsy with fluorescence in situ hybridization confirmation of ETV6 rearrangement. The patient underwent lobectomy demonstrating a large endobronchial mass. To our knowledge, this is the first report of MASC arising as a primary pulmonary tumor. This tumor was unusual in that it is the largest (8.5 cm) MASC ever reported, showed an increased mitotic count (6/10 high-power fields) without high-grade cytology, and presented with advanced-stage disease that included visceral pleural invasion and lymph node metastasis.

    View details for PubMedID 29104113

  • The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. Journal of leukocyte biology Weyand, C. M., Berry, G. J., Goronzy, J. J. 2018; 103 (3): 565–75


    Because of their vital function, the wall structures of medium and large arteries are immunoprivileged and protected from inflammatory attack. That vascular immunoprivilege is broken in atherosclerosis and in vasculitis, when wall-invading T cells and macrophages (Mϕ) promote tissue injury and maladaptive repair. Historically, tissue-residing T cells were studied for their antigen specificity, but recent progress has refocused attention to antigen-nonspecific regulation, which determines tissue access, persistence, and functional differentiation of T cells. The coinhibitory receptor PD-1, expressed on T cells, delivers negative signals when engaged by its ligand PD-L1, expressed on dendritic cells, Mϕ, and endothelial cells to attenuate T cell activation, effector functions, and survival. Through mitigating signals, the PD-1 immune checkpoint maintains tissue tolerance. In line with this concept, dendritic cells and Mϕs from patients with the vasculitic syndrome giant cell arteritis (GCA) are PD-L1lo ; including vessel-wall-embedded DCs that guard the vascular immunoprivilege. GCA infiltrates in the arterial walls are filled with PD-1+ T cells that secrete IFN-gamma, IL-17, and IL-21; drive inflammation-associated angiogenesis; and facilitate intimal hyperplasia. Conversely, chronic tissue inflammation in the atherosclerotic plaque is associated with an overreactive PD-1 checkpoint. Plaque-residing Mϕs are PD-L1hi , a defect induced by their addiction to glucose and glycolytic breakdown. PD-L1hi Mϕs render patients with coronary artery disease immunocompromised and suppress antiviral immunity, including protective anti-varicella zoster virus T cells. Thus, immunoinhibitory signals affect several domains of vascular inflammation; failing PD-L1 in vasculitis enables unopposed immunostimulation and opens the flood gates for polyfunctional inflammatory T cells, and excess PD-L1 in the atherosclerotic plaque disables tissue-protective T cell immunity.

    View details for PubMedID 28848042

  • Validation and Application of Predicted Tumor Mutational Burden (pTMB) Using a 130-Gene Sequencing Panel in Lung Adenocarcinoma Yang, S., Steiner, D., Stehr, H., Berry, G., Zehnder, J. L., Kunder, C. NATURE PUBLISHING GROUP. 2018: 758–59
  • Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis JOURNAL OF NEURO-OPHTHALMOLOGY Uribe, J. A., Aggarwal, I., Witthayaweerasak, J., Liao, Y., Berry, G. J., Sab, U. K., Weyand, C. M. 2018; 38 (1): 17–23


    We describe a 75-year-old woman who experienced vision loss in her left eye due to biopsy-proven giant cell arteritis (GCA). She subsequently developed pachymeningitis causing refractory headaches and bilateral optic neuropathy and maculopathy.Case report with literature review.Eighteen months after the initial diagnosis of GCA, imaging studies in our patient demonstrated pachymeningeal enhancement, and meningeal biopsy confirmed lymphoplasmacytic tissue infiltrates with low frequencies of IgG4+ plasma cells. Laboratory investigation revealed the presence of 3 antiretinal antibodies and antimyeloperoxidase antibodies, consistent with autoimmune retinopathy. Treatment with B-cell-depleting anti-CD20 antibodies suppressed meningeal inflammation and prevented further vision loss.This case illustrates that bilateral vision loss and chronic headaches in patients with GCA may result from retina-directed autoimmunity and pachymeningitis.

    View details for PubMedID 29059089

    View details for PubMedCentralID PMC5811389

  • Dysphagia and Pharyngeal Obstruction in a Nonsmoker JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Nuyen, B. A., Berry, G., Megwalu, U. 2018; 144 (2): 171–72

    View details for PubMedID 29222562

  • Acute Limited Intimal Tears of the Thoracic Aorta. Journal of the American College of Cardiology Chin, A. S., Willemink, M. J., Kino, A. n., Hinostroza, V. n., Sailer, A. M., Fischbein, M. P., Mitchell, R. S., Berry, G. J., Miller, D. C., Fleischmann, D. n. 2018; 71 (24): 2773–85


    Limited intimal tears (LITs) of the aorta (Class 3 dissection variant) are the least common form of aortic pathology in patients presenting with acute aortic syndrome (AAS). LITs are difficult to detect on imaging and may be underappreciated.This study sought to describe the frequency, pathology, treatment, and outcome of LITs compared with other AAS, and to demonstrate that LITs can be detected pre-operatively by contemporary imaging.The authors retrospectively reviewed 497 patients admitted for 513 AAS events at a single academic aortic center between 2003 and 2012. AAS were classified into classic dissection (AD), intramural hematoma, LIT, penetrating atherosclerotic ulcer, and rupturing thoracic aortic aneurysm. The prevalence, pertinent risk factors, and detailed imaging findings with surgical and pathological correlation of LITs are described. Management, early outcomes, and late mortality are reported.Among 497 patients with AAS, the authors identified 24 LITs (4.8% of AAS) in 16 men and 8 women (17 type A, 7 type B). Patients with LITs were older than those with AD, and type A LITs had similarly dilated ascending aortas as type A AD. Three patients presented with rupture. Eleven patients underwent urgent surgical aortic replacement, and 2 patients underwent endovascular repair. Medial degeneration was present in all surgical specimens. In-hospital mortality was 4% (1 of 24), and in total, 5 patients with LIT died subsequently at 1.5 years (interquartile range [IQR]: 0.3 to 2.5 years). Computed tomography imaging detected all but 1 LIT, best visualized on volume-rendered images.LITs are rare acute aortic lesions within the dissection spectrum, with similar presentation, complications, and outcomes compared with AD and intramural hematoma. Awareness of this lesion allows pre-operative diagnosis using high-quality computed tomography angiography.

    View details for PubMedID 29903350

  • Non-Small Cell Lung Cancer Radiogenomics Map Identifies Relationships between Molecular and Imaging Phenotypes with Prognostic Implications. Radiology Zhou, M. n., Leung, A. n., Echegaray, S. n., Gentles, A. n., Shrager, J. B., Jensen, K. C., Berry, G. J., Plevritis, S. K., Rubin, D. L., Napel, S. n., Gevaert, O. n. 2018; 286 (1): 307–15


    Purpose To create a radiogenomic map linking computed tomographic (CT) image features and gene expression profiles generated by RNA sequencing for patients with non-small cell lung cancer (NSCLC). Materials and Methods A cohort of 113 patients with NSCLC diagnosed between April 2008 and September 2014 who had preoperative CT data and tumor tissue available was studied. For each tumor, a thoracic radiologist recorded 87 semantic image features, selected to reflect radiologic characteristics of nodule shape, margin, texture, tumor environment, and overall lung characteristics. Next, total RNA was extracted from the tissue and analyzed with RNA sequencing technology. Ten highly coexpressed gene clusters, termed metagenes, were identified, validated in publicly available gene-expression cohorts, and correlated with prognosis. Next, a radiogenomics map was built that linked semantic image features to metagenes by using the t statistic and the Spearman correlation metric with multiple testing correction. Results RNA sequencing analysis resulted in 10 metagenes that capture a variety of molecular pathways, including the epidermal growth factor (EGF) pathway. A radiogenomic map was created with 32 statistically significant correlations between semantic image features and metagenes. For example, nodule attenuation and margins are associated with the late cell-cycle genes, and a metagene that represents the EGF pathway was significantly correlated with the presence of ground-glass opacity and irregular nodules or nodules with poorly defined margins. Conclusion Radiogenomic analysis of NSCLC showed multiple associations between semantic image features and metagenes that represented canonical molecular pathways, and it can result in noninvasive identification of molecular properties of NSCLC. Online supplemental material is available for this article.

    View details for PubMedID 28727543

  • Gastrointestinal Tract Vasculopathy: Clinicopathology and Description of a Possible "New Entity" With Protean Features. The American journal of surgical pathology Louie, C. Y., DiMaio, M. A., Charville, G. W., Berry, G. J., Longacre, T. A. 2018


    Noninfectious gastrointestinal (GI) vasculopathic disorders are rare and are often overlooked in histopathologic examination or when forming differential diagnoses due to their rarity. However, involvement of the GI tract may lead to serious complications, including ischemia and perforation. Since awareness of the types of vasculopathy that may involve the GI tract is central to arriving at a correct diagnosis, we reviewed our institutional experience with GI tract vasculopathy in order to enhance diagnostic accuracy of these rare lesions. We report the clinical and histologic features of 16 cases (excluding 16 cases of immunoglobulin A vasculitis) diagnosed over a 20-year period. Of the 16 patients, 14 presented with symptoms related to the GI vasculopathy (including 2 presenting with a mass on endoscopic examination). The remaining 2 patients presented with incarcerated hernia and invasive adenocarcinoma. The vasculopathy was not associated with systemic disease and appeared limited to the GI tract in 8 patients. Eight had associated systemic disease, but only 6 had a prior diagnosis. The underlying diagnoses in these 6 patients included systemic lupus erythematosus (1), dermatomyositis (2), rheumatoid arthritis (1), eosinophilic granulomatosis with polyangiitis (1), and Crohn disease (1). One patient with granulomatous polyangiitis and 1 patient with systemic lupus erythematosus initially presented with GI symptoms. The 8 cases of isolated GI tract vasculopathy consisted of enterocolic lymphocytic phlebitis (4), idiopathic myointimal hyperplasia of the sigmoid colon (1), idiopathic myointimal hyperplasia of the ileum (1), granulomatous vasculitis (1), and polyarteritis nodosa-like arteritis (1). Isolated GI tract vasculopathy is rare, but appears to be almost as common as that associated with systemic disease. The chief primary vasculopathies are enterocolic lymphocytic colitis and idiopathic myointimal hyperplasia. Although the latter occurs predominantly in the left colon, rare examples occur in the small bowel and likely represent a complex, more protean disorder.

    View details for PubMedID 29624512

  • Association of Omics Features with Histopathology Patterns in Lung Adenocarcinoma CELL SYSTEMS Yu, K., Berry, G. J., Rubin, D. L., Re, C., Altman, R. B., Snyder, M. 2017; 5 (6): 620-+


    Adenocarcinoma accounts for more than 40% of lung malignancy, and microscopic pathology evaluation is indispensable for its diagnosis. However, how histopathology findings relate to molecular abnormalities remains largely unknown. Here, we obtained H&E-stained whole-slide histopathology images, pathology reports, RNA sequencing, and proteomics data of 538 lung adenocarcinoma patients from The Cancer Genome Atlas and used these to identify molecular pathways associated with histopathology patterns. We report cell-cycle regulation and nucleotide binding pathways underpinning tumor cell dedifferentiation, and we predicted histology grade using transcriptomics and proteomics signatures (area under curve >0.80). We built an integrative histopathology-transcriptomics model to generate better prognostic predictions for stage I patients (p = 0.0182 ± 0.0021) compared with gene expression or histopathology studies alone, and the results were replicated in an independent cohort (p = 0.0220 ± 0.0070). These results motivate the integration of histopathology and omics data to investigate molecular mechanisms of pathology findings and enhance clinical prognostic prediction.

    View details for PubMedID 29153840

    View details for PubMedCentralID PMC5746468

  • Anaplastic Lymphoma Kinase Testing: IHC vs. FISH vs. NGS CURRENT TREATMENT OPTIONS IN ONCOLOGY Niu, X., Chuang, J. C., Berry, G. J., Wakelee, H. A. 2017; 18 (12): 71


    Personalized targeted therapy has emerged as a promising strategy in lung cancer treatment, with current attention focused on elucidation and detection of oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, several oncogenic drivers have been reported, triggering the application of tyrosine kinase inhibitors (TKIs) to target these dysfunctional genes. The anaplastic lymphoma kinase (ALK) rearrangement is responsible for about 4-7% of all non-small cell lung cancers (NSCLCs) and perhaps as high as a third in specific patient populations such as younger, male, non-smokers with advanced stage, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) wild type, and signet ring cell adenocarcinoma with abundant intracytoplasmic mucin. The selection of patients based on their ALK status is vital on account of the high response rates with the ALK-targeted agents in this subset of patients. Standardization and validation of ALK rearrangement detection methods is essential for accurate and reproducible results. There are currently three detection methods widely available in clinical practice, including fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and polymerase chain reaction (PCR)-based next generation sequencing (NGS) technology. However, the choice of diagnostic methodology for ALK rearrangement detection in clinical practice remains a matter of debate. With accumulating data enumerating the advantages and disadvantages of each of the three methods, combining more than one testing method for ALK fusion detection may be beneficial for patients. In this review, we will discuss the current methods used in ALK rearrangement detection with emphasis on their key advantages and disadvantages.

    View details for PubMedID 29143897

  • Comparative Analysis of the Macrophage Glycolytic Machinery in Giant Cell Arteritis (GCA) and in Coronary Artery Disease (CAD) Weyand, C. M., Watanabe, R., Shirai, T., Zhang, H., Berry, G., Goronzy, J. WILEY. 2017
  • The Microvascular Niche Instructs Pathogenic T Cells in Medium and Large Vessel Vasculitis Weyand, C. M., Wen, Z., Shen, Y., Berry, G., Liao, J., Goronzy, J. WILEY. 2017
  • Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Agbor-Enoh, S., Tunc, I., De Vlaminck, I., Fideli, U., Davis, A., Cuttin, K., Bhatti, K., Marishta, A., Solomon, M. A., Jackson, A., Graninger, G., Harper, B., Luikart, H., Wylie, J., Wang, X., Berry, G., Marboe, C., Khush, K., Zhu, J., Valantine, H. 2017; 36 (9): 1004–12


    Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts.After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts.We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R2 > 0.99, p < 10-6), as well as across manual and automated platforms (slope = 0.80, R2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001).The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation.

    View details for PubMedID 28624139

  • Spectral Doppler Waveforms for Diagnosis of Appendicitis: Potential Utility of Point Peak Systolic Velocity and Resistive Index Values. Radiology Shin, L. K., Jeffrey, R. B., Berry, G. J., Olcott, E. W. 2017: 162251-?


    Purpose To test the hypothesis that appendiceal spectral Doppler waveforms can distinguish patients with and patients without appendicitis. Materials and Methods In this retrospective study, Doppler waveforms were obtained from intramural appendiceal arteries identified with color Doppler imaging in 60% (93 of 155) of consecutive patients whose appendices were visualized at graded compression ultrasonography (US) performed for suspected appendicitis (53 male and 40 female; age, 1-56 years; mean, 14.5 years) over the 5-month period from November 2015 through March 2016. Point, non-angle-corrected peak systolic velocity (PSV) and resistive index (RI) values were compared between patients with and patients without appendicitis by utilizing histopathologically proven appendicitis and 6-week clinical follow-up as diagnostic reference standards. Data were assessed by using the Student t test, exact binomial distribution, two-sample test of proportions, and receiver operating characteristic analysis. Results Among the 93 patients, 36 (38.7%) had proven appendicitis (mean PSV, 19.7 cm/sec; mean RI, 0.69) and 57 patients (61.2%) did not (mean PSV, 7.1 cm/sec, P < .0001; mean RI, 0.50, P < .0001). The area under the receiver operating characteristic curve for the diagnosis of appendicitis was 0.97 (95% confidence interval [CI]: 0.95, 1.00) for PSV and 0.86 (95% CI: 0.78, 0.95; P = .011) for RI. Chosen discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 94.7% and 96.5% with sensitivity of 88.9% and 63.9% (P = .013) and negative predictive value of 93.1% and 80.9% (P = .045), respectively. Original clinical graded compression US interpretations based on established US findings demonstrated specificity of 96.2% and sensitivity of 100.0%. Considering the subset of 20 patients whose maximum outer diameter measured 6-8 mm, the discriminatory criteria of PSV greater than 10 cm/sec and RI greater than 0.65 yielded specificity for appendicitis of 88.9% each, with sensitivity of 100.0% and 63.6% and negative predictive value of 100.0% and 66.6%, respectively. Conclusion In patients with visualized appendices at US, those with appendicitis exhibit significantly higher point PSV and point RI values than do patients without appendicitis and are distinguishable with high specificity by using a PSV greater than 10 cm/sec and an RI greater than 0.65 as diagnostic criteria. (©) RSNA, 2017.

    View details for DOI 10.1148/radiol.2017162251

    View details for PubMedID 28582634

  • REDUCED CARBOXYLESTERASE 1 IS ASSOCIATED WITH ENDOTHELIAL INJURY IN METHAMPHETAMINE INDUCED PULMONARY ARTERIAL HYPERTENSION. American journal of physiology. Lung cellular and molecular physiology Orcholski, M. E., Khurshudyan, A., Shamskhou, E. A., Yuan, K., Chen, I. Y., Kodani, S. D., Morisseau, C., Hammock, B. D., Hong, E. M., Alexandrova, L., Alastalo, T., Berry, G., Zamanian, R. T., de Jesus Perez, V. A. 2017: ajplung 00453 2016-?


    Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH) but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. While no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH. Furthermore, whole exome sequencing data from 18 METH-PAH patients revealed that 94.4% of METH-PAH patients were heterozygous carriers of a single nucleotide variant (SNV, rs115629050) predicted to reduce CES1 activity. PMVECs transfected with this CES1 variant demonstrated significantly higher rates of METH-induced apoptosis. METH exposure results in increased formation of reactive oxygen species (ROS) and a compensatory autophagy response. Compared to healthy cells, CES1-deficient PMVECs lack a robust autophagy response despite higher ROS, which correlates with increased apoptosis. We propose that reduced CES1 expression/activity could promote development of METH-PAH by increasing PMVEC apoptosis and small vessel loss.

    View details for DOI 10.1152/ajplung.00453.2016

    View details for PubMedID 28473326

  • Immune checkpoint dysfunction in large and medium vessel vasculitis. American journal of physiology. Heart and circulatory physiology Watanabe, R., Zhang, H., Berry, G., Goronzy, J. J., Weyand, C. M. 2017; 312 (5): H1052-H1059


    Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

    View details for DOI 10.1152/ajpheart.00024.2017

    View details for PubMedID 28314758

  • Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhang, H., Watanabe, R., Berry, G. J., Vaglio, A., Liao, Y. J., Warrington, K. J., Goronzy, J. J., Weyand, C. M. 2017; 114 (6): E970-E979


    Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4(+) T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1(lo), whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD-1(+) effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1(+) effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.

    View details for DOI 10.1073/pnas.1616848114

    View details for Web of Science ID 000393422200011

    View details for PubMedID 28115719

    View details for PubMedCentralID PMC5307483

  • Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages. Clinical cancer research : an official journal of the American Association for Cancer Research Wang, D., Lee, H., Yoon, D., Berry, G., Wheeler, T. M., Sugarbaker, D. J., Kheradmand, F., Engleman, E., Burt, B. M. 2017; 23 (3): 778-788


    Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors.To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs.EGFR oncogene-dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR-targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma.Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778-88. ©2016 AACR.

    View details for DOI 10.1158/1078-0432.CCR-15-2597

    View details for PubMedID 27496865

  • Predictive radiogenomics modeling of EGFR mutation status in lung cancer SCIENTIFIC REPORTS Gevaert, O., Echegaray, S., Khuong, A., Hoang, C. D., Shrager, J. B., Jensen, K. C., Berry, G. J., Guo, H. H., Lau, C., Plevritis, S. K., Rubin, D. L., Napel, S., Leung, A. N. 2017; 7


    Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient's tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies.

    View details for DOI 10.1038/srep41674

    View details for PubMedID 28139704

  • Pulmonary Crohn's Disease DIGESTIVE DISEASES AND SCIENCES Regalia, K., Shelton, A., Berry, G., Triadafilopoulos, G., Cartwright, C. A. 2017; 62 (1): 64-67

    View details for DOI 10.1007/s10620-015-3993-1

    View details for Web of Science ID 000392312200011

    View details for PubMedID 26685911

  • Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. The Journal of clinical investigation Watanabe, R. n., Shirai, T. n., Namkoong, H. n., Zhang, H. n., Berry, G. J., Wallis, B. B., Schaefgen, B. n., Harrison, D. G., Tremmel, J. A., Giacomini, J. C., Goronzy, J. J., Weyand, C. M. 2017; 127 (7): 2725–38


    Patients with coronary artery disease (CAD) are at high risk for reactivation of the varicella zoster virus (VZV) and development of herpes zoster (HZ). Here, we found that macrophages from patients with CAD actively suppress T cell activation and expansion, leading to defective VZV-specific T cell immunity. Monocyte-derived and plaque-infiltrating macrophages from patients with CAD spontaneously expressed high surface density of the immunoinhibitory ligand programmed death ligand-1 (PD-L1), thereby providing negative signals to programmed death-1+ (PD-1+) T cells. We determined that aberrant PD-L1 expression in patient-derived macrophages was metabolically controlled. Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, CAD macrophages respond to nutrient excess by activating the immunoinhibitory PD-1/PD-L1 checkpoint, leading to impaired T cell immunity. This finding indicates that metabolite-based immunotherapy may be a potential strategy for restoring adaptive immunity in CAD.

    View details for PubMedID 28604383

  • Pulmonary Adenocarcinoma with Enteric Differentiation Presenting with Bronchorrhea. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Prakobkit, R., Churk-Nam Auyeung, W., Xu, L., Berry, G. J. 2017; 12 (8): e120–e123

    View details for PubMedID 28748820

  • Comprehensive Genomic Profiling of Malignant Effusions in Patients with Metastatic Lung Adenocarcinoma. The Journal of molecular diagnostics : JMD Yang, S. R., Lin, C. Y., Stehr, H. n., Long, S. R., Kong, C. S., Berry, G. J., Zehnder, J. L., Kunder, C. A. 2017


    Cytology samples are being increasingly utilized for comprehensive molecular testing. Although fine-needle aspirates are adequate substrates for high-throughput sequencing, the suitability of malignant body fluids remains largely unexplored. Herein, we investigated the adequacy and utility of performing targeted next-generation sequencing (NGS) on malignant effusions from patients with metastatic lung adenocarcinoma. Thirty-two effusion samples that were submitted for hybrid capture-based NGS using a clinically validated solid tumor genotyping panel were examined. All cases showed ≥5% tumor cellularity; however, 28 (88%) provided sufficient DNA for NGS (≥1 ng/μL). The sequencing reads showed satisfactory quality control statistics, and the variant allele frequencies were correlated with tumor cellularity. Furthermore, pathogenic or likely pathogenic genomic alterations were identified in 26/28 samples (93%), whereas clinically actionable alterations were present in 18 (64%). Notably, nine patients had additional molecular testing performed on preceding/subsequent biopsies, and the results across multiple samples were compared. In two patients, the NGS-based fluid analysis identified clinically actionable alterations that were not detected by other hotspot testing. In four patients treated with tyrosine kinase inhibitors, malignant fluid sequencing confirmed driver alterations from prior testing and revealed new resistance mechanisms. Hence, given adequate DNA input and tumor cellularity, comprehensive genomic profiling of malignant effusions may be used to establish mutational status at diagnosis and inform treatment resistance during targeted therapy.

    View details for PubMedID 29269277

  • The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Science translational medicine Wen, Z. n., Shen, Y. n., Berry, G. n., Shahram, F. n., Li, Y. n., Watanabe, R. n., Liao, Y. J., Goronzy, J. J., Weyand, C. M. 2017; 9 (399)


    Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating the expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients' blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway, and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.

    View details for PubMedID 28724574

  • Features and Outcomes of Methamphetamine Associated Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Zamanian, R. T., Hedlin, H. n., Greuenwald, P. n., Wilson, D. M., Segal, J. I., Jorden, M. n., Kudelko, K. n., Liu, J. n., Hsi, A. n., Rupp, A. n., Sweatt, A. J., Tuder, R. n., Berry, G. J., Rabinovitch, M. n., Doyle, R. L., De Jesus Perez, V. n., Kawut, S. M. 2017


    While amphetamines are recognized as "likely" agents to cause drugs and toxins associated pulmonary arterial hypertension (PAH), (meth)amphetamine associated PAH (Meth-APAH) has not been well described.To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared to those of idiopathic PAH (iPAH).We performed a prospective cohort study of Meth-APAH and iPAH patients presenting to the Stanford University Pulmonary Hypertension Program between 2003-2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine abusers hospitalized in California.The study sample included 90 Meth-APAH and 97 iPAH patients. Meth-APAH patients were less likely to be female, but similar in age, body mass index, and six minute walk distance to iPAH patients. Meth-PAH patients reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7±6.8 vs. 9.8±5.1 mmHg, p=0.001), and lower stroke volume index (22.2±7.1 vs 25.5±8.7 mL/m2, p=0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years respectively, representing more than double the risk of clinical worsening or death compared to iPAH (HR 2.04, 95% CI 1.28-3.25, p=0.003) independent of confounders. California data demonstrated a 2.6 fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users.Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

    View details for PubMedID 28934596

  • Recurrent Pyogenic Cholangitis: Got Stones? Digestive diseases and sciences Gholami, S., Wood, L., Berry, G., Triadafilopoulos, G., Visser, B. C., Dua, M. M. 2016; 61 (11): 3147-3150

    View details for PubMedID 26602913

  • Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis. Joint, bone, spine : revue du rhumatisme Watanabe, R., Hosgur, E., Zhang, H., Wen, Z., Berry, G., Goronzy, J. J., Weyand, C. M. 2016


    Giant cell arteritis is an autoimmune disease defined by explicit tissue tropism to the walls of medium and large arteries. Pathognomic inflammatory lesions are granulomatous in nature, emphasizing the functional role of CD4T cells and macrophages. Evidence for a pathogenic role of antibodies and immune complexes is missing. Analysis of T cell populations in giant cell arteritis, both in the tissue lesions and in the circulation, has supported a model of broad, polyclonal T cell activation, involving an array of functional T cell lineages. The signature of T cell cytokines produced by vasculitic lesions is typically multifunctional, including IL-2, IFN-γ, IL-17, IL-21, and GM-CSF, supportive for a general defect in T cell regulation. Recent data describing the lack of a lymph node-based population of anti-inflammatory T cells in giant cell arteritis patients offers a fresh look at the immunopathology of this vasculitis. Due to defective CD8(+)NOX2(+) regulatory T cells, giant cell arteritis patients appear unable to curtail clonal expansion within the CD4T cell compartment, resulting in widespread CD4T cell hyperimmunity. Why unopposed expansion of committed CD4 effector T cells would lead to invasion of the walls of medium and large arteries needs to be explored in further investigations.

    View details for DOI 10.1016/j.jbspin.2016.07.005

    View details for PubMedID 27663755

  • Design and rationale of a prospective, multi-institutional registry for patients with sinonasal malignancy. Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W., Colevas, A. D., Le, Q., Berry, G. J., Hwang, P. H. 2016; 126 (9): 1977-1980


    Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

    View details for DOI 10.1002/lary.25996

    View details for PubMedID 27283472

  • Giant Cell Arteritis: From Pathogenesis to Therapeutic Management. Current treatment options in rheumatology Watanabe, R., Goronzy, J. J., Berry, G., Liao, Y. J., Weyand, C. M. 2016; 2 (2): 126-137

    View details for PubMedID 27298757

  • Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. journal of heart and lung transplantation Levine, D. J., Glanville, A. R., Aboyoun, C., Belperio, J., Benden, C., Berry, G. J., Hachem, R., Hayes, D., Neil, D., Reinsmoen, N. L., Snyder, L. D., Sweet, S., Tyan, D., Verleden, G., Westall, G., Yusen, R. D., Zamora, M., Zeevi, A. 2016; 35 (4): 397-406


    Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

    View details for DOI 10.1016/j.healun.2016.01.1223

    View details for PubMedID 27044531

  • Banff study of pathologic changes in lung allograft biopsy specimens with donor-specific antibodies JOURNAL OF HEART AND LUNG TRANSPLANTATION Wallace, W. D., Li, N., Andersen, C. B., Arrossi, A. V., Askar, M., Berry, G. J., Denicola, M. M., Neil, D. A., Pavlisko, E. N., Reed, E. F., Remmelink, M., Weigt, S. S., Weynand, B., Zhang, J. Q., Budev, M. M., Farver, C. F. 2016; 35 (1): 40-48


    The diagnosis of antibody-mediated rejection (AMR) in the lung transplant is still an area under investigation. We performed a blinded multicenter study to determine if any statistically significant histologic findings in transbronchial biopsy specimens from lung transplant patients correlate with the presence of donor-specific antibodies (DSAs).We asked 9 pathologists with experience in lung transplantation to evaluate 161 lung transplant biopsy specimens for various histologic parameters. The findings were correlated with antibody status positive for DSAs, positive for non-DSAs, and no antibodies (NABs) present. The significance of each histologic variable was reviewed.We found no statistically significant association with acute cellular rejection, airway inflammation, or bronchiolitis obliterans and the presence or absence of antibodies. However, biopsy specimens with DSAs had a statistically significant difference vs NABs in the setting of acute lung injury, with or without diffuse alveolar damage (p = 0.0008), in the presence of capillary neutrophilic inflammation (p = 0.0014), and in samples with endotheliitis (p = 0.0155). In samples with complement 4d staining, there was a trend but no statistically significant difference between specimens associated with DSAs and specimens with NABs.Capillary inflammation, acute lung injury, and endotheliitis significantly correlated with DSAs. The infrequently observed diffuse staining for complement 4d limits the usefulness of this stain.

    View details for DOI 10.1016/j.healun.2015.08.021

    View details for Web of Science ID 000370113600005

    View details for PubMedID 26601715

  • Design and rationale of a prospective multi-institutional registry for patients with sinosodal malignancy The Laryngoscope Beswick, D. M., Holsinger, F. C., Kaplan, M. J., Fischbein, N. J., Hara, W. Y., Colevas, A. D., Le, Q. T., Berry, G. J., Hwang, P. H. 2016


    Assessment of patients with sinonasal malignancy is challenging due to the low disease incidence and diverse histopathology. The current literature is composed mainly of retrospective studies with heterogeneous cohorts, and the rarity of cases limits our understanding of disease characteristics and treatment outcomes. We describe the development of a prospective, multi-institutional registry that utilizes cloud-based computing to evaluate treatment outcomes in patients with sinonasal cancer.A web-based, secure database was built to prospectively capture longitudinal outcomes and quality-of-life (QoL) data in patients diagnosed with sinonasal malignancy. Demographics, tumor staging, and treatment outcomes data are being collected. The Sinonasal Outcome Test-22 and University of Washington Quality of Life Questionnaire are administered at presentation and at recurring intervals. To date, seven institutions are participating nationally.This prospective, multi-institutional registry will provide novel oncological and QoL outcomes on patients with sinonasal malignancy to inform management decisions and disease prognostication. The application of cloud-based computing facilitates secure multi-institutional collaboration and may serve as a model for future registry development for the study of rare diseases in otolaryngology.2C. Laryngoscope, 2016.

    View details for DOI 10.1002/lary.25996

  • Erionite-associated malignant pleural mesothelioma in Mexico INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY Oczypok, E. A., Sanchez, M. S., Van Orden, D. R., Berry, G. J., Pourtabib, K., Gunter, M. E., Roggli, V. L., Kraynie, A. M., Oury, T. D. 2016; 9 (5): 5722-5732
  • Predicting non-small cell lung cancer prognosis by fully automated microscopic pathology image features. Nature communications Yu, K., Zhang, C., Berry, G. J., Altman, R. B., Ré, C., Rubin, D. L., Snyder, M. 2016; 7: 12474-?


    Lung cancer is the most prevalent cancer worldwide, and histopathological assessment is indispensable for its diagnosis. However, human evaluation of pathology slides cannot accurately predict patients' prognoses. In this study, we obtain 2,186 haematoxylin and eosin stained histopathology whole-slide images of lung adenocarcinoma and squamous cell carcinoma patients from The Cancer Genome Atlas (TCGA), and 294 additional images from Stanford Tissue Microarray (TMA) Database. We extract 9,879 quantitative image features and use regularized machine-learning methods to select the top features and to distinguish shorter-term survivors from longer-term survivors with stage I adenocarcinoma (P<0.003) or squamous cell carcinoma (P=0.023) in the TCGA data set. We validate the survival prediction framework with the TMA cohort (P<0.036 for both tumour types). Our results suggest that automatically derived image features can predict the prognosis of lung cancer patients and thereby contribute to precision oncology. Our methods are extensible to histopathology images of other organs.

    View details for DOI 10.1038/ncomms12474

    View details for PubMedID 27527408

  • Idelalisib-associated Enterocolitis: Clinicopathologic Features and Distinction From Other Enterocolitides. American journal of surgical pathology Louie, C. Y., DiMaio, M. A., Matsukuma, K. E., Coutre, S. E., Berry, G. J., Longacre, T. A. 2015; 39 (12): 1653-1660


    Idelalisib is a highly specific small-molecule phosphoinositide-3-kinase δ inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. The known side effects of idelalisib include severe diarrhea and colitis. Here we report the histologic findings in idelalisib-associated enterocolitis in 11 patients with chronic lymphocytic leukemia or follicular lymphoma receiving idelalisib over a 5-year period (2011 to 2015) at our institution. All 11 patients were receiving idelalisib and underwent colonoscopy for the evaluation of diarrhea. None of the patients had previously received a stem cell transplant. Histologically, the colon biopsies in all 11 cases showed some degree of apoptosis within crypts, with 5 cases showing moderate to severe apoptosis involving the majority of the crypts with loss of goblet cells. No viral inclusions were seen in any case and immunohistochemical stains for cytomegalovirus performed in 9/11 cases were negative. All cases showed at least focal acute cryptitis, and 8 of these cases showed mild architectural distortion. Increased inflammation within the lamina propria was seen in 7 cases, and increased intraepithelial lymphocytes within crypts was seen in 8 cases; the lymphocytes were mostly T cells with a predominance of CD8 T cells, with the majority expressing the α/β T-cell receptor. Diagnoses of graft-versus-host disease, autoimmune enteropathy, infectious enterocolitis, and although thought to be less likely, inflammatory bowel disease were considered in each case. The presence of numerous intraepithelial lymphocytes in addition to severe villous blunting and apoptosis in the small intestinal biopsies from a subset of these patients additionally raised the possibility of autoimmune enteropathy, common variable immunodeficiency, or less likely, celiac disease. Awareness of the histologic features of idelalisib-associated enterocolitis is important to distinguish it from potential mimics, particularly graft-versus-host disease, autoimmune enteropathy, and cytomegalovirus/infectious enterocolitis.

    View details for DOI 10.1097/PAS.0000000000000525

    View details for PubMedID 26426383

  • Inflammatory Pseudotumors of the Skull Base: Meta-Analysis OTOLOGY & NEUROTOLOGY Alyono, J. C., Shi, Y., Berry, G. J., Recht, L. D., Harsh, G. R., Jackler, R. K., Corrales, C. E. 2015; 36 (8): 1432-1438


    To describe the presentation, treatment, and outcome of inflammatory pseudotumors (IPs) of the skull base.English-language articles in PubMed, Web of Science, and EMBASE from earliest available through April 2014.Articles were identified using a keyword search for "inflammatory pseudotumor," "inflammatory myofibroblastoma," or "plasma cell granuloma," including a keyword localizing to the skull base.One hundred papers with 157 cases met inclusion criteria. History, tumor site, initial and subsequent treatment, outcomes, and complications were extracted. Student t test, z test, and analysis of variance were used to analyze demographics, symptoms, sites involved, and outcomes. Odds ratios for site versus initial treatment were calculated.At diagnosis, average patient age was 41 years. Approximately 70% of lesions primarily involved the anterior skull base, 29% the lateral skull base, and 1.2% the occiput. The most common initial treatments were steroids (44%), surgery (28%), and surgery with steroids (16%). Anterior lesions were 55.8 times more likely than lateral lesions to be treated initially with steroids (CI, 14.7-212). Seventy-six percent of patients had stable or resolved symptoms after a single course of treatment.Diagnosis of skull base IP requires ruling out other aggressive pathologies, such as malignancy and infection, and maintaining a high index of suspicion. Surgery is favored for lesions that can be removed in toto with minimal morbidity, as well as steroids for those sites where anatomy limits complete resection, such as within the orbit, cavernous sinus, or brain. An option for larger lesions involving vital anatomy is debulking, followed by postoperative steroids.

    View details for DOI 10.1097/MAO.0000000000000818

    View details for Web of Science ID 000360488000023

  • Inflammatory Pseudotumors of the Skull Base: Meta-Analysis. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Alyono, J. C., Shi, Y., Berry, G. J., Recht, L. D., Harsh, G. R., Jackler, R. K., Corrales, C. E. 2015; 36 (8): 1432-8


    To describe the presentation, treatment, and outcome of inflammatory pseudotumors (IPs) of the skull base.English-language articles in PubMed, Web of Science, and EMBASE from earliest available through April 2014.Articles were identified using a keyword search for "inflammatory pseudotumor," "inflammatory myofibroblastoma," or "plasma cell granuloma," including a keyword localizing to the skull base.One hundred papers with 157 cases met inclusion criteria. History, tumor site, initial and subsequent treatment, outcomes, and complications were extracted. Student t test, z test, and analysis of variance were used to analyze demographics, symptoms, sites involved, and outcomes. Odds ratios for site versus initial treatment were calculated.At diagnosis, average patient age was 41 years. Approximately 70% of lesions primarily involved the anterior skull base, 29% the lateral skull base, and 1.2% the occiput. The most common initial treatments were steroids (44%), surgery (28%), and surgery with steroids (16%). Anterior lesions were 55.8 times more likely than lateral lesions to be treated initially with steroids (CI, 14.7-212). Seventy-six percent of patients had stable or resolved symptoms after a single course of treatment.Diagnosis of skull base IP requires ruling out other aggressive pathologies, such as malignancy and infection, and maintaining a high index of suspicion. Surgery is favored for lesions that can be removed in toto with minimal morbidity, as well as steroids for those sites where anatomy limits complete resection, such as within the orbit, cavernous sinus, or brain. An option for larger lesions involving vital anatomy is debulking, followed by postoperative steroids.

    View details for DOI 10.1097/MAO.0000000000000818

    View details for PubMedID 26164448

  • Hodgkin Lymphoma Following Adalimumab for the Treatment of Crohn's Disease in an Adolescent DIGESTIVE DISEASES AND SCIENCES Rodriguez, A. A., Kerner, J., Luna-Fineman, S., Berry, G. J. 2014; 59 (10): 2403-2405
  • Hodgkin lymphoma following adalimumab for the treatment of Crohn's disease in an adolescent. Digestive diseases and sciences Rodriguez, A. A., Kerner, J., Luna-Fineman, S., Berry, G. J. 2014; 59 (10): 2403-2405

    View details for DOI 10.1007/s10620-014-3191-6

    View details for PubMedID 24817339

  • T cell-macrophage interactions and granuloma formation in vasculitis FRONTIERS IN IMMUNOLOGY Hilhorst, M., Shirai, T., Berry, G., Goronzy, J. J., Weyand, C. M. 2014; 5: 1-14
  • Classic biphasic pulmonary blastoma demonstrated by 18F-FDG PET/CT. Clinical nuclear medicine Keu, K. V., Berry, G. J., Quon, A. 2014; 39 (4): 346-348


    A 75-year-old nonsmoker woman was referred for the evaluation of a nonsecretory left adrenal lesion. An abdominal contrast-enhanced CT showed an incidental left lower lobe mass, which was confirmed on a chest contrast-enhanced CT. A F-FDG PET/CT showed a hypermetabolic tumor without nodal or distant metastasis. She underwent a lobectomy, and the final pathology reported a classic biphasic pulmonary blastoma, which is an uncommon histological form of malignant lung neoplasm. This case highlighted the glucose avidity of this rare and aggressive cancer.

    View details for DOI 10.1097/RLU.0b013e31828e987c

    View details for PubMedID 23989445

  • Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging. Proceedings of the National Academy of Sciences of the United States of America Eberlin, L. S., Tibshirani, R. J., Zhang, J., Longacre, T. A., Berry, G. J., Bingham, D. B., Norton, J. A., Zare, R. N., Poultsides, G. A. 2014; 111 (7): 2436-2441


    Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastric-tissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastric-cancer surgery.

    View details for DOI 10.1073/pnas.1400274111

    View details for PubMedID 24550265

  • Endothelial fate mapping in mice with pulmonary hypertension. Circulation Qiao, L., Nishimura, T., Shi, L., Sessions, D., Thrasher, A., Trudell, J. R., Berry, G. J., Pearl, R. G., Kao, P. N. 2014; 129 (6): 692-703


    Pulmonary endothelial injury triggers a reparative program, which in susceptible individuals is characterized by neointima formation, vascular narrowing, and the development of pulmonary arterial hypertension. The neointimal cells in human pathological plexiform lesions frequently coexpress smooth muscle α-actin and the endothelial von Willebrand antigen, creating a question about their cellular lineage of origin.Experimental pulmonary hypertension with neointima formation develops in C57Bl/6 mice subjected to left pneumonectomy followed 1 week later by jugular vein injection of monocrotaline pyrrole (20 μg/μL and 1 μL/g; group P/MCTP). Compared with the group vehicle, by day 35, group P/MCTP developed higher right ventricular systolic pressure (54±5 versus 25±2 mm Hg; P<0.01) and right ventricular hypertrophy (0.58±0.16 versus 0.26±0.05; P<0.01). Transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted green fluorescent protein. In control mice, few endothelial lineage-marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin. Concurrent with the development of pulmonary hypertension, endothelial lineage-marked cells are prominent in the neointima and exhibit expression of smooth muscle α-actin and smooth muscle myosin heavy chain. Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen and smooth muscle α-actin.Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of smooth muscle α-actin and smooth muscle myosin heavy chain.

    View details for DOI 10.1161/CIRCULATIONAHA.113.003734

    View details for PubMedID 24201301

  • A critical role for the mTORC2 pathway in lung fibrosis. PloS one Chang, W., Wei, K., Ho, L., Berry, G. J., Jacobs, S. S., Chang, C. H., Rosen, G. D. 2014; 9 (8)


    A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-β and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-β of pro-fibrotic pathways. Recent studies show that mTORC2, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis. We examined the effect of MLN0128 on TGF-β-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-β-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-β induces the Rictor component of mTORC2 in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it (1) inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-β-stimulated IPF fibroblasts; (2) inhibited fibrosis in a murine bleomycin lung model; and (3) protected lung epithelial cells from injury caused by TGF-β-stimulated IPF fibroblasts. Our findings support a role for mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.

    View details for DOI 10.1371/journal.pone.0106155

    View details for PubMedID 25162417

    View details for PubMedCentralID PMC4146613

  • A Critical Role for the mTORC2 Pathway in Lung Fibrosis. PloS one Chang, W., Wei, K., Ho, L., Berry, G. J., Jacobs, S. S., Chang, C. H., Rosen, G. D. 2014; 9 (8): e106155


    A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-β and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-β of pro-fibrotic pathways. Recent studies show that mTORC2, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis. We examined the effect of MLN0128 on TGF-β-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-β-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-β induces the Rictor component of mTORC2 in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it (1) inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-β-stimulated IPF fibroblasts; (2) inhibited fibrosis in a murine bleomycin lung model; and (3) protected lung epithelial cells from injury caused by TGF-β-stimulated IPF fibroblasts. Our findings support a role for mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.

    View details for DOI 10.1371/journal.pone.0106155

    View details for PubMedID 25162417

    View details for PubMedCentralID PMC4146613

  • T cell-macrophage interactions and granuloma formation in vasculitis. Frontiers in immunology Hilhorst, M., Shirai, T., Berry, G., Goronzy, J. J., Weyand, C. M. 2014; 5: 432-?


    Granuloma formation, bringing into close proximity highly activated macrophages and T cells, is a typical event in inflammatory blood vessel diseases, and is noted in the name of several of the vasculitides. It is not known whether specific properties of the microenvironment in the blood vessel wall or the immediate surroundings of blood vessels contribute to granuloma formation and, in some cases, generation of multinucleated giant cells. Granulomas provide a specialized niche to optimize macrophage-T cell interactions, strongly activating both cell types. This is mirrored by the intensity of the systemic inflammation encountered in patients with vasculitis, often presenting with malaise, weight loss, fever, and strongly upregulated acute phase responses. As a sophisticated and highly organized structure, granulomas can serve as an ideal site to induce differentiation and maturation of T cells. The granulomas possibly seed aberrant Th1 and Th17 cells into the circulation, which are known to be the main pathogenic cells in vasculitis. Through the induction of memory T cells, aberrant innate immune responses can imprint the host immune system for decades to come and promote chronicity of the disease process. Improved understanding of T cell-macrophage interactions will redefine pathogenic models in the vasculitides and provide new avenues for immunomodulatory therapy.

    View details for DOI 10.3389/fimmu.2014.00432

    View details for PubMedID 25309534

    View details for PubMedCentralID PMC4162471

  • Aortic wall thickness: an independent risk factor for aortic dissection? journal of heart valve disease Shiran, H., Odegaard, J., Berry, G., Miller, D. C., Fischbein, M., Liang, D. 2014; 23 (1): 17-24


    Aortic aneurysm size is known to portend a higher likelihood of aortic complications in patients with connective tissue disorders (CTD), but other objective tools are needed to determine which patients are at greatest risk of dissection, especially those which reflect the structural integrity and strength of the aortic wall.The aortic wall pathology was evaluated in CTD patients with and without acute aortic dissection to identify parameters that affect the risk of dissection. A retrospective review was performed of aneurysm pathology from patients with Marfan syndrome (MFS; n = 53) without dissection undergoing prophylactic aortic root surgery, and acute type A aortic dissection patients (AAAoD; n = 16). Patients without a cardiovascular cause of death (n = 19) served as controls. The minimal aortic medial wall thickness was measured, and medial myxoid degeneration (MMD) and the degree of elastin loss and fragmentation were graded.The mean minimal aortic wall thickness was 1,625 +/- 364 microm in controls, and 703 +/- 256 microm and 438 +/- 322 microm for MFS and AAAoD patients, respectively. Aortic root diameters did not correlate with aortic wall thickness. A comparison of aortic medial thickness showed that the media was significantly thinner among acute dissection patients than either elective surgical patients (p = 0.02) or controls (p < 0.001). Aortic size, degree of MMD, and elastin loss did not vary significantly between CTD patients.A diminished aortic wall medial thickness may be linked to aortic dissection. High-resolution imaging techniques in the future may lead to the morphological assessment of aortic medial wall thickness in vivo becoming a reality which, in theory, could provide a more refined risk prognostication for acute aortic dissection.

    View details for PubMedID 24779324

  • The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Berry, G. J., Burke, M. M., Andersen, C., Bruneval, P., Fedrigo, M., Fishbein, M. C., Goddard, M., Hammond, E. H., Leone, O., Marboe, C., Miller, D., Neil, D. L., Rassl, D., Revelo, M. P., Rice, A., Rodriguez, E. R., Stewart, S., Tan, C. D., Winters, G. L., West, L., Mehra, M. R., Angelini, A. L. 2013; 32 (12): 1147-1162


    During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.

    View details for DOI 10.1016/j.healun.2013.08.011

    View details for PubMedID 24263017

  • Orthotopic heart transplantation in two infants with histiocytoid cardiomyopathy and left ventricular non-compaction PEDIATRIC TRANSPLANTATION Siehr, S. L., Bernstein, D., Yeh, J., Berry, G. J., Rosenthal, D. N., Hollander, S. A. 2013; 17 (7): E165-E167


    HC is a rare cause of congestive heart failure that typically presents with malignant ventricular arrhythmias in infants, often requiring urgent intervention. Successful heart transplantation in a patient with HC has only been reported once (J Heart Lung Transplant 2004: 23: 902). The combination of HC with concurrent LVNC has only been described three times (Int J Legal Med 2009: 123: 47; Hum Pathol 2005: 36: 403; Pediatr Dev Pathol 2012: 15: 397). We report two rare cases of HC with LVNC in two infants presenting with cardiogenic shock, one requiring ECMO support who was successfully bridged to orthotopic heart transplantation with a Berlin Heart LVAD.

    View details for DOI 10.1111/petr.12141

    View details for Web of Science ID 000325369400004

    View details for PubMedID 24099092

  • Clinical and Echocardiographic Presentation of Rejection Episodes Following Heart Transplantation 33rd Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation Sudini, N. L., Huo, J., Pan, S., Montoya, J., Leon, S., Vu, T., Beygui, R. E., Vrtovec, B., Wu, J. C., Pham, M., KUSH, K., Berry, G., Hunt, S., Haddad, F. ELSEVIER SCIENCE INC. 2013: S254–S254
  • Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology. Case reports in pulmonology Kunder, R., Kunder, C., Sun, H. Y., Berry, G., Messner, A., Frankovich, J., Roth, S., Mark, J. 2013; 2013: 649365-?


    Plastic bronchitis (PB) is a pathologic condition in which airway casts develop in the tracheobronchial tree causing airway obstruction. There is no standard treatment strategy for this uncommon condition. We report an index patient treated using an emerging multimodal strategy of directly instilled and inhaled tissue plasminogen activator (t-PA) as well as 13 other cases of PB at our institution between 2000 and 2012. The majority of cases (n = 8) occurred in patients with congenital heart disease. Clinical presentations, treatments used, histopathology of the casts, and patient outcomes are reviewed. Further discussion is focused on the epidemiology of plastic bronchitis and a systematic approach to the histologic classification of casts. Comorbid conditions identified in this study included congenital heart disease (8), pneumonia (3), and asthma (2). Our institutional prevalence rate was 6.8 per 100,000 patients, and our case fatality rate was 7%.

    View details for DOI 10.1155/2013/649365

    View details for PubMedID 23662235

  • Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT JOURNAL OF HEART AND LUNG TRANSPLANTATION Berry, G., Burke, M., Andersen, C., Angelini, A., Bruneval, P., Calbrese, F., Fishbein, M. C., Goddard, M., Leone, O., Maleszewski, J., Marboe, C., Miller, D., Neil, D., Padera, R., Rassi, D., Revell, M., Rice, A., Stewart, S., Yousem, S. A. 2013; 32 (1): 14-21

    View details for DOI 10.1016/j.healun.2012.11.005

    View details for PubMedID 23260701

  • Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II) TRANSPLANTATION Crespo-Leiro, M. G., Zuckermann, A., Bara, C., Mohacsi, P., Schulz, U., Boyle, A., Ross, H. J., Parameshwar, J., Zakliczynski, M., Fiocchi, R., Stypmann, J., Hoefer, D., Lehmkuhl, H., Deng, M. C., Leprince, P., Berry, G., Marboe, C. C., Stewart, S., Tazelaar, H. D., Baron, H. M., Coleman, I., Vanhaecke, J. 2012; 94 (11): 1172-1177


    There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs).We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers).Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both.The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

    View details for DOI 10.1097/TP.0b013e31826e19e2

    View details for Web of Science ID 000312072600021

    View details for PubMedID 23222738

  • 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology CARDIOVASCULAR PATHOLOGY Leone, O., Veinot, J. P., Angelini, A., Baandrup, U. T., Basso, C., Berry, G., Bmneval, P., Burke, M., Butany, J., Calabrese, F., D'Amati, G., Edwards, W. D., Fallon, J. T., Fishbein, M. C., Gallagher, P. J., Halushka, M. K., McManus, B., Pucci, A., Rodriguez, E. R., Saffitz, J. E., Sheppard, M. N., Steenbergen, C., Stone, J. R., Tan, C., Thiene, G., van der Wal, A. C., Winters, G. L. 2012; 21 (4): 245-274
  • Antibody-mediated rejection of the cardiac allograft: where do we stand in 2012? CURRENT OPINION IN ORGAN TRANSPLANTATION Berry, G. J. 2012; 17 (3): 303-308


    The review will discuss the current pathological criteria for the diagnosis and classification of antibody-mediated rejection (AMR) in the cardiac allograft.Until recently, the diagnosis of AMR required clinical dysfunction, presence of donor specific antibodies and pathological alterations. The concept of asymptomatic AMR and its adverse long-term outcomes created, in part the need to reevaluate diagnostic criteria. The results of a recent consensus meeting sponsored by International Society For Heart And Lung Transplantation are discussed.The diagnosis of AMR rests on histopathological and immunophenotypic findings. These provide the basis for a new grading scheme.

    View details for DOI 10.1097/MOT.0b013e328353660f

    View details for Web of Science ID 000303826900015

    View details for PubMedID 22498650

  • AORTIC WALL THICKNESS MAY BE AN INDEPENDENT RISK FACTOR FOR AORTIC DISSECTION 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC)/Conference on ACC-i2 with TCT Shiran, H., Odegaard, J., Berry, G., Miller, D. C., Fischbein, M., Liang, D. ELSEVIER SCIENCE INC. 2012: E831–E831
  • Cardiac Paraganglioma: Diagnostic and Surgical Challenges JOURNAL OF CARDIAC SURGERY Huo, J. L., Choi, J. C., DeLuna, A., Lee, D., Fleischmann, D., Berry, G. J., Deuse, T., Haddad, F. 2012; 27 (2): 178-182


    Primary cardiac paragangliomas are rare extra-adrenal tumors. Though they account for less than 1% of all primary cardiac tumors, they are considerable sources of morbidity and mortality. In this case review, we discuss the challenges associated with the diagnosis and management of cardiac paragangliomas.

    View details for DOI 10.1111/j.1540-8191.2011.01378.x

    View details for Web of Science ID 000302172800009

    View details for PubMedID 22273468

  • miR-29b Participates in Early Aneurysm Development in Marfan Syndrome CIRCULATION RESEARCH Merk, D. R., Chin, J. T., Dake, B. A., Maegdefessel, L., Miller, M. O., Kimura, N., Tsao, P. S., Iosef, C., Berry, G. J., Mohr, F. W., Spin, J. M., Alvira, C. M., Robbins, R. C., Fischbein, M. P. 2012; 110 (2): 312-?


    Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

    View details for DOI 10.1161/CIRCRESAHA.111.253740

    View details for PubMedID 22116819

  • beta 2-adrenergic receptors mediate cardioprotection through crosstalk with mitochondrial cell death pathways JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Fajardo, G., Zhao, M., Berry, G., Wong, L., Mochly-Rosen, D., Bernstein, D. 2011; 51 (5): 781-789


    β-adrenergic receptors (β-ARs) modulate cardiotoxicity/cardioprotection through crosstalk with multiple signaling pathways. We have previously shown that β2-ARs are cardioprotective during exposure to oxidative stress induced by doxorubicin (DOX). DOX cardiotoxicity is mediated in part through a Ca(2+)-dependent opening of the mitochondrial permeability transition (MPT), however the signals linking a cell surface receptor like the β2-AR to regulators of mitochondrial function are not clear. The objective of this study was to assess mechanisms of crosstalk between β2-ARs and mitochondrial cell death pathways. DOX administered to WT mice resulted in no acute mortality, however 85% of β2-/- mice died within 30 min. Several pro- and anti-survival pathways were altered. The pro-survival kinase, εPKC, was decreased by 64% in β2-/- after DOX vs WT (p<0.01); the εPKC activator ψεRACK partially rescued these mice (47% reduction in mortality). Activity of the pro-survival kinase Akt decreased by 76% in β2-/- after DOX vs WT (p<0.01). The α1-antagonist prazosin restored Akt activity to normal and also partially reversed the mortality (45%). Deletion of the β2-AR increased rate of Ca(2+) release by 75% and peak [Ca(2+)](i) by 20% respectively in isolated cardiomyocytes; the Ca(2+) channel blocker verapamil also partially rescued the β2-/- (26%). Mitochondrial architecture was disrupted and complex I and II activities decreased by 40.9% and 34.6% respectively after DOX only in β2-/-. The MPT blocker cyclosporine reduced DOX mortality by 41% and prazosin plus cyclosporine acted synergistically to decrease mortality by 85%. β2-ARs activate pro-survival kinases and attenuate mitochondrial dysfunction during oxidative stress; absence of β2-ARs enhances cardiotoxicity via negative regulation of survival kinases and enhancement of intracellular Ca(2+), thus predisposing the mitochondria to opening of the MPT.

    View details for DOI 10.1016/j.yjmcc.2011.06.019

    View details for PubMedID 21756913

  • The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: Evolution and current status (2005-2011) JOURNAL OF HEART AND LUNG TRANSPLANTATION Berry, G. J., Angelini, A., Burke, M. M., Bruneval, P., Fishbein, M. C., Hammond, E., Miller, D., Neil, D., Revelo, M. P., Rodriguez, E. R., Stewart, S., Tan, C. D., Winters, G. L., Kobashigawa, J., Mehra, M. R. 2011; 30 (6): 601-611

    View details for DOI 10.1016/j.healun.2011.02.015

    View details for PubMedID 21555100

  • Primary cervical tracheal monophasic synovial sarcoma confirmed by SYT-SSX gene rearrangement JOURNAL OF LARYNGOLOGY AND OTOLOGY Corrales, C. E., Berry, G., Damrose, E. J. 2011; 125 (6): 651-654


    To review the existing diagnostic modalities and treatment for primary tracheal synovial sarcoma, and to report a case of primary cervical synovial sarcoma arising in the trachea.Retrospective.Head and neck surgery unit at a tertiary university centre.One case of primary cervical tracheal monophasic synovial sarcoma diagnosed by SYT-SSX gene rearrangement.This patient underwent surgical resection of the synovial sarcoma, together with tracheal resection and primary anastomosis assisted by laryngeal-releasing manoeuvres, without complication.Clinical, radiographical, pathological and surgical information were collected.One year post-operatively, there was no evidence of recurrence.Synovial sarcoma arising in the trachea is very rare. Diagnosis is confirmed by demonstrating the SYT-SSX gene rearrangement. The first-line treatment is surgery.

    View details for DOI 10.1017/S0022215110002975

    View details for Web of Science ID 000292101800023

    View details for PubMedID 21281530

  • Identification and Classification of Acute Cardiac Rejection by Intragraft Transcriptional Profiling CIRCULATION Holweg, C. T., Potena, L., Luikart, H., Yu, T., Berry, G. J., Cooke, J. P., Valantine, H. A., Mocarski, E. S. 2011; 123 (20): 2236-U154


    Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation.Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings.The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.

    View details for DOI 10.1161/CIRCULATIONAHA.109.913921

    View details for Web of Science ID 000290852200018

    View details for PubMedID 21555702

    View details for PubMedCentralID PMC3115694

  • Report from a consensus conference on antibody-mediated rejection in heart transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Kobashigawa, J., Crespo-Leiro, M. G., Ensminger, S. M., Reichenspurner, H., Angelini, A., Berry, G., Burke, M., Czer, L., Hiemann, N., Kfoury, A. G., Mancini, D., Mohacsi, P., Patel, J., Pereira, N., Platt, J. L., Reed, E. F., Reinsmoen, N., Rodriguez, E. R., Rose, M. L., Russell, S. D., Starling, R., Suciu-Foca, N., Tallaj, J., Taylor, D. O., Van Bakel, A., West, L., Zeevi, A., Zuckermann, A. 2011; 30 (3): 252-269


    The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation.The conference included 83 participants (transplant cardiologists, surgeons, immunologists and pathologists) representing 67 heart transplant centers from North America, Europe, and Asia who all participated in smaller break-out sessions to discuss the various topics of AMR and attempt to achieve consensus.A tentative pathology diagnosis of AMR was established, however, the pathologist felt that further discussion was needed prior to a formal recommendation for AMR diagnosis. One of the most important outcomes of this conference was that a clinical definition for AMR (cardiac dysfunction and/or circulating donor-specific antibody) was no longer believed to be required due to recent publications demonstrating that asymptomatic (no cardiac dysfunction) biopsy-proven AMR is associated with subsequent greater mortality and greater development of cardiac allograft vasculopathy. It was also noted that donor-specific antibody is not always detected during AMR episodes as the antibody may be adhered to the donor heart. Finally, recommendations were made for the timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed. Recommendations for management and future clinical trials were also provided.The AMR Consensus Conference brought together clinicians, pathologists and immunologists to further the understanding of AMR. Progress was made toward a pathology AMR grading scale and consensus was accomplished regarding several clinical issues.

    View details for DOI 10.1016/j.healun.2010.11.003

    View details for Web of Science ID 000287550800004

    View details for PubMedID 21300295

  • Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients JOURNAL OF HEART AND LUNG TRANSPLANTATION Chin, C., Chen, G., Sequeria, F., Berry, G., Siehr, S., Bernstein, D., Rosenthal, D., Reinhartz, O., Tyan, D. 2011; 30 (2): 158-163


    Donor-specific antibodies (DSA) against human leukocyte antigens complicate transplantation with the potential for acute antibody-mediated rejection (AMR). Complement-fixing antibodies are required to initiate the complement cascade. Not all DSAs, however, can fix complement.A novel C1q assay was developed to detect the sub-set of immunoglobulin G (IgG) antibodies capable of fixing complement. Sera from 18 pediatric heart transplant patients were analyzed for DSAs using a Luminex platform (Luminex Inc, Austin, TX) and commercially available single-antigen bead assay kits. Biopsy specimens were assessed for AMR using histopathologic criteria and immunohistochemical staining.During the study period, 5 patients had AMR; of these, 2 were C1q virtual crossmatch positive (VXM+) and had persistent C1q DSAs after transplant, and 3 were C1q VXM- but antibody developed immediately after transplant. A positive C1q assay in the immediate post-transplant period had a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 100%, with 100% sensitivity and 100% specificity (Fisher exact p = 0.001). Of 11 patients who were IgG VXM+, 5 had AMR; the IgG VXM had a PPV of 45% and NPV of 100%, with 100% sensitivity and 54% specificity (Fisher exact p = 0.101).The C1q assay can detect a sub-set of antibodies capable of fixing complement and predicts AMR early after transplant. Avoiding only the donor antigens that would be recognized by the C1q assay may accelerate time to transplant by expansion of the donor pool and potentially allows transplantation of previously "incompatible" organs.

    View details for DOI 10.1016/j.healun.2010.08.020

    View details for Web of Science ID 000286545200008

    View details for PubMedID 20951058

  • Pathologic Interpretation of Transbronchial Biopsy for Acute Rejection of Lung Allograft Is Highly Variable AMERICAN JOURNAL OF TRANSPLANTATION Arcasoy, S. M., Berry, G., Marboe, C. C., Tazelaar, H. D., Zamora, M. R., Wolters, H. J., Fang, K. C., Keshavjee, S. 2011; 11 (2): 320-328


    Despite the standardization of pathologic grading of acute rejection in transbronchial lung biopsies following lung transplantation, the reproducibility of pathologic diagnosis has not been adequately evaluated. To determine the interobserver variability for pathologic grading of acute rejection, 1566 biopsies from 845 subjects in the Lung Allograft Rejection Gene Expression Observational study were regraded by a pathology panel blinded to the original diagnosis and compared to the grade of acute rejection assigned by individual center pathologists. The study panel confirmed 49.1% of center pathologists' A0 grades, but upgraded 5.7% to A1 and 2.7% to grade ≥ A2 rejection; 42.5% were regraded as AX. Of 268 grade A1 samples, 21.2% were confirmed by the pathology panel; 18.7% were upgraded to ≥ A2 and 35.8% were downgraded to A0 with 24.3% being regraded as AX. Lastly, 53.5% of ≥ A2 cases were confirmed, but 15.7% were downgraded to grade A0 and 18.4% cases to A1, while 12.4% were regraded as AX. The kappa value for interobserver agreement was 0.183 (95%CI 0.147-0.220, p < 0.001). The results for B grade interpretation were similar. Suboptimal sampling is common and a high degree of variability exists in the pathologic interpretation of acute rejection in transbronchial biopsies.

    View details for DOI 10.1111/j.1600-6143.2010.03382.x

    View details for Web of Science ID 000286626700019

    View details for PubMedID 21219569

  • Marked Tumor Response and Fatal Hemoptysis During Radiation for Lung Cancer in a Human Immunodeficiency Virus-Positive Patient Taking Nelfinavir JOURNAL OF THORACIC ONCOLOGY Chapman, C. H., Shen, J., Filion, E. J., Tran, P. T., Hara, W., Asuncion, A., Marko, D., Wakelee, H., Berry, G. J., Dimmick, K. W., Loo, B. W., Green, J. 2009; 4 (12): 1587-1589

    View details for PubMedID 20009915

  • Salivary Gland Anlage Tumor in a Neonate Presenting with Respiratory Distress: Radiographic and Pathologic Correlation AMERICAN JOURNAL OF NEURORADIOLOGY Mogensen, M. A., Lin, A. C., Chang, K. W., Berry, G. J., Barnes, P. D., Fischbein, N. J. 2009; 30 (5): 1022-1023


    We present a case of congenital salivary gland anlage tumor (SGAT) of the nasal septum in a 2-week-old infant who had difficulty breathing through her nose since birth. CT and MR imaging demonstrated a circumscribed mass within the nasal cavity that did not communicate with the intracranial compartment. Differential diagnosis and clinical significance of recognizing this rare lesion are reviewed.

    View details for DOI 10.3174/ajnr.A1364

    View details for PubMedID 19112069

  • Right Ventricular Dysfunction Predicts Poor Outcome Following Hemodynamically Compromising Rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Fisher, P., Pham, M., Berry, G., Weisshaar, D., Kuppahally, S., Vrtovec, B., Deuse, T., Virani, S., Fearon, W., Valantine, H., Hunt, S. 2009; 28 (4): 312-319


    Hemodynamically compromising rejection (HCR) is a major cause of mortality and morbidity after heart transplantation. Right ventricular (RV) function is a strong predictor of outcome in patients with heart failure and myocarditis. The objective of the current study is to determine whether RV dysfunction predicts event-free survival in patients with HCR.Medical records of 548 heart transplant patients followed at Stanford University between January 1998 and January 2007 were reviewed. HCR was defined as a rejection episode requiring hospitalization for heart failure. Univariate and multivariate analyses were performed to identify risk factors for death or retransplantation at 1 year.HCR occurred in 71 patients (12.9%). Death or retransplantation at 1 year occurred in 28 patients (39%). Univariate analysis identified non-cellular rejection (odds ratio [OR] = 3.20, p = 0.021), the need for inotropic support (OR = 4.80, p = 0.007), RV dysfunction (OR = 4.63, p = 0.006), left ventricular ejection fraction (OR = 0.941, p = 0.031) and acute renal failure (OR = 3.82, p = 0.010) as predictors of death or retransplantation at 1 year. Multivariate analysis identified RV dysfunction (OR = 4.80, p = 0.007) and the need for inotropic support (OR = 5.00, p = 0.009) as predictors of death or retransplantation at 1 year.In the modern era of immunosuppression, HCR remains a major complication after heart transplantation. RV dysfunction was identified as a novel risk factor for death or retransplantation following HCR.

    View details for DOI 10.1016/j.healun.2008.12.023

    View details for PubMedID 19332256

  • Inter-Observer Variability hi the Interpretation of Cardiac Biopsies Remains a Challenge: Results of the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II Study 29th Annual Meeting and Scientific Session of the International-Society-for-Heart-and-Lung-Transplantation Crespo-Leiro, M. G., Schulz, U., Vanhaecke, J., Zuckermann, A., Bara, C., Mohacsi, P., Bogaev, R. C., Boyle, A., Ross, H., Parameshwar, J., Zakliczynski, M., Fiocchi, R., Stypmann, J., Hoefer, D., Lehmkuhl, H., Deng, M. C., LEPRINCE, P., Berry, G., Marboe, C. C., Stewart, S., Tazelaar, H. D., Brown, M., Baron, H. M. ELSEVIER SCIENCE INC. 2009: S230–S230
  • Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Stewart, S., Fishbein, M. C., Snell, G. I., Berry, G. J., Boehler, A., Burke, M. M., Glanville, A., Gould, F. K., Magro, C., Marboe, C. C., McNeil, K. D., Reed, E. F., Reinsmoen, N. L., Scott, J. P., Studer, S. M., Tazelaar, H. D., Wallwork, J. L., Westall, G., Zamora, M. R., Zeevi, A., Yousem, S. A. 2007; 26 (12): 1229-1242


    In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.

    View details for DOI 10.1016/j.healun.2007.10.017

    View details for Web of Science ID 000251993500002

    View details for PubMedID 18096473

  • Active bacterial myocarditis: A case report and review of the literature JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Berry, G., Doyle, R. L., Martineau, P., Leung, T., Racine, N. 2007; 26 (7): 745-749


    Bacterial myocarditis (BM) is an uncommon cause of infectious myocarditis. BM is usually seen in the context of overwhelming sepsis or as part of a specific bacterial syndrome. The definitive diagnosis of bacterial myocarditis requires biopsy or morphologically proven active myocarditis with evidence of bacterial invasion or positive tissue cultures. The management of bacterial myocarditis consists of aggressive and early antibiotic or anti-toxin treatment, appropriate hemodynamic support, and treatment of arrhythmias or mechanical complications. We present a case of acute Listeria monocytogenes myocarditis in an immunocompetent patient and highlight the challenges in the diagnosis and treatment of bacterial myocarditis.

    View details for DOI 10.1016/j.healun.2007.04.010

    View details for Web of Science ID 000248195700014

    View details for PubMedID 17613408

  • Rapid aneurysmal degeneration of a Stanford type B aortic dissection in a patient with Loeys-Dietz syndrome JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Lee, R. S., Fazel, S., Schwarze, U., Fleischmann, D., Berry, G. J., Liang, D., Miller, D. C., Mitchell, R. S. 2007; 134 (1): 242-U32

    View details for DOI 10.1016/j.jtcvs.2007.03.004

    View details for PubMedID 17599521

  • Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice BLOOD Nakae, S., Suto, H., Berry, G. J., Galli, S. J. 2007; 109 (9): 3640-3648


    Both mast cells and IL-17 can contribute to host defense and pathology in part by orchestrating neutrophil recruitment, but the possible role of mast cells in IL-17-induced inflammation remains to be defined. We found that mast cells and IL-17, but neither IFN-gamma nor FcRgamma signaling, contributed significantly to the antigen (Ag)-dependent airway neutrophilia elicited in ovalbumin-specific T-cell receptor (TCR)-expressing C57BL/6-OTII mice, and that IFN-gamma significantly suppressed IL-17-dependent airway neutrophilia in this setting. IL-18, IL-1beta, and TNF each contributed significantly to the development of Ag- and T helper 17 (Th17 cell)-mediated airway neutrophilia. Moreover, IL-17 enhanced mast cell TNF production in vitro, and mast cell-associated TNF contributed significantly to Ag- and Th17 cell-mediated airway neutrophilia in vivo. By contrast, we detected no significant role for the candidate mediators histamine, PGD(2), LTB(4), CXCL10, or IL-16, each of which can be produced by mast cells and other cell types, in the neutrophil infiltration elicited in this model. These findings establish that mast cells and mast cell-derived TNF can significantly enhance, by FcRgamma-independent mechanisms, the Ag- and Th17 cell-dependent development of a neutrophil-rich inflammatory response at a site of Ag challenge.

    View details for DOI 10.1182/blood-2006-09-046128

    View details for Web of Science ID 000246091400014

    View details for PubMedID 17197430

    View details for PubMedCentralID PMC1874568

  • Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo BLOOD Nishimura, T., Myles, T., Piliposky, A. M., Kao, P. N., Berry, G. J., Leung, L. L. 2007; 109 (5): 1992-1997


    Plasma procarboxypeptidase B (proCPB) is activated by the endothelial thrombin-thrombomodulin [corrected] complex. Activated proCPB [corrected] (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPB-deficient mice (proCPB-/-). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB-/- mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB-/- mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury.

    View details for DOI 10.1182/blood-2006-03-012567

    View details for PubMedID 17105819

  • Influence of mast cells on outcome after heterotopic cardiac transplantation in rats TRANSPLANT INTERNATIONAL Boerma, M., Fiser, W. P., Hoyt, G., Berry, G. J., Joseph, L., Joseph, J., Wang, J., Crew, M. D., Robbins, R. C., Hauer-Jensen, M. 2007; 20 (3): 256-265


    Correlative data suggest that mast cells adversely affect cardiac transplantation. This study uses a mast cell-deficient rat model to directly address the role of mast cells in cardiac allotransplantation. Standardized cardiac heterotopic transplantation with cyclosporine immunosuppression was performed in mast cell-deficient and mast cell-competent rats. Rejection, ischemia, fibrosis, fibrin deposition, numbers of T-cell receptor alpha/beta positive cells, expression of transforming growth factor-beta (TGF-beta), and of endothelin-1 (ET-1) and its receptors ETA and ETB were assessed. Differences in baseline cardiac gene expression were quantified by real-time PCR in a separate group of untransplanted animals. Baseline cardiac gene expression levels of all investigated growth factors, cytokines, ET-1, ETA, and ETB were similar in mast cell-deficient and mast cell-competent rats. Surprisingly, upon heterotopic transplantation, donor heart survival was significantly reduced in mast cell-deficient rats. Moreover, in mast cell-deficient donor hearts rejection was more severe, although nonsignificant, and extracellular matrix associated TGF-beta immunoreactivity was significantly lower than in mast cell-competent donor hearts. Fibrin immunoreactive area, on the other hand, was only increased in mast cell-deficient donor hearts, but not in mast cell-competent donor hearts. Histopathological changes in all donor hearts were accompanied by increased immunoreactivity for ET-1. In conclusion, this study shows that mast cells play a protective role after cardiac transplantation.

    View details for DOI 10.1111/j.1432-2277.2006.00420.x

    View details for Web of Science ID 000243975500006

    View details for PubMedID 17291219

  • Gene expression profiling distinguishes moderate to severe from mild acute cellular rejection in cardiac allograft recipients Bernstein, D., Berry, G., Billingham, M., Marboe, C. C., Deng, M. C., Mital, S., Eisen, H., Williams, G. E., Baron, H., Klingler, T. M., Wohlgemuth, J. G., Kobashigawa, J. ELSEVIER SCIENCE INC. 2007: S121–S121
  • Refining the identification of discriminatory genes for rejection in lung transplantation: The Largo study Keshavjee, S., Berry, G., Marboe, C. C., Wilt, J. S., Trulock, E. P., Corris, P. A., Doyle, R. L., McCurry, K. R., Arcasoy, S. M., Davis, R. D., Golden, J. G., Strueber, M., Sweet, S., Jaksch, P., Mehta, A. C., Mulligan, M. S., Pajaro, O. E., Sun, J. T., Klingler, T. M., Rosenberg, S., Dedrick, R. D., Wolters, H., Fang, K. C., Zamora, M. R. ELSEVIER SCIENCE INC. 2007: S185–S186
  • Respiratory epithelial adenomatoid hamartoma: Diagnostic pitfalls with emphasis on differential diagnosis ADVANCES IN ANATOMIC PATHOLOGY Sangoi, A. R., Berry, G. 2007; 14 (1): 11-16


    In the upper aerodigestive tract, respiratory epithelial adenomatoid hamartoma (REAH) is described as a polypoid proliferation of glands lined by ciliated respiratory epithelium that seem to invaginate downward into the submucosa while maintaining direct continuity with the surface mucosa. The lesion can be confused with a variety of benign and malignant entities, including inflammatory polyp, inverted schneiderian papilloma, and low-grade sinonasal adenocarcinoma. In reviewing the historical, clinical, gross, and histopathologic features of REAH and its subtypes, we elucidate how the distinction of REAH with florid mucinous metaplasia from low-grade adenocarcinoma can be challenging particularly in the setting of small biopsy samples. Diagnostic criteria are reviewed with emphasis on key distinguishing characteristics. The significance of this distinction is paramount in preventing unwarranted surgery and untoward consequences for the patient.

    View details for Web of Science ID 000243573000002

    View details for PubMedID 17198306

  • Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy TRANSPLANT INTERNATIONAL Rousvoal, G., Si, M., Lau, M., Zhang, S., Berry, G. J., Flores, M. G., Changelian, P. S., Reitz, B. A., Borie, D. C. 2006; 19 (12): 1014-1021


    Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common gamma chain. The rationally designed inhibitor of JAK3, CP-690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP-690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1(a)) or Lewis (RT1(l)) rats were heterotopically transplanted into the infra-renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP-690,550 by osmotic pumps (mean drug exposure of 110 +/- 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 +/- 0.85% vs. 0.43 +/- 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 +/- 2.4% vs. 0.38 +/- 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP-690,550-treated animals also had a significant reduction of donor-specific IgG production and of the gene expression for suppressor of cytokine signaling-3 and with unchanged levels of expression of RANTES, IP-10 and transforming growth factor-beta1. These results are the first to show that JAK3 blockade by CP-690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.

    View details for DOI 10.1111/j.1432-2277.2006.00387.x

    View details for Web of Science ID 000241740200009

    View details for PubMedID 17081232

  • Isolated giant cell myocarditis in the atrium: An incidental finding? PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Ahmad, I., Miller, D. C., Berry, G. J., Hsia, H. H., Wang, P. J., Al-Ahmad, A. 2006; 29 (10): 1179-1180


    Giant cell myocarditis (GCM) is an uncommon disorder that affects ventricular myocardium causing severe left ventricular dysfunction and ventricular arrhythmias. We report a case of GCM that only affected the atrium sparing the ventricle.

    View details for PubMedID 17038151

  • The use of endobronchial valve device to eliminate air leak RESPIRATORY MEDICINE Fann, J. I., Berry, G. J., Burdon, T. A. 2006; 100 (8): 1402-1406


    We evaluated an endobronchial valve device in the treatment of surgically created air leak or pneumothorax by eliminating antegrade flow.Six sheep underwent general anesthesia with positive pressure ventilation and left thoracotomy. After division of the mediastinal pleura, the contralateral cranial lobe was identified and a 2.5 cmx1.5 cm laceration created with resultant air leak. Using bronchoscopy, we deployed a valve device in the bronchus of the injured segment. Chest drainage tube was placed and the thoracotomy closed. At 1 week (n=3) and 4 weeks (n=3), the animals underwent general anesthesia, bronchoscopy and right thoracotomy.All animals survived the procedure. Bronchoscopic valve device placement in the segmental bronchus resolved the air leak immediately. After closure of thoracotomy, the chest tube demonstrated minimal drainage with no air leak. At 1 and 4 weeks, bronchoscopy showed no change in device location, and the treated segments were atelectatic with fibrous scar at the injured site.Collapse of a selected lung segment with resolution of air leak can be achieved using bronchoscopically implanted valve device. The valve device may facilitate treatment of patients with post-surgical or post-traumatic persistent air leak.

    View details for DOI 10.1016/j.rmed.2005.11.011.

    View details for Web of Science ID 000239219000014

    View details for PubMedID 16376535

  • Images in cardiovascular medicine. Cardiac magnetic resonance imaging for myocarditis: effective use in medical decision making. Circulation Fenster, B. E., Chan, F. P., Valentine, H. A., Yang, E., McConnell, M. V., Berry, G. J., Yang, P. C. 2006; 113 (22): e842-3

    View details for PubMedID 16754807

  • CD4+ invariant T-cell-receptor plus natural killer T cells in bronchial asthma. NEW ENGLAND JOURNAL OF MEDICINE Akbari, O., Faul, J. L., Hoyte, E. G., Berry, G. J., Wahlstrom, J., Kronenberg, M., DeKruyff, R. H., Umetsu, D. T. 2006; 354 (11): 1117-1129


    Bronchial asthma is associated with an inflammatory process that is characterized by the presence in the airways of large numbers of CD4+ T cells producing interleukin-4 and interleukin-13. However, the CD4 antigen is expressed not only by class II major histocompatibility complex (MHC)-restricted CD4+ T cells, but also by a newly identified subgroup of T cells, CD1d-restricted natural killer T cells. These cells express a conserved (invariant) T-cell receptor and have a potent immunoregulatory function. Because mouse models of allergic asthma indicate that natural killer T cells are required for the development of allergen-induced airway hyperreactivity, we hypothesized that natural killer T cells play an important role in human asthma.We used CD1d-tetramers, antibodies specific for natural killer T cells, as well as reverse-transcriptase-polymerase-chain-reaction analysis of the invariant T-cell receptor of natural killer T cells to assess the frequency and distribution of natural killer T cells in the lungs and in the circulating blood of 14 patients with asthma.About 60 percent of the pulmonary CD4+CD3+ cells in patients with moderate-to-severe persistent asthma were not class II MHC-restricted CD4+ T cells but, rather, natural killer T cells. The natural killer T cells expressed an invariant T-cell receptor and produced type 2 helper cytokines. In contrast, the CD4+ T cells found in the lungs of patients with sarcoidosis were conventional CD4+CD3+ T cells, not natural killer T cells.Together with studies in mice indicating a requirement for natural killer T cells in the development of allergen-induced airway hyperreactivity, our results strongly suggest that CD4+ natural killer T cells play a prominent pathogenic role in human asthma.

    View details for Web of Science ID 000235981700005

    View details for PubMedID 16540612

  • Primary cardiac angiosarcoma: case report and review of the literature CARDIOVASCULAR PATHOLOGY Kurian, K. C., Weisshaar, D., Parekh, H., Berry, G. J., Reitz, B. 2006; 15 (2): 110-112


    We report of a young man who was referred for evaluation of the right atrial mass. He had presented outside the hospital with shortness of breath. A transthoracic echocardiogram (TTE) done there showed a bright echodensity in the right atrium with moderate pericardial effusion. He was treated for presumed viral pericarditis. Pericardiocentesis showed a bloody effusion. Four weeks after this initial presentation, a repeat TTE was done to evaluate for recurrent pericardial effusion due to shortness of breath. The right atrial mass had increased in size and no effusion was noted. He was referred to us for further evaluation. The tumor was successfully resected during surgery, and the pathological examination revealed primary cardiac angiosarcoma. The case highlights the misdiagnosis in initial clinical presentation, current diagnostic modalities, and treatment options for cardiac angiosarcoma.

    View details for DOI 10.1016/j.carpath.2005.10.003

    View details for Web of Science ID 000236664600007

    View details for PubMedID 16533700

  • Glycolipid activation of invariant T cell receptor(+) NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4(+) T cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Meyer, E. H., Goya, S., Akbari, O., Berry, G. J., Savage, P. B., Kronenberg, M., Nakayama, T., DeKruyff, R. H., Umetsu, D. T. 2006; 103 (8): 2782-2787


    Asthma is an inflammatory lung disease, in which conventional CD4+ T cells producing IL-4/IL-13 appear to play an obligatory pathogenic role. Here we show, in a mouse model of asthma, that activation of pulmonary IL-4/IL-13 producing invariant TCR+ CD1d-restricted natural killer T (NKT) cells is sufficient for the development of airway hyperreactivity (AHR), a cardinal feature of asthma, in the absence of conventional CD4+ T cells and adaptive immunity. Respiratory administration of glycolipid antigens that specifically activate NKT cells (alpha-GalactosylCeramide and a Sphingomonas bacterial glycolipid) rapidly induced AHR and inflammation typically associated with protein allergen administration. Naïve MHC class II-deficient mice, which lack conventional CD4+ T but have NKT cells, showed exaggerated baseline AHR and, when challenged with alpha-GalactosylCeramide, demonstrated even greater AHR. These studies demonstrate an expanded role for NKT cells, in which NKT cells not only produce cytokines that influence adaptive immunity but also function as critical effector cells that can induce AHR. These results suggest that NKT cells responding to glycolipid antigens, as well as conventional CD4+ T cells responding to peptide antigens, may be synergistic in the induction of AHR, although in some cases, each may independently induce AHR.

    View details for DOI 10.1073/pnas.0510282103

    View details for Web of Science ID 000235554900055

    View details for PubMedID 16478801

    View details for PubMedCentralID PMC1413796

  • Recurrence of pulmonary intravascular bronchoalveolar tumor with mediastinal metastasis 20 years later RESPIRATORY MEDICINE Chen, T. M., Donington, J., Mak, G., Berry, G. J., Ruoss, S. J., Rosen, G. D., Upadhyay, D. 2006; 100 (2): 367-370


    Pulmonary intravascular bronchoalveolar tumor (IVBAT) also recognized as pulmonary epithelioid hemangioendothelioma, is a rare malignant vascular tumor of unknown etiology. IVBAT is a tumor of multicentric origin and the lungs are rarely involved, with only about 60 cases of pulmonary IVBAT described in the literature. The prognosis is unpredictable, with life expectancy ranging from 1 to 15 years. We report an unusual case of pulmonary IVBAT that recurred in the lung with metastasis to the mediastinum.

    View details for DOI 10.1016/j.rmed.2005.05.010

    View details for Web of Science ID 000235243000024

    View details for PubMedID 15990286

  • Early detection of Cardiac Allograft Vasculopathy through gene expression - Profiling insights of the cargo study Deng, M. C., Cadeiras, M., Baron, H. M., Marboe, H. M., Starling, R. C., Eisen, H., Valantine, H., Hunt, S. A., Kobashigawa, J., Mehra, M. R., Pauly, D. F., Murali, S., Mital, S., Berry, G., Billingham, M., Wohlgemuth, J., Dedrick, R. ELSEVIER SCIENCE INC. 2006: S98–S98
  • Increased molecular testing scores associated with agreement among cardiac pathologists for the diagnosis of ISHLT 3A and higher rejection Marboe, C. C., Deng, M. C., Berry, G., Billingham, M., Eisen, H. J., Pauly, D., Baron, H., Klingler, T., Lal, P., Mahmood, I., Wohlgemuth, J., Starling, R. ELSEVIER SCIENCE INC. 2006: S105–S106
  • Probabilistic modeling of rejection in cardiac allograft patients as measured by biopsy and molecular diagnostics Danaher, P. J., Klingler, T. M., Berry, G. J., Billingham, M. E., Eisen, H. J., Wohlgemuth, J. G., Baron, H. M., Deng, M. C., Marboe, C. C. ELSEVIER SCIENCE INC. 2006: S186–S186
  • Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 T MAGNETIC RESONANCE IN MEDICINE Arai, T., Kofidis, T., Bulte, J. W., de Bruin, J., Venook, R. D., Berry, G. J., McConnell, M. V., Quertermous, T., Robbins, R. C., Yang, P. C. 2006; 55 (1): 203-209


    Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC-treated myocardium was conducted over a 4-week period using a 1.5 T clinical scanner. During the 4-week duration, the mESC-treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium.

    View details for DOI 10.1002/mrm.20702

    View details for PubMedID 16315206

  • Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling AMERICAN JOURNAL OF TRANSPLANTATION Deng, M. C., Eisen, H. J., Mehra, M. R., Billingham, M., Marboe, C. C., Berry, G., Kobashigawa, J., Johnson, F. L., Starling, R. C., Murali, S., Pauly, D. F., Baron, H., Wohlgemuth, J. G., Woodward, R. N., Klingler, T. M., Walther, D., Lal, P. G., Rosenberg, S., Hunt, S. 2006; 6 (1): 150-160


    Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT > or = 3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0-40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

    View details for DOI 10.1111/j.1600-6143.2005.01175.x

    View details for Web of Science ID 000234344900024

    View details for PubMedID 16433769

  • Cyclin D1 and p16 expression in recurrent nasopharyngeal carcinoma. World journal of surgical oncology Lin, H., Berry, G. J., Sun, Z., Fee, W. E. 2006; 4: 62-?


    Cyclin D1 and p16 are involved in the regulation of G1 checkpoint and may play an important role in the tumorigenesis of nasopharyngeal carcinoma (NPC). Previous studies have examined the level of expression of cyclin D1 and p16 in primary untreated NPC but no such information is available for recurrent NPC. We set out in this study to examine the expression level of cyclin D1 and p16 in recurrent NPC that have failed previous treatment with radiation +/- chemotherapy.A total of 42 patients underwent salvage nasopharyngectomy from 1984 to 2001 for recurrent NPC after treatment failure with radiation +/- chemotherapy. Twenty-seven pathologic specimens were available for immunohistochemical study using antibodies against cyclin D1 and p16.Positive expression of cyclin D1 was observed in 7 of 27 recurrent NPC specimens (26%) while positive p16 expression was seen in only 1 of 27 recurrent NPC (4%).While the level of expression of cyclin D1 in recurrent NPC was similar to that of previously untreated head and neck cancer, the level of p16 expression in recurrent NPC samples was much lower than that reported for previously untreated cancer. The finding that almost all (96%) of the recurrent NPC lack expression of p16 suggested that loss of p16 may confer a survival advantage by making cancer cells more resistant to conventional treatment with radiation +/- chemotherapy. Further research is warranted to investigate the clinical use of p16 both as a prognostic marker and as a potential therapeutic target.

    View details for PubMedID 16953893

    View details for PubMedCentralID PMC1569377

  • Recurrence of iron deposition in the cardiac allograft in a patient with non-HFE hemochromatosis JOURNAL OF HEART AND LUNG TRANSPLANTATION Kuppahally, S. S., Hunt, S. A., Valantine, H. A., Berry, G. J. 2006; 25 (1): 144-147


    We report the case of a 36-year-old woman with a diagnosis of idiopathic dilated cardiomyopathy who underwent cardiac transplantation. The results of her initial iron studies were normal, but hemochromatosis was suspected after microscopy of the explanted heart revealed iron deposition. By 6 months post-transplantation, iron deposition was detected in her surveillance endomyocardial biopsy specimens and studies then confirmed the existence of non-HFE hemochromatosis. The patient has been stable on treatment with regular phlebotomies and a low vitamin C diet.

    View details for DOI 10.1016/j.healun.2005.08.002

    View details for Web of Science ID 000234610200025

    View details for PubMedID 16399547

  • Differential cardioprotective/cardiotoxic effects mediated by ss-adrenergic receptor subtypes AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Bernstein, D., Fajardo, G., Zhao, M. M., Urashima, T., Powers, J., Berry, G., Kobilka, B. K. 2005; 289 (6): H2441-H2449


    Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta1- vs. beta2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta1, beta2, and beta1/beta2 knockout (-/-) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta1-/- mice showed no acute cardiovascular effects, whereas beta2-/- mice all died within 30 min. The additional deletion of the beta1-receptor (beta1/beta2-/-) totally rescued this toxicity. beta2-/- mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued beta2-/- mice from this acute toxicity. The enhanced toxicity in beta2-/- mice was also recapitulated in wild-type mice with the beta2-selective antagonist ICI-118,551, although the rescue effect of the beta1-deletion was not recapitulated using the beta1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate beta-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these beta-adrenergic receptor subtypes in vivo.

    View details for DOI 10.1152/ajpheart.00005.2005

    View details for Web of Science ID 000233176600023

    View details for PubMedID 16040722

  • Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection JOURNAL OF HEART AND LUNG TRANSPLANTATION Stewart, S., Winters, G. L., Fishbein, M. C., Tazelaar, H. D., Kobashigawa, J., Abrams, J., Andersen, C. B., Angelini, A., Berry, G. J., Burke, M. M., Demetris, A. J., Hammond, E., Itescu, S., Marboe, C. C., McManus, B., Reed, E. F., Reinsmoen, N. L., Rodriguez, E. R., ROSE, A. G., Rose, M., Suciu-Focia, N., Zeevi, A., Billingham, M. E. 2005; 24 (11): 1710-1720


    In 1990, an international grading system for cardiac allograft biopsies was adopted by the International Society for Heart Transplantation. This system has served the heart transplant community well, facilitating communication between transplant centers, especially with regard to patient management and research. In 2004, under the direction of the International Society for Heart and Lung Transplantation (ISHLT), a multidisciplinary review of the cardiac biopsy grading system was undertaken to address challenges and inconsistencies in its use and to address recent advances in the knowledge of antibody-mediated rejection. This article summarizes the revised consensus classification for cardiac allograft rejection. In brief, the revised (R) categories of cellular rejection are as follows: Grade 0 R--no rejection (no change from 1990); Grade 1 R--mild rejection (1990 Grades 1A, 1B and 2); Grade 2 R--moderate rejection (1990 Grade 3A); and Grade 3 R--severe rejection (1990 Grades 3B and 4). Because the histologic sub-types of Quilty A and Quilty B have never been shown to have clinical significance, the "A" and "B" designations have been eliminated. Recommendations are also made for the histologic recognition and immunohistologic investigation of acute antibody-mediated rejection (AMR) with the expectation that greater standardization of the assessment of this controversial entity will clarify its clinical significance. Technical considerations in biopsy processing are also addressed. This consensus revision of the Working Formulation was approved by the ISHLT Board of Directors in December 2004.

    View details for DOI 10.1016/j.healun.2005.03.019

    View details for Web of Science ID 000233412300002

    View details for PubMedID 16297770

  • Lymphocytic myocarditis after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Weinkauf, J., Walia, R., Berry, G. J., Vagelos, R., Faul, J. L. 2005; 24 (8): 1163-1165


    This study reports the development of lymphocytic myocarditis in a bilateral lung allograft recipient. A 23-year-old woman developed congestive heart failure and severe left ventricular dysfunction 32 months after a bilateral lung allograft for cystic fibrosis. She had taken oral acyclovir for infectious mononucleosis that was diagnosed 11 months previously. Her viral load for Epstein-Barr virus (EBV) increased, and an echocardiogram revealed a left ventricular ejection fraction of 25% and endomyocardial biopsy revealed lymphocytic myocarditis. She received valacyclovir (1 g x 3 times daily) and made a full recovery 6 months later.

    View details for DOI 10.1016/j.healun.2004.07.012

    View details for Web of Science ID 000231300600040

    View details for PubMedID 16102466

  • Nodular endocardial infiltrates (Quilty lesions) cause significant variability in diagnosis of ISHLT Grade 2 and 3A rejection in cardiac allograft recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Marboe, C. C., Billingham, M., Eisen, H., Deng, M. C., Baron, H., Mehra, M., Hunt, S., Wohlgemuth, J., Mahmood, I., Prentice, J., Berry, G. 2005; 24 (7): S219-S226


    Endomyocardial biopsy is used to guide therapy after heart transplantation. An accurate and reliable diagnosis of rejection is critical for proper patient management.A sub-set of 827 biopsies from 273 patients were identified from 8 centers participating in the Cardiac Allograft Gene Expression Observational Study. These included all biopsies graded by local center pathologists as International Society for Heart and Lung Transplantation (ISHLT) Grade 1B or higher and also randomly chosen Grade 0 and 1A biopsies. Each of these cases was reviewed in a blinded manner by 3 study pathologists in the absence of clinical data. The study pathologists were assigned an ISHLT grade and noted nodular endocardial infiltrates (Quilty lesions).The study pathologists were significantly more likely than local pathologists to diagnose ISHLT Grade 0, 1A and 3B rejection and significantly less likely to diagnose ISHLT Grade 1B, 2 and 3A rejection. Concordance between local and study pathologists was lowest for Grade 2 (17% agreement). Quilty lesions were noted in 3.3% of local Grade 0 cases and in 31% and 37% of local Grade 2 and 3A cases, respectively. Quilty lesions were recognized by study pathologists in 35% of local Grade 2 cases "downgraded" to Grade 0 or 1, but in only 10% of local Grade 2 cases confirmed by study pathologists.The greatest variability between pathologists in application of the ISHLT grading system is in Grade 2 biopsies, and Quilty lesions are a major contributing factor to the lack of concordance. Accurate application of the ISHLT grading system requires improved recognition and understanding of Quilty lesions.

    View details for DOI 10.1016/j.healun.2005.04.001

    View details for Web of Science ID 000230496000002

    View details for PubMedID 15993777

  • Pathology of radiation and anthracycline cardiotoxicity 8th International Conference on Long-Term Complications of Treatment of Children and Adolescents with Cancer Berry, G. J., Jorden, M. WILEY-LISS. 2005: 630–37


    Radiation-induced heart disease (RIHD) and anthracycline cardiotoxicity are two patterns of cardiac dysfunction caused by therapeutic interventions to treat malignancies. They occur in both the pediatric and adult populations and there is evidence to suggest that pediatric patients are at greater risk. This is due in part to the longer survival rates but also reflects increased susceptibility to the attendant complications caused by both therapies. Radiation can cause injury to all the components of the heart, including the vasculature, while anthracycline toxicity is generally limited to the myocardium.

    View details for DOI 10.1002/pbc.20346

    View details for Web of Science ID 000228789300010

    View details for PubMedID 15825155

  • TIM-1 induces T cell activation and inhibits the development of peripheral tolerance NATURE IMMUNOLOGY Umetsu, S. E., Lee, W. L., McIntire, J. J., Downey, L., Sanjanwala, B., Akbari, O., Berry, G. J., Nagumo, H., Freeman, G. J., Umetsu, D. T., DeKruyff, R. H. 2005; 6 (5): 447-454


    We have examined the function of TIM-1, encoded by a gene identified as an 'atopy susceptibility gene' (Havcr1*), and demonstrate here that TIM-1 is a molecule that costimulates T cell activation. TIM-1 was expressed on CD4(+) T cells after activation and its expression was sustained preferentially in T helper type 2 (T(H)2) but not T(H)1 cells. In vitro stimulation of CD4(+) T cells with a TIM-1-specific monoclonal antibody and T cell receptor ligation enhanced T cell proliferation; in T(H)2 cells, such costimulation greatly enhanced synthesis of interleukin 4 but not interferon-gamma. In vivo, the use of antibody to TIM-1 plus antigen substantially increased production of both interleukin 4 and interferon-gamma in unpolarized T cells, prevented the development of respiratory tolerance, and increased pulmonary inflammation. Our studies suggest that immunotherapies that regulate TIM-1 function may downmodulate allergic inflammatory diseases.

    View details for DOI 10.1038/ni1186

    View details for PubMedID 15793575

  • Recurrent lymphoma of the lung - Computed tomography appearance JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Hwang, G. L., Leung, A. N., Zinck, S. E., Berry, G. J. 2005; 29 (2): 228-230


    To describe the computed tomography findings of recurrent lymphoma involving the lung.Computed tomography scans of 15 patients with biopsy-proven recurrent lymphoma involving the lung were reviewed. Group mean age of enrolled patients was 38 years (range: 14-68 years). Pathologic specimens were obtained by thoracoscopic or open wedge biopsy (n = 8), transbronchial biopsy (n = 5), and fine needle aspiration (n = 2).Nodules, the most common manifestation, were present in all patients; nodules were greater than 10 in number in 12 (80%) of 15 cases and predominantly 6-10 mm in size in 8 cases (53%). Nodular distribution was bilateral and multilobar except in 2 patients, in whom a solitary pulmonary nodule was found. Lymphadenopathy was the second most common finding; it was seen in 13 (87%) of 15 cases and involved an average of 5 nodal stations.Recurrent lymphoma in the lung most commonly manifests as multiple pulmonary nodules that are typically bilateral and multilobar in distribution.

    View details for Web of Science ID 000228030400014

    View details for PubMedID 15772542

  • Split-thickness skin graft attachment to bone lacking periosteum ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Tran, L. E., Berry, G. J., Fee, W. E. 2005; 131 (2): 124-128


    To develop an animal model to investigate the survival of split-thickness skin grafts (STSGs) on bone without periosteum, to compare STSG attachment to bone with and without periosteum, and to determine the effect of fibrin glue on STSG attachment to bone.Prospective laboratory study.University laboratory.Sprague-Dawley rats.Percentage of survival of the STSGs at 2 weeks determined independently by the authors and a third, blinded head and neck surgeon.In experiment 1, which included 40 rats, the sutured STSGs showed an average survival rate of 38% when attached to bone with periosteum, 6% when attached to bare bone, and 10% when attached to bare bone using fibrin glue. The poor survival rate was thought to be attributable to the animals scratching at their bolster dressings. In experiment 2, 18 animals underwent a posteriorly based U-shaped flap of skin and subcutaneous tissue. The grafts were placed and isolated from the overlying flap with a biosynthetic wound dressing. The sutured STSG survival rates were as follows: 87% when attached to bone with periosteum, 94% when attached to bare bone, and 74% when attached to bare bone using fibrin glue.The survival of STSGs attached to bare bone was comparable to that of STSGs attached to bone with periosteum when grafts were protected with the skin-subcutaneous flap. The STSGs that were fixed with 0.1 cc of fibrin glue demonstrated poorer survival rates than those attached with sutures and were associated with more seromas.

    View details for Web of Science ID 000226817900006

    View details for PubMedID 15723943

  • Improved assessment of graft function by echocardiography in cynomolgus monkey recipients of hDAF-transgenic pig cardiac xenografts JOURNAL OF HEART AND LUNG TRANSPLANTATION Stalder, M., Tye, T., Lam, T. T., Chan, M. C., Berry, G. J., Borie, D. C., Morris, R. E. 2005; 24 (2): 215-221


    The current practice of evaluating heterotopic heart xenografts by palpation allows only detection of severe graft dysfunction, which indicates terminal graft failure. Therefore, we evaluated whether echocardiography is a better method of detecting early graft dysfunction as a marker of rejection in abdominal pig heart xenografts in cynomolgus monkeys.Six cynomolgus monkeys received heterotopic heart transplants from pig donors transgenic for human decay-accelerating factor (hDAF). Induction therapy consisted of either cyclophosphamide or rabbit anti-thymocyte globulin. Maintenance therapy consisted of cyclosporine or tacrolimus, steroids, and sodium mycophenolate or mycophenolate mofetil, GAS914 (alphaGal oligosaccharide containing glycoconjugate), and for some animals TP10 (soluble complement receptor type 1). Echocardiography was performed immediately after transplantation and 3 times a week after surgery. We scored contractility and measured left ventricular wall thickness. Impaired contractility or increased wall thickness were considered graft dysfunction and were treated with pulse steroids. Palpation score was recorded daily. We also obtained myocardial biopsy specimens.Palpation score remained at 4 out of 4 in all animals until 2 to 5 days before final graft failure, whereas echocardiography detected several episodes of impaired graft function, either decreased left ventricular contractility or increased left ventricular wall thickness before graft failure. Treatment with pulse steroids improved graft function only during early episodes of graft impairment. Final graft failure was steroid resistant and caused by severe vascular rejection.Echocardiography is a better method of assessing graft dysfunction than is palpation. Therefore, echocardiography may detect early rejection episodes of heterotopic heart xenografts in non-human primates.

    View details for DOI 10.1016/j.healun.2003.09.041

    View details for Web of Science ID 000226922800017

    View details for PubMedID 15701440

  • Scedosporium apiospermum soft tissue infection successfully treated with voriconazole: Potential pitfalls in the transition from intravenous to oral therapy JOURNAL OF CLINICAL MICROBIOLOGY Schaenman, J. M., DiGiulio, D. B., Mirels, L. F., McClenny, N. M., Berry, G. J., Fothergill, A. W., Rinaldi, M. G., Montoya, J. G. 2005; 43 (2): 973-977


    An immunocompromised patient with an invasive soft tissue infection due to Scedosporium apiospermum was successfully treated with voriconazole and surgical debridement. After transition from intravenous to oral therapy, successive adjustments of the oral dose were required to achieve complete resolution. For soft tissue infections due to molds characterized by thin, septate hyphae branching at acute angles, voriconazole should be considered a first-line antifungal agent. The potential usefulness of plasma voriconazole levels for guiding optimal therapy should be investigated.

    View details for DOI 10.1128/JCM.43.2.973-977.2005

    View details for PubMedID 15695722

  • Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus. Lupus Chung, L., Berry, G. J., Chakravarty, E. F. 2005; 14 (2): 166-169


    Giant cell myocarditis (GCM) is a rare form of myocarditis with a median survival of less than one year. It has been reported to occur in patients with various underlying autoimmune diseases; however, no cases of GCM have been described in patients with clear evidence of underlying systemic lupus erythematosus (SLE). The presentation of GCM may mimic that of lupus myocarditis, including an initial response to immunosuppression. Despite initial clinical similarities, lupus myocarditis and GCM are histologically distinct entities with dramatic differences in prognosis. We report herein a patient with a longstanding history of SLE, who presented acutely with myocarditis, responded well to initial immunosuppression and then subsequently died of progressive heart failure that was found to be due to GCM. Endomyocardial biopsy can help define diagnosis and prognosis of lupus patients presenting with myocarditis, and early referral for cardiac transplantation should be considered in patients diagnosed with GCM.

    View details for PubMedID 15751823

  • Glycolipid mediated activation of iNKT cells is sufficient to induce airway hyperreactivity independent of conventional CD4 T cells. 5th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Meyer, E. H., Akbari, O., Berry, G., Savage, P., DeKruyff, R. H., Umetsu, D. T. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: S14–S15
  • Hyperacute rejection of hDAF-transgenic pig organ xenografts in cynomolgus monkeys: influence of pre-existing anti-pig antibodies and prevention by the alpha GAL glycoconjugate GAS914 XENOTRANSPLANTATION Lam, T. T., Hausen, B., Boeke-Purkis, K., Paniagua, R., Lau, M., Hook, L., Berry, G., Higgins, J., Duthaler, R. O., Katopodis, A. G., Robbins, R., Reitz, B., Borie, D., Schuurman, H. J., Morris, R. E. 2004; 11 (6): 517-524


    Our introductory pig-to-cynomolgus monkey heart or kidney transplantation using organs from pigs transgenic for human decay-accelerating factor (hDAF), showed a high incidence of hyperacute rejection (HAR), which was ascribed to extraordinary high levels of anti-pig antibodies. We evaluated the efficacy of GAS914, a Gal alpha 1-3Gal trisaccharide linked to a poly-l-lysine backbone, in inhibition of HAR.hDAF transgenic heterotopic heart (n = 15) or life-supporting kidney (n = 8) transplantation included induction with cyclophosphamide or anti-thymocyte globulin, and maintenance with cyclosporine or tacrolimus, steroids and mycophenolate sodium/mofetil. Four doses of GAS914 were given before transplantation. Rejection was confirmed by graft histology, and anti-pig antibody levels were determined in various assays.Four of six heart transplants without GAS914 treatment showed HAR. Nine subsequent transplants with GAS914 pre-treatment, did not show HAR (chi-square, P < 0.05). Two of four kidney transplants without GAS914 treatment ended with HAR. Four subsequent transplants with GAS914 did not show HAR. Animals with HAR showed extremely high antibody levels. Samples just before transplantation showed significantly higher antibody levels in recipients presenting with HAR. In all assays antibody levels were significantly lowered by GAS914 pre-treatment.HAR of hDAF solid organs could be ascribed to high levels of anti-pig antibodies. It is hypothesized that the hDAF transgene shows a threshold in efficacy, above which an overwhelming attack by antibodies and complement activation cannot be modulated to prevent HAR. HAR does not occur when animals with lower levels are used, or when antibodies are effectively depleted from the circulation by GAS914 treatment.

    View details for DOI 10.1111/j.1399-3089.2004.00173.x

    View details for Web of Science ID 000224432900005

    View details for PubMedID 15479461

  • Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity NATURE IMMUNOLOGY Stock, P., Akbari, O., Berry, G., Freeman, G. J., DeKruyff, R. H., Umetsu, D. T. 2004; 5 (11): 1149-1156


    The range of regulatory T cell (T(R) cell) types that control immune responses is poorly understood. We describe here a population of T(R) cells that developed in vivo from naive CD4(+)CD25(-) T cells during a T helper type 1 (T(H)1)-polarized response, distinct from CD25(+) T(R) cells. These antigen-specific T(R) cells were induced by CD8alpha(+) DCs, produced both interleukin 10 and interferon-gamma, and potently inhibited the development of airway hyper-reactivity. These T(R) cells expressed the transcription factors Foxp3 and T-bet, indicating that these T(R) cells are related to T(H)1 cells. Thus, adaptive T(R) cells are heterogeneous and comprise T(H)1-like T(R) cells as well as previously described T(H)2-like T(R) cells, which express Foxp3 and are induced during the development of respiratory tolerance by CD8alpha(-) DCs.

    View details for DOI 10.1038/ni1122

    View details for Web of Science ID 000224692700012

    View details for PubMedID 15448689

  • Clinical and pathological absence of cardiotoxicity after liposomal doxorubicin LANCET ONCOLOGY Jones, R. L., Berry, G. J., Rubens, R. D., Miles, D. W. 2004; 5 (9): 575-577

    View details for Web of Science ID 000224076300022

    View details for PubMedID 15337488

  • Gastric pacing for severe gastroparesis in a heart-lung transplant recipient JOURNAL OF HEART AND LUNG TRANSPLANTATION Yiannopoulos, A., Shafazand, S., Ziedalski, T., Berry, G. J., Robbins, R. C., Theodore, J., Faul, J. L. 2004; 23 (3): 371-374


    Gastroparesis is a serious complication of lung and heart-lung transplantation that can lead to malnutrition, gastroesophageal reflux, aspiration pneumonia and deteriorating lung function. Some patients with severe gastroparesis have symptoms that are refractory to dietary modifications and gastric promotility agents and require surgery. We describe the successful use of gastric pacing for the management of intractable gastroparesis, malnutrition and recurrent aspiration in a heart-lung allograft recipient. Lung transplant recipients with severe gastroparesis may benefit from gastric pacing.

    View details for DOI 10.1016/S1053-2498(03)00188-8

    View details for Web of Science ID 000220155700015

    View details for PubMedID 15019648

  • Identification of tyrosine kinases overexpressed in head and neck cancer ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Lin, H. S., Berry, G. J., Fee, W. E., Terris, D. J., Sun, Z. J. 2004; 130 (3): 311-316


    To identify protein-tyrosine kinases (PTKs) that may be involved in the development and progression of head and neck squamous cell carcinoma (HNSCC).Messenger RNA from 7 HNSCC specimens was reverse transcribed to complementary DNA, and selective amplification of PTK complementary DNA was achieved using polymerase chain reaction (PCR) with degenerate PTK primers. The resulting PTK PCR products from these 7 HNSCC specimens were then cloned and randomly selected for sequencing. The PTKs that were represented multiple times in these randomly selected clones were selected as candidate PTKs that may be overexpressed in HNSCC. Antibodies against these candidate PTKs were then used for immunohistochemical studies on 8 other HNSCC specimens not used in the original selection of the candidate PTKs.Three known (EphA1, Brk, and Ron) and 2 novel (KIAA0728 and KIAA0279) PTKs were found to be highly expressed in the 7 HNSCC samples studied, based on the technique of reverse transcriptase-PCR with degenerate primers. Immunohistochemical studies with antibodies against the 3 known PTKs in 8 other HNSCC specimens not used in the previous reverse transcriptase-PCR reaction demonstrated overexpression of EphA1, Brk, and Ron in 12.5%, 37.5%, and 75% of these specimens.In this study, we identified 5 PTKs that were overexpressed in HNSCC using a reverse transcriptase-PCR technique and confirmed the overexpression of 3 known PTKs in some of the 8 archival HNSCC specimens studied. Our finding suggests that the signaling pathways mediated through EphA1, Brk, and Ron may be involved in the development and progression of HNSCC.

    View details for Web of Science ID 000220067500008

    View details for PubMedID 15023838

  • Noncirrhotic portal hypertension in association with juvenile nephropathic cystinosis: Case presentation and review of the literature JOURNAL OF INHERITED METABOLIC DISEASE DiDomenico, P., Berry, G., Bass, D., Fridge, J., Sarwal, M. 2004; 27 (5): 693-699


    We report a case of portal hypertension and oesophageal varices arising in an 18-year-old female renal transplant recipient with juvenile nephropathic cystinosis diagnosed at 6 years of age. The patient had a history of poor compliance with her prescribed cysteamine therapy. Routine examination revealed normal liver function without hepatomegaly but asymptomatic splenomegaly. An abdominal ultrasound suggested mild oesophageal varices, confirmed later on endoscopy. A liver biopsy revealed an abundance of cystine crystals within the hepatic Kupffer cells, with preserved hepatic architecture. Although the pathophysiology of this rare complication is unclear, in the absence of other aetiologies the likely cause is the patient's poorly controlled cystinosis. As cystinotic patients live longer with improved renal transplant management and cysteamine therapy, it is of interest to characterize the long-term course of the illness after renal transplantation. An understanding of the pathophysiology of hepatic dysfunction will be required to manage this potential late complication of the disease.

    View details for Web of Science ID 000224100100019

    View details for PubMedID 15669688

  • Obliterative bronchiolitis is prevented by JAK3 inhibition with the new immunosuppressant CP-690,550. 5th American Transplant Congress Rousvoal, G., Zhang, S., Larson, M., Berry, G., Si, M. S., Holm, B., Paniagua, R., Hawkins, J., Lau, M., Flores, M., Morris, R., Reitz, B., Borie, D. WILEY-BLACKWELL. 2004: 286–286
  • Superarray analysis of tracheal allografts under JAK3-targeted immunosuppression reveals a role for the B-cell chemoattractant BLC-BCA1. 5th American Transplant Congress Lau, M., Zhang, S., Larson, M., Flores, M., Si, M. S., Rousvoal, G., Hawkins, J., Holm, B., Berry, G., Morris, R., Reitz, B., Borie, D. WILEY-BLACKWELL. 2004: 197–197
  • Matrix metalloproteinase inhibition decreases ischemia-reperfusion injury after lung transplantation AMERICAN JOURNAL OF TRANSPLANTATION Soccal, P. M., Gasche, Y., Miniati, D. N., Hoyt, G., Berry, G. J., Doyle, R. L., Theodore, J., Robbins, R. C. 2004; 4 (1): 41-50


    Increased microvascular permeability and extravasation of inflammatory cells are key events of lung ischemia-reperfusion (IR) injury. The purpose of this study was to investigate the role of matrix metalloproteinases (MMP) in IR-induced alveolar capillary membrane disruption after experimental lung transplantation. We used a rat model of lung orthotopic transplantation (n = 86) with a prolonged cold ischemic phase. MMP2 and MMP9 were elevated 4 h after the onset of ischemia and further increased during reperfusion. Compared to sham values, the alveolar-capillary membrane permeability increased by 105% and 82.6% after 4 h of ischemia and 2 h or 24 h of reperfusion, respectively. A 4- and 5-fold increase of the infiltration of ischemic tissue by neutrophils was also observed after 2 h and 24 h of reperfusion. The PO2/FIO2 ratio dropped significantly from 244 to 76.6 after 2 h of reperfusion and from 296.4 to 127.6 after 24 h of reperfusion. A nonselective inhibitor of MMP, administered to the rats and added to the preservation solution, reduced significantly the alveolar-capillary leakage, the transmigration of neutrophils and improved gas exchanges in animals submitted to 4 h of ischemia combined with 2 h or 24 h of reperfusion. We conclude that inhibition of MMP attenuates IR injury after experimental lung transplantation.

    View details for DOI 10.1046/j.1600-6135.2003.00277.x

    View details for Web of Science ID 000187242700008

    View details for PubMedID 14678033

  • Thoracic lymphatic disorders. Lymphatic research and biology Davis, K. K., Berry, G. J., Raffin, T. A., Faul, J. L. 2004; 2 (3): 131-137


    Thoracic complications of lymphatic disorders can culminate in respiratory failure and death and should be considered in any patient with a lymphatic disease and clinical or radiographic evidence of chest disease. Congenital lymphatic disorders are being increasingly recognized in the adult population. The spectrum of thoracic manifestations of lymphatic disorders ranges from incidental radiographic findings to diffuse lymphatic disease with respiratory failure. This article serves to review some recent advances that allow improved diagnosis and management of thoracic lymphatic disorders. Herein, we describe their anatomical and physiologic effects, the time course of their progression, and the therapies that are currently available. The management of malignant (cancerous) lymphatic disorders of the thorax is beyond the scope of this paper.

    View details for PubMedID 15609812

  • Epstein-Barr virus infection is not associated with fibroadenomas of the breast in immunosuppressed patients after organ transplantation MODERN PATHOLOGY Lau, S. K., Chen, Y. Y., Berry, G. J., Yousem, S. A., Weiss, L. M. 2003; 16 (12): 1242-1247


    Epstein-Barr virus has been linked to an increasing number of nonhematolymphoid conditions. Epstein-Barr virus was recently described in association with fibroadenomas of the breast occurring in immunosuppressed patients. To further investigate the potential association of Epstein-Barr virus with fibroadenoma in the context of immune dysfunction, 11 cases of fibroadenoma of the breast in immunosuppressed organ transplant recipients were examined. Cases were evaluated for the presence of Epstein-Barr virus by polymerase chain reaction, in situ hybridization, and immunohistochemical methods. The presence of Epstein-Barr virus genomic DNA was studied by polymerase chain reaction amplification using primers flanking the BamHI-W fragment of the Epstein-Barr virus genome, as well as the Epstein-Barr virus nuclear antigen-4 and latent membrane protein-1 genes. Cases were also evaluated for the presence of defective heterogeneous Epstein-Barr virus DNA. In addition, morphologic analysis by in situ hybridization for Epstein-Barr virus-encoded RNA-1 and immunohistochemistry for latent membrane protein-1 were performed. Epstein-Barr virus DNA was detected in 4 of 11 (36%) cases with BamHI-W polymerase chain reaction. Polymerase chain reaction studies for Epstein-Barr virus nuclear antigen-4 and latent membrane protein-1 genes were positive in two and four cases, respectively. No defective Epstein-Barr virus genomes were identified in any of the cases. Quantitative polymerase chain reaction demonstrated low levels of Epstein-Barr virus in the fibroadenomas studied. Despite the detection of Epstein-Barr virus genomes in a subset of the cases examined, the constituent epithelial and stromal components of all fibroadenomas demonstrated no evidence of Epstein-Barr virus-encoded RNA-1 by in situ hybridization or latent membrane protein-1 expression by immunohistochemistry. Rare Epstein-Barr virus-encoded RNA-1-positive lymphocytes were observed in some cases, which may account for the positive polymerase chain reaction results. The findings of the present study argue against a significant relationship between Epstein-Barr virus and fibroadenomas of the breast in the setting of transplant-associated immunosuppression.

    View details for DOI 10.1097/01.MP.0000097363.72401.00

    View details for Web of Science ID 000187672300009

    View details for PubMedID 14681325

  • Cardiac allograft monitoring using a novel clinical algorithm based on peripheral leukocyte gene expression profiling 76th Annual Scientific Session of the American-Heart-Association Deng, M. C., Mehra, M. C., Eisen, H. J., Billingham, M., Berry, G., Marboe, C., Itescu, S., Kobashigawa, J., Wohlgemuth, J. G., Quertermous, T., Hunt, S. LIPPINCOTT WILLIAMS & WILKINS. 2003: 389–89
  • Ablation of mitral annular and leaflet muscle: effects on annular and leaflet dynamics AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Timek, T. A., Lai, D. T., Dagum, P., Tibayan, F., Daughters, G. T., Liang, D., Berry, G. J., Miller, D. C., Ingels, N. B. 2003; 285 (4): H1668-H1674


    Mitral annular (MA) and leaflet three-dimensional (3-D) dynamics were examined after circumferential phenol ablation of the MA and anterior mitral leaflet (AML) muscle. Radiopaque markers were sutured to the left ventricle, MA, and both mitral leaflets in 18 sheep. In 10 sheep, phenol was applied circumferentially to the atrial surface of the mitral annulus and the hinge region of the AML, whereas 8 sheep served as controls. Animals were studied with biplane video fluoroscopy for computation of 3-D mitral annular area (MAA) and leaflet shape. MAA contraction (MAACont) was determined from maximum to minimum value. Presystolic MAA (PS-MAACont) reduction was calculated as the percentage of total reduction occurring before end diastole. Phenol ablation decreased PS-MAACont (72 +/- 6 vs. 47 +/- 31%, P = 0.04) and delayed valve closure (31 +/- 11 vs. 57 +/- 25 ms, P = 0.017). In control, the AML had a compound sigmoid shape; after phenol, this shape was entirely concave to the atrium during valve closure. These data indicate that myocardial fibers on the atrial side of the valve influence the 3-D dynamic geometry and shape of the MA and AML.

    View details for DOI 10.1152/ajpheart.00179.2003

    View details for PubMedID 12969884

  • Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells CIRCULATION Nishimura, T., Vaszar, L. T., Faul, J. L., Zhao, G. H., Berry, G. J., Shi, L. F., Qiu, D. M., Benson, G., Pearl, R. G., Kao, P. N. 2003; 108 (13): 1640-1645


    Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension.Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg x kg(-1) x d(-1) by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a.Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.

    View details for DOI 10.1161/01.CIR.0000087592.47401.37

    View details for PubMedID 12963647

  • Treatment by mycophenolate mofetil of advanced graft vascular disease in non-human primate recipients of orthotopic aortic allografts AMERICAN JOURNAL OF TRANSPLANTATION Klupp, J., Dambrin, C., Hibi, K., Luna, J., Suzuki, T., Hausen, B., Birsan, T., van Gelder, T., Fitzgerald, P. J., Berry, G., Morris, R. E. 2003; 3 (7): 817-829


    Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm(3)) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = -0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD.

    View details for Web of Science ID 000184032600007

    View details for PubMedID 12814473

  • Sirolimus (rapamycin) monotherapy prevents graft vascular disease in nonhuman primate recipients of orthotopic aortic allografts CIRCULATION Dambrin, C., Klupp, J., Birsan, T., Luna, J., Suzuki, T., Lam, T., Stahr, P., Hausen, B., Christians, U., Fitzgerald, P., Berry, G., Morris, R. 2003; 107 (18): 2369-2374


    Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD.Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction-mismatched, blood group-compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean+/-SEM SRL plasma levels were 14.5+/-9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls (P<0.05 to P<0.001). On day 105, in the grafts from SRL-treated NHPs compared with grafts from controls, values (mean+/-SEM) were IA, 2.9+/-0.9 versus 5.5+/-0.7 mm2, P<0.001 and IV, 29.6+/-4.6 versus 55.2+/-2.8 mm3, P<0.001; IA and IV values for grafts from SRL-treated NHPs did not increase significantly between days 21 and 105.We show that SRL monotherapy prevented GVD in NHP aortic allograft recipients, suggesting the value of SRL for controlling GVD in clinical transplantation.

    View details for DOI 10.1161/01.CIR.0000065576.80196.A4

    View details for Web of Science ID 000182807000028

    View details for PubMedID 12719285

  • Effect of a surgical aortocaval fistula on mono crotaline-induced pulmonary hypertension CRITICAL CARE MEDICINE Nishimura, T., Faul, J. L., Berry, G. J., Kao, P. N., Pearl, R. G. 2003; 31 (4): 1213-1218


    Increased pulmonary blood flow is believed to contribute to the development of pulmonary hypertension. We investigated the effect of overcirculation via an aortocaval fistula, on the development of monocrotaline-induced pulmonary hypertension in rats. Monocrotaline was administered 1 wk after the creation of an aortocaval fistula.Randomized, controlled study.Research laboratory of an academic institution.Male Sprague-Dawley rats.Overcirculation was induced by pneumonectomy and by surgical creation of aortocaval fistula. Pulmonary artery hypertension was induced by administration of monocrotaline.Aortic blood flow, Pao(2), and pulmonary arterial pressure were measured 4 wks later. A blinded investigator quantified pulmonary arterial neointimal formation in small pulmonary arteries. Compared with animals that received monocrotaline and/or underwent pneumonectomy but did not undergo aortocaval fistula, the presence of a surgical aortocaval fistula was associated with increased aortic blood flow (p <.001), increased Pao(2) (p <.001), and lower mean pulmonary arterial pressure (p <.001). In addition, rats with aortocaval fistula had less pulmonary arterial neointimal formation than matched animals without an aortocaval fistula (p =.034).The presence of a surgical aortocaval fistula attenuates, rather than worsens, the development of monocrotaline-induced pulmonary hypertension in rats.

    View details for DOI 10.1097/01.CCM.0000059440.44597.07

    View details for PubMedID 12682495

  • Graft thrombosis in hDAF-transgenic pig hearts transplanted into rhesus monkeys XENOTRANSPLANTATION Lam, T. T., Borie, D., Masek, M., Berry, G., Larson, M., Morris, R. E. 2003; 10 (2): 185-186

    View details for Web of Science ID 000181030100010

    View details for PubMedID 12588651

  • A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Okura, Y., Dec, G. W., Hare, J. M., Kodama, M., Berry, G. J., Tazelaar, H. D., Bailey, K. R., Cooper, L. T. 2003; 41 (2): 322-328


    The goal of this study was to determine the prognostic value of clinical data available at presentation and histology in cardiac sarcoidosis (CS) and idiopathic giant cell myocarditis (IGCM).The prognosis of patients with nonischemic cardiomyopathy is partly dependent on the histologic diagnosis. Survival in IGCM is poor. The prognosis of a histologically related entity, cardiac sarcoidosis (CS), is less well established, and the prognostic value of the distinction between CS and IGCM on endomyocardial biopsy (EMB) is unknown.We identified 115 patients from the Multicenter IGCM Registry with CS (n = 42) and IGCM (n = 73). We compared the clinical data for these two groups using Cox proportional-hazards models to assess the association between histologic diagnosis and survival. In order to determine whether histologic features could reliably differentiate these two entities, two cardiac pathologists semiquantitatively graded the inflammatory infiltrate components and compared the results between groups.Black race was more frequent in the CS group (31% vs. 4%, p < 0.0001). Syncope and atrioventricular block were also more frequently observed in CS than IGCM (31% vs. 5%, p = 0.0002 and 50% vs. 15%, p < 0.0001, respectively). Left-sided heart failure was more common in IGCM (40% vs. 64%, p = 0.013). In CS patients diagnosed by EMB, the five-year transplant-free survival after diagnosis was 69.8% versus 21.9% for IGCM (p < 0.0001, log-rank test). In multivariate models, presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS. Eosinophils, myocyte damage, and foci of lymphocytic myocarditis were more frequent in IGCM, while granulomas and fibrosis were more frequent in CS.Transplant-free survival is better for patients with CS than for IGCM diagnosed by EMB. Presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS.

    View details for Web of Science ID 000180362800026

    View details for PubMedID 12535829

  • Feasibility and safety of linear microwave ablation in the left atrium 12th World Congress on Cardiac Pacing and Electrophysiology Liem, L. B., Law, M. F., Leung, G., Ormsby, T., Berry, G. J. MEDIMOND S R L. 2003: 99–106
  • PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model JOURNAL OF HEART AND LUNG TRANSPLANTATION Leonard, C. T., Soccal, P. M., Berry, G. J., Doyle, R. L., Theodore, J., Duncan, S. R., Rosen, G. D. 2002; 21 (12): 1314-1318


    The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

    View details for Web of Science ID 000179959800009

    View details for PubMedID 12490278

  • Lymphoid interstitial pneumonia - A narrative review CHEST Swigris, J. J., Berry, G. J., Raffin, T. A., Kuschner, W. G. 2002; 122 (6): 2150-2164


    Lymphoid interstitial pneumonia (LIP) is regarded as both a disease and a nonneoplastic, inflammatory pulmonary reaction to various external stimuli or systemic diseases. It is an uncommon condition with incidence and prevalence rates that are largely unknown. Liebow and Carrington originally classified LIP as an idiopathic interstitial pneumonia in 1969. Although LIP had since been removed from that category, the most recent consensus classification sponsored by the American Thoracic Society and the European Respiratory Society recognizes that some cases remain idiopathic in origin, and its clinical, radiographic, and pathologic features warrant the return of LIP to its original classification among the idiopathic interstitial pneumonias. LIP also belongs within a spectrum of pulmonary lymphoproliferative disorders that range in severity from benign, small, airway-centered cellular aggregates to malignant lymphomas. It is characterized by diffuse hyperplasia of bronchus-associated lymphoid tissue. The dominant microscopic feature of LIP is a diffuse, polyclonal lymphoid cell infiltrate surrounding airways and expanding the lung interstitium. Classically, LIP occurs in association with autoimmune diseases, most often Sjögren syndrome. This has led to consideration of an autoimmune etiology for LIP, but its pathogenesis remains poorly understood. Persons who are seropositive for HIV, and children in particular, are at increased risk of acquiring LIP. Some studies suggest causal roles for both HIV and Epstein-Barr virus. The incidence of LIP is approximately twofold greater in women than men. The average age at diagnosis is between 52 years and 56 years. Symptoms of progressive cough and dyspnea predominate. There is great variability in the clinical course of LIP, from resolution without treatment to progressive respiratory failure and death. Although LIP is often regarded as a steroid-responsive condition, and oral corticosteroids continue to be the mainstay of therapy, response is unpredictable. Approximately 33 to 50% of patients die within 5 years of diagnosis, and approximately 5% of cases of LIP transform to lymphoma.

    View details for Web of Science ID 000179985600047

    View details for PubMedID 12475860

  • Donor cardiac allografts from p53 knockout mice exhibit apoptosis-independent prolongation of survival TRANSPLANTATION PROCEEDINGS Kown, M. H., Murata, S., Jahncke, C. L., Mari, C., Berry, G. J., Lijkwan, M. A., Blankenberg, F. G., Strauss, H. W., Robbins, R. C. 2002; 34 (8): 3274-3276

    View details for Web of Science ID 000179983100078

    View details for PubMedID 12493444

  • Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nishimura, T., Faul, J. L., Berry, G. J., Vaszar, L. T., Qiu, D. M., Pearl, R. G., Kao, P. N. 2002; 166 (10): 1403-1408


    Hypertensive pulmonary vascular disease is characterized by abnormal proliferation of vascular endothelial and smooth muscle cells, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure, and death. Compounds with antiproliferative effects on vascular endothelial and smooth muscle cells, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may prevent the development of experimental hypertensive pulmonary vascular disease. Pneumonectomized rats injected with monocrotaline at 7 days develop severe hypertensive pulmonary vascular disease with neointimal formation. Rats were randomized to receive either vehicle or treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (53 +/- 2 mm Hg) and right ventricular hypertrophy (right ventricle/[left ventricle plus septum] [RV/LV+S] = 0.78 +/- 0.09) than rats in Group PMS5-35 that received simvastatin from Day 5 to 35 (mean pulmonary arterial pressure = 27 +/- 3 mm Hg, RV/LV+S = 0.34 +/- 0.08; p < or = 0.001). Pulmonary vascular remodeling with neointimal formation consisting of vascular smooth muscle cells was more severe in vehicle-treated rats (vascular occlusion score, 1.98 +/- 0.02) than in Group PMS5-35 (vascular occlusion score, 0.59 +/- 0.46; p < 0.001). In addition, lung endothelial nitric oxide synthase gene expression was decreased in vehicle-treated animals but was restored toward normal levels in simvastatin-treated animals. Simvastatin attenuates monocrotaline-induced pulmonary vascular remodeling with neointimal formation, pulmonary arterial hypertension, and right ventricular hypertrophy in rats.

    View details for DOI 10.1164/rccm.200203-268OC

    View details for PubMedID 12406854

  • Imaging for suspected appendicitis: Negative appendectomy and perforation rates RADIOLOGY Bendeck, S. E., Nino-Murcia, M., Berry, G. J., Jeffrey, R. B. 2002; 225 (1): 131-136


    To determine which patients suspected of having acute appendicitis benefit from preoperative imaging.The medical records of 462 consecutive patients who underwent appendectomy for clinically suspected acute appendicitis and underwent preoperative evaluation at our institution were retrospectively reviewed. Patients were divided into four groups: women (n = 166), girls (n = 46), men (n = 178), and boys (n = 72). Preoperative computed tomography (CT) or ultrasonography (US), requested by the referring clinician, was performed in 313 of the 462 patients. Unnecessary, or negative, appendectomy and perforation rates were calculated for each group for preoperative evaluation with CT, with US, and with neither CT nor US. In addition, the sensitivity and positive predictive value of CT and US were calculated for diagnosing appendicitis.In women, the negative appendectomy rate was significantly lower for those who underwent preoperative CT (7% [six of 85 patients], P =.005) or US (8% [four of 49 patients], P =.019), as compared with 28% [nine of 32 patients] for those who underwent no preoperative imaging (P >.35 for all groups). The negative appendectomy rates for girls, men, and boys were not significantly affected by preoperative imaging. The sensitivity of CT and US for diagnosing acute appendicitis exceeded 93% and 77%, respectively, in all groups. The positive predictive values for both CT and US were greater than 92% in all groups.Women suspected of having appendicitis benefit the most from preoperative CT or US, with a statistically significantly lower negative appendectomy rate than women who undergo no preoperative imaging. Therefore, we propose that preoperative imaging be considered part of the routine evaluation of women suspected of having acute appendicitis.

    View details for DOI 10.1148/radiol.2251011780

    View details for Web of Science ID 000178264300021

    View details for PubMedID 12354996

  • Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity NATURE MEDICINE Akbari, O., Freeman, G. J., Meyer, E. H., Greenfield, E. A., Chang, T. T., Sharpe, A. H., Berry, G., DeKruyff, R. H., Umetsu, D. T. 2002; 8 (9): 1024-1032


    Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (T(R)) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of T(R) cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS-ICOS-ligand pathway. The T(R) cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, T(R) cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS-ICOS-ligand interactions. These studies demonstrate that T(R) cells and the ICOS-ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.

    View details for DOI 10.1038/nm745

    View details for Web of Science ID 000177757900039

    View details for PubMedID 12145647

  • The use of (99m)Technetium-labeled MCP-1 to assess, graft coronary artery disease in rat cardiac allografts JOURNAL OF HEART AND LUNG TRANSPLANTATION Kown, M. H., Jahncke, C. L., Lijkwan, M. A., Koransky, M. L., Mari, C., Berry, G. J., Blankenberg, F. G., Strauss, H. W., Robbins, R. C. 2002; 21 (9): 1009-1015


    Monocyte chemoattractant protein-1 (MCP-1) is associated with the development of graft coronary artery disease (GCAD) following cardiac transplantation. This study assessed whether technetium 99m ((99m)Tc)-labeled MCP-1 binds its receptors in chronic cardiac transplants and thereby provides a potential modality to assess GCAD.Allogeneic (PVG-->ACI, n = 9) and syngeneic (ACI-->ACI, n = 9) rat heterotopic heart transplants were performed. Allograft recipients were treated with 7.5 mg/kg per day of Cyclosporin A for 10 days until tolerance was achieved. After 90 days, animals were injected intravenously with (99m)Tc-MCP-1 and killed after 1 hour. Radioactivity of heart tissues was measured and standardized to uptake in the overall blood pool. Two-dimensional (99m)Tc-MCP-1 uptake (autoradiographs) was imaged by exposing 50-microm sections on a phosphoimager overnight. ED-1 staining of monocyte/macrophages was performed on serial sections. Additional sections were stained with elastin von Gieson and hematoxylin. Hearts were scored for luminal narrowing and intima/media ratio (I/M) with computerized image analysis.Allografts exhibited significantly more luminal narrowing (22.5 +/- 10.7% vs 2.6 +/- 4.6, p = 0.0005) and higher I/M (0.173 +/- 0.151 vs 0.015 +/- 0.029, p = 0.0088) than isografts. The ratio of (99m)Tc-MCP-1 uptake in allografts (1.04 +/- 0.4) was greater than that of isograft controls (0.72 +/- 0.11, p = 0.03). Pixel counts of autoradiographs and ED-1-stained sections demonstrated a modest correlation between the two (R(2) = 0.50). No significant differences were seen in acute rejection scores.(99m)Tc-MCP-1 uptake was higher in allografts vs isografts and was consistent with a greater degree of GCAD. These data demonstrating increased radiopharmaceutical uptake in hearts with GCAD provide a foundation for the development of a potentially non-invasive imaging assay of this disease process in heart transplantation.

    View details for PubMedID 12231372

  • CD4 T-helper cells engineered to produce IL-10 prevent allergen-induced airway hyperreactivity and inflammation JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Oh, J. W., Seroogy, C. M., Meyer, E. H., Akbari, O., Berry, G., Fathman, C. G., DeKruyff, R. H., Umetsu, D. T. 2002; 110 (3): 460-468


    T(H)2 cells play a critical role in the pathogenesis of asthma, but the precise immunologic mechanisms that inhibit T(H)2 cell function in vivo are not well understood.The purpose of our studies was to determine whether T cells producing IL-10 regulate the development of asthma.We used gene therapy to generate ovalbumin-specific CD4 T-helper cells to express IL-10, and we examined their capacity to regulate allergen-induced airway hyperreactivity.We demonstrated that the CD4 T-helper cells engineered to express IL-10 abolished airway hyperreactivity and airway eosinophilia in BALB/c mice sensitized and challenged with ovalbumin and in SCID mice reconstituted with ovalbumin-specific T(H)2 effector cells. The inhibitory effect of the IL-10-secreting T-helper cells was accompanied by the presence of increased quantities of IL-10 in the bronchoalveolar lavage fluid, was antigen-specific, and was reversed by neutralization of IL-10. Moreover, neutralization of IL-10 by administration of anti-IL-10 mAb in mice sensitized and challenged with ovalbumin seriously exacerbated airway hyperreactivity and airway inflammation.Our results demonstrate that T cells secreting IL-10 in the respiratory mucosa can indeed regulate T(H)2-induced airway hyperreactivity and inflammation, and they strongly suggest that IL-10 plays an important inhibitory role in allergic asthma.

    View details for DOI 10.1067/mai.2002.127512

    View details for Web of Science ID 000177936900018

    View details for PubMedID 12209095

  • Pulmonary cryptococcosis: CT and pathologic findings JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Zinck, S. E., Leung, A. N., Frost, M., Berry, G. J., Muller, N. L. 2002; 26 (3): 330-334


    The purpose of this work was to describe the CT and pathologic findings of pulmonary cryptococcosis.CT scans of 11 patients (7 immunocompromised, 4 immunocompetent) with proven pulmonary cryptococcosis were analyzed for number, morphologic characteristics, and distribution of parenchymal abnormalities as well for presence of lymphadenopathy and pleural effusion. Pathology of lung specimens obtained by open biopsy or resection (n = 5) and transbronchial biopsy (n = 1) was reviewed by one dedicated pulmonary pathologist.Pulmonary nodules, either solitary or multiple, were the most common CT finding, present in 10 of 11 patients (91%); associated findings included masses (n = 4), CT halo sign (n = 3), and consolidation (n = 2). On histologic examination, focal areas of ground-glass attenuation surrounding or adjacent to nodules were found to represent airspace collections of macrophages and proteinaceous fluid.Pulmonary cryptococcosis should be considered in the differential diagnosis of solitary or multiple pulmonary nodules (with or without associated CT halo sign), particularly in immunocompromised patients.

    View details for DOI 10.1097/01.RCT.0000014445.78.502.F9

    View details for Web of Science ID 000175799800002

    View details for PubMedID 12016357

  • The pathology of hibernating myocardium NUCLEAR MEDICINE COMMUNICATIONS Berry, G. J., Masek, M. 2002; 23 (4): 303-309


    Myocardial hibernation represents a protective mechanism of muscle preservation in the setting of atherosclerotic coronary artery disease. Long-standing myocardial hypoperfusion leads to diminished myocardial contractility that reverses with improved blood flow after revascularization. The morphologic changes in both animal models and humans are described.

    View details for Web of Science ID 000175245600003

    View details for PubMedID 11930183

  • The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis 48th Annual Scientific Session of the American-College-of-Cardiology Shields, R. C., Tazelaar, H. D., Berry, G. J., Cooper, L. T. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2002: 74–78


    Idiopathic giant cell myocarditis (GCM) is an uncommon cause of cardiac failure distinguished clinically from lymphocytic myocarditis by rapidly progressive heart failure, arrhythmias, and heart block. Unlike fulminant lymphocytic myocarditis, patients with fulminant cardiac failure caused by GCM may respond to certain immunosuppressive agents; however, right ventricular endomyocardial biopsy (EMB) is infrequently used to establish the diagnosis partly because the sensitivity of EMB for GCM is unknown. The purpose of this study was to estimate the sensitivity of right ventricular EMB for GCM in a referral population.Twenty subjects (of 63 total) in the Multicenter Giant Cell Myocarditis Registry underwent both right ventricular EMB and heart pathology (HRTP) evaluation from apical wedge, explantation, or autopsy. The false-negative rate of right ventricular EMB was defined as the ratio of negative EMB to positive HRTP results. Ten of the 20 subjects were women. The mean age was 38 years (range, 16-53 years). Twelve (60%) subjects had a positive EMB and positive HRTP confirming GCM. Three (15%) had a negative EMB and positive HRTP for GCM. Five had a positive EMB and negative HRTP evaluation for GCM. The resulting sensitivity of EMB for GCM was 80% (12/15) with a positive predictive value of 71%. Assuming the 5 subjects with a positive EMB and negative HRTP are true positives, the sensitivity improves to 85% (17/20). Predictors of negative HRTP after positive EMB were time from symptom onset to HRTP (P.006) and time from EMB to HRTP (P.03).The sensitivity of right ventricular EMB is high in patients with GCM who have early disease presentation and a fulminant clinical course. Although these results may not apply to individuals with less aggressive disease, EMB may be used selectively to distinguish fulminant heart failure caused by GCM from other causes in which the prognosis may differ.

    View details for DOI 10.1054/jcaf.2002.32196

    View details for Web of Science ID 000176748900006

    View details for PubMedID 12016630

  • Nodular invasive tracheobronchitis due to Aspergillus in a patient with systemic lupus erythematosus LUPUS Angelotti, T., Krishna, G., Scott, J., Berry, G., Weinacker, A. 2002; 11 (5): 325-328


    Nodular or pseudomembranous tracheobronchitis due to infection by Aspergillus species is an uncommon presentation of invasive aspergillosis. Most cases have been described in severely immunocompromised hosts. We describe the case of a 23-year-old woman, with recently diagnosed systemic lupus erythematosus, who developed worsening respiratory function. Bronchoscopy revealed rapid development and progression of multiple nodular plaques in her trachea and bronchi. Endobronchial biopsy demonstrated invasive fungal infection with tissue necrosis and the presence of hyphal elements consistent with aspergillosis. To the best of our knowledge, this is only the second report of fulminant invasive tracheobronchitis due to Aspergillus in a patient with an autoimmune disease.

    View details for DOI 10.1191/0961203302lu206cr

    View details for Web of Science ID 000176537200011

    View details for PubMedID 12090570

  • Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation - A comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone TRANSPLANTATION Valantine, H. A., Luikart, H., Doyle, R., Theodore, J., Hunt, S., Oyer, P., Robbins, R., Berry, G., Reitz, B. 2001; 72 (10): 1647-1652


    Cytomegalovirus (CMV) disease was previously shown to be unaltered by a 28-day course of ganciclovir compared with placebo in seronegative recipients of hearts from seropositive donors (D+/R-). This study tests the hypothesis that a combination of ganciclovir plus CMV hyperimmune globulin (CMVIG) is more effective than ganciclovir alone for preventing acute CMV illness and its long-term sequelae.The study population receiving CMVIG (n=80) included 27 heart transplant recipients (D+/R-) and 53 heart-lung and lung transplant recipients (R+ and/or D+). Each group was matched with historical controls who underwent transplantation within the preceding 2-3 years. Outcome measures compared were as follows: 3-year incidence of CMV disease; fungal infection; acute rejection; survival; rates and severity of transplant coronary artery disease (in heart patients) defined by intimal thickness (ultrasound) and coronary artery stenosis (angiographic); and incidence and death from obliterative bronchiolitis defined by pathological criteria on endobronchial biopsy specimens (in heart-lung/lung patients).Patients treated with CMVIG had a higher disease-free incidence of CMV, lower rejection incidence, and higher survival rate compared with the patients treated with ganciclovir alone. The coronary artery intimal thickness and the prevalence of intimal thickening were lower in the patients receiving CMVIG. Heart-lung and lung transplant patients treated with CMVIG had lower incidences of obliterative bronchiolitis and death from obliterative bronchiolitis and longer survival compared with the patients treated with ganciclovir alone.CMVIG plus ganciclovir seems to be more effective that ganciclovir alone for preventing the sequelae of CMV infection. A prospective randomized study is required to confirm these observations.

    View details for Web of Science ID 000172614200012

    View details for PubMedID 11726825

  • CT of noninfectious granulomatous lung disease RADIOLOGIC CLINICS OF NORTH AMERICA Zinck, S. E., Schwartz, E., Berry, G. J., Leung, A. N. 2001; 39 (6): 1189-?


    Noninfectious granulomatous diseases of the lung consist of a diverse group of disorders that logically can be subdivided into those with and without associated vasculitis. This article reviews the epidemiologic, clinical, pathologic, and radiologic features of sarcoidosis, hypersensitivity pneumonitis, berylliosis, and the five entities traditionally classified as pulmonary angiitis and granulomatosis.

    View details for Web of Science ID 000172023200008

    View details for PubMedID 11699668

  • Cellulose granulomatosis presenting as centrilobular nodules: CT and histologic findings AMERICAN JOURNAL OF ROENTGENOLOGY Bendeck, S. E., Leung, A. N., Berry, G. J., Daniel, D., Ruoss, S. J. 2001; 177 (5): 1151-1153

    View details for Web of Science ID 000171732700034

    View details for PubMedID 11641191

  • A cystic upper lobe lesion in a healthy nonsmoking man - Angiosarcoma of the left upper lobe, presumed metastatic CHEST Leonard, C. T., Weinacker, A., Berry, G., Whyte, R. I. 2001; 120 (5): 1725-1727

    View details for Web of Science ID 000172274300051

    View details for PubMedID 11713159

  • Sirolimus (rapamycin) monotherapy prevents graft vascular disease in non-human primates. Dambrin, C., Klupp, J., Birsan, T., Luna, J., Suzuki, T., Kitamura, K., Staher, P., Fitzgerald, P., Jacobsen, W., Christians, U., Berry, G., Lam, T., Hausen, B., Hook, L., Morris, R. LIPPINCOTT WILLIAMS & WILKINS. 2001: 759–59
  • Critical role for IL-13 in the development of allergen-induced airway hyperreactivity JOURNAL OF IMMUNOLOGY Walter, D. M., McIntire, J. J., Berry, G., McKenzie, A. N., Donaldson, D. D., DeKruyff, R. H., Umetsu, D. T. 2001; 167 (8): 4668-4675


    Airway hyperresponsiveness to a variety of specific and nonspecific stimuli is a cardinal feature of asthma, which affects nearly 10% of the population in industrialized countries. Eosinophilic pulmonary inflammation, eosinophil-derived products, as well as Th2 cytokines IL-13, IL-4, and IL-5, have been associated with the development of airway hyperreactivity (AHR), but the specific immunological basis underlying the development of AHR remains controversial. Herein we show that mice with targeted deletion of IL-13 failed to develop allergen-induced AHR, despite the presence of vigorous Th2-biased, eosinophilic pulmonary inflammation. However, AHR was restored in IL-13(-/-) mice by the administration of recombinant IL-13. Moreover, adoptive transfer of OVA-specific Th2 cells generated from TCR-transgenic IL-13(-/-) mice failed to induce AHR in recipient SCID mice, although such IL-13(-/-) Th2 cells produced high levels of IL-4 and IL-5 and induced significant airway inflammation. These studies definitively demonstrate that IL-13 is necessary and sufficient for the induction of AHR and that eosinophilic airway inflammation in the absence of IL-13 is inadequate for the induction of AHR. Therefore, treatment of human asthma with antagonists of IL-13 may be very effective.

    View details for Web of Science ID 000171858300066

    View details for PubMedID 11591797

  • Modified cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone therapy for posttransplantation lymphoproliferative disease in pediatric patients undergoing solid organ transplantation JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Suryanarayan, K., Natkunam, Y., Berry, G., Bangs, C. D., Cherry, A., Dahl, G. 2001; 23 (7): 452-455


    The authors report the use of a cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP)-based chemotherapy regimen in treating six children with posttransplantation lymphoproliferative disorder (PTLD) that developed after solid organ transplantation.The chemotherapy regimen consisted of a 29-day induction with CHOP and then as many as 15 cycles of maintenance therapy using methotrexate and cytarabine alternating with vincristine, adriamycin, mercaptopurine, and prednisone.All patients attained remission. One patient died of sepsis while in remission. Four of the five remaining patients have been followed-up in remission for as long as 8 years without losing the graft. One of the patients experienced relapse after completing therapy and subsequently died with disease.The authors conclude that pediatric patients with PTLD after solid organ transplantation that fails conservative management can be treated successfully with CHOP-based chemotherapy.

    View details for Web of Science ID 000171516000011

    View details for PubMedID 11878581

  • In vivo Imaging of acute cardiac rejection in human patients using (99m)Technetium labeled annexin V AMERICAN JOURNAL OF TRANSPLANTATION Kown, M. H., Strauss, H. W., Blankenberg, F. G., Berry, G. J., Stafford-Cecil, S., Tait, J. F., Goris, M. L., Robbins, R. C. 2001; 1 (3): 270-277


    Annexin V binds phosphatidylserine moieties on apoptotic cells. This study reports the initial experience at Stanford University Medical Center with 99mTc-labeled annexin V imaging as a noninvasive measure of apoptosis in acute cardiac rejection. Ten cardiac transplant patients had 99mTc Annexin V imaging and endomyocardial biopsy (EMB) performed within 24 h. No complications related to 99mTc annexin V administration occurred. Eight patients had ISHLT grade of acute rejection of 1A or less. Five patients had two or more areas of uptake noted in the right ventricle on imaging studies. Two of these patients had positive biopsies: one patient had grade 2 rejection with two focal uptake areas and another had grade 3A rejection with three foci. An additional five patients had either one or zero hot spot areas and corresponding negative EMBs. 99mTc-annexin V appears to be well tolerated and may identify patients with acute cardiac rejection.

    View details for Web of Science ID 000173466800011

    View details for PubMedID 12102261

  • Viral serine proteinase inhibitor (SERP-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts TRANSPLANTATION Hausen, B., Boeke, K., Berry, G. J., Morris, R. E. 2001; 72 (3): 364-368


    Graft vascular disease (GVD) is the most common cause of late graft failure in solid organ transplantation. Recent studies have shown good efficacy of a novel nontoxic viral-derived serine proteinase inhibitor (SERP-1) in preventing postangioplasty restenosis. The current study was designed to test whether short-term treatment with SERP-1 was effective in reducing the incidence of GVD in a solid organ transplant.Piebald-Virol-Glaxo (PVG) donor hearts were transplanted into August-Copenhagen-Irish (ACI) recipients and observed for 90 days. All recipients (n=60) were treated with microemulsion cyclosporine (CsA) 7.5 mg/kg per gavage from day 0 to day 9 and randomized into 4 groups. SERP-1 was given intravenously. Group I received CsA monotherapy; group II, CsA+SERP-1 1 ng/g (postoperative days 0-9); group III, CsA+SERP-1 10 ng/g (postoperative days 0-9); and group IV, CsA+SERP-1 10 ng/g (postoperative days 0-9, 30, and 60). Graft viability was monitored by palpation, and GVD was assessed by morphometry.Two animals in group I rejected their allografts on postoperative days 7 and 14, 1 animal in group II rejected the allograft (postoperative day 31), and none in group III and IV rejected the allografts. At 90 days postoperative, 23.8% of all coronary vessels showed evidence of GVD in group I, 18.4% in group II, 12.9% in group III, and 11.8% in group IV. The difference in incidence of GVD was significant between groups I and III (P<0.05) and groups I and IV (P<0.05). Treatment with SERP-1 was well tolerated, and all animals regained weight quickly postsurgery.Treatment of allograft recipients with SERP-1 in combination with CsA early after transplantation significantly decreases the incidence of GVD when compared to grafts treated with only CsA. These results demonstrate the clinical potential for this novel serine protease inhibitor to prevent GVD in solid organ transplantation.

    View details for Web of Science ID 000170587000003

    View details for PubMedID 11502962

  • Nasal-pulmonary relations in allergic fungal sinusitis and allergic bronchopulmonary aspergillosis CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY Leonard, C. T., Berry, G. J., Ruoss, S. J. 2001; 21 (1): 5-15

    View details for Web of Science ID 000169702700002

    View details for PubMedID 11471340

  • Prolonged inhibition of obliterative airway disease in murine tracheal allografts by brief treatment with anti-leukocyte function-associated antigen-1 (CD11a) monoclonal antibody 16th Annual Meeting of the American-Society-of-Transplant-Physicians Morikawa, M., Brazelton, T. R., Berry, G. J., Morris, R. E. LIPPINCOTT WILLIAMS & WILKINS. 2001: 1616–21


    We have previously shown that anti-leukocyte function-associated antigen (LFA)-1 (CD11a) monoclonal antibody (mAb) prevents acute rejection and produces donor-specific unresponsiveness in murine recipients of heterotopic heart allografts. Here, we investigate the ability of this mAb to prevent the development of obliterative airway disease (OAD) in murine recipients of tracheal allografts.BALB/c tracheae were heterotopically transplanted into C3H mice. OAD developed by day 28 after transplantation and was characterized histologically by a loss of epithelial cell coverage and luminal obliteration of the tracheal allograft with a proliferation of fibrogenic mesenchymal cells, which is a lesion comparable to obliterative bronchiolitis in human lung transplant recipients. Monotherapy with anti-LFA-1 mAb preserved graft epithelium, prevented the development of OAD, and maintained unresponsiveness to donor antigen for more than 42 days after the final mAb administration.These findings suggest the potential for anti-LFA-1 mAb therapy to suppress both acute and chronic rejection in clinical lung transplantation.

    View details for Web of Science ID 000169420900022

    View details for PubMedID 11435974

  • IL-18 gene transfer by adenovirus prevents the development of and reverses established allergen-induced airway hyperreactivity JOURNAL OF IMMUNOLOGY Walter, D. M., Wong, C. P., DeKruyff, R. H., Berry, G. J., Levy, S., Umetsu, D. T. 2001; 166 (10): 6392-6398


    We examined the role of IL-18 in preventing the development of and in reversing established allergen-induced airway inflammation and airway hyperreactivity (AHR), the cardinal features of asthma. IL-18, which potently induces IFN-gamma, was administered into the respiratory tract as cDNA in a replication-deficient adenovirus (Adv). Treatment of OVA-sensitized mice with the IL-18-expressing Adv reduced allergen-specific IL-4 production, airway eosinophilia, and mucus production, increased IFN-gamma production, and prevented the development of AHR. The effects of the IL-18 Adv treatment were dependent on the presence of IFN-gamma and IL-12. Moreover, administration of the IL-18 Adv to mice with established AHR greatly reduced AHR and IL-4 production and increased IFN-gamma production. These results demonstrate that IL-18, when administered by Adv into the respiratory tract, effectively reduces AHR and replaces an established Th2-biased immune response with a Th1-biased response.

    View details for Web of Science ID 000170948500068

    View details for PubMedID 11342664

  • Paclitaxel-induced hypersensitivity pneumonitis: radiographic and CT findings. AJR. American journal of roentgenology Wong, P., Leung, A. N., Berry, G. J., Atkins, K. A., Montoya, J. G., Ruoss, S. J., Stockdale, F. E. 2001; 176 (3): 718-720

    View details for PubMedID 11222212

  • Case report - Paclitaxel-induced hypersensitivity pneumonitis: Radiographic and CT findings AMERICAN JOURNAL OF ROENTGENOLOGY Wong, P., Leung, A. N., Berry, G. J., Atkins, K. A., Montoya, J. G., Ruoss, S. J., Stockdale, F. E. 2001; 176 (3): 718-720
  • 40-O-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Nishimura, T., Faul, J. L., Berry, G. I., Veve, I., Pearl, R. G., Kao, P. N. 2001; 163 (2): 498-502


    Pneumonectomized rats develop pulmonary hypertension (PH) and pulmonary vascular neointimal formation 4 wk after monocrotaline (MCT) administration. Male Sprague-Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Three groups (n = 5) received 40-O-(2-hydroxyethyl)-rapamycin (RAD, 2.5 mg/kg/d, by gavage): Group PMR(5-35) from Day 5 to Day 35, Group PMR5-14 from Day 5 to Day 14, and Group PMR15-35 from Day 15 to Day 35. By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (Ppa = 41 +/- 3 mm Hg) (p < 0.001), right ventricular systolic pressures (Prv,s = 45 +/- 2 mm Hg) (p < 0.01), and right ventricle/(left ventricle plus septum) (0.55 +/- 0.05) (p = 0.028) than rats in Groups PMR5-35 (Ppa = 25 +/- 3 mm Hg, Prv,s = 32 +/- 7 mm Hg, RV/LV&S = 0.42 +/- 0.06) and PMR5-14 (Ppa = 29 +/- 4 mm Hg, Prv,s = 30 +/- 5 mm Hg, RV/LV&S = 0.43 +/- 0.07). Pulmonary arterial neointimal formation (quantified by a vascular occlusion score) was more severe in vehicle-treated rats (1.93 +/- 0.03) than in Groups PMR5-14 (1.56 +/- 0.27) and PMR(5-35) (1.57 +/- 0.1) (p < 0.01). RAD attenuates the development of MCT-induced pulmonary arterial hypertension in the pneumonectomized rat.

    View details for Web of Science ID 000167050900038

    View details for PubMedID 11179130

  • In vivo monitoring of myoblast transplantation into rat myocardium. journal of heart and lung transplantation Koransky, M. L., Ip, T. K., Wu, S., Cao, Y., Berry, G., Contag, C., Blau, H., Robbins, R. 2001; 20 (2): 188-189

    View details for PubMedID 11250320

  • Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Faul, J. L., Nishimura, T., Berry, G. J., BENSON, G. V., Pearl, R. G., Kao, P. N. 2000; 162 (6): 2252-2258


    This paper reports the effect of triptolide (a diterpenoid triepoxide) on the development of monocrotaline (MCT)-induced pulmonary hypertension in pneumonectomized rats. Male Sprague- Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Rats received therapy from Day 5 to 35 with triptolide (0.25 mg/kg intraperitoneally, every other day, n = 10), or vehicle (0.1 ml of ethanol/cremophor intraperitoneally, every other day, n = 10). By Day 35, triptolide-treated rats demonstrated lower mean pulmonary arterial pressure (mPAP) than vehicle-treated rats (mPAP 21 +/- 3 versus 42 +/- 5 mm Hg, p < 0.001). Triptolide-treated rats also had significantly less right ventricular hypertrophy (RVH) and pulmonary arterial neointimal formation. In a rescue experiment, rats initiated therapy on Day 21. At Day 35, vehicle-treated rats (n = 4) had higher mPAP (40 +/- 9 mm Hg), greater RVH, and more severe pulmonary arterial neointimal formation than rats that received triptolide (0.25 mg/kg every other day, n = 7, mPAP 30 +/- 4 mm Hg) and rats that received triptolide (0.2 mg/kg daily, n = 7, mPAP 25 +/- 5 mm Hg, p < 0.01). In pneumonectomized rats that receive MCT, triptolide attenuates the development of pulmonary hypertension and RVH, and promotes regression of pulmonary arterial neointimal formation.

    View details for Web of Science ID 000165794700050

    View details for PubMedID 11112148

  • Zinc-mediated reduction of apoptosis in cardiac allografts. Circulation Kown, M. H., van der Steenhoven, T., Blankenberg, F. G., Hoyt, G., Berry, G. J., Tait, J. F., Strauss, H. W., Robbins, R. C. 2000; 102 (19): III228-32


    Apoptosis is thought to occur during immune-mediated acute rejection of cardiac allografts. In vitro studies have shown that zinc inhibits the activity of the proapoptotic enzyme caspase-3. We hypothesized that ZnCl(2) would reduce acute cardiac rejection in vivo via the blockade of caspase-3-dependent apoptosis. (99m)Tc-labeled annexin V was used to measure apoptosis in cardiac allografts through nuclear imaging. Annexin V binds to phosphatidylserines, which are externalized to the outer membrane of apoptotic cells.Twenty-seven PVG rat hearts were transplanted heterotopically into the abdomen of untreated ACI rats as controls (group 1). Fifteen were scanned and euthanized on postoperative day 4, and 12 were assessed for graft survival. Group 2 and 3 rats (n=15 each) received 1 and 5 mg/kg ZnCl(2) BID IP, respectively. Nine of each of these groups were scanned and euthanized on postoperative day 4, and 6 were studied for allograft survival. Group 4 rats (n=3) received isografts. Region-of-interest analysis demonstrated a dose-dependent reduction in (99m)Tc annexin uptake in ZnCl(2)-treated allografts: 2.43+/-0.37% for group 1, 1. 97+/-0.41% for group 2, 1.21+/-0.47% for group 3, and 0.55+/-0.19% for group 4 (ANOVA, P:=0.001). Graft survival times of 6.4+/-1.7, 9. 3+/-3.0, and 11.5+/-3.4 days for groups 1, 2, and 3, respectively, were also observed (ANOVA, P:=0.001). Caspase-3 activity in the allografts showed a 3.7-fold reduction in group 3 animals compared with group 1 animals (P:=0.004).Apoptosis that occurs in acute cardiac allograft rejection is reduced with ZnCl(2) in a dose-dependent manner via caspase-3 inhibition.

    View details for PubMedID 11082392

  • Zinc-mediated reduction of apoptosis in cardiac allografts CIRCULATION Kown, M. H., van der Steenhoven, T., Blankenberg, F. G., Hoyt, G., Berry, G. J., Tait, J. F., Strauss, H. W., Robbins, R. C. 2000; 102 (19): 228-232
  • Rapid deployment of a vein to aorta anastomosis with a novel integrated and automated anastomosis system: Preclinical results from an aorto-coronary bypass study in sheep Hausen, B., Gruenenfelder, J., Yencho, S. A., Morris, R. E., Green, B. A., Berry, G. J., Molho, C., Vargas, J., Sheehan, D., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2000: 766–66
  • Tissue characterization of atherosclerotic plaques by intravascular ultrasound radiofrequency signal analysis: An in vitro study of human coronary arteries AMERICAN HEART JOURNAL Komiyama, N., Berry, G. J., Kolz, M. L., Oshima, A., Metz, J. A., Preuss, P., Brisken, A. F., Moore, M. P., Yock, P. G., Fitzgerald, P. J. 2000; 140 (4): 565-574


    Conventional gray-scale images of intravascular ultrasound (IVUS) cannot accurately differentiate histologic subtypes of sonolucent coronary plaques with or without a lipid core.We analyzed radiofrequency signals obtained in vitro from 24 regions of interest (ROI) of noncalcified (sonolucent) plaques in 10 atherosclerotic coronary artery specimens pressure-fixed by formalin. Radiofrequency signals were sampled with a 30-MHz IVUS catheter and digitized at 500 MHz in 8-bit resolution. The ROIs were histologically categorized into 12 plaques with a lipid core and 12 plaques without it. Integrated backscatter and statistical parameters of the radiofrequency envelope (mean/SD ratio [MSR], skewness, and kurtosis) within the ROI were calculated offline, and their ability to detect a lipid core was compared with visual analysis of the IVUS video images. In the group with lipid cores, percent area of a lipid core in each ROI was measured in a digitized histologic image by a computerized planimeter.Sensitivity and specificity of MSR, skewness, and kurtosis for lipid core detection were substantially greater than visual video image analysis (83.3% and 91.7%, 100% and 91.7%, 100% and 91.7% vs 53.3% and 71.7%). Furthermore, the parameters of integrated backscatter, MSR, skewness, and kurtosis were significantly correlated to percent of core area (r = -0.64, -0.73, 0.78, and 0.63, respectively; P<.05).Compared with IVUS video images, the parameters of radiofrequency signal analysis may be used to aid in more accurate detection and quantitative evaluation of a lipid core, which is one of the major factors of a vulnerable coronary plaque.

    View details for Web of Science ID 000089692600005

    View details for PubMedID 11011329

  • Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates TRANSPLANTATION Ikonen, T. S., Gummert, J. F., Hayase, M., Honda, Y., Hausen, B., Christians, U., Berry, G. J., Yock, P. G., Morris, R. E. 2000; 70 (6): 969-975


    Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS).Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105.Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05).Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

    View details for Web of Science ID 000089710700014

    View details for PubMedID 11014651

  • Epithelial re-growth is associated with inhibition of obliterative airway disease in orthotopic tracheal allografts in non-immunosuppressed rats TRANSPLANTATION Ikonen, T. S., Brazelton, T. R., Berry, G. J., Shorthouse, R. S., Morris, R. E. 2000; 70 (6): 857-863


    Because epithelial cells are targets of alloimmune injury leading ultimately to airway obliteration, we tested whether epithelial re-growth could prevent obliterative airway disease (OAD) in orthotopic tracheal allografts.Brown Norway tracheal segments were orthotopically transplanted into nonimmunosuppressed Lewis rats. Allografts were removed on days 2-10 (n=13), 30 (n=4), and 60 (n=5) for histology, computerized morphometry (obliteration), and immunohistochemical detection of mononuclear cells, smooth muscle alpha-actin, and tissue phenotype. Normal tracheas, host tracheas, and heterotopically transplanted allografts served as controls.Orthotopic allografts removed on days 2-10 exhibited epithelial damage and re-growth and mononuclear cell infiltration. On days 30 and 60, partially ciliated cuboidal or attenuated epithelium completely covered the lumen. Although mononuclear cells declined, numerous T cells with a high CD4/CD8 ratio were found in the epithelium till day 60. Orthotopic allograft epithelium expressed donor phenotype on day 7, but recipient phenotype on days 30 and 60. Despite subepithelial alpha-actin positive myofibroblast proliferation, obliteration did not progress from day 7 to 30 and 60 (35, 30, and 33%, respectively). Although more than in normal or host tracheas, the obliteration in orthotopic allografts on days 30 and 60 was significantly less (P<0.001) than in heterotopic allografts.We describe, for the first time, longterm patency of fully histoincompatible orthotopic tracheal allografts in nonimmunosuppressed rats. Despite acute alloimmune injury and induction of myofibroblast proliferation, epithelial re-growth from the host limited the progression of OAD, thus emphasizing the role of epithelium in the control of airway obliteration.

    View details for Web of Science ID 000089710700001

    View details for PubMedID 11014638

  • Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens JOURNAL OF IMMUNOLOGY Tsitoura, D. C., Kim, S., Dabbagh, K., Berry, G., Lewis, D. B., Umetsu, D. T. 2000; 165 (6): 3484-3491


    Viral respiratory infections have been implicated in influencing allergen sensitization and the development of asthma, but their exact role remains controversial. Because respiratory exposure to Ag normally engenders T cell tolerance and prevents the development of airway hyperreactivity (AHR) and inflammation, we examined the effects of influenza A virus infection on tolerance induced by exposure to intranasal (i.n.) OVA and the subsequent development of AHR. We found that concurrent infection with influenza A abrogated tolerance induced by exposure to i.n. OVA, and instead led to the development of AHR accompanied by the production of OVA-specific IgE, IL-4, IL-5, IL-13, and IFN-gamma. When both IL-4 and IL-5 were neutralized in this system, AHR was still induced, suggesting that influenza-induced cytokines such as IL-13, or mechanisms unrelated to cytokines, might be responsible for the development of AHR. The length of time between influenza A infection and i.n. exposure to OVA was crucial, because mice exposed to i.n. OVA 15-30 days after viral inoculation developed neither AHR nor OVA-specific tolerance. These mice instead acquired Th1-biased OVA-specific immune responses associated with vigorous OVA-induced T cell proliferation, and reduced production of OVA-specific IgE. The protective effect of influenza A on AHR was dependent on IFN-gamma, because protection was abrogated with a neutralizing anti-IFN-gamma mAb. These results suggest that viral respiratory infection interferes with the development of respiratory allergen-induced tolerance, and that the time interval between viral infection and allergen exposure is critical in determining whether viral infection will enhance, or protect against, the development of respiratory allergen sensitization and AHR.

    View details for Web of Science ID 000165938100073

    View details for PubMedID 10975869

  • Giant cell myocarditis as a manifestation of drug hypersensitivity CARDIOVASCULAR PATHOLOGY Daniels, P. R., Berry, G. J., Tazelaar, H. D., Cooper, L. T. 2000; 9 (5): 287-291


    Adverse drug effects on the myocardium are often classified into toxic and hypersensitivity forms of myocarditis, each with distinct histologic findings. In contrast, giant cell myocarditis (GCM) is generally not associated with adverse drug reactions and has unique histopathologic features. We report four cases of adverse drug reactions in which the histologic findings were characteristic of GCM. The clinical recognition that GCM may be a manifestation of an adverse drug reaction is important, since the prognosis and treatment of this entity may be different from that of other forms of myocarditis.

    View details for Web of Science ID 000165215100006

    View details for PubMedID 11064276

  • Survival outcomes of patients with giant cell myocarditis bridged by ventricular assist devices ASAIO JOURNAL Brilakis, E. S., Olson, L. J., Berry, G. J., Daly, R. C., Loisance, D., Zucker, M., Cooper, L. T. 2000; 46 (5): 569-572


    Giant cell myocarditis is a highly lethal disorder characterized by rapidly progressive congestive heart failure. The aim of this study was to describe the clinical course of patients with giant cell myocarditis who received a ventricular assist device. Patients with giant cell myocarditis were identified from the Multicenter Giant cell Myocarditis Registry. Bridging to cardiac transplantation in the giant cell myocarditis patients who received a ventricular assist device was compared with bridging in the general population of heart failure patients, as reported in the literature. Median posttransplantation survival for patients with giant cell myocarditis who received and did not receive ventricular assist devices was calculated by the Kaplan-Meier method and compared with use of the log-rank test. Nine patients with giant cell myocarditis who received ventricular assist devices were identified. Seven patients survived to transplantation, four were alive 30 days posttransplantation, and two survived to 1 year. The rate of successful bridging to transplantation in seven of nine patients (78%) is similar to that reported for other ventricular assist device recipients. Posttransplantation survival of 57% (4 of 7) at 30 days and 29% (2 of 7) at 1 year was significantly lower compared with 93% 1-year survival of the 30 patients with giant cell myocarditis who did not receive ventricular assist devices before transplantation (p<0.001). Ventricular assist devices can be an effective bridge to transplantation for patients with heart failure caused by giant cell myocarditis. Although their posttransplantation survival was poor in our series, a few patients had long-term survival.

    View details for Web of Science ID 000089329900011

    View details for PubMedID 11016508

  • Mechanisms preventing allergen-induced airways hyperreactivity: Role of tolerance and immune deviation JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Tsitoura, D. C., Blumenthal, R. L., Berry, G., DeKruyff, R. H., Umetsu, D. T. 2000; 106 (2): 239-246


    Aeroallergens continuously enter the respiratory tract of atopic individuals and provoke the development of asthma characterized by airway hyperreactivity (AHR) and inflammation. By contrast, nonatopic individuals are exposed to the same aeroallergens, but airway inflammation does not develop. However, the mechanisms that prevent allergen-induced respiratory diseases in nonatopic subjects are poorly characterized.In this study we compared the role of allergen-specific T-cell tolerance and immune deviation in conferring protection against the development of allergen-induced AHR.We exposed mice to intranasal ovalbumin (OVA) to induce T-cell tolerance and examined its effects on the subsequent development of AHR and inflammation.We demonstrated that exposure of mice to intranasal OVA resulted in peripheral CD4(+) T-cell unresponsiveness that very efficiently prevented not only the development of AHR but also greatly inhibited airway inflammation and OVA-specific IgE production. The induction of peripheral T-cell tolerance and protection against AHR were not dependent on the presence of IFN-gamma or IL-4. The development of AHR was also prevented by an OVA-specific T(H)1-biased immune response induced by inhalation of OVA in the presence of IL-12. However, the OVA-specific T(H)1 response was associated with a significant degree of pulmonary inflammation.These results indicate that both allergen-specific T-cell tolerance and T(H)1-biased immune deviation prevent the development of AHR, but T(H)1 responses are associated with significantly greater inflammation in the lung than is associated with T-cell unresponsiveness. Therefore CD4(+) T-cell unresponsiveness critically regulates immune responses to aeroallergens and protects against the development of allergic disease and asthma.

    View details for Web of Science ID 000088708100004

    View details for PubMedID 10932065

  • Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: Interaction with cyclosporine JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Serkova, N., Hausen, B., Berry, G. J., Jacobsen, W., Benet, L. Z., Morris, R. E., Christians, U. 2000; 294 (1): 323-332


    We report the tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD ¿40-O-(2-hydroxyethyl)-rapamycin and its metabolites in monkey lung transplant recipients as well as its interaction with cyclosporine as the Neoral formulation. After left unilateral lung transplantation, cynomolgus monkeys received by oral administration either 1) 1.5 mg/kg/day SDZ-RAD (n = 4); 2) 100 mg/kg/day cyclosporine (n = 4); 3) 0.3 mg/kg/day SDZ-RAD + 100 mg/kg/day cyclosporine (n = 6); 4) 1.5 mg/kg/day SDZ-RAD + 50 mg/kg/day cyclosporine (n = 5); or 5) SDZ-RAD and cyclosporine doses adjusted according to trough blood concentration measurements (n = 6). At the end of the observation period (usually 29 days after transplantation), and 24 h after the last doses, tissue samples were collected and analyzed with HPLC/mass spectrometry. Gall bladder, pancreas, the transplant lung, cerebellum, kidneys, and spleen had the highest SDZ-RAD concentrations. Coadministration of cyclosporine increased SDZ-RAD concentrations in most tissues as well as tissue-to-blood distribution coefficients. In contrast, SDZ-RAD had only a small effect on cyclosporine blood and tissue concentrations. Rejection in lung grafts in monkeys treated with either of the cyclosporine/SDZ-RAD combinations was significantly less than in the monotherapy groups (P <.002). Histological rejection scores were inversely correlated with SDZ-RAD concentrations in blood (r = -0. 68; P <.001; n = 24), lymph nodes (P = -0.58; P <.003; n = 24), thymus (r = -0.63; P <.001; n = 23) and transplant lung tissue (r = -0.58; P <.003; n = 24). We conclude that, in addition to the synergistic pharmacodynamic interaction, a pharmacokinetic interaction resulting in higher SDZ-RAD tissue concentrations contributed to the significantly better immunosuppressive efficacy when both drugs were combined compared with monotherapy.

    View details for Web of Science ID 000087896200040

    View details for PubMedID 10871329

  • Immunosuppressive therapies for the prevention and treatment of obliterative airway disease in heterotopic rat trachea allografts TRANSPLANTATION Adams, B. F., Berry, G. J., Huang, X. F., Shorthouse, R., Brazelton, T., Morris, R. E. 2000; 69 (11): 2260-2266


    Obliterative bronchiolitis remains a major long-term complication after lung transplantation. Using a reproducible model of heterotopically transplanted rat tracheas, this study examined the role of several novel immunosuppresive compounds to prevent and reverse obliterative airway disease in these animals.Brown Norway rat trachea were transplanted into the greater omentum of Lewis (allografts) or Brown Norway (isografts) animals. Recipient animals were treated with rapamycin, cyclosporine, 15-deoxyspergulin, mycophenolate mofetil, or leflunomide from day 0, 7, or 14 until day of graft removal, either day 28 or 50. Trachea segments were evaluated for degree of lumenal occlusion, as well as percent and type of lumen epithelial cell coverage.All untreated allografted tracheas obliterated completely, although isografts appeared patent with normal respiratory epithelium when they were removed. Leflunomide, rapamycin, and cyclosporine effectively prevented obliteration when treatment was initiated at day 0, with rapamycin showing continued efficacy when initiated as late as day 7. 15-deoxyspergulin and mycophenolate mofetil failed to consistently inhibit obliteration with any treatment schedule. An inverse correlation was found between epithelial coverage and degree of obliteration, and was especially pronounced in grafts from cyclosporine-treated animals.Immunosuppressive drug therapy will inhibit airway obliteration, but efficacy sharply diminishes if initiation of treatment is delayed. Efficacy also varies among immunosuppressive compounds, and results indicate those drugs that enable epithelial regrowth most effectively inhibit airway graft obliteration.

    View details for Web of Science ID 000087669400007

    View details for PubMedID 10868623

  • Viral serine proteinase inhibitor (SERP-1) effectively decreases the incidence of graft vasculopathy in heterotopic heart allografts. Hausen, B., Boeke, K., Berry, G. J., Acklin, S., Morris, R. E. LIPPINCOTT WILLIAMS & WILKINS. 2000: S344–S344
  • IL-18 gene transfer by adenovirus (ADV) into the lungs prevents and reverses allergen induced airway hyperreactivity (AHR). Walter, D. M., Wong, C., DeKruyff, R. H., Berry, G., Levy, S., Umetsu, D. T. FEDERATION AMER SOC EXP BIOL. 2000: A1066–A1066
  • Dendritic cells and macrophages in lung allografts a role in chronic rejection? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Leonard, C. T., Soccal, P. M., Singer, L., Berry, G. J., Theodore, J., Holt, P. G., Doyle, R. L., Rosen, G. D. 2000; 161 (4): 1349-1354


    Antigen presentation by lung macrophages/dendritic cells (DC) is thought to be important in obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS), which severely limits survival post-lung transplantation. However, a recent study found minimal numbers of DC in lung allografts. We looked at numbers and phenotype of macrophages/DC in lung allografts using endobronchial biopsy (EBB) and transbronchial biopsy (TBB) from 22 lung transplant patients. Biopsies were stained with monoclonal markers of DC (CD1a, RFD1, and major histocompatibility complex [MHC] Class II), and "suppressor macrophages" (RFD1 and RFD7). Dendritic cells were also stained for the costimulatory molecules CD80 and CD86. Significantly greater numbers of DC/high-power field (HPF) were seen in biopsies when we defined DC using dendritic morphology and Class II MHC expression instead of CD1a expression. Dendritic cell numbers were significantly higher in eight patients with OB/BOS compared with 14 stable patients. Fifty percent of DC expressed CD86 and 20% expressed CD80. There was no difference in CD80 or CD86 expression between OB/BOS patients and stable patients. There was no correlation between DC numbers and presence or absence of acute rejection (AR), and/or cytomegalovirus (CMV) pneumonitis on current or prior biopsies. There were significantly more MHC Class II DC in EBB compared with TBB. We found minimal staining for lung macrophages capable of suppressing T-cell inflammation. We conclude that studies of lung allografts may underestimate DC numbers if relying on CD1a as the sole marker of DC. DC are increased in patients with OB/BOS compared with stable patients. EBB may be more important than TBB in looking for inflammatory changes of OB. DC expressing costimulatory molecules are present in lung allografts, and costimulatory pathway blockade may be useful in human lung allografts. Also, the absence of "suppressor" macrophages may increase susceptibility of human lung allografts to the rejection process.

    View details for Web of Science ID 000086573400044

    View details for PubMedID 10764333

  • Successful treatment of acute, ongoing rat lung allograft rejection with the novel immunosuppressant SDZ-RAD ANNALS OF THORACIC SURGERY Hausen, B., Boeke, K., Berry, G. J., Christians, U., Schuler, W., Morris, R. E. 2000; 69 (3): 904-909


    Recent experimental data have shown that coadministration of microemulsion cyclosporine and the novel immunosuppressant SDZ-RAD potentiates the immunosuppressive efficacies of both drugs to suppress allograft rejection. Our study was designed to assess the potential of delayed SDZ-RAD administration, in addition to cyclosporine maintenance therapy, to reverse acute rejection in an allogeneic rat lung transplant model.Unilateral left lung transplantation was performed using Brown-Norway donors implanted into Lewis recipients. An untreated control group and a cyclosporine monotherapy group (7.5 mg/kg) were followed for 7 days. An additional cyclosporine monotherapy group (7.5 mg/kg), and a combined therapy group treated with cyclosporine (7.5 mg/kg) plus SDZ-RAD (2.5 mg/kg), were followed for 21 days. For treatment of ongoing rejection, 7.5 mg/kg cyclosporine was given as maintenance therapy, and SDZ-RAD (2.5 mg/kg) was added on postoperative day 7. Drugs were given orally, and in the combined therapy regimens, administered 6 hours apart. Outcome variables included daily weight, radiographs, and histology.Radiographs on postoperative day 7 showed mild and moderate opacification of the left chest in the cyclosporine monotherapy groups and the untreated control group. Addition of SDZ-RAD to cyclosporine treatment on postoperative day 7 reversed opacification by postoperative days 14 and 21. Monotherapy with microemulsion CsA resulted in mild histological rejection by day 7, which progressed to moderate rejection by day 21. Addition of SDZ-RAD on postoperative day 7 reversed acute rejection, resulting in none or minimal rejection at day 21.SDZ RAD reverses acute rejection under cyclosporine maintenance therapy in a stringent lung allotransplant model.

    View details for Web of Science ID 000086022000056

    View details for PubMedID 10750781

  • Radionuclide imaging of acute lung transplant rejection with annexin V 29th Annual Meeting of the Fleischner-Society Blankenberg, F. G., Robbins, R. C., Stoot, J. H., Vriens, P. W., Berry, G. J., Tait, J. F., Strauss, H. W. AMER COLL CHEST PHYSICIANS. 2000: 834–40


    Early detection and treatment of lung transplant rejection is critical for preservation of pulmonary graft function. Damage to pulmonary allografts is mediated by apoptotic cell death induced by the alloreactive T lymphocytes that infiltrate lung grafts. Previous studies demonstrate that acute cardiac allograft rejection can be visualized using radiolabeled annexin V. This study was done to determine whether this technique could visualize acute rejection in a rodent model of unilateral orthotopic lung transplantation.Eighteen Sprague-Dawley ACI rats underwent removal of their left lung followed by orthotopic transplant of either an allogeneic (PVG, immunologically mismatched; N = 10) or a syngeneic (ACI, immunologically matched) pulmonary graft (N = 8). Animals were imaged 1 h after IV injection of 1 mCi (37.0 MBq) of (99m)Tc-annexin V 1 to 7 days after transplantation.Lungs receiving the allograft demonstrated moderate to marked mononuclear infiltration of the perivascular, interstitial, and peribronchial tissues. No mononuclear infiltrates were noted in the native right lungs nor in the syngeneic transplants. Region of interest image analysis revealed significant (p < 0.0005) increases of transplant to normal lung activity ratios 3 to 7 days after allograft surgery. The increased annexin V uptake in these lungs was confirmed at biodistribution assay (allograft 151% greater than isograft activity, p < 0.005).Acute experimental lung transplant rejection can be noninvasively identified using (99m)Tc-annexin V. Radiolabeled annexin V may be a clinically useful noninvasive screening tool for acute rejection.

    View details for Web of Science ID 000085884000037

    View details for PubMedID 10713014

  • Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Faul, J. L., Berry, G. J., Colby, T. V., Ruoss, S. J., Walter, M. B., Rosen, G. D., Raffin, T. A. 2000; 161 (3): 1037-1046

    View details for Web of Science ID 000085996400058

    View details for PubMedID 10712360

  • Prevention of acute allograft rejection in nonhuman primate lung transplant recipients - Induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressive activity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin TRANSPLANTATION Hausen, B., Gummert, J., Berry, G. J., Christians, U., Serkova, N., Ikonen, T., Hook, L., Legay, F., Schuler, W., Schreier, M. H., Morris, R. E. 2000; 69 (4): 488-496


    In previous studies of cynomolgus monkey lung allograft recipients, we demonstrated significant immunosuppressive efficacy but reduced tolerability after combined treatment with high doses of microemulsion cyclosporine (CsA) and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin). The current study was designed to compare efficacy and tolerability of a combination of low-dose CsA and high-dose SDZ RAD (CTL group) to triple therapy using the chimeric anti-interleukin-2 (IL-2) receptor (CD25) monoclonal antibody (mAb) basiliximab (anti-IL-2 receptor mAb) for induction therapy (basiliximab: 5 mg intravenously on days 0 and 4) plus low-dose CsA and low-dose SDZ RAD for maintenance immunosuppression (CD25 group). CsA and anti-IL-2 receptor mAb are drugs that reduce cytokine synthesis and block IL-2-mediated lymphocyte stimulation, respectively. SDZ RAD blocks lymphocyte stimulation by other cytokines (e.g., IL-15) that are not inhibited by anti-IL-2 receptor mAb.Twelve unilateral lung transplants were performed. Recipients were observed for 49 days by daily weight assessment, hemograms, blood chemistries, radiographs, and lung biopsies. Monkeys were euthanized before day 49 in the event of excessive weight loss (>25%) or organ failure. Target CsA trough levels were 100-200 ng/ml. Target SDZ RAD trough levels in the CTL group (no mAb) were 20-40 ng/ml, and 10-20 ng/ml in the CD25 group.None of the monkeys in the CD25 group needed to be euthanized early due to signs of drug toxicity. In contrast, four monkeys in the CTL group were sacrificed on days 28-35 as a result of excessive weight loss (n=3) and renal functional impairment (n=1). Three recipients in the CD25 group were euthanized on days 36, 38, and 46 as a result of persistent high fever associated with severe rejection. The median animal survival in the CTL group was 32 vs. 46 days in the CD25 group (P<0.04). The only two long-term survivors in the CTL group showed moderate rejection at day 49. The median rejection scores at day 14 (A0) and day 28 (A2) were identical in the two groups, despite the fact that the mean SDZ RAD trough level was significantly lower in the CD25 group (CTL: 38+/-3 ng/ml, CD25: 18+/-2 ng/ml, P<0.0001). After basiliximab levels fell below the minimum therapeutic level (1 mg/ml) on day 28, the median rejection score at day 49 increased to A4 in the CD25 group.This is the first study to combine an anti-IL-2 receptor mAb with a drug from the rapamycin class plus CsA. Our study shows that induction therapy with basiliximab enabled SDZ RAD blood levels to be significantly reduced, which led to improved tolerability without the penalty of increased rejection.

    View details for Web of Science ID 000085611500005

    View details for PubMedID 10708100

  • The role of respiratory epithelium in a rat model of obliterative airway disease TRANSPLANTATION Adams, B. F., Brazelton, T., Berry, G. J., Morris, R. E. 2000; 69 (4): 661-664


    The etiology and pathogenesis of obliterative bronchiolitis after lung transplantation remain to be fully elucidated. Using a rat model of heterotopically transplanted trachea grafts, we have examined the role airway epithelium plays in obliterative airway disease (OAD).Rat trachea isografts were denuded of epithelium by protease digestion. Grafts were inoculated either with or without native airway epithelial cells and transplanted into the omentum of recipient animals.Airway epithelium removal resulted in OAD in denuded isogeneic trachea grafts. Reseeding of the denuded grafts with epithelial cells significantly reduced airway obliteration from 78% to 22% luminal occlusion.Non-immune-mediated injury will cause OAD, and epithelial cell replacement in denuded isografts can significantly reduce the fibrotic progression of the disease.

    View details for Web of Science ID 000085611500031

    View details for PubMedID 10708126

  • Particulate emboli capture by an intra-aortic filter device during cardiac surgery 79th Annual Meeting of the American-Association-for-Thoracic-Surgery Reichenspurner, H., Navia, J. A., Berry, G., Robbins, R. C., Barbut, D., Gold, J. P., Reichart, B. MOSBY-ELSEVIER. 2000: 233–40


    Particulate embolization is associated with neurologic morbidity after cardiac surgery. Crossclamp manipulation has been identified as the single most significant cause of particulate emboli release during cardiac surgery. A new intra-aortic filtration method has been assessed with regard to its safety and its ability to capture particulate emboli before they enter the central circulation.Patients undergoing cardiac surgery with cardiopulmonary bypass through standard median sternotomy were selected for emboli management by means of intra-aortic filtration. A novel intra-aortic filter device was inserted through a modified 24F arterial cannula immediately before releasing the crossclamp in 77 patients. Filters remained in the aorta until cardiopulmonary bypass was discontinued and the heart was fully ejecting. The procedure was assessed for facility, safety, and effect on routine cardiopulmonary bypass operation and function.The insertion and removal of the intra-aortic filter were safe, easy, and uneventful in most patients. Patient hemodynamics and bypass flow rates remained normal throughout the filter dwell period. No strokes or gross neurologic defects were noted. Electron microscopic analysis of 12 filters revealed an insignificant degree of platelet adhesion on filter surfaces. Histology samples (n = 44) were examined, and 66% (n = 29) showed evidence of atheromatous material, 36% (n = 16) with platelet-fibrin, 25% (n = 11) with true thrombus and/or blood clot, 7% (n = 3) with normal vessel wall, and 2% (n = 1) with aggregates of cholesterol or grumous portion of atheromatous plaque.The intra-aortic filter can be safely deployed and captures particulate emboli, the predominant origin of which is atheromatous. The beneficial effects of this device on neurologic outcomes have yet to be determined.

    View details for Web of Science ID 000085509800007

    View details for PubMedID 10649198

  • Combined immunosuppression with cyclosporine (Neoral) and SDZ RAD in non-human primate lung transplantation: Systematic pharmacokinetic-based trials to improve efficacy and tolerability TRANSPLANTATION Hausen, B., Ikonen, T., Briffa, N., Berry, G. J., Christians, U., Robbins, R. C., Hook, L., Serkova, N., Benet, L. Z., Schuler, W., Morris, R. E. 2000; 69 (1): 76-86


    We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy.Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy.Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean +/- SE trough level (MTL): 292+/-17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15+/-1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82+/-18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217+/-16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24+/-2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143+/-13 and for RAD 38+/-3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection.Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

    View details for Web of Science ID 000084860100015

    View details for PubMedID 10653384

  • Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: Role of CD8(+) T cells and IL-18 JOURNAL OF IMMUNOLOGY Hansen, G., Yeung, V. P., Berry, G., Umetsu, D. T., DeKruyff, R. H. 2000; 164 (1): 223-230


    Asthma is a respiratory disorder characterized by airway hyperreactivity (AHR) and inflammation and is associated with high serum IgE and overproduction of IL-4, IL-5, and IL-13 by allergen-specific Th2 cells. Our previous studies demonstrated that heat-killed Listeria monocytogenes (HKL) as an adjuvant in immunotherapy successfully reversed ongoing Ag-specific Th2-dominated responses toward Th1-dominated responses, but it was unclear if such immune modulation could reverse ongoing, established disease in target organs such as the lung. In this paper we show that a single dose of Ag plus HKL as adjuvant significantly reduced AHR in a murine model for asthma and reversed established AHR when given late after allergen sensitization. HKL as adjuvant also dramatically inhibited airway inflammation, eosinophilia, and mucus production, significantly reduced Ag-specific IgE and IL-4 production, and dramatically increased Ag-specific IFN-gamma synthesis. The inhibitory effect of HKL on AHR depended on the presence of IL-12 and CD8+ T cells and was associated with an increase of IL-18 mRNA expression. Thus, our results demonstrate that HKL as an adjuvant for immunotherapy mediates immune deviation from a pathological Th2-dominated response toward a protective immune response in peripheral lymphoid tissues and in the lungs and may be clinically effective in the treatment of patients with established asthma and allergic disease.

    View details for Web of Science ID 000084321200033

    View details for PubMedID 10605015

  • Influenza pneumonia in a paediatric lung transplant recipient TRANSPLANT INTERNATIONAL Faul, J. L., Akindipe, O. A., Berry, G. J., Theodore, J. 2000; 13 (1): 79-81


    Although a common cause of morbidity and mortality in the general population, influenza infections are uncommon in lung transplant recipients and, to date, have only been associated with transient declines in pulmonary function and a relatively benign clinical course. This paper describes severe influenza pneumonia in a 13-year-old paediatric lung transplant recipient (5 months after double lung transplantation). Influenza pneumonia was diagnosed by direct fluorescent antibody testing and viral culture of bronchoalveolar lavage fluid. The patient required mechanical ventilation for 2 days due to respiratory failure and fatigue. Since his recovery from this pneumonia, he has developed obliterative bronchiolitis and currently awaits re-transplantation.

    View details for Web of Science ID 000085936000013

    View details for PubMedID 10743695

  • Electrophysiological correlates of transmural linear ablation PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Liem, L. B., Pomeranz, M., Riseling, K., Anderson, S., Berry, G. J. 2000; 23 (1): 40-46


    The purpose of this study is to describe the characteristics of lesions created using radiofrequency (RF) energy delivered through a saline/foam electrode that is designed to simplify ablation of the isthmus between the tricuspid annulus (TA) and the inferior vena cava (IVC). We compared the changes in the electrophysiological parameters produced by the ablation to histological findings. In search of a more practical and effective atrial flutter ablation method, various energy modifications and catheter designs have been tested. It was shown that the efficiency of RF ablation could be improved using an endocardial cooled catheter; resulting in increased lesion size. Thus, we postulate that a similar advantage of the cooled catheter system would allow efficient RF delivery through specially designed long foam electrodes, therefore improving the practicality of TA-IVC isthmus ablation for atrial flutter. The study was performed in two acute and five subacute sheep under general anesthesia and with adequate heparinization. We used a linear ablation catheter system equipped with two 2-cm saline bipole electrode pockets with 1.5-mm separation, each consisting of two 8-mm electrodes with 1-mm spacing, allowing for bipolar pacing and recording. This saline/foam electrode pair were positioned on a support loop. RF energy was applied to the saline electrodes at 50 watts for 90 seconds with a saline flow rate of 0.4 mL/s. Bipolar atrial signal amplitude and pacing thresholds were measured before and after ablation. If necessary, the catheter was pulled back and additional ablation was applied to any viable tissue. Transisthmus ablations were created with a single catheter positioning in five sheep using both saline electrodes in four and one electrode in the other. Pullback and additional ablation to one saline electrode was required in two sheep; in one after RF was delivered to only one electrode. After ablation, atrial signal amplitude was reduced by an average of 76% (range 51%-92%) and its pacing threshold was increased by an average of 617% (range 150%-400%). Transmural lesions were found in all sheep, measuring 8-20 mm in length, 4-10 mm in width, and 1.5-2.0 mm in depth. No charring, coagulum, or remote structural damage was found in any preparation. Continuous transmural TA-IVC isthmus lesions could be produced with stationary RF linear ablation using a saline/foam electrode catheter system. This system allowed for assessment of electrophysiological parameters that correlated with complete necrosis.

    View details for Web of Science ID 000084952100007

    View details for PubMedID 10666752

  • CD4(+) T helper cells engineered to produce latent TGF-beta 1 reverse allergen-induced airway hyperreactivity and inflammation JOURNAL OF CLINICAL INVESTIGATION Hansen, G., McIntire, J. J., Yeung, V. P., Berry, G., Thorbecke, G. J., Chen, L. Z., DeKruyff, R. H., Umetsu, D. T. 2000; 105 (1): 61-70


    T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.

    View details for Web of Science ID 000084579300009

    View details for PubMedID 10619862

  • Feasibility of in vivo intravascular ultrasound tissue characterization in the detection of early vascular transplant rejection CIRCULATION Jeremias, A., Kolz, M. L., Ikonen, T. S., Gummert, J. F., Oshima, A., Hayase, M., Honda, Y., Komiyama, N., Berry, G. J., Morris, R. E., Yock, P. G., Fitzgerald, P. J. 1999; 100 (21): 2127-2130


    Unprocessed ultrasound radiofrequency (RF) signal analysis has been shown to distinguish different tissue structures more reliably than gray-scale interpretation of conventional ultrasound images.The objective of this study was to test the feasibility of in vivo intravascular ultrasound (IVUS) RF signal analysis in an animal model of allograft rejection. Six cynomolgus monkeys underwent transplantation of 3-cm aortic allograft segments distal to the renal arteries from immunologically mismatched donors. IVUS imaging with a 30-MHz system was performed 84 to 105 days after the operation. RF signals were acquired from cross sections of the recipient and the allograft aortas in real time with a digitizer at 500 MHz with 8-bit resolution. Sixty-five cross sections and 68 regions of interest (31 in host aorta and 37 in allograft) were analyzed in the adventitial layer with a total number of 8568 vectors processed. For each region of interest, a weighted-average attenuation was calculated on the basis of the attenuation and length for each individual vector. Histological examination was performed at every cross section imaged by IVUS. When the gray-scale images of conventional IVUS scored by an independent observer were compared, no distinction between adventitia of the native aorta and allograft was possible. Analysis of the average RF backscatter power also showed no significant difference (70.32+/-3.55 versus 70.72+/-3.38 dB). However, the average attenuation of allografts was significantly lower than that of the host aortas (2.64+/-1.38 versus 4.02+/-1.16 dB/mm, P<0.001). Histology demonstrated a marked adventitial inflammatory response in all allografts, with no inflammation observed in the host aortas.In vivo IVUS tissue characterization can be performed during routine imaging. In this model of transplant vasculopathy, RF attenuation measurements were more sensitive than visual or quantitative gray-scale analysis.

    View details for Web of Science ID 000083945000005

    View details for PubMedID 10571969

  • Mitral annular dilatation and papillary muscle dislocation without mitral regurgitation in sheep. Circulation Green, G. R., Dagum, P., Glasson, J. R., Daughters, G. T., Bolger, A. F., Foppiano, L. E., Berry, G. J., Ingels, N. B., Miller, D. C. 1999; 100 (19): II95-102


    Asymmetrical mitral annular (MA) dilatation and papillary muscle dislocation are implicated in the pathogenesis of functional mitral regurgitation (MR).To determine the mechanism by which annular and papillary muscle geometric alterations result in MR, we implanted radiopaque markers in the left ventricle, mitral annulus, anterior and posterior mitral leaflets, and papillary muscle tips and bases in 2 groups of sheep. One group served as controls (CTL, n=7); an experimental group (EXP, n=9) underwent topical phenol application to obliterate anterior annular and leaflet muscle (confirmed histologically ex vivo). After 1 week of recovery, markers were imaged with biplane videofluoroscopy, and hemodynamic data were recorded. MA area (computed from 3-dimensional marker coordinates) was 11% to 13% larger in the EXP group than in the CTL group (P<0.05 by ANOVA). This area increase resulted exclusively from intercommissural axis increase except in 1 heart with large (>1 cm) increases in both the intercommissural and septolateral annular axes. The anterior papillary muscle tip in EXP was displaced from CTL by 2.9+/-0.23 mm toward the anterolateral left ventricle and 2.5+/-0.12 mm toward the mitral annulus at end systole; the posterior papillary muscle geometry was unchanged. Transthoracic echocardiography revealed MR only in the heart exhibiting biaxial annular enlargement.MA dilatation in the intercommissural dimension with anterior papillary muscle tip displacement toward the annulus is insufficient to produce MR in sheep. Functional MR may require MA dilatation in the septolateral axis, as observed with proximal circumflex coronary occlusion.

    View details for PubMedID 10567285

  • Mitral annular dilatation and papillary muscle dislocation without mitral regurgitation in sheep CIRCULATION Green, G. R., Dagum, P., Glasson, J. R., Daughters, G. T., Bolger, A. F., Foppiano, L. E., Berry, G. J., Ingels, N. B., Miller, D. C. 1999; 100 (19): 95-102
  • Superior vena cava syndrome caused by pulmonary artery sarcoma JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Faul, J. L., Wahl, T., Ihnken, K., Berry, G. J., Doyle, R. L., Whyte, R. I. 1999; 118 (4): 749-750

    View details for Web of Science ID 000083129400034

    View details for PubMedID 10504645

  • Constrictive pericarditis due to coccidiomycosis ANNALS OF THORACIC SURGERY Faul, J. L., Hoang, K., Schmoker, J., Vagelos, R. H., Berry, G. J. 1999; 68 (4): 1407-1409


    Coccidiomycosis is a fungal infection that rarely causes cardiac disease. Constrictive pericarditis in the setting of disseminated coccidiomycosis can be fatal, despite antifungal therapy and pericardiectomy. We report on a patient with constrictive pericarditis due to localized infection by Coccidioides immitis. The patient underwent successful surgical pericardiectomy and antifungal chemotherapy, and remains well 1 year later.

    View details for Web of Science ID 000083265800076

    View details for PubMedID 10543521

  • The histology of subcutaneously implanted donor bronchial rings correlates with rejection scores of lung allografts in a primate lung transplant model JOURNAL OF HEART AND LUNG TRANSPLANTATION Hausen, B., Berry, G. J., Dagum, P., Ikonen, T., Christians, U., Briffa, N., Hook, L., Morris, R. E. 1999; 18 (7): 714-724


    The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information.Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression.In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage.The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.

    View details for Web of Science ID 000081667900013

    View details for PubMedID 10452349

  • Coadministration of neoral and the novel rapamycin analog, SDZ RAD, to rat lung allograft recipients - Potentiation of immunosuppressive efficacy and improvement of tolerability by staggered versus simultaneous treatment 17th Annual Meeting of the American-Society-of-Transplant-Physicians Hausen, B., Boeke, K., Berry, G. J., Segarra, I., Benet, L. Z., Christians, U., Morris, R. E. LIPPINCOTT WILLIAMS & WILKINS. 1999: 956–62


    Neoral and rapamycin derivative (RAD) have complementary mechanisms for inhibition of lymphocyte activation and are substrates for the same pathways of drug metabolism. Therefore, we investigated treatment regimens designed to minimize pharmacokinetic interactions and to potentiate immunosuppressive efficacy in a highly stringent rat lung allograft model.Lewis recipients of Brown Norway lungs received the following daily oral doses: (A) RAD at 2.5 mg/kg (n=9); (B) Neoral at 7.5 mg/kg (n=8); (C) RAD at 2.5 mg/kg + Neoral at 7.5 mg/kg simultaneously (n=8); or (D) RAD at 2.5 mg/kg + Neoral at 7.5 mg/kg (n=6) staggered 6 hr apart. Rats were assessed by daily weights, chest radiographs, drug trough levels (high-performance liquid chromatography/mass spectrometry), and blinded scoring of graft histology at death (day 21).Radiographs were completely opacified in all grafts of control and RAD monotherapy groups on days 7 and 14, respectively. Grafts were mildly opacified (Neoral monotherapy) and completely clear (both RAD + Neoral groups) on day 21. Simultaneous or staggered combined treatment dramatically reduced histologic rejection compared with treatment with either drug alone. Simultaneous treatment caused poor tolerability (poor grooming, lethargy) and significantly higher day-14 RAD and cyclosporine (CsA) trough levels (49+/-5 and 638+/-106 ng/ml; P<0.04) than in the staggered group (28+/-3 and 318+/-25 ng/ml) in which all animals were clinically normal. RAD and CsA day-14 trough levels in the staggered group were the same or lower than trough levels in animals treated with either drug alone (RAD 27+/-3/Neoral 815+/-67 ng/ml).(1) Administration of RAD + Neoral suppressed lung rejection more effectively than treatment with either drug alone. (2) Trough levels did not differ between monotherapy and staggered combination therapy for RAD but were lower for CsA. These results suggested that pharmacological, rather than pharmacokinetic, interactions between the parent drugs were responsible for the potentiation of immunosuppression when these drugs were coadministered. 3) Staggered administration of RAD+Neoral avoided the pharmacokinetic interactions that caused the elevated drug blood levels and poor tolerability caused by simultaneous administration. Thus, we could potentiate efficacy and improve tolerability by staggering administration of RAD and Neoral.

    View details for Web of Science ID 000079910700005

    View details for PubMedID 10221478

  • Chronic rejection in non-human primates: Sirolimus (rapamycin), but not cyclosporin, prevents graft vascular disease (GVD) in aortic allografts alter acute rejection. Ikonen, T. S., Gummert, J. F., Hayase, M., Honda, Y., Kobayashi, Y., Christians, U., Hausen, B. A., Berry, G. J., Yock, P. G., Morris, R. E. LIPPINCOTT WILLIAMS & WILKINS. 1999: S252–S252
  • Recurrent Pneumocystis carinii colonization in a heart-lung transplant recipient on long-term trimethoprim-sulfamethoxazole prophylaxis JOURNAL OF HEART AND LUNG TRANSPLANTATION Faul, J. L., Akindipe, O. A., Berry, G. J., Doyle, R. L., Theodore, J. 1999; 18 (4): 384-387


    In the setting of organ transplantation, prior to prophylaxis, Pneumocystis carinii pneumonia (PCP) had been a common clinical problem, particularly in heart-lung and lung recipients who receive long-term immunosuppressive therapy to prevent allograft rejection. Continuous oral trimethoprim-sulfamethoxazole (TMP-SMX) has been highly effective in preventing PCP in these patients.In this paper we report a case of recurrent Pneumocystis carinii infection in a chronic (> 15 years) heart-lung allograft recipient on long-term TMP-SMX prophylaxis. Twice, in 1995 and again in 1998, Pneumocystis carinii infection was diagnosed by bronchoalveolar lavage (BAL), in the same patient, despite continued oral TMP-SMX (960 mg TMP/4800 mg SMX per week) prophylaxis. The subject was not lymphopenic (his CD4 count was 569/mm3) and there was no associated deterioration in pulmonary function, nor evidence of hypoxemia.This case demonstrates that asymptomatic Pneumocystis carinii lung infections may recur in chronic heart-lung transplant recipients who take standard oral PCP prophylaxis.

    View details for Web of Science ID 000079923800017

    View details for PubMedID 10226906

  • Quality of computer enhanced totally endoscopic coronary bypass graft anastomosis - comparison to conventional technique EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Falk, V., Gummert, J. F., Walther, T., Hayase, M., Berry, G. J., Mohr, F. W. 1999; 15 (3): 260-264


    Aims of the study were to develop an endoscopic technique to perform robot assisted coronary anastomoses, using a computer enhanced telemanipulator and to compare the quality of the anastomoses with those performed using a standard open technique.A surgical telemanipulator with two instrument arms and a central videoscopic arm was used to perform remote endoscopic coronary artery bypass grafting on isolated porcine hearts. The end effectors and the videoscope were placed through three 10 mm port incisions. All anastomoses (Cx to LAD) were performed using a double armed 7-0 Prolene suture of 5 or 7 cm in length. All operations were performed remotely from the master console using ten times magnification, tremor filtering and 3:1 motion scaling. Initially 20 anastomoses were performed to develop and train the technique. Then, 20 robot-assisted anastomoses (group I) were compared with 20 anastomoses using a standard open parachute technique (group II). All anastomoses were checked for patency and leakage. Patency was confirmed by bench angiography. After fixation, all anastomoses were macroscopically evaluated for patency, intactness, alignment, intimal tears and dehiscence. Both angiographic and pathologic evaluations were performed with the examiners blinded to the technique of anastomosis.In the initial feasibility series, time for anastomosis was 18.2 +/- 9.1 min. All anastomoses were patent although minor stenoses were found in two and minor leakage was noted in five anastomoses. In the second series all anastomoses were patent, not leaking and showed a good run-off at angiography. Mean time for anastomosis in group I was 12.8 +/- 2.4 min as compared with 6.3 +/- 0.2 min in group II (P < 0.001), respectively. Macroscopic analysis demonstrated equal quality for both groups. There were no stenoses, no intimal tears and no dehiscences. All anastomoses had a normal alignment and intact suture lines.Using the Intuitive surgical telemanipulator, it is possible to remotely perform endoscopic coronary anastomoses with the same quality as with an open standard technique after a brief learning curve. This will enable true endoscopic coronary artery bypass grafting with a precision that has not been achieved with any other previously applied endoscopic technique.

    View details for Web of Science ID 000079851300010

    View details for PubMedID 10333020

  • Potentiation of immunosuppressive efficacy by combining the novel leflunomide analog, HMR 279, with microemulsion cyclosporine in a rat lung transplant model TRANSPLANTATION Hausen, B., Boeke, K., Berry, G. J., Gummert, J. F., Christians, U., Morris, R. E. 1999; 67 (3): 354-359


    The novel leflunomide (LFM) analog, HMR 279, potentiates the immunosuppressive efficacy of microemulsion cyclosporine (Neoral) in rodent heart transplantation. The present study was designed to evaluate the immunosuppressive efficacy of this combination in comparison to the combination of Neoral and LFM in a stringent allogeneic rodent lung transplant model.Donor lungs from Brown Norway rats were implanted into Lewis recipients and were followed for 21 days. Postoperative monitoring included daily weight assessment, chest radiographs, drug trough levels measured by high-performance liquid chromatography (LFM/HMR 279) and high-performance liquid chromatography/mass spectrometry (Neoral), and blinded histology assessment of the transplanted lung on the day of death based on the International Society for Heart and Lung Transplantation working formulation. Untreated lung recipients served as controls (group I, n=5). Rats were assigned to the following treatment groups: II, 7.5 mg/kg/day Neoral (n=6); III, 10 mg/kg/day LFM (n=6); IV, 10 mg/kg/day HMR 279 (n=6); V, 10 mg/kg/day LFM plus 7.5 mg/kg/day Neoral given simultaneously (n=13); and VI, 10 mg/kg/day HMR 279 plus 7.5 mg/kg/day Neoral given simultaneously (n=6). Drugs were given daily by oral gavage.All rats except for one in the HMR 279 monotherapy group survived the follow-up period. The chest radiographs in the control, LFM, and HMR 279 monotherapy groups showed moderate to complete opacification of the left chest by postoperative day 7 (controls) and day 14 (LFM, 279). At postoperative day 21, the Neoral monotherapy and the combination groups showed no signs of opacification in the radiographs. Combination therapies of Neoral plus HMR 279 or Neoral plus LFM were most successful in preventing histologic allograft rejection. Combining Neoral and HMR 279 resulted in a significant decrease in the cyclosporine trough levels. Co-administration of LFM plus Neoral resulted in significantly higher LFM trough levels when compared to LFM monotherapy. Of all treatments studied, the combination of HMR 279 plus Neoral was tolerated best as assessed by percentage of weight change.This study showed for the first time in a stringent rodent lung transplant model that combined treatment of LFM or HMR 279 plus Neoral potentiates the immunosuppressive efficacies of these drugs and successfully prevents allograft rejection.

    View details for Web of Science ID 000078730800003

    View details for PubMedID 10030278

  • Suppression of acute rejection in allogeneic rat lung transplantation: A study of the efficacy and pharmacokinetics of rapamycin derivative (SDZ RAD) used alone and in combination with a microemulsion formulation of cyclosporine JOURNAL OF HEART AND LUNG TRANSPLANTATION Hausen, B., Boeke, K., Berry, G. J., Segarra, I., Christians, U., Morris, R. E. 1999; 18 (2): 150-159


    The novel immunosuppressant SDZ RAD, 40-0 (2-hydroxyethyl)rapamycin, is an orally active rapamycin analogue developed for use in combination with cyclosporine (Neoral). The present study was designed to evaluate the efficacy of SDZ RAD, Neoral, or a combination of both drugs for suppression of acute rejection in an allogeneic, unilateral rat lung transplant model.Brown-Norway (RT1n) donor lungs were implanted into Lewis (RT1l) recipients that were observed for 21 days. Postoperative evaluation included daily weights, serial chest radiographs, drug trough levels, and histology scores of the transplanted lung on the day of sacrifice. Treatment groups were comprised of rats treated orally with the RAD vehicle as controls (n = 6); SDZ RAD 2.5 mg/kg/day (n = 9); Neoral 7.5 mg/kg/day (n = 8); Neoral 2.5 mg/kg/day (n = 6); SDZ RAD 2.5 mg/kg/day plus Neoral 7.5 mg/kg/day (n = 7); and Neoral 2.5 mg/kg/day plus SDZ RAD 2.5 mg/kg/day (n = 6).The results of this study showed that neither monotherapy with 2.5 mg/kg/day of Neoral, nor 2.5 mg/kg/day of SDZ RAD prevented severe acute rejection in unilateral lung transplant recipients. Furthermore, despite high dose (7.5 mg/kg/day) Neoral treatment, graft histology showed moderate rejection. However, addition of 2.5 mg/kg/day of SDZ RAD to 7.5 mg/kg/day of Neoral completely prevented histologic rejection in four of seven grafts, although the remaining 3 grafts showed minimal rejection. This combination resulted in significantly higher RAD trough levels when compared to SDZ RAD treatment alone. Combining a lower dose of Neoral (2.5 mg/ kg/day) with 2.5 mg/kg/day of SDZ RAD resulted in less weight loss and improved animal health; however, the histology of lung grafts in these rats showed mild rejection.This is the first study on the efficacy of the novel rapamycin derivative SDZ RAD for the control of acute lung allograft rejection. Results showed that acute unilateral rat lung allograft rejection is refractory to monotherapy with either high dose Neoral or SDZ RAD. The two regimens of combined treatment with Neoral plus SDZ RAD used in these studies produced either minimal rejection and reduced tolerability or mild rejection and better tolerability and showed potentiation of immunosuppression when both drugs were used together. Additional investigation of these two drugs is needed, however, to devise regimens that produce both high immunosuppressive efficacy and good tolerability.

    View details for Web of Science ID 000079340500008

    View details for PubMedID 10194039

  • Alterations in inducible nitric oxide synthase (iNOS) and nitrotyrosine (NitroY) during re-epithelialization of heterotopic rat tracheal composite grafts XVIIth World Congress of the Transplantation-Society Ikonen, T. S., Romanska, H. M., Bishop, A. E., Berry, G. J., Polak, J. M., Morris, R. E. ELSEVIER SCIENCE INC. 1999: 182–82

    View details for Web of Science ID 000078960600076

    View details for PubMedID 10083067

  • Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation JOURNAL OF CLINICAL INVESTIGATION Hansen, G., Berry, G., DeKruyff, R. H., Umetsu, D. T. 1999; 103 (2): 175-183


    Allergic asthma, which is present in as many as 10% of individuals in industrialized nations, is characterized by chronic airway inflammation and hyperreactivity induced by allergen-specific Th2 cells secreting interleukin-4 (IL-4) and IL-5. Because Th1 cells antagonize Th2 cell functions, it has been proposed that immune deviation toward Th1 can protect against asthma and allergies. Using an adoptive transfer system, we assessed the roles of Th1, Th2, and Th0 cells in a mouse model of asthma and examined the capacity of Th1 cells to counterbalance the proasthmatic effects of Th2 cells. Th1, Th2, and Th0 lines were generated from ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic mice and transferred into lymphocyte-deficient, OVA-treated severe combined immunodeficiency (SCID) mice. OVA-specific Th2 and Th0 cells induced significant airway hyperreactivity and inflammation. Surprisingly, Th1 cells did not attenuate Th2 cell-induced airway hyperreactivity and inflammation in either SCID mice or in OVA-immunized immunocompetent BALB/c mice, but rather caused severe airway inflammation. These results indicate that antigen-specific Th1 cells may not protect or prevent Th2-mediated allergic disease, but rather may cause acute lung pathology. These findings have significant implications with regard to current therapeutic goals in asthma and allergy and suggest that conversion of Th2-dominated allergic inflammatory responses into Th1-dominated responses may lead to further problems.

    View details for Web of Science ID 000078247400004

    View details for PubMedID 9916129

  • The use of technetium Tc 99m annexin V for in vivo imaging of apoptosis during cardiac allograft rejection 78th Annual Meeting of the American-Association-for-Thoracic-Surgery Vriens, P. W., Blankenberg, F. G., Stoot, J. H., Ohtsuki, K., Berry, G. J., Tait, J. F., Strauss, H. W., Robbins, R. C. MOSBY-ELSEVIER. 1998: 844–52


    Apoptosis, or programmed cell death, has been suggested as a mechanism of immunologic injury during cardiac allograft rejection. We tested the hypothesis that technetium Tc 99m annexin V, a novel radiopharmaceutical used to detect apoptosis, can be used to detect cardiac allograft rejection by nuclear imaging.Untreated ACI rats served as recipients of allogeneic PVG rat (n = 66) or syngeneic ACI rat (n = 30) cardiac grafts. Untreated recipient animals underwent 99mTc-annexin V imaging daily for 7 days. Region of interest analysis was used to quantify the uptake of 99mTc-annexin V. Immediately after imaging grafts were procured for histopathologic analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling of apoptotic nuclei. One group was treated with 10 mg/kg/d cyclosporine (INN: ciclosporin) commencing on day 4 after transplantation (n = 6).Untreated allografts showed histologic signs of rejection 4 days after transplantation. Apoptotic nuclei could be demonstrated in myocytes, endothelial cells, and graft-infiltrating cells of all rejecting allografts. Nuclear imaging revealed a significantly greater uptake of 99mTc-annexin V in rejecting allogeneic grafts than in syngeneic grafts on day 4 (P = .05), day 5 (P < .001), day 6 (P < .001), and day 7 (P = .013) after transplantation. A correlation between the histologic grade of acute rejection and uptake of 99mTc-annexin V was observed (r2 = 0.87). After treatment of rejection with cyclosporine, no apoptotic nuclei could be identified in allografts and uptake of 99mTc-annexin V decreased to baseline.Apoptosis occurs during acute cardiac allograft rejection and disappears after treatment of rejection. 99mTc-annexin V can be used to detect and monitor cardiac allograft rejection.

    View details for Web of Science ID 000076693300031

    View details for PubMedID 9806391

  • Sirolimus (rapamycin) reverses the progression of graft vascular disease in primate aortic allografts Ikonen, T. S., Gummert, J. F., Honda, Y., Hayase, M., Kobayashi, Y., Hausen, B., Barlow, C. W., Perlroth, J. D., Berry, G. J., Yock, P. G., Morris, R. E. LIPPINCOTT WILLIAMS & WILKINS. 1998: 751–51
  • The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin ANNALS OF ONCOLOGY Berry, G., Billingham, M., Alderman, E., Richardson, P., Torti, F., Lum, B., Patek, A., Martin, F. J. 1998; 9 (7): 711-716


    Pegylated liposomal doxorubicin (PL-DOX) has been shown in preclinical models to induce less cardiotoxicity than non-liposomal doxorubicin. Endomyocardial biopsy is a highly sensitive and specific method for detecting anthracycline-induced cardiac damage.Myocardial tissue from ten KS patients who had received cumulative PL-DOX (20 mg/m2/biweekly) of 440-840 mg/m2 was evaluated for evidence of anthracycline-induced cardiac damage. Controls were assembled from patients who had received cumulative doxorubicin doses of 174-671 mg/m2 in two earlier cardiac biopsy protocols. Two control groups were selected on the basis of both cumulative (+/- 10 mg/m2) and peak doxorubicin dose (60 or 20 mg/m2, control group 1), or peak dose alone (20 mg/m2, control group 2).PL-DOX patients had significantly lower biopsy scores compared with those of doxorubicin controls despite higher cumulative doses of anthracycline. The median biopsy scores for the PL-DOX and doxorubicin groups, respectively, were 0.3 vs. 3.0 (P = 0.002, Cochran-Mantel-Haenszel row mean difference test) for group 1 and 1.25 for group 2 (P < 0.001, Wilcoxon rank-sum test).Less severe cardiac changes were seen in patients given PL-DOX relative to historical control patients given comparable cumulative doses of doxorubicin.

    View details for Web of Science ID 000075448300008

    View details for PubMedID 9739435

  • Enhancement of obliterative airway disease in rat tracheal allografts infected with recombinant rat cytomegalovirus JOURNAL OF HEART AND LUNG TRANSPLANTATION Reichenspurner, H., Soni, V., Nitschke, M., Berry, G. J., Brazelton, T., Shorthouse, R., Huang, X. F., Boname, J., Girgis, R., Raitz, B. A., Mocarski, E., SANDFORD, G., Morris, R. E. 1998; 17 (5): 439-451


    Cytomegalovirus infection has been identified as a significant risk factor for the development of obliterative bronchiolitis in human lung transplant recipients. This study was designed to assess the influence of rat cytomegalovirus (RCMV) on the pathogenesis and development of obliterative bronchiolitis in an experimental model of obliterative airway disease, which occurs after allogenic heterotopic tracheal transplantation in rodents.Sixty Lewis rats were infected intraperitoneally with 10(7) plaque-forming units of recombinant lac-Z-tagged RCMV expressing the gene for beta-galactosidase. Rats were either infected at the time of surgery (acute infection, n = 30) or 56 days before surgery (chronic infection, n = 30). Tracheae from Brown Norway (allograft) or Lewis (isograft) rats were implanted and wrapped in the greater omentum of infected Lewis rats. RCMV infection was verified in different recipient tissues by in vitro plaque-assays and by direct in situ staining for beta-galactosidase activity. The tracheal grafts were harvested on days 7, 14, and 21 after transplantation and stained with hematoxylin-eosin and Masson's trichrome. The peritracheal cellular inflammation was scored visually. The cellular density of the infiltrating cells and the extent of airway obliteration were analyzed by use of computer-digitized morphometry and compared with uninfected allografts as control.Both acute and chronic cytomegalovirus infection produced significantly higher mononuclear cell density values on days 7 and 14 compared with noninfected controls, indicating a more intense immune response in the infected allografts. Tracheal allograft obliteration was also more extensive after acute and, in particular, after chronic cytomegalovirus infection (64% narrowing after 21 days compared with 36% in grafts from noninfected control animals).Our experimental results provide direct evidence that the tracheal grafts were infected with RCMV and that the development of obliterative airway disease was enhanced in the acutely and chronically infected allografts compared with grafts from noninfected control animals.

    View details for Web of Science ID 000073855800001

    View details for PubMedID 9628562

  • Bronchiolitis obliterans after lung transplantation - Detection using expiratory HRCT CHEST Leung, A. N., Fisher, K., Valentine, V., Girgis, R. E., Berry, G. J., Robbins, R. C., Theodore, J. 1998; 113 (2): 365-370


    The objective of this study was to determine if air trapping, as detected on expiratory high-resolution CT (HRCT), is useful as an indicator of bronchiolitis obliterans (BO) in lung transplant recipients. MATERIALS andCorresponding inspiratory and expiratory HRCT images at five different levels and spirometry were obtained in 21 lung transplant recipients. Eleven patients had BO proved by transbronchial biopsy specimens; the remaining 10 patients had no pathologic or functional evidence of airways disease. Two "blinded" observers assessed the inspiratory images for the presence of bronchiectasis and mosaic pattern of lung attenuation, and the expiratory images for presence and extent of air trapping. Statistical comparison of the frequency of HRCT findings between patients with and without BO was performed using Fisher's Exact Test.On inspiratory images, bronchiectasis and mosaic pattern of lung attenuation were present in 4 (36%) and 7 (64%) of 11 patients with BO, and 2 (20%) and 1 (10%) of 10 patients without BO (p>0.05 and p<0.05), respectively. The sensitivity, specificity, and accuracy of bronchiectasis and mosaic pattern for BO were 36%, 80%, and 57%, and 64%, 90%, and 70%, respectively. On expiratory images, air trapping was found in 10 of 11 (91%) patients with BO compared to 2 of 10 (20%) patients without BO (p<0.002). Air trapping was found to have a sensitivity of 91%, specificity of 80%, and accuracy of 86% for BO. Air trapping was identified in one patient with BO who had normal results of baseline spirometric function tests.Air trapping, as detected on expiratory HRCT, was the most sensitive and accurate radiologic indicator of BO in the lung transplant population.

    View details for Web of Science ID 000072002900022

    View details for PubMedID 9498953

  • Validity of clinic biopsy specimens in classifying histopathologic characteristics of recurrent nasopharyngeal carcinoma ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY Brown, J. J., Berry, G. J., Moretto, J., KEATING, W. F., Fee, W. E. 1997; 123 (9): 950-955


    To evaluate nasopharyngeal carcinoma resection specimens for heterogeneity of histologic patterns to determine if preoperative histologic characteristics of the clinic biopsy specimen are representative of the entire lesion. The null hypothesis is that clinic biopsy specimens are not necessarily representative.Preoperative clinic biopsy specimens were measured to calculate their average size. Resection specimens were then sectioned and evaluated in increments corresponding to this size. Each of these increments was then histologically classified according to the World Health Organization (WHO) criteria. This classification of the preoperative biopsy specimens was compared with that of the resection specimen as a whole.University referral center.Twenty-six consecutive patients with recurrent nasopharyngeal carcinoma who underwent surgical resection. Radiation therapy failed in all patients.The presence or absence of WHO histologic heterogeneity in the nasopharyngectomy specimen was recorded. Disparity between preoperative clinic biopsy and resection specimens was recorded.The mean clinic biopsy specimen size was 13.9 mm2 or less than 1% of the available surface area of the nasopharynx. Of 26 resection specimens classified in 5 increments of this size, 15 (57.7%) were a single WHO type, and 11 (42.3%) were found to be mixtures of WHO types I, II, and III. Of 16 cases with preoperative biopsy specimens available, 4 (25%) were a different WHO classification than their corresponding resection specimen.Most clinic biopsy specimens were representative of their corresponding tumor resection specimens in their entirety; however, tumor heterogeneity is such that some biopsy specimens will not be representative. This finding may interfere with WHO classification data determined on the basis of clinic biopsy specimens and hence confound any meaningful data on treatment outcomes. It is recommended then that multiple nasopharyngeal biopsy specimens be obtained from disparate areas of the lesion and each subjected to independent histopathologic review.

    View details for Web of Science ID A1997XX18900008

    View details for PubMedID 9305245

  • Obliterative airway disease after heterotopic tracheal xenotransplantation: Pathogenesis and prevention using new immunosuppressive agents TRANSPLANTATION Reichenspurner, H., Soni, V., Nitschke, M., Berry, G. J., Brazelton, T. R., Shorthouse, R., Huang, X. F., Reitz, B. A., Morris, R. E. 1997; 64 (3): 373-383


    The purpose of this study was to investigate whether obliterative bronchiolitis might occur after xenogenic pulmonary transplantation. A model for obliterative airway disease (OAD) after tracheal allograft transplantation in the rat undergoes tracheal obliteration with histologic features characteristic of obliterative bronchiolitis in human lung transplant recipients. Using this model, the pathogenesis of OAD and its prevention with immunosuppressive drugs was studied in rat recipients of hamster tracheal grafts.Tracheae from 30 hamsters (xenografts) or 23 Brown-Norway rats (allografts) were implanted and wrapped in the greater omentum of untreated Lewis rats. The grafts were removed on day 1, 3, 7, 14, 21, or 28 after transplantation and stained with hematoxylin and eosin and Masson's trichrome and by immunohistochemistry and immunofluorescence (IFL) techniques. In addition, 25 recipients were treated with cyclosporine (CsA, 10 mg/kg p.o.), leflunomide (LFM, 20 mg/kg p.o.), or rapamycin (RPM, 6 mg/kg i.p.) for 14 or 21 days (5 animals per treatment group). Visual and morphometric analyses were used to evaluate the extent of airway obliteration, luminal coverage by respiratory or flattened cuboidal epithelium, and extent and density of peritracheal cellular inflammation.In all xenografts, a neutrophilic infiltration of the mucosa and submucosa was observed from day 1 until day 14 and was associated with complete loss of tracheal epithelium by day 14. A marked peritracheal mononuclear cellular infiltrate mixed with plasma cells and eosinophils was seen on days 7 and 14. Both the extent of peritracheal inflammation and the density of the mononuclear cell infiltrate were significantly increased in xenograft tracheae when compared with the allografts. Tracheal obliteration began on day 14 and reached a maximum of 43% on day 21 with evidence of intraluminal fibrosis. In contrast to IFL of allografts, IFL of xenografts demonstrated marked deposition of rat immunoglobulin in the peritracheal tissue on days 7 and 14. The effects of treatment with immunosuppressive drugs on tracheal graft narrowing and protection of respiratory epithelium were as follows: After 14 days of treatment, the percentage of tracheal graft narrowing was 12%, 23%, and 19% in the no treatment, CsA, and LFM groups, respectively; the percentage of respiratory epithelium at 14 days was 0%, 21%, and 95%. After 21 days of treatment, the percentage of tracheal graft narrowing was 43%, 49%, 12%, and 5% for the no treatment, CsA, LFM, and RPM groups, respectively; the percentage of respiratory epithelium at 21 days was 0%, 39%, 86%, and 0%. Using computerized morphometry, the extent and densities of the peritracheal cellular infiltrates were significantly reduced in LFM- and CsA-treated groups when compared with untreated xenograft controls. LFM and RPM, but not CsA, significantly reduced the degree of luminal obliteration compared with no treatment (P<0.05). LFM and, to a lesser extent, CsA were able to prevent the loss of normal respiratory epithelium. Analysis by IFL revealed a marked decrease in rat immunoglobulin deposition in xenografts from LFM- and RPM-treated groups compared with xenografts from CsA-treated or untreated rats.(1) OAD occurs not only after tracheal allotransplantation but also after xenotransplantation. (2) Subepithelial infiltration of neutrophils and the appearance of plasma cells and eosinophils in the peritracheal infiltrates distinguished the histology of rejected xenografts from allografts. (3) Antibody deposition was detected by IFL only in xenografts. (4) Treatment with LFM or RPM significantly decreased the severity of luminal obliteration. Importantly, LFM also prevented the loss of respiratory epithelium.

    View details for Web of Science ID A1997XR62400001

    View details for PubMedID 9275099

  • Idiopathic giant-cell myocarditis - Natural history and treatment NEW ENGLAND JOURNAL OF MEDICINE Cooper, L. T., Berry, G. J., Shabetai, R. 1997; 336 (26): 1860-1866


    Idiopathic giant-cell myocarditis is a rare and frequently fatal disorder. We used a multicenter data base to define the natural history of giant-cell myocarditis and the effect of treatment.We identified 63 patients with idiopathic giant-cell myocarditis through journal announcements and direct mailings to cardiovascular centers worldwide.The patients consisted of 33 men and 30 women with an average age of 42.6 years; 88 percent were white, 5 percent were black, 5 percent were Southeast Asian or Indian, and 2 percent were Middle Eastern. Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent), although in some cases the initial symptoms resembled those of acute myocardial infarction (4 patients). Nineteen percent had associated autoimmune disorders. The rate of survival was worse than among 111 patients with lymphocytic myocarditis in the Myocarditis Treatment Trial (P<0.001); among our patients, the rate of death or cardiac transplantation was 89 percent, and median survival was only 5.5 months from the onset of symptoms. The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001). Of the 34 patients who underwent heart transplantation, 9 (26 percent) had a giant-cell infiltrate in the transplanted heart and 1 died of recurrent giant-cell myocarditis.Giant-cell myocarditis is a disease of relatively young, predominantly healthy adults. Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed. Despite the possibility of fatal disease recurrence, transplantation is the treatment of choice for most patients.

    View details for Web of Science ID A1997XF75600003

    View details for PubMedID 9197214

  • Pulmonary tumor embolism AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Bassiri, A. G., Haghighi, B., Doyle, R. L., Berry, G. J., Rizk, N. W. 1997; 155 (6): 2089-2095

    View details for Web of Science ID A1997XD76000040

    View details for PubMedID 9196119

  • The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Hasegawa, N., Oka, Y., Nakayama, M., Berry, G. J., Bursten, S., Rice, G., Raffin, T. A. 1997; 155 (3): 928-936


    The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthine] (LSF), an inhibitor of de novo phosphatidic acid (PA) generation, on sepsis-induced acute lung injury was studied using Hanford minipigs weighing 18 to 25 kg. Sepsis was induced by an intravenous infusion of Pseudomonas aeruginosa (1 x 10(6)/colony-forming units/kg/min over 2 h). Saline was used as the control vehicle. Six groups were studied: saline control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF control group (LSF: n = 5), which received a 25-mg/kgbolus of LSF 30 min before time zero followed by continuous infusion of 10 mg/kg/h throughout the study; LSF-treated septic groups, which were treated with LSF 30 min prior to sepsis (Pre: n = 5), 1 h postonset (Post-1 h: n = 8) or h postonset (Post-2 h: n = 8) of the bacterial infusion. Hemodynamics PaO2, neutrophil counts, and plasma porcine tumor necrosis factor-alpha concentrations were monitored for 6 h. After the minipigs were killed, lung tissue was sampled to measured wet-to-dry weight ratio (W/D), tissue albumin index (TAI), thiobarbituric acid-reactive material content (TBARM), and myeloperoxidase (MPO) activity. Compared with the SALINE group, the SEPSIS group showed significant systemic hypotension, pulmonary hypertension, arterial hypoxemia, neutropenia, and increase in TNF-alpha, MPO activity, W/D, TBARM, and TAI. LSF treatment attenuated sepsis-induced pulmonary hypertension, neutropenia, and hypoxemia, and increased MPO activity and lung injury measurements in the Pre and Post-1 h groups, but its efficacy was blunted in the Post-2 h group. Plasma TNF-alpha was decreased only in the Pre group. Thus, inhibition of intracellular PA generation through de novo pathways attenuates sepsis-induced acute lung injury.

    View details for Web of Science ID A1997WN85700024

    View details for PubMedID 9117028

  • Rapamycin inhibits development of obliterative airway disease in a murine heterotopic airway transplant model TRANSPLANTATION Fahrni, J. A., Berry, G. J., Morris, R. E., Rosen, G. D. 1997; 63 (4): 533-537


    Obliterative bronchiolitis is the major cause of long-term morbidity and mortality in heart-lung and lung transplant recipients. There is presently no completely effective therapy for the treatment of obliterative bronchiolitis. We have examined the effects of rapamycin (RPM) on the development of obliterative airway disease in murine recipients of heterotopically transplanted allograft tracheas. In this model, an untreated allograft develops almost complete occlusion of the airway lumen with fibroblastic tissue and collagen scar by day 28 after transplantation. RPM administered intraperitoneally at the time of transplantation or even as late as day 14 after transplantation markedly inhibited obliteration of the airway lumen by fibroblastic tissue. Also, RPM significantly inhibited infiltration of the graft by macrophages. In the RPM-treated animals, the airway was reconstituted with an attenuated squamous epithelium rather than a normal pseudostratified epithelium. No adverse side effects were observed with RPM doses up to 12 mg/kg/ day. These findings suggest a potential role for RPM, perhaps in combination with cyclosporine, in preventing and treating obliterative bronchiolitis in heart-lung and lung allograft recipients.

    View details for Web of Science ID A1997WL85500008

    View details for PubMedID 9047146

  • Risk factors for the development of obliterative bronchiolitis after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Girgis, R. E., Tu, I. P., Berry, G. J., Reichenspurner, H., Valentine, V. G., Conte, J. V., Ting, A., Johnstone, I., Miller, J., Robbins, R. C., Reitz, B. A., Theodore, J. 1996; 15 (12): 1200-1208


    Acute rejection has emerged as an important risk factor for obliterative bronchiolitis after lung transplantation. We performed a multivariate analysis to assess the impact of additional variables.Seventy-four recipients (48 heart-lung, 18 single-lung, and 8 bilateral-lung recipients) who survived longer than 90 days and underwent transplantation more than 15 months before data analysis were included in this study. Several variables were entered into a Cox regression analysis to determine their association with the development of bronchiolitis obliterans syndrome.Bronchiolitis obliterans syndrome developed in 48 (65%) of 74 patients. Significant correlations were detected for acute rejection score, defined as the sum of pathologic grades of each separate acute rejection episode (p = 0.0004, likelihood ratio test value = 12.4) and for lymphocytic bronchiolitis (p = 0.03). In a bivariate model, episodes of organizing pneumonia and bacterial or fungal pneumonia significantly increased the likelihood ratio test value of the acute rejection score. The addition of the cytomegalovirus infection score, reflecting the frequency and severity of infection, to the combination of the acute rejection score and episodes of bacterial or fungal pneumonia resulted in a further significant increase in the likelihood ratio test value. Significant risk factors for moderate to severe stages of airflow limitation were at least one episode of acute rejection of grade > or = 2, younger recipient age, and any acute rejection episode 180 days or longer after transplantation.Increasing frequency and severity of acute rejection episodes are strongly associated with the development of bronchiolitis obliterans syndrome. Lymphocytic bronchiolitis appeared to be significant by univariate analysis, but in a two-risk factor model, it did not augment the influence of acute rejection. Organizing pneumonia, bacterial or fungal pneumonia, and increasing severity and frequency of cytomegalovirus infections potentiate the effect of acute rejection. Late episodes of acute rejection and younger recipient age increase the risk for development of advanced disease.

    View details for PubMedID 8981205

  • Increased accumulation of tissue ACE in human atherosclerotic coronary artery disease CIRCULATION Diet, F., Pratt, R. E., Berry, G. J., Momose, N., Gibbons, G. H., Dzau, V. J. 1996; 94 (11): 2756-2767


    Angiotensin may play a pathophysiological role in experimental and human cardiovascular disease. Clinical studies have shown that ACE inhibitors reduce mortality, recurrent myocardial infarction, and ischemic events in patients with left ventricular dysfunction. Animal studies suggest that tissue ACE, particularly within blood vessels, may be an important target.To study tissue ACE in human coronary artery disease and to identify potential mechanisms of ACE inhibitor action, we examined ACE expression immunohistochemically in nonatherosclerotic and diseased human coronary arteries. In nonatherosclerotic arteries, ACE immunoreactivity was found in luminal and adventitial vasa vasorum endothelium. In early- and intermediate-stage atherosclerotic lesions, ACE was detected prominently in regions of fat-laden macrophages and in association with T lymphocytes. In advanced lesions, ACE immunoreactivity was also localized to the endothelium of the microvasculature throughout the plaques. Immunoreactive angiotensin II was also detected in these areas. ACE expression in macrophages was further examined by in vitro experiments with a monocytoid cell line. ACE activity was induced threefold after differentiation of the cells into macrophages and was further increased after stimulation with acetylated LDL.These observations demonstrate that significant sources of tissue ACE in human atherosclerotic plaques are regions of inflammatory cells, especially areas of clustered macrophages as well as microvessel endothelial cells. These results suggest that ACE accumulation within the plaque may contribute to an increased production of local angiotensin that may participate in the pathobiology of coronary artery disease. Plaque ACE probably is an important target of drug action.

    View details for Web of Science ID A1996VV27400017

    View details for PubMedID 8941100

  • Pulmonary capillaritis and alveolar hemorrhage - Update on diagnosis and management CHEST Green, R. J., Ruoss, S. J., KRAFT, S. A., Berry, G. J., Raffin, T. A. 1996; 110 (5): 1305-1316


    Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.

    View details for Web of Science ID A1996VR83500037

    View details for PubMedID 8915239

  • Stanford experience with obliterative bronchiolitis after lung and heart lung transplantation 32nd Annual Meeting of the Society-of-Thoracic-Surgeons Reichenspurner, H., Girgis, R. E., Robbins, R. C., Yun, K. L., Nitschke, M., Berry, G. J., Morris, R. E., Theodore, J., Reitz, B. A. ELSEVIER SCIENCE INC. 1996: 1467–72


    Obliterative bronchiolitis (OB) is the main chronic complication after heart-lung (HLTx) and lung transplantation (LTx), limiting the long-term success of both transplant procedures.Since 1981, 135 HLTxs and 61 isolated LTxs were performed in 184 patients at Stanford University.The overall prevalence of OB in patients surviving longer than 3 months postoperatively was 64% after HLTx and 68% after LTx. The actuarial freedom from OB was 72%, 51%, 44%, and 29% at 1, 2, 3, and 5 years, respectively, after HLTx and LTx. An analysis of potential risk factors revealed that the frequency and severity of acute rejection episodes (p < 0.001) and the appearance of lymphocytic bronchiolitis on biopsy (p < 0.05) were significantly associated with the development of OB. With regard to diagnosis of OB, pulmonary function tests show early reductions of the forced expiratory flow between 25% and 75% of the forced vital capacity with subsequent decreases in the forced expiratory volume in 1 second. The sensitivity of transbronchial biopsies has increased to 71% since 1993. Current treatment consists of augmented immunosuppression. Concurrent acute rejection episodes or active OB on biopsy have been treated aggressively with high-dose steroid pulses. Analysis of data from 73 patients with OB after HLTx and LTx revealed actuarial 1-, 3-, 5-, and 10-year survival of 89%, 71%, 44%, and 17% versus 86%, 77%, 63% and 56% in patients without OB (p < 0.05 by log-rank analysis). The main complication and cause of death in patients with OB was superimposed respiratory tract infection, which was treated aggressively.Early diagnosis of OB using pulmonary function tests or transbronchial biopsy is possible and important, because immediate treatment initiation has led to acceptable survival rates, with nearly 50% of affected patients still alive 5 years after transplantation. Current experimental research on OB suggests that immune injury is the main pathogenetic event of airway obliteration in animal models; rapamycin and leflunomide are new immunosuppressive agents that may have the potential to prevent and treat airway obliteration.

    View details for Web of Science ID A1996VQ16700050

    View details for PubMedID 8893585

  • Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients JOURNAL OF HEART AND LUNG TRANSPLANTATION Soghikian, M. V., Valentine, V. G., Berry, G. J., Patel, H. R., Robbins, R. C., Theodore, J. 1996; 15 (9): 881-887


    Cytomegalovirus infection threatens pulmonary allograft survival and function. This retrospective study details the experience of ganciclovir prophylaxis against cytomegalovirus infection and its sequelae.Eight-nine lung and heart-lung transplant recipients with positive cytomegalovirus serology were analyzed. The 37 recipients who underwent transplantation before September 1989 received no prophylaxis. The 52 subsequent recipients received ganciclovir prophylaxis.Thirty-six non-prophylaxed versus 42 prophylaxed patients had cytomegalovirus events with cumulative incidences of 100% and 86% (p < < 0.01), and median onsets of 37 +/- 21 versus 85 +/- 35 days, respectively (p < < 0.01); 22 non-prophylaxed versus 27 prophylaxed patients had cytomegalovirus pneumonitis with cumulative incidences of 60% and 55% (p < < 0.01), and median onsets of 34 +/- 14 and 84 +/- 26 days, respectively (p < < 0.01). Respiratory failure caused by cytomegalovirus pneumonitis developed in nine of the non-prophylaxed versus two of the prophylaxed patients (p < < 0.01). The significant estimated survival benefit in patients who received prophylaxis (p = 0.04) was not apparent when reanalysis was performed after exclusion of patients with respiratory failure (p = 0.36). Ganciclovir prophylaxis produced a significant delay in the development of obliterative bronchiolitis with a median time to onset of 1072 +/- 280 days versus 432 +/- 189 days for the non-prophylaxis cohort (p < < 0.01).Ganciclovir prophylaxis (1) improves recipient survival by reducing the severity of disease and essentially eliminating respiratory failure caused by cytomegalovirus pneumonitis, (2) reduces the incidence and delays the onset of cytomegalovirus events and pneumonitis, and (3) delays the onset of obliterative bronchiolitis.

    View details for Web of Science ID A1996VU01300004

    View details for PubMedID 8889983

  • Port-access coronary artery bypass with cardioplegic arrest: Acute and chronic canine studies 32nd Annual Meeting of the Society-of-Thoracic-Surgeons Stevens, J. H., Burdon, T. A., Siegel, L. C., Peters, W. S., Pompili, M. F., STGOAR, F. G., Berry, G. J., Ribakove, G. H., Vierra, M. A., Mitchell, R. S., Toomasian, J. M., Reitz, B. A. ELSEVIER SCIENCE INC. 1996: 435–40


    Our goal is to perform minimally invasive coronary artery bypass grafting without sacrificing the benefits of myocardial protection with cardioplegia.Twenty-three dogs underwent acute studies and 4 dogs underwent survival studies. The left internal mammary artery was taken down using a thoracoscope. Cardiopulmonary bypass was conducted via femoral cannulas and using an endovascular balloon catheter for ascending aortic occlusion, root venting, and delivery of antegrade blood cardioplegia. Pulmonary artery venting was achieved with a jugular vein catheter. An internal mammary artery-to-coronary artery anastomosis was performed using a microscope through a 10 mm port.All animals were weaned from cardiopulmonary bypass in sinus rhythm without inotropes. Cardiopulmonary bypass duration was 104 +/- 28 minutes and aortic clamp duration was 61 +/- 22 minutes. Cardiac output and pulmonary artery occlusion pressure were unchanged. The internal mammary artery was anastomosed to the left anterior descending artery (25) or the first diagonal (2) with patency shown in 25 of 27. One dog in the survival study had a very short internal mammary artery pedicle under tension and was euthanized for excessive postoperative hemorrhage. Three weeks postoperatively the remaining dogs had angiographically patent anastomoses, normal transthoracic echocardiograms, and histologically normal healing and patent grafts.Endovascular cardiopulmonary bypass using a balloon catheter is effective in arresting and protecting the heart to allow thoracoscopic internal mammary artery-to-coronary artery anastomosis.

    View details for PubMedID 8694602

  • Obliterative airway disease after heterotopic tracheal xenotransplantation in a concordant rodent model: Pathogenesis and treatment 3rd International Congress for Xenotransplantation Reichenspurner, H., Adams, B., Soni, V., Brazelton, T., Shorthouse, R., Reitz, B. A., Berry, G. J., Morris, R. E. ELSEVIER SCIENCE INC. 1996: 729–30

    View details for Web of Science ID A1996UG38300121

    View details for PubMedID 8623368

  • Endoluminal aortic grafting: A preliminary animal study of graft healing JOURNAL OF SURGICAL RESEARCH Harris, E. J., Harris, E. J., Berry, G. J., Mitchell, R. S. 1996; 61 (2): 404-412


    Our purpose was to evaluate the placement, long term performance, and healing of a transluminally delivered endoluminal graft and attachment system, in an animal model using large adult sheep. Nineteen sheep in the weight range of 105-125 kg were entered into this study. Under fluoroscopic guidance in anesthetized animals, an endoluminal delivery system was inserted through a common femoral arteriotomy into the infrarenal aorta, and the graft and attachment system were deployed. Fixation of the proximal and distal ends of the graft to the aortic wall was achieved by hooks on the self expanding attachment system, and seated by balloon expansion. Explantation of the prosthesis was performed prior to euthanasia at 1-, 3-, and 6-month intervals. Aortograms were obtained before and after implantation and before explantation for evaluation of placement, patency, anastomotic seal, migration, and graft infolding. In situ gross examination of the prosthesis under anesthesia prior to sacrifice was performed in all animals. Histologic sections were obtained from both attachment sites ("anastomoses"), from the midgraft and hook insertion sites, and from normal aorta inferior and superior to the endoluminal prosthesis. Scanning electron microscopy was performed randomly on specimens derived from the superior and inferior anastomotic sites at each time point. Selected intervals of healing were 1 month (N=5), 3 months (N=5), and 6 months (N=8). One sheep was euthanized at 1 week due to paraplegia. At all intervals, all prostheses were patent, were well incorporated at the aortic wall-anastomotic sites, and were without mural thrombus. The attachment hooks penetrated the aortic adventitia in all animals. There was no graft migration. At one month, initial pannus formation covered the anastomoses and the entire luminal graft, yet the endothelial-like surface coverage was incomplete. At 3 months and at 6 months, the anastomoses and luminal surfaces displayed more uniform pannus and endothelial-like surface coverage. We conclude that this endoluminal delivery system, passed through a femoral arteriotomy, can effectively deploy an endoluminal graft with self expanding attachment system having consistent patency, secure fixation, and incorporation of the anastomoses with the aortic wall in this animal model.

    View details for Web of Science ID A1996TZ90100018

    View details for PubMedID 8656616

  • Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung rejection study group JOURNAL OF HEART AND LUNG TRANSPLANTATION Yousem, S. A., Berry, G. J., Cagle, P. T., CHAMBERLAIN, D., Husain, A. N., Hruban, R. H., Marchevsky, A., Ohori, N. P., Ritter, J., Stewart, S., Tazelaar, H. D. 1996; 15 (1): 1-15


    In 1990, an international grading scheme for the grading of pulmonary allograft rejection was instituted. The use of this classification has resulted in a uniformity of grading which has allowed inter-institutional collaborations and communication unique in allograft monitoring. In 1995 an expanded group of international pathologists convened and revised the original proposal. This article summarizes the updated classification for pulmonary allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates. Each grade of acute rejection should mention the presence of coexistent airway inflammation, the intensity of which may also be graded. Chronic rejection is divided into bronchiolitis obliterans--active or inactive--and vascular atherosclerosis--accelerated arterial or venous sclerosis.

    View details for Web of Science ID A1996TU97900001

    View details for PubMedID 8820078

  • Obliterative bronchiolitis after lung and heart-lung transplantation ANNALS OF THORACIC SURGERY Reichenspurner, H., Girgis, R. E., Robbins, R. C., Conte, J. V., Nair, R. V., Valentine, V., Berry, G. J., Morris, R. E., Theodore, J., Reitz, B. A. 1995; 60 (6): 1845-1853


    Obliterative bronchiolitis (OB) has emerged as the main cause of morbidity and mortality in the long-term follow-up after lung and heart-lung transplantation. The pathogenesis of OB is multifactorial, with acute rejection and cytomegalovirus infection being the main risk factors for the development of OB. The final common pathway of all inciting events seems to be an alloimmune injury, with subsequent release of immunologic mediators and production of growth factors leading to luminal obliteration and fibrous scarring of the small airways. Analyzing the 14 years of experience in 163 patients at Stanford University, we found a current incidence of bronchiolitis obliterans syndrome or histologically proven OB within the first 3 years after lung and heart-lung transplantation of 36.3%, with an overall prevalence of 58.1% after heart-lung and 51.4% after lung transplantation. Both pulmonary function indices (forced expiratory flow between 25% and 75% of forced vital capacity and forced expiratory volume in 1 second) and transbronchial biopsies have proven helpful in diagnosing bronchiolitis obliterans syndrome or OB at an early stage. Early diagnosis of OB and improved management have achieved survival rates in patients with OB after 1, 3, 5, and 10 years of 83%, 66%, 46%, and 22%, compared with 86%, 83%, 67%, and 67% in patients without OB. Recently, different experimental models have been developed to investigate the cellular and molecular events leading to OB and to evaluate new treatment strategies for this complication, which currently limits the long-term success of heart-lung and lung transplantation.

    View details for Web of Science ID A1995TV39200074

    View details for PubMedID 8787504



    Sengers' syndrome is a rare condition consisting of congenital cataracts, mitochondrial myopathy, and hypertrophic cardiomyopathy. The syndrome is transmitted in an autosomal recessive pattern. Progressive cardiac failure is the cause of death in most patients. This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome.

    View details for PubMedID 8526648

  • STUDIES IN EXPERIMENTAL-MODELS OF CHRONIC REJECTION - USE OF RAPAMYCIN (SIROLIMUS) AND ISOXAZOLE DERIVATIVES (LEFLUNOMIDE AND ITS ANALOG) FOR THE SUPPRESSION OF GRAFT VASCULAR-DISEASE AND OBLITERATIVE BRONCHIOLITIS 5th International Alexis Carrel Conference: Genesis, Prevention, Diagnosis and Treatment of Chronic Rejection, Obliterative Bronchiolitis and Graft Vessel Disease after Organ Transplantation Morris, R. E., Huang, X., Gregory, C. R., Billingham, M. E., Rowan, R., Shorthouse, R., Berry, G. J. ELSEVIER SCIENCE INC. 1995: 2068–69

    View details for Web of Science ID A1995RE11800053

    View details for PubMedID 7792888

  • ARTERIAL SWITCH AND RESECTION OF HEPATIC HEMANGIOENDOTHELIOMA ANNALS OF THORACIC SURGERY Robbins, R. C., Chin, C., Yun, K. L., Berry, G. J., Bernstein, D., Reitz, B. A. 1995; 59 (6): 1575-1577


    We report on the management of a neonate undergoing arterial switch for transposition of the great arteries and concomitant resection of a hepatic infantile hemangioendothelioma. A preoperative aortogram demonstrated the arterial supply of the hepatic hemangioendothelioma. Pulmonary artery hypertension and myocardial ischemia were noted after separation from cardiopulmonary bypass. Resection of the hepatic malformation produced an immediate reduction in pulmonary hypertension and resolution of the myocardial ischemia. The patient had an uneventful postoperative recovery.

    View details for Web of Science ID A1995RB62100052

    View details for PubMedID 7771849

  • GIANT-CELL MYOCARDITIS JOURNAL OF HEART AND LUNG TRANSPLANTATION Cooper, L. T., Berry, G. J., Rizeq, M., Schroeder, J. S. 1995; 14 (2): 394-401


    Giant cell myocarditis is a rare and frequently fatal disorder of unknown origin that is defined histopathologically as diffuse myocardial necrosis with multinucleated giant cells in the absence of sarcoidlike granulomata. The clinical and pathologic features of lymphocytic myocarditis have been described in several recent publications, but the features of idiopathic giant cell myocarditis have not been adequately addressed.We describe five patients with idiopathic giant cell myocarditis who were seen at Stanford University over the past 10 years. In each case the onset was subacute congestive heart failure. After diagnosis each patient received immunosuppressive therapy and was evaluated for heart transplantation. Progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly, two of progressive heart failure and one of sudden cause. Two patients underwent orthotopic heart transplantation and are currently alive, one with disease recurrence. Pathologic studies, including endomyocardial biopsy and evaluation of postmortem or explanted material at transplantation were reviewed. The pathologic studies provided additional support that the giant cells derive from a monocytic/histiocytic lineage. Segmental wall motion abnormalities suggest giant cell myocarditis can be a focal, as well as diffuse process at certain stages of its course. This experience is compared with published cases and implications for diagnosis and treatment are discussed.In view of the uniformly fatal nature of the disease, heart transplantation should be a serious consideration, and the patients evaluated once the diagnosis is established. Triple-drug immunosuppressive therapy should be considered at the time of diagnosis.

    View details for Web of Science ID A1995QQ92700027

    View details for PubMedID 7779862

  • Neoplastic disorders after pediatric heart transplantation. Circulation Bernstein, D., Baum, D., Berry, G., Dahl, G., Weiss, L., Starnes, V. A., Gamberg, P., Stinson, E. B. 1993; 88 (5): II230-7


    Because of their life-long requirement for immunosuppressive therapy, neoplastic disorders could represent a significant threat to long-term survival in infants and children after heart transplantation. This study determined the incidence and clinical spectrum of neoplastic disorders in 80 pediatric patients who underwent heart transplantation between 1974 and 1992.Follow-up ranged from 6 to 189 months (mean, 50.0 months). Tumors occurred in 10 patients (12.5%). Time to detection ranged from 3.3 to 139.2 months (mean, 52.7 months). Tumor incidence was greatest in 9 patients transplanted before the cyclosporine era (44%) compared with the subsequent 71 patients (8.5%, P < .05). There was no increase in risk related to sex, age, underlying disease, or blood type; however, patients with tumors received higher initial doses of cyclosporine and prednisone and had more rejection episodes in the first 3 months (P < .05). There was an increased risk associated with anti-thymocyte globulin (33%, P < .05) but not with OKT3 (6%, P = NS). There were eight lymphoproliferative disorders (four B-cell, one T-cell, three not determined) and one hepatocellular and one squamous cell carcinomas. Six cases of lymphoproliferative disorder had in situ evidence of Epstein-Barr virus. Patients were treated by reducing immunosuppression (7), radiotherapy (2), and chemotherapy (1). There were five deaths: two tumor related and the others due to rejection, renal failure, and infection. Of 5 survivors, 1 had tumor recurrence 4 years after diagnosis, and 4 are disease free.Tumors represent a small but serious long-term risk to pediatric heart transplant recipients. The incidence in children transplanted in the cyclosporine era is similar to that in adults, and the majority of tumors are lymphoproliferative disorders that often regress by reducing immunosuppression.

    View details for PubMedID 8222159

  • GRAFT CORONARY-DISEASE IN PEDIATRIC HEART AND COMBINED HEART-LUNG TRANSPLANT RECIPIENTS - A STUDY OF 15 CASES 2nd Loma Linda International Conference on Pediatric Heart Transplantation Berry, G. J., Rizeq, M. N., Weiss, L. M., Billingham, M. E. MOSBY-YEAR BOOK INC. 1993: S309–S319


    Graft coronary disease (GCD) has emerged as the most important deterrent to long-term survival in adult heart transplant recipients. The incidence, natural history, and pathobiology of GCD is less well understood in the pediatric transplant population. This study evaluated the histopathologic and immunohistochemical features of GCD in the Stanford pediatric heart and heart-lung group. Eighty-eight patients, ages 1 week to 18 years, received heart transplants between 1974 and 1992, and 15 patients, ages 1 month to 18 years received heart-lung transplants between 1981 and 1992 at Stanford University Hospital. There were 50 males and 38 females in the heart transplant group; 39 (11%) had idiopathic cardiomyopathy, 26 (30%) had congenital heart disease, 13 (15%) had viral cardiomyopathy, seven (8%) had familial cardiomyopathy, two (2%) had cardiomyopathy resulting from doxorubicin therapy, and one other case was not further delineated. In the heart-lung transplant group, there were eight males and seven females; pretransplantation diagnoses included nine (60%) with congenital heart disease and Eisenmenger's physiology, three (20%) with primary pulmonary hypertension, and one (7%) each with cystic fibrosis, bronchopulmonary dysplasia, and congenital lymphangiectasia. Fifteen (17%) of the heart transplant recipients and three (20%) of the heart-lung transplant recipients had GCD on angiographic or pathologic examination. Histopathologic samples were available on 14 cases (11 heart transplants and three heart-lung transplants).(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1993MP74800027

    View details for PubMedID 8312350



    Primary myocardial diseases in the pediatric age group encompass a variety of metabolic, infectious, congenital, and acquired disorders, one of which is "histiocytoid cardiomyopathy." We describe clinical and pathologic features in two infants. Autopsy findings in the first case were consistent with sudden cardiac death. The second infant has survived for 2 years on antiarrhythmic therapy with amiodarone. Microscopically, cells with vacuolated to granular cytoplasm were grouped in fascicles, imparting a pseudonodular appearance, but following a distribution reminiscent of conduction fibers. Ultrastructurally, the cells lack a T-tubule system, possess scattered lipid droplets and desmosomes rather than side-to-side junctions, and contain leptomeric fibrils that predominantly marginate to the cell periphery without sarcomeres. Immunostaining of paraffin-embedded tissue reveals perimembranous immunoreactivity for muscle-specific actin, but not for the histiocytic markers CD68 (KP1) and lysozyme. Immunohistochemistry may be a practical alternative when tissue is not saved for electron microscopy. The clinical and pathologic features of this disorder in light of the current literature suggest that it may be hamartoma, possibly of conduction system origin.

    View details for Web of Science ID A1993MK50900012

    View details for PubMedID 8244322



    Obliterative bronchiolitis is the most significant long-term complication of lung and heart-lung transplantation characterized by the rapid development of obstructive airway disease. It is thought to be a manifestation of chronic rejection and has been treated, with limited success, with augmentation of immunosuppression. Early detection of obliterative bronchiolitis and prompt initiation of therapy may result in an improved outcome. The role of transbronchial biopsy has been reported in the diagnosis of acute rejection and infection but not for obliterative bronchiolitis. To study this problem we retrospectively reviewed the transbronchial biopsy results of patients with advanced clinical obliterative bronchiolitis, as defined physiologically. Between January 1, 1988, and December 31, 1991, 46 "sets" of adequate transbronchial biopsy specimens were obtained from 16 patients (15 heart-lung recipients and one double lung recipient). Seven sets of transbronchial biopsy specimens (15.2%) showed obliterative bronchiolitis by pathologic study. In four patients with severe clinical obliterative bronchiolitis, only one transbronchial biopsy specimen of seven (14.3%) showed obliterative bronchiolitis. The pathologic diagnosis of obliterative bronchiolitis was confirmed in three of these patients at the time of autopsy or retransplantation. Twelve patients were still alive at the end of the study period, and all experienced further deterioration of lung function typical for obliterative bronchiolitis. We conclude that the sensitivity of transbronchial biopsy for obliterative bronchiolitis is poor. Possible explanations for these results are explored.

    View details for Web of Science ID A1993LP82800018

    View details for PubMedID 8369329


    View details for PubMedID 8390736



    Wegener's granulomatosis may present with a variety of findings and be difficult to diagnose. We report a case of a 55-year-old woman presenting with right middle lobe obstruction who was found to have limited Wegener's granulomatosis. Extensive medical evaluation was nondiagnostic and open lung biopsy specimens were required to establish the diagnosis.

    View details for PubMedID 8486064

  • THE ROLE OF TRANSBRONCHIAL BIOPSIES IN THE MANAGEMENT OF LUNG-TRANSPLANT RECIPIENTS JOURNAL OF HEART AND LUNG TRANSPLANTATION Sibley, R. K., Berry, G. J., Tazelaar, H. D., KRAEMER, M. R., Theodore, J., Marshall, S. E., Billingham, M. E., Starnes, V. A. 1993; 12 (2): 308-324


    We examined the utility of the transbronchial biopsy in the management of 53 lung transplant patients. One hundred thirty-three protocol biopsies were performed to ascertain the frequency and nature of abnormalities in clinically stable or asymptomatic patients; 128 diagnostic biopsies were performed in clinically ill patients to assess the morphologic abnormalities before the institution of therapy, and 105 biopsies were performed to assess the response to therapy. Histologic evidence of acute rejection was found in 24% of the protocol biopsies, and infection was found in 17%. Twenty-five patients with grade 1 or grade 2 perivascular infiltrates in protocol biopsies did not receive antirejection therapy. Follow-up biopsy in these patients showed spontaneous resolution of the infiltrates in 19% and increased infiltrates in 6. Only two of these patients became clinically ill, representing "progression" to clinical rejection in only 8% of the nontreated patients. Forty percent of the biopsies performed to rule out acute rejection or infection had histologic features of acute rejection, and another 23% had features of infection. Treatment of patients with clinical and histologic evidence of rejection was associated with rapid resolution of clinical symptoms in nearly 90% of the patients, but follow-up biopsies showed residual infiltrates compatible with ongoing or resolving rejection in 52%. Despite repeat antirejection therapy in some patients, these infiltrates persisted for an average of 30 days after the diagnostic biopsy. Follow-up biopsies also showed asymptomatic infection, usually cytomegalovirus pneumonitis, which often persisted for weeks despite the lack of symptoms. Perivascular infiltrates compatible with acute rejection were also found in 38% of biopsy specimens with evidence of infection. These perivascular infiltrates resolved with antibiotic treatment alone in nearly 50% of the patients with these features. Although perivascular mononuclear cell infiltrates are the cardinal histologic feature of acute rejection, similar infiltrates occur in patients who apparently have infection alone and other patients who have both infection and rejection; infiltrates compatible with minimal, mild, and moderate acute rejection also occur in clinically asymptomatic patients. These histologic findings are a challenge to both the pathologists' and the clinicians' skills in the management of the lung transplant patient.

    View details for Web of Science ID A1993KW40400020

    View details for PubMedID 8476904



    The purpose of this study was to evaluate the significance of bronchial dilatation identified on high-resolution CT scans obtained after heart-lung transplantation. Bronchial dilatation has been identified on pathologic specimens and on high-resolution CT scans of patients with severe bronchiolitis obliterans after lung transplantation, but this finding has not previously been systematically studied as a manifestation of this complication.We studied the high-resolution CT scans of 16 patients who had had heart and lung transplantation at least 1 year before, and compared the percentage of dilated bronchi with evidence of small airways disease shown on pulmonary function tests.We found a close correlation between the percentage of bronchi in the lower lobes that were dilated and the percent predicted forced expiratory volume in 1 sec, forced vital capacity, and forced expiratory flow between 25% and 75% of vital capacity. No other feature identified on high-resolution CT scans correlated with pulmonary function abnormalities.We conclude that dilatation of the lower lobe bronchi is a good indicator of bronchiolitis obliterans in this population, and that the percentage of dilated bronchi generally increases with increasing pulmonary dysfunction.

    View details for Web of Science ID A1992JJ98300003

    View details for PubMedID 1503006



    Correlation between the effective refractory period of the conduction system and the histopathologic grade of the ventricle was examined in the rat cardiac allograft during acute rejection. Lewis rats were recipients of intraabdominal heart grafts from brown Norway rats (allogeneic group, n = 42) or Lewis rats (syngeneic group, n = 15). No immunosuppressant was given. The effective refractory period of the conduction system was measured by the programmed atrial extrastimulus method (basic cycle length, 150 msec) just before the time of death. Specimens of the transplanted hearts were examined histopathologically and the histopathologic grade of rejection was scored according to the standardized grading system of the International Society for Heart and Lung Transplantation. The effective refractory period of the allogeneic heart was significantly longer starting on the third day after transplantation (p less than 0.01). The effective refractory period of the allogeneic heart was more prolonged as the severity of rejection increased. The correlation between the effective refractory period (Y) and the histopathologic grade (X) of the allogeneic group was statistically significant (r = 0.955; Y = 10.3X + 81.0; p less than 0.01). The effective refractory period of all syngeneic hearts and allogeneic hearts of postoperative day 1 and 2 were statistically equivalent to the period of native rat hearts (81.0 +/- 2.0 msec; n = 6). The histopathologic grade of the conduction system was the same as that of the ventricle. We conclude that the effective refractory period of the conduction system could be a useful measure to predict the histopathologic grade of cardiac allograft rejection.

    View details for Web of Science ID A1992HN91000008

    View details for PubMedID 1576134



    Warthin-Finkeldey polykaryocytes have been described in various benign and malignant lymphoid conditions since their initial identification in tonsils of patients in the prodromal stage of measles. However, the nature of these multinucleated giant cells is obscure. The authors studied the immunohistochemical profile of the Warthin-Finkeldey-type giant cells in three cases of lymphoid proliferations (two reactive, one neoplastic) containing many multinucleated cells using a panel of paraffin-reactive antibodies. Warthin-Finkeldey polykaryocytes demonstrated reactivity with Leu22 (CD43), anti-CD3, and OPD4, indicating that these cells are multinucleated T lymphocytes. The significance of these results with respect to the disorders in which these cells are found and their possible role in pathogenesis of disease are discussed.

    View details for Web of Science ID A1992HC49900005

    View details for PubMedID 1312298



    The expression of T-cell antigen receptor beta-chain variable genes (V beta) was evaluated in 28 cases of mycosis fungoides. A novel polymerase chain reaction (PCR) technique was used to associate expression of particular V beta genes with monoclonal T-cell populations. In addition, the same biopsies used for PCR analysis were also examined for reactivity with a panel of seven monoclonal antibodies that specifically recognized V beta proteins from four different families. Only three cases clearly stained with the antibodies, a result consistent with a diverse set of V beta genes being used. This was confirmed by PCR analysis, which indicated that V beta genes from many different families were expressed by these tumors. Preferential use of the V beta 8 family, which had been previously use of the V beta 8 family, which had been previously reported for this disease, was not evident among the cases analyzed.

    View details for Web of Science ID A1992GZ63600002

    View details for PubMedID 1731519



    Invasive aspergillosis is frequently a fatal disease in the setting of immunosuppression, including organ transplant recipients. The fungus usually affects lung parenchyma and may disseminate from there. We have recently noted tracheobronchitis in six patients with heart-lung and lung transplants, three of whom had deep mucosal ulceration and histologic evidence of invasive aspergillosis. This apparently new form of invasive disease is initially limited to the anastomosis site and large airways. Ulceration, necrosis, cartilage invasion, and formation of a pseudomembrane are the pathologic features. In two patients subsequent disseminated aspergillosis occurred with a fatal outcome. In the two single-lung recipients, disease was limited to the transplanted side emphasizing the importance of abnormal local defense mechanisms in the airways of lung transplant recipients. Routine bronchoscopic examination of the airways is important in early detection of this complication. Oral therapy with the new, antifungal agent itraconazole was successful in five of the six patients, with fatal relapse in one. A classification of the various forms of saprophytic, allergic, and invasive forms of aspergillus tracheobronchitis, to include this new entity, is proposed.

    View details for PubMedID 1654038

  • CYTOLOGY OF ANGIOSARCOMA IN EFFUSIONS ACTA CYTOLOGICA Berry, G. J., Anderson, C. J., Pitts, W. C., NEITZEL, G. F., Weiss, L. M. 1991; 35 (5): 538-542


    The cytologic and immunocytochemical findings in pleural effusions from three cases of angiosarcoma are presented. In two of the cases, the primary lesion was on the scalp; in the third case, an angiosarcoma of the small intestine developed after radiotherapy for Hodgkin's disease. Single malignant cells and small clusters of cells were seen in cytologic preparations from two cases while only single cells were seen in preparations from one case. The malignant cells had delicate, finely vacuolated cytoplasm with distinct borders. No specific morphologic features were noted. Immunoperoxidase studies revealed binding of Ulex europaeus and reactivity for vimentin in all three cases and expression of Factor VIII-related protein in two of the cases but no expression of epithelial markers. The clinical history and immunoperoxidase studies are necessary to distinguish angiosarcoma from metastatic adenocarcinoma and other malignancies in effusions.

    View details for Web of Science ID A1991GG70900011

    View details for PubMedID 1927194



    The immunohistochemical detection of PCNA/Cyclin, a nuclear protein associated with cell proliferation, represents a potentially useful tool for the study of tumor proliferative activity. Previous studies investigating the reactivity of anti-PCNA/Cyclin monoclonal antibody 19A2 have not clearly defined the population of proliferating cells with which 19A2 reacts in tissue sections. The authors describe a method for detection of PCNA/Cyclin in formalin-fixed, paraffin-embedded tissue using a routine biotin-streptavidin immunohistochemical system that employs an anti-IgM, mu-chain-specific second-stage antibody. The authors used this method to study the proliferative activity of 24 malignant lymphomas, consisting of 12 low-grade lymphomas (LGLs) and 12 intermediate-grade lymphomas (IGLs), and five reactive tonsils. 19A2 data was compared with Ki-67 labeling in frozen sections in the same group of cases. 19A2 provided easily detectable nuclear staining of proliferating cells with reactive cells demonstrating varying intensity of staining, this latter finding most likely due to the varying nuclear concentration of PCNA/Cyclin protein during the cell cycle. In tonsils, 19A2 reacted with germinal center cells and basal keratinocytes. In the malignant lymphomas, there was good correlation between 19A2 and Ki-67 data (r = 0.90, P less than 0.001). The subgroup of LGLs showed a mean PCNA/Cyclin of 26% and a mean Ki-67 of 28%. In the subgroup of IGLs, mean PCNA/Cyclin = 54% and mean Ki-67 = 59%. These results indicate that 19A2 detects a fraction of proliferating cells that is similar to that detected by Ki-67, ie, the growth fraction, and that 19A2 is a reliable marker of proliferative activity in uniformly handled, formalin-fixed, paraffin-embedded tissue.

    View details for Web of Science ID A1991FR74600018

    View details for PubMedID 1675840

    View details for PubMedCentralID PMC1886388


    View details for Web of Science ID A1991EV39100122

    View details for PubMedID 1989192


    View details for Web of Science ID A1991EV39000342

    View details for PubMedID 1703717



    The occurrence of pseudomalignant ulcerative change in seven specimens from the colon and rectum of six patients is described. In all cases, there was surface ulceration of a polypoid lesion which contained granulation tissue and acute and chronic inflammation. There was an underlying inflammatory pseudopolyp in four lesions, a juvenile polyp in one lesion, an adenomatous polyp in one lesion, and a benign retention polyp in one lesion. Within the stroma of all cases were numerous atypical cells that mimicked a malignant neoplasm. The atypical cells expressed vimentin in immunohistochemical studies; no expression of keratins, leukocyte common antigen, factor VIII, Ulex europaeus, carcinoembryonic antigen, actin, or desmin was found. Recognition of this lesion is important, as confusion with carcinoma, lymphoma, sarcoma, or a viral infection may easily occur.

    View details for Web of Science ID A1991ET39500010

    View details for PubMedID 1985079

  • A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. journal of heart transplantation Berry, G. J., Brunt, E. M., CHAMBERLAIN, D., Hruban, R. H., Sibley, R. K., Stewart, S., Tazelaar, H. D. 1990; 9 (6): 593-601

    View details for PubMedID 2277294



    We examined the chest radiography, CT, and high resolution CT (HRCT) of 14 patients with proven Pneumocystis carinii pneumonia. We compared the radiographic and HRCT patterns of abnormal lung parenchyma with histologic sections obtained in those 11 patients who had had transbronchial lung biopsies. Diffuse bilateral perihilar airspace disease was the most common radiographic pattern. Both CT and HRCT showed "ground glass" opacity in the lungs, through which the vessels remained visible in all patients. No enlarged lymph nodes or pleural effusions were seen in patients without associated lymphoproliferative disorders.

    View details for Web of Science ID A1990DZ41600014

    View details for PubMedID 2398155



    This retrospective study was performed to determine if the chest radiograph could serve as a predictor for acute lung rejection in heart-lung transplantation patients. The findings on chest radiographs were correlated with the results of transbronchial biopsies in 16 heart-lung transplantation patients. The chest radiographs immediately preceding 83 biopsies were evaluated for a variety of findings. The histopathologic results of the lung biopsies were divided into five categories: (1) acute lung rejection (n = 25); (2) suggestive, but not diagnostic, of acute lung rejection (n = 8); (3) nonspecific (n = 26); (4) infection (n = 17); and (5) normal lung (n = 9). Biopsies from two patients showed both acute lung rejection and cytomegalovirus infection and were included in both categories. These histopathologic results were then correlated with the radiologic observations. We found that the combination of septal lines and new or increasing pleural effusions, without concomitant increase in cardiac size or vascular pedicle width, or evidence of vascular redistribution, indicated acute lung rejection with a sensitivity of 68% (17/25), specificity of 90% (52/58), and overall accuracy of 83% (69/83). We conclude that the chest radiograph is a useful indicator of acute lung rejection.

    View details for Web of Science ID A1990DK48700003

    View details for PubMedID 2112858

  • THE PATHOPHYSIOLOGY OF THE ANOPHTHALMIC SOCKET .2. ANALYSIS OF ORBITAL FAT OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY Kronish, J. W., Gonnering, R. S., Dortzbach, R. K., RANKIN, J. H., Reid, D. L., Phernetton, T. M., Pitts, W. C., Berry, G. J. 1990; 6 (2): 88-95


    The pathophysiologic mechanisms responsible for the clinical features of the anophthalmic socket are poorly understood. Atrophy of orbital fat has been thought to be a major contributing cause of enophthalmos and the superior sulcus deformities that develop after enucleation, but it has never been demonstrated histopathologically or confirmed by scientific analysis. This study was undertaken to investigate the changes that occur in the orbital fat compartment of the anophthalmic socket in an animal model by measuring orbital soft tissue mass and evaluating adipocyte cell size. Instead of reduction in the tissue mass, a statistically significant greater weight of the fat and connective tissue compartment was found in the anophthalmic orbit by nearly 13% compared to the control orbit in the animals in the long-term group. No significant change in the mean maximal diameter of adipocytes developed 7 months after enucleation. These analyses do not support the concept that orbital fat atrophy or a reduction of metabolic activity occurs in the anophthalmic socket in this animal model. From these results and our previous findings that the circulation dynamics and blood flow to orbital tissues do not change after enucleation, we propose that the pathophysiologic basis of the problems associated with anophthalmos is a disturbance in the spatial architecture and interrelationships of the multiple tissue components of the orbit, not a change in the orbital blood flow or development of fat atrophy.

    View details for Web of Science ID A1990DF45900002

    View details for PubMedID 2285670



    In situ hybridization has been shown to be a useful technique for the identification of specific viruses in pathologic tissues. The authors studied 313 lung and 164 heart biopsies from 20 heart-lung recipients to assess its utility in this clinical setting, employing biotinylated probes for the cytomegalovirus, herpes simplex, and adenovirus genomes. Twenty-five lung biopsies and one heart biopsy had detectable cytomegalovirus DNA by in situ hybridization. As compared to histopathology, in situ hybridization had a sensitivity of 85% and a specificity of 99%. None of the biopsies had detectable herpes simplex or adenovirus by either in situ hybridization or routine histopathology. In situ hybridization studies may be of greatest use when the results of conventional histopathology are equivocal and in the patients with radiologic or clinical evidence of pulmonary disease.

    View details for Web of Science ID A1990DB55100014

    View details for PubMedID 2158226



    Primary spindle cell neoplasms involving hematolymphoid organs are extremely rare. We present four cases of spindle cell neoplasms of unusual phenotype arising within lymph nodes. Two of the four cases showed morphologic and immunophenotypic features suggestive of interdigitating reticulum cell lineage; these cases expressed several macrophage antigens and S-100 protein but not CD1. The other two cases showed evidence suggestive of dendritic reticulum cell lineage. Both cases expressed HLA-DR, several macrophage antigens, complement receptors C3b and C3d; one case expressed R4/23; both showed the presence of desmosomes on ultrastructural examination. A germline configuration for the immunoglobulin heavy chain and beta-T--cell receptor genes was detected in all four cases. Of the two patients in the first group, one had local recurrence of tumor; the other died of widespread metastases. Of the two patients in the second group, both are alive and well at 12 and 27 months follow-up, respectively.

    View details for Web of Science ID A1990DA42600001

    View details for PubMedID 2158241



    The insidious development of obliterative bronchiolitis after heart-lung transplantation is thought to be due to rejection and possibly infection (cytomegalovirus). To evaluate further, we prospectively managed the last 16 consecutive heart-lung transplant recipients with serial transbronchial biopsies with lavage and pulmonary function studies as part of a surveillance protocol or as dictated by clinical presentation. A total of 123 transbronchial biopsies with lavage were performed, 77 for clinical indications (group I) and 46 for routine surveillance (group II). Results of 64 (83.1%) group I biopsies were positive for rejection or infection. Thirty-one of these biopsy specimens showed signs of rejection (29 in group I and two in group II), characterized by a perivascular mononuclear infiltrate, lymphocytic bronchiolitis, and occasionally alveolar septal mononuclear infiltrate. Forty-six serial pulmonary function tests were performed. The forced expiratory volume in 1 second (percent predicted), forced expiratory flow rate between 25% and 75% of the forced vital capacity (percent predicted), and arterial oxygen tension (millimeters of mercury) were significantly reduced from baseline values during rejection episodes: forced expiratory volume in 1 second, 75.7% +/- 20.1% versus 52.7% +/- 18.3% (p less than or equal to 0.05); forced expiratory flow rate between 25% and 75% of the forced vital capacity, 97.6% +/- 30.5% versus 49.8% +/- 22.3% (p less than or equal to 0.05); and arterial oxygen tension, 92.1 +/- 8.8 mm Hg versus 71.4 +/- 18.8 mm Hg (p less than or equal to 0.05). The fall in pulmonary function was reversible with pulse methylprednisolone. Asynchronous heart and lung rejection was documented. Of the 29 episodes of pulmonary rejection, 18 (62%) occurred asynchronously. Ten of the 16 (62%) heart-lung recipients had at least one episode of cardiac rejection. Thirteen of 16 (81%) had at least one episode of lung rejection. Serial transbronchial biopsies with lavage, as dictated by pulmonary function tests and clinical status, have guided early and more specific therapy directed against rejection and infection. With early detection, small airway dysfunction has been reversible.

    View details for Web of Science ID A1989AZ79100004

    View details for PubMedID 2554067



    A case of metastatic follicular carcinoma to the iliac bone in a 78-yr-old woman is presented. Fine-needle aspiration biopsy (FNAB) smears showed numerous, cohesive tumor cell groups with moderately abundant cytoplasm and distinctive, peripherally situated pink-staining vacuoles on May-Grünwald-Giemsa stain. The presence of marginal vacuoles strongly suggested the possibility of metastatic thyroid carcinoma. Immunohistochemical studies performed on a concomitant needle core biopsy showed immunoreactivity for thyroglobulin, supporting a thyroid derivation for this metastasis. To our knowledge, this is the first reported case in which marginal vacuoles ("flame cells") have been identified in a malignant thyroid condition.

    View details for Web of Science ID A1989AB53200015

    View details for PubMedID 2776601



    Kikuchi's necrotizing lymphadenitis has now become recognized in many parts of the world as a well-defined clinicopathologic entity with a remarkable predilection for cervical lymph nodes of young women. The morphologic features encountered in lymph nodes are distinctive and should enable pathologists to establish the diagnosis with confidence. Nonetheless, this analysis of 108 cases, encountered over a 15-year period, has emphasized the difficulty that many pathologists have in recognizing this disorder, and in particular, in distinguishing it from malignant lymphoma. Although in the vast majority of cases, lymphadenopathy and other symptomatology resolves spontaneously, two of our patients, thought initially to have Kikuchi's disease, developed systemic lupus erythematosus. This raises consideration for the proposal that Kikuchi's disease may reflect a self-limited SLE-like auto-immune condition (a "forme fruste" of SLE), perhaps induced by virus-infected transformed lymphocytes. Moreover, such observations indicate that patients with Kikuchi's disease should be kept under observation for several years to ensure that they are not at risk for the development of systemic lupus erythematosus.

    View details for Web of Science ID A1988R247100003

    View details for PubMedID 3217625