Carlos Jose Suarez

All Publications

• Clinical characteristics, treatment patterns, and outcomes of cytotoxic cutaneous T-cell lymphomas. American journal of hematology Mou, E., Fernandez-Pol, S., Li, S., Rieger, K. E., Novoa, R., Suarez, C. J., Wieland, R., Weng, W., Kim, Y. H., Khodadoust, M. S. 2024

  View details for DOI 10.1002/ajh.27266

  View details for PubMedID 38391088

• Two cases of mycosis fungoides with large cell transformation with KMT2A rearrangements. Journal of hematopathology Wadsworth, P. A., Lawrence, L., Suarez, C. J., Saleem, A., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Fernandez-Pol, S. 2023; 16 (4): 227-234

  Abstract

  Cutaneous T-cell lymphomas (CTCL) are a clinically and molecularly heterogeneous class of lymphomas of the skin-homing T cell, and their genetic profiles are not fully characterized. Previously, rearrangements of the Lysine Methyltransferase 2A (KMT2A) gene have been identified as driver mutations only in acute leukemias. KMT2A plays a role in epigenetic regulation, and cancers with such rearrangements are responsive to epigenetic therapy including hypomethylating agents. Here, we report two cases of CTCL with novel genetic profiles. KMT2A rearrangements were identified in two aggressive cases of mycosis fungoides with large cell transformation. A KMT2A::DSCAML1 gene rearrangement was seen in Case 1, while a KMT2A::MAPRE1 fusion was identified in Case 2. These cases demonstrate that KMT2A rearrangements can be found in primary CTCLs rather than solely acute leukemias, illustrating the importance of correlating molecular findings with clinical and histologic features in diagnosis. Additionally, this finding suggests that the subset of CTCLs driven by aberrancy of the KMT2A pathway may be responsive to therapy with hypomethylating agents or menin inhibitors, as seen in acute leukemias.

  View details for DOI 10.1007/s12308-023-00567-2

  View details for PubMedID 38175436

  View details for PubMedCentralID 5854542

• Time to diagnosis in rapid exome/genome sequencing in the clinical inpatient setting. American journal of medical genetics. Part A Schildt, A., Stevenson, D. A., Yu, L., Anguiano, B., Suarez, C. J. 2023

  Abstract

  Exome and genome sequencing are clinically available, with many laboratories offering expedited testing (e.g., "rapid" and "ultra-rapid"). With the increase in uptake of expedited testing, there is a need for the development of inpatient protocols for best practices based on real-life data. A retrospective 2-year review (October 2019-November 2021) of the utilization of rapid exome and genome sequencing for inpatient cases at a tertiary care center using a utilization management tracking database with subsequent chart review was performed. Thirty-three expedited "rapid/priority" exome/genome tests were performed clinically. The average total turnaround time (TAT) was 17.88 days (5-43 days) with an average TAT of 13.97 days (3-41 days) for the performing laboratory. There were 5 positive diagnostic results (15.2%), 3 likely positive diagnostic results (9%), 2 noncontributory results (6%), and 26 nondiagnostic results (69.7%). Real-life data suggest that there is an approximately 3.91-day lag in getting samples to the performing laboratory. Although laboratories may advertise their expected TAT, a number of factors can potentially impact the actual time from test order placement to communication of the results for clinical use. Understanding the points of delay will enable the development of internal protocols and policies to improve time to diagnosis.

  View details for DOI 10.1002/ajmg.a.63483

  View details for PubMedID 38017634

• Diagnostic impact of RNA-based next-generation sequencing fusion panel for solid tumors: A single-institution experience. American journal of clinical pathology Fei, F., Kunder, C. A., Ho, C., Zehnder, J. L., Tomasello, G., Fung, E., Suarez, C. J. 2023

  Abstract

  Gene rearrangements frequently act as oncogenic driver mutations and determine the onset and progression of cancer. RNA-based next-generation sequencing (NGS) is being used with increasing frequency for solid tumors. The purpose of our study is to investigate the feasibility and utility of an RNA-based NGS fusion panel for solid tumors.We conducted a retrospective, single-institution review of fusion panels requested between May 2022 and March 2023. Demographic, clinical, pathologic, and molecular findings of the patients were reviewed. The utility of the RNA-based NGS fusion panel for the pathologic diagnosis of solid tumors was assessed.Our study included 345 cases, and a fusion event was identified in 24.3% (78/321) of cases. Among the 110 cases submitted for diagnostic purposes, a fusion event was detected in 42.7% (47/110) of cases. The results led to refinement or clarification of the initial diagnosis in 31.9% (15/47) of cases and agreement or support for the initial diagnosis in 59.6% (28/47) of cases. Furthermore, our study indicated that the overall cellularity (tumor and normal tissue) of the tested specimen influences the success of the testing process.In summary, this study demonstrated the feasibility and utility of an RNA-based NGS fusion panel for a wide variety of solid tumors in the appropriate clinicopathologic context. These findings warrant further validation in larger studies involving multiple institutional patient cohorts.

  View details for DOI 10.1093/ajcp/aqad148

  View details for PubMedID 38001052

• Two cases of mycosis fungoides with large cell transformation with KMT2A rearrangements JOURNAL OF HEMATOPATHOLOGY Wadsworth, P. A., Lawrence, L., Suarez, C. J., Saleem, A., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Fernandez-Pol, S. 2023

  View details for DOI 10.1007/s12308-023-00567-2

  View details for Web of Science ID 001107258900001

• Deterministic evolution and stringent selection during preneoplasia. Nature Karlsson, K., Przybilla, M. J., Kotler, E., Khan, A., Xu, H., Karagyozova, K., Sockell, A., Wong, W. H., Liu, K., Mah, A., Lo, Y. H., Lu, B., Houlahan, K. E., Ma, Z., Suarez, C. J., Barnes, C. P., Kuo, C. J., Curtis, C. 2023

  Abstract

  The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

  View details for DOI 10.1038/s41586-023-06102-8

  View details for PubMedID 37258665

  View details for PubMedCentralID 5656752

• In silico approaches to proficiency testing: Considerations for continued feasibility. The Journal of molecular diagnostics : JMD Hagemann, I. S., Zehir, A., Suarez, C. J., Furtado, L. V., Halley, J., Kane, M., Mot, N., Vasalos, P., Moncur, J. T., Konnick, E. Q. 2023

  View details for DOI 10.1016/j.jmoldx.2023.04.002

  View details for PubMedID 37088136

• Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals. American journal of human genetics Truty, R., Rojahn, S., Ouyang, K., Kautzer, C., Kennemer, M., Pineda-Alvarez, D., Johnson, B., Stafford, A., Basel-Salmon, L., Saitta, S., Slavotinek, A., Chandrasekharappa, S. C., Suarez, C. J., Burnett, L., Nussbaum, R. L., Aradhya, S. 2023

  Abstract

  DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred to for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.

  View details for DOI 10.1016/j.ajhg.2023.02.013

  View details for PubMedID 36933558

• Mutational Profiling of Epstein Barr Virus-Positive Mucocutaneous Ulcer Volaric, A., Kumar, J., Nicholas, V., Saleem, A., Suarez, C., Natkunam, Y. ELSEVIER SCIENCE INC. 2023: S1250-S1252

  View details for Web of Science ID 000990969802350

• Therapeutic Implications of Oncogenic Missense HER2 (ERBB2) Mutations in Gastric Adenocarcinoma. JCO precision oncology King, D. A., Weiel, J. J., Reyes, R., Mills, M., Itchon, A., Fisher, G. A., Ford, J. M., Suarez, C. J. 2023; 7: e2200093

  View details for DOI 10.1200/PO.22.00093

  View details for PubMedID 36787506

• A Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients with Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211). Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kunz, P. L., Graham, N. T., Catalano, P. J., Nimeiri, H. S., Fisher, G. A., Longacre, T. A., Suarez, C. J., Martin, B. A., Yao, J. C., Kulke, M. H., Hendifar, A. E., Shanks, J. C., Shah, M. H., Zalupski, M. M., Schmulbach, E. L., Reidy-Lagunes, D. L., Strosberg, J. R., O'Dwyer, P. J., Benson, A. B. 2022: 101200JCO2201013

  Abstract

  Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective responses. Retrospective and small prospective studies suggest that capecitabine and temozolomide are associated with high response rates (RR) and long progression-free survival (PFS).E2211 was a multicenter, randomized, phase II trial comparing temozolomide vs. capecitabine/temozolomide in patients with advanced low or intermediate grade pancreatic NETs. Key eligibility criteria included: progression within the preceding 12 months and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were overall survival (OS), RR, safety, and MGMT by immunohistochemistry (IHC) and promoter methylation.144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine and temozolomide (n = 72); the primary analysis population included 133 eligible patients. At the scheduled interim analysis in 1/2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for the primary endpoint (stratified log rank p = 0.022). In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42). MGMT deficiency was associated with response.The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared to temozolomide alone in patients with advanced pancreatic NETs. The median PFS and RR observed with capecitabine/temozolomide are the highest reported in a randomized study for pancreatic NETs. MGMT deficiency was associated with response and, although, routine MGMT testing is not recommended, it can be considered for select patients in need of objective response. NCT01824875.

  View details for DOI 10.1200/JCO.22.01013

  View details for PubMedID 36260828

• Colorectal cancer metastases in the liver establish immunosuppressive spatial networking between tumor associated SPP1+ macrophages and fibroblasts. Clinical cancer research : an official journal of the American Association for Cancer Research Sathe, A., Mason, K., Grimes, S. M., Zhou, Z., Lau, B. T., Bai, X., Su, A., Tan, X., Lee, H., Suarez, C. J., Nguyen, Q., Poultsides, G., Zhang, N. R., Ji, H. P. 2022

  Abstract

  The liver is the most frequent metastatic site for colorectal cancer (CRC). Its microenvironment is modified to provide a niche that is conducive for CRC cell growth.This study focused on characterizing the cellular changes in the metastatic CRC (mCRC) liver tumor microenvironment (TME).We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue and peripheral blood mononuclear cells using single cell RNA-seq (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand receptor pairs with the potential to mutually influence their gene expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking.In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene expression data. An increased proportion of TME fibroblasts was associated with a worst prognosis in these patients.We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports CRC growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune checkpoint resistant MSS tumors.

  View details for DOI 10.1158/1078-0432.CCR-22-2041

  View details for PubMedID 36239989

• Recommendations for the Use of In silico Approaches for Next Generation Sequencing Bioinformatic Pipeline Validation: A Joint Report of the Association for Molecular Pathology, Association for Pathology Informatics, and College of American Pathologists. The Journal of molecular diagnostics : JMD Duncavage, E. J., Coleman, J. F., de Baca, M. E., Kadri, S., Leon, A., Routbort, M., Roy, S., Suarez, C. J., Vanderbilt, C., Zook, J. M. 2022

  Abstract

  In silico approaches for next generation sequencing (NGS) data modeling have utility in the clinical laboratory as a tool for clinical assay validation. In silico NGS data can take a variety of forms including pure simulated data or manipulated data files in which variants are inserted into existing data files. In silico data enables simulation of a range of variants that may be difficult to obtain from a single physical sample. Such data allows laboratories to more accurately test the performance of clinical bioinformatics pipelines without sequencing additional cases. For example, clinical laboratories may use in silico data to simulate low variant allele fraction variants to test the analytical sensitivity of variant calling software or simulate a range of insertion/deletion sizes to determine the performance of indel calling software. In this manuscript, the Working Group reviews the different types of in silico data with their strengths and limitations, methods to generate in silico data, and how it can be used in the clinical molecular diagnostic laboratory. Survey data indicates how in silico NGS data is currently being used. Finally, potential applications for which in silico data may become useful in the future are presented.

  View details for DOI 10.1016/j.jmoldx.2022.09.007

  View details for PubMedID 36244574

• Circulating tumor DNA monitoring for early recurrence detection in epithelial ovarian cancer. Gynecologic oncology Hou, J. Y., Chapman, J. S., Kalashnikova, E., Pierson, W., Smith-McCune, K., Pineda, G., Vattakalam, R. M., Ross, A., Mills, M., Suarez, C. J., Davis, T., Edwards, R., Boisen, M., Sawyer, S., Wu, H., Dashner, S., Aushev, V. N., George, G. V., Malhotra, M., Zimmermann, B., Sethi, H., ElNaggar, A. C., Aleshin, A., Ford, J. M. 2022

  Abstract

  OBJECTIVE: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. We examined the utility of circulating tumor DNA (ctDNA) as a prognostic biomarker for EOC by assessing its relationship with patient outcome and CA-125, pre-surgically and during post-treatment surveillance.METHODS: Plasma samples were collected from patients with stage I-IV EOC. Cohort A included patients with pre-surgical samples (N = 44, median follow-up: 2.7 years), cohort B and C included: patients with serially collected post-surgically (N = 12) and, during surveillance (N = 13), respectively (median follow-up: 2 years). Plasma samples were analyzed using a tumor-informed, personalized multiplex-PCR NGS assay; ctDNA status and CA-125 levels were correlated with clinical features and outcomes.RESULTS: Genomic profiling was performed on the entire cohort and was consistent with that seen in TCGA. In cohort A, ctDNA-positivity was observed in 73% (32/44) of presurgical samples and was higher in high nuclear grade disease. In cohort B and C, ctDNA was only detected in patients who relapsed (100% sensitivity and specificity) and preceded radiological findings by an average of 10 months. The presence of ctDNA at a single timepoint after completion of surgery +/- adjuvant chemotherapy and serially during surveillance was a strong predictor of relapse (HR:17.6, p = 0.001 and p < 0.0001, respectively), while CA-125 positivity was not (p = 0.113 and p = 0.056).CONCLUSIONS: The presence of ctDNA post-surgically is highly prognostic of reduced recurrence-free survival. CtDNA outperformed CA-125 in identifying patients at highest risk of recurrence. These results suggest that monitoring ctDNA could be beneficial in clinical decision-making for EOC patients.

  View details for DOI 10.1016/j.ygyno.2022.09.004

  View details for PubMedID 36117009

• Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas. The American journal of surgical pathology Singh, K., Lezama, L. S., Kurzer, J., Oak, J., Schultz, L. M., Walkush, A., Cheng, T. C., Chen, E. H., May, W. A., Chang, C., Link, M. P., Advani, R. H., Suarez, C. J., Natkunam, Y. 2022

  Abstract

  Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

  View details for DOI 10.1097/PAS.0000000000001956

  View details for PubMedID 36001451

• Factors associated with the time to complete clinical exome sequencing in a pediatric patient population. Genetics in medicine : official journal of the American College of Medical Genetics Lee, G., Yu, L., Suarez, C. J., Stevenson, D. A., Ling, A., Killer, L. 2022

  Abstract

  Exome sequencing (ES) is becoming increasingly important for diagnosing rare genetic disorders. Patients and clinicians face several barriers when attempting to obtain ES. This study is aimed to describe factors associated with a longer time interval between provider recommendation of testing and sample collection for ES.A retrospective chart review was conducted for insurance-authorized, completed pediatric ES in which initial requests were reviewed by Stanford's Genetic Testing Optimization Service between November 2018 and December 2019. Regression analysis was used to determine the association between the geocoded median household income and 3 different time point intervals defined as time to test, insurance decision, and scheduling/consent.Of the 281 charts reviewed, 115 cases were included in the final cohort. The average time from provider preauthorization request to sample collection took 104.4 days, and income was negatively correlated with the length of the insurance decision interval.Pediatric patients undergo a lengthy, uncertain process when attempting to obtain ES, some of which is associated with income. More research and clinician interventions are required to clarify specific socioeconomic factors that influence the ability to obtain timely ES and develop optimal protocols.

  View details for DOI 10.1016/j.gim.2022.06.006

  View details for PubMedID 35951015

• A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: Final analysis of efficacy and evaluation of MGMT as a predictive biomarker (ECOG-ACRIN E2211). Kunz, P. L., Graham, N., Catalano, P. J., Nimeiri, H., Fisher, G. A., Longacre, T. A., Suarez, C. J., Rubin, D., Yao, J. C., Kulke, M. H., Hendifar, A., Shanks, J., Shah, M. H., Zalupski, M., Schmulbach, E. L., Reidy, D., Strosberg, J. R., Wong, T. Z., O'Dwyer, P. J., Benson, A. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301172

• A deep learning model for molecular label transfer that enables cancer cell identification from histopathology images. NPJ precision oncology Su, A., Lee, H., Tan, X., Suarez, C. J., Andor, N., Nguyen, Q., Ji, H. P. 2022; 6 (1): 14

  Abstract

  Deep-learning classification systems have the potential to improve cancer diagnosis. However, development of these computational approaches so far depends on prior pathological annotations and large training datasets. The manual annotation is low-resolution, time-consuming, highly variable and subject to observer variance. To address this issue, we developed a method, H&E Molecular neural network (HEMnet). HEMnet utilizes immunohistochemistry as an initial molecular label for cancer cells on a H&E image and trains a cancer classifier on the overlapping clinical histopathological images. Using this molecular transfer method, HEMnet successfully generated and labeled 21,939 tumor and 8782 normal tiles from ten whole-slide images for model training. After building the model, HEMnet accurately identified colorectal cancer regions, which achieved 0.84 and 0.73 of ROC AUC values compared to p53 staining and pathological annotations, respectively. Our validation study using histopathology images from TCGA samples accurately estimated tumor purity, which showed a significant correlation (regression coefficient of 0.8) with the estimation based on genomic sequencing data. Thus, HEMnet contributes to addressing two main challenges in cancer deep-learning analysis, namely the need to have a large number of images for training and the dependence on manual labeling by a pathologist. HEMnet also predicts cancer cells at a much higher resolution compared to manual histopathologic evaluation. Overall, our method provides a path towards a fully automated delineation of any type of tumor so long as there is a cancer-oriented molecular stain available for subsequent learning. Software, tutorials and interactive tools are available at: https://github.com/BiomedicalMachineLearning/HEMnet.

  View details for DOI 10.1038/s41698-022-00252-0

  View details for PubMedID 35236916

• Factors associated with the time to complete clinical exome sequencing in a pediatric patient population Lee, G., Yu, L., Suarez, C., Stevenson, D., Ling, A., Derby, L. ELSEVIER SCIENCE INC. 2022: S268-S269

  View details for DOI 10.1016/j.gim.2022.01.463

  View details for Web of Science ID 000796586200202

• Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma. Blood cancer discovery Mundy-Bosse, B. L., Weigel, C., Wu, Y., Abdelbaky, S., Youssef, Y., Casas, S. B., Polley, N., Ernst, G., Young, K. A., McConnell, K. K., Nalin, A. P., Wu, K. G., Broughton, M., Lordo, M. R., Altynova, E., Hegewisch-Solloa, E., Enriquez-Vera, D. Y., Duenas, D., Barrionuevo, C., Yu, S., Saleem, A., Suarez, C. J., Briercheck, E. L., Molina-Kirsch, H., Loughran, T. P., Weichenhan, D., Plass, C., Reneau, J. C., Mace, E. M., Gamboa, F. V., Weinstock, D. M., Natkunam, Y., Caligiuri, M. A., Mishra, A., Porcu, P., Baiocchi, R. A., Brammer, J. E., Freud, A. G., Oakes, C. C. 2022; 3 (2): 154-169

  Abstract

  Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.

  View details for DOI 10.1158/2643-3230.BCD-21-0098

  View details for PubMedID 35247900

• Applications of Machine Learning in Routine Laboratory Medicine: Current State and Future Directions. Clinical biochemistry Rabbani, N., Kim, G. Y., Suarez, C. J., Chen, J. H. 2022

  Abstract

  Machine learning is able to leverage large amounts of data to infer complex patterns that are otherwise beyond the capabilities of rule-based systems and human experts. Its application to laboratory medicine is particularly exciting, as laboratory testing provides much of the foundation for clinical decision making. In this article, we provide a brief introduction to machine learning for the medical professional in addition to a comprehensive literature review outlining the current state of machine learning as it has been applied to routine laboratory medicine. Although still in its early stages, machine learning has been used to automate laboratory tasks, optimize utilization, and provide personalized reference ranges and test interpretation. The published literature leads us to believe that machine learning will be an area of increasing importance for the laboratory practitioner. We envision the laboratory of the future will utilize these methods to make significant improvements in efficiency and diagnostic precision.

  View details for DOI 10.1016/j.clinbiochem.2022.02.011

  View details for PubMedID 35227670

• Potential pitfalls in multiplex PCR-based next-generation sequencing: a case-based report. Journal of clinical pathology Tung, J. K., Devereaux, K. A., Erdmann, A. L., Schrijver, I., Zehnder, J., Suarez, C. J. 2022

  Abstract

  Amplicon-based next-generation sequencing (NGS) assays employ highly sensitive, rapid, and cost-effective methods to detect clinically actionable mutations for the diagnosis, prognosis, and treatment of patients with cancer. However, recognition of certain limitations inherent to amplicon-based NGS assays is crucial for the correct interpretation and reporting of variants in the clinical setting. In this report, we illustrate three different potential pitfalls related to amplicon-based NGS assays based on our institutional experience and highlight how the risk of such events can be minimised.

  View details for DOI 10.1136/jclinpath-2021-208105

  View details for PubMedID 35145018

• A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Exonuclease Domain Mutations in Endometrial Carcinoma. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Devereaux, K. A., Steiner, D. F., Ho, C., Gomez, A. J., Gilks, B., Longacre, T. A., Zehnder, J. L., Howitt, B. E., Suarez, C. J. 1800

  Abstract

  Determining the replicative DNA polymerase epsilon (POLE) mutation status in endometrial carcinomas (ECs) has important clinical implications given that the majority of "ultramutated" tumors harboring pathogenic exonuclease domain mutations in POLE (POLEmut) have a favorable prognosis, even among high-grade histotypes. Currently, there are no specific morphologic or immunophenotypic features that allow accurate detection of POLEmut tumors without molecular testing. Consequently, identifying POLEmut tumors has been challenging without employing costly and/or time-consuming DNA sequencing approaches. Here we developed a novel SNaPshot assay to facilitate routine and efficient POLE mutation testing in EC. The SNaPshot assay interrogates 15 nucleotide sites within exons 9, 11, 13, and 14 encoding the POLE exonuclease domain. The variant sites were selected based on recurrence, evidence of functional impact, association with high tumor mutation burden and/or detection in EC clinical outcome studies. Based on the pathogenic somatic variants reported in the literature, the assay is predicted to have a clinical sensitivity of 90% to 95% for ECs. Validation studies showed 100% specificity and sensitivity for the variants covered, with expected genotypic results for both the positive (n=11) and negative (n=20) patient controls on multiple repeat tests and dilution series. Analytic sensitivity was conservatively approximated at a 10% variant allele fraction (VAF), with documented detection as low as 5% VAF. As expected, the SNaPshot assay demonstrated greater sensitivity than Sanger sequencing for VAFs below 20%, an important characteristic for somatic mutation detection. Here we have developed and validated the first SNaPshot assay to detect hotspot POLE mutations. While next-generation sequencing and Sanger sequencing-based approaches have also been used to detect POLE mutations, a SNaPshot approach provides useful balance of analytical sensitivity, cost-effectiveness, and efficiency in a high-volume case load setting.

  View details for DOI 10.1097/PGP.0000000000000841

  View details for PubMedID 34907997

• Two Cases of Mycosis Fungoides With PCM1-JAK2 Fusion. JCO precision oncology Fernandez-Pol, S., Neishaboori, N., Chapman, C. M., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Suarez, C. J. 2021; 5: 646-652

  View details for DOI 10.1200/PO.20.00366

  View details for PubMedID 34994608

• Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8. Genome medicine Shin, G., Greer, S. U., Hopmans, E., Grimes, S. M., Lee, H., Zhao, L., Miotke, L., Suarez, C., Almeda, A. F., Haraldsdottir, S., Ji, H. P. 2021; 13 (1): 145

  Abstract

  We developed a sensitive sequencing approach that simultaneously profiles microsatellite instability, chromosomal instability, and subclonal structure in cancer. We assessed diverse repeat motifs across 225 microsatellites on colorectal carcinomas. Our study identified elevated alterations at both selected tetranucleotide and conventional mononucleotide repeats. Many colorectal carcinomas had a mix of genomic instability states that are normally considered exclusive. An MSH3 mutation may have contributed to the mixed states. Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.

  View details for DOI 10.1186/s13073-021-00958-z

  View details for PubMedID 34488871

• Circulating tumor DNA predicts disease recurrence in ovarian cancer patients. Chapman, J. S., Pierson, W. E., Smith-McCune, K., Pineda, G., Vattakalam, R. M., Ross, A., Mills, M. A., Suarez, C. J., Davis, T., Edwards, R. P., Boisen, M., Ford, J. M., Hou, J. Y., Wu, H., Dashner, S., Kalashnikova, E., Rodriguez, A., Zimmermann, B., Sawyer, S., Sethi, H., Aleshin, A. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263505279

• Two Cases of Mycosis Fungoides With PCM1-JAK2 Fusion JCO PRECISION ONCOLOGY Fernandez-Pol, S., Neishaboori, N., Chapman, C. M., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Suarez, C. J. 2021; 5: 646-652

  View details for DOI 10.1200/PO.20.00366

  View details for Web of Science ID 000721836700009

• Targeted replacement of full-length CFTR in human airway stem cells by CRISPR/Cas9 for pan-mutation correction in the endogenous locus. Molecular therapy : the journal of the American Society of Gene Therapy Vaidyanathan, S. n., Baik, R. n., Chen, L. n., Bravo, D. T., Suarez, C. J., Abazari, S. M., Salahudeen, A. A., Dudek, A. M., Teran, C. A., Davis, T. H., Lee, C. M., Bao, G. n., Randell, S. H., Artandi, S. E., Wine, J. J., Kuo, C. J., Desai, T. J., Nayak, J. V., Sellers, Z. M., Porteus, M. H. 2021

  Abstract

  Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR/Cas9 and two adeno-associated viruses (AAV) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial basal stem cells (HBECs). The modified cells were enriched to obtain 60-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.

  View details for DOI 10.1016/j.ymthe.2021.03.023

  View details for PubMedID 33794364

• Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Devereaux, K. A., Weiel, J. J., Pors, J., Steiner, D. F., Ho, C., Charu, V., Suarez, C. J., Renz, M., Diver, E., Karam, A., Litkouhi, B., Dorigo, O., Kidd, E. A., Yang, E. J., Folkins, A. K., Longacre, T. A., Howitt, B. E. 2021

  Abstract

  The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.

  View details for DOI 10.1038/s41379-021-00963-y

  View details for PubMedID 34743187

• Accurate detection and quantification of FLT3 internal tandem duplications in clinical hybrid capture next-generation sequencing data. The Journal of molecular diagnostics : JMD Tung, J. K., Suarez, C. J., Chiang, T., Zehnder, J. L., Stehr, H. 2021

  Abstract

  FLT3 internal tandem duplications (ITDs) are found in approximately one third of patients with acute myeloid leukemia (AML) and have important prognostic and therapeutic implications that have supported its assessment in routine clinical practice. Conventional methods for assessing FLT3-ITD status and allele burden have been primarily limited to PCR fragment size analysis due to the inherent difficulty in detecting large ITD variants by next-generation sequencing (NGS). In this study, we assess the performance of publicly available bioinformatic tools for the detection and quantification of FLT3-ITDs in clinical hybridization-capture NGS data. We found that FLT3_ITD_ext had the highest overall accuracy for detecting FLT3-ITDs and was able to accurately quantify allele burden. Although all other tools evaluated were able to detect FLT3-ITDs reasonably well, allele burden was consistently underestimated. We were able to significantly improve quantification of FLT3-ITD allelic burden independent of the detection method by utilizing soft-clipped reads and/or ITD junctional sequences. In addition, we show that identifying mutant reads by previously identified junctional sequences further improves the sensitivity of detecting FLT3-ITDs in post-treatment samples. Our results demonstrate that FLT3-ITDs can be reliably detected in clinical NGS data using available bioinformatic tools. We further describe how accurate quantification of FLT3-ITD allele burden can be added on to existing clinical NGS pipelines for routine assessment of FLT3-ITD status in patients with AML.

  View details for DOI 10.1016/j.jmoldx.2021.07.012

  View details for PubMedID 34363960

• Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma. The American journal of surgical pathology Koo, M., Zhang, J., Tan, B., Kurzer, J., Gratzinger, D., Zhao, S., Suarez, C., Lossos, I. S., Warnke, R. A., Natkunam, Y. 2021

  Abstract

  The diagnosis of angioimmunoblastic T-cell lymphoma (AITL) is complex and requires the demonstration of a T-follicular helper (TFH) phenotype. Immunophenotypic markers that detect the TFH phenotype are highly variable, thereby necessitating the use of 3 to 5 TFH markers to substantiate a TFH phenotype. We tested the utility of germinal center markers human germinal center-associated lymphoma (HGAL) and LIM-domain only 2 (LMO2) in detecting a TFH phenotype. We compared their staining to that of 6 TFH markers in current use, PD-1, ICOS, CXCL13, SAP, CD10, and BCL6, in a cohort of 23 AITL. Our results show that although both markers can detect a TFH phenotype, HGAL was superior to LMO2 in the percent of cells stained and the intensity of staining, 2 variables used to generate H-scores. Using H-scores as the metric, HGAL was most comparable to BCL6 among the currently used TFH markers and was more sensitive than CXCL13, SAP, CD10, and LMO2. PD-1 and ICOS emerged as the most robust of the 8 markers tested in this study in detecting a TFH phenotype. We conclude that HGAL is a reliable marker of TFH cells and can aid in the diagnosis of lymphomas of TFH derivation, particularly in the recognition of early patterns of AITL.

  View details for DOI 10.1097/PAS.0000000000001852

  View details for PubMedID 34907996

• Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations. The American journal of surgical pathology Fernandez-Pol, S., Petersen, B., Murphy, J., Oak, J. S., Wang, E. B., Rieger, K. E., Kim, Y. H., Khodadoust, M. S., Suarez, C. J. 2020

  Abstract

  Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES.

  View details for DOI 10.1097/PAS.0000000000001604

  View details for PubMedID 33060403

• A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Mutations in Endometrial Carcinoma Devereaux, K., Steiner, D., Ho, C., Gomez, A., Gojenola, L., Gilks, C., Longacre, T., Zehnder, J., Howitt, B., Suarez, C. NATURE PUBLISHING GROUP. 2020: 1040

  View details for Web of Science ID 000518328902227

• Molecular Classification of Metastatic and Recurrent Endometrial Endometrioid Carcinoma Devereaux, K., Chow, S., Steiner, D., Peters-Schulze, G., Ho, C., Suarez, C., Folkins, A., Howitt, B. NATURE PUBLISHING GROUP. 2020: 1041–42

  View details for Web of Science ID 000518328802228

• Molecular Classification of Metastatic and Recurrent Endometrial Endometrioid Carcinoma Devereaux, K., Chow, S., Steiner, D., Peters-Schulze, G., Ho, C., Suarez, C., Folkins, A., Howitt, B. NATURE PUBLISHING GROUP. 2020: 1041–42

  View details for Web of Science ID 000518328902228

• A Multiplex SNaPshot Assay is a Rapid and Cost-Effective Method for Detecting POLE Mutations in Endometrial Carcinoma Devereaux, K., Steiner, D., Ho, C., Gomez, A., Gojenola, L., Gilks, C., Longacre, T., Zehnder, J., Howitt, B., Suarez, C. NATURE PUBLISHING GROUP. 2020: 1040

  View details for Web of Science ID 000518328802227

• Joint single cell DNA-seq and RNA-seq of gastric cancer cell lines reveals rules of in vitro evolution. NAR genomics and bioinformatics Andor, N. n., Lau, B. T., Catalanotti, C. n., Sathe, A. n., Kubit, M. n., Chen, J. n., Blaj, C. n., Cherry, A. n., Bangs, C. D., Grimes, S. M., Suarez, C. J., Ji, H. P. 2020; 2 (2): lqaa016

  Abstract

  Cancer cell lines are not homogeneous nor are they static in their genetic state and biological properties. Genetic, transcriptional and phenotypic diversity within cell lines contributes to the lack of experimental reproducibility frequently observed in tissue-culture-based studies. While cancer cell line heterogeneity has been generally recognized, there are no studies which quantify the number of clones that coexist within cell lines and their distinguishing characteristics. We used a single-cell DNA sequencing approach to characterize the cellular diversity within nine gastric cancer cell lines and integrated this information with single-cell RNA sequencing. Overall, we sequenced the genomes of 8824 cells, identifying between 2 and 12 clones per cell line. Using the transcriptomes of more than 28 000 single cells from the same cell lines, we independently corroborated 88% of the clonal structure determined from single cell DNA analysis. For one of these cell lines, we identified cell surface markers that distinguished two subpopulations and used flow cytometry to sort these two clones. We identified substantial proportions of replicating cells in each cell line, assigned these cells to subclones detected among the G0/G1 population and used the proportion of replicating cells per subclone as a surrogate of each subclone's growth rate.

  View details for DOI 10.1093/nargab/lqaa016

  View details for PubMedID 32215369

  View details for PubMedCentralID PMC7079336

• An N-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer. Cold Spring Harbor molecular case studies Tung, J. K., Neishaboori, N. n., Haraldsdottir, S. n., Suarez, C. J. 2020

  Abstract

  Although combination therapy with RAF and EGFR inhibitors have improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating Ras mutations, MAP2K mutations, and amplifications in BRAF, Ras, and EGFR. In this report, we describe a patient with BRAF-mutated CRC who acquired a N-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. N-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC where there is only one prior report in the literature.

  View details for DOI 10.1101/mcs.a005140

  View details for PubMedID 32669268

• Single cell genomic characterization reveals the cellular reprogramming of the gastric tumor microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research Sathe, A. n., Grimes, S. M., Lau, B. T., Chen, J. n., Suarez, C. n., Huang, R. J., Poultsides, G. A., Ji, H. P. 2020

  Abstract

  The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. Its characteristics havean impact on treatments such as immunotherapy. These features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that scRNA-seq analysis ofgastric cancer (GC) together with paired normal tissue and peripheral blood mononuclear cells (PBMCs) would identify critical elements of cellular deregulation not apparent with other approaches.scRNA-seq was conducted on seven patients with GC and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising GC (32,407 cells), paired normal tissue (18,657 cells) and PBMCs (5,103 cells). Protein expression was validated by multiplex immunofluorescence.Tumor epithelium had copy number alterations, a distinct gene expression program from normal, with intra-tumor heterogeneity. GC TME was significantly enriched for stromal cells, macrophages, dendritic cells (DCs) and Tregs. TME-exclusive stromal cells expressed distinct extracellular matrix components than normal. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Tumor-DCs had a unique gene expression program compared to PBMC DCs. TME-specific cytotoxic T cells were exhausted with two heterogenous subsets. Helper, cytotoxic T, Treg and NK cells expressed multiple immune checkpoint or costimulatory molecules. Receptor-ligand analysis revealed TME-exclusive inter-cellular communication.Single-cell gene expression studies revealed widespread reprogramming across multiple cellular elements in the GC TME. Cellular remodeling was delineated by changes in cell numbers, transcriptional states and inter-cellular interactions. This characterization facilitates understanding of tumor biology and enables identification of novel targets including for immunotherapy.

  View details for DOI 10.1158/1078-0432.CCR-19-3231

  View details for PubMedID 32060101

• Complete and Prolonged Response to Immune Checkpoint Blockade in POLE-Mutated Colorectal Cancer. JCO precision oncology Silberman, R., F Steiner, D., Lo, A. A., Gomez, A., Zehnder, J. L., Chu, G., Suarez, C. J. 2019; 3: 1-5

  View details for DOI 10.1200/PO.18.00214

  View details for PubMedID 35100706

• Comprehensive characterization of gastric cancer at single-cell resolution Chen, J., Sathe, A., Grimes, S., Greer, S., Lau, B., Renschler, A., Poultsides, G., Suarez, C., Ji, H. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.SABCS18-151

  View details for Web of Science ID 000488129901333

• Complete and Prolonged Response to Immune Checkpoint Blockade in POLE-Mutated Colorectal Cancer JCO PRECISION ONCOLOGY Silberman, R., Steiner, D. F., Lo, A. A., Gomez, A., Zehnder, J. L., Chu, G., Suarez, C. J. 2019; 3: 1–5

  View details for DOI 10.1200/PO.18.00214

  View details for Web of Science ID 000473546800001

• Quantitative evidence for early metastatic seeding in colorectal cancer. Nature genetics Hu, Z., Ding, J., Ma, Z., Sun, R., Seoane, J. A., Scott Shaffer, J., Suarez, C. J., Berghoff, A. S., Cremolini, C., Falcone, A., Loupakis, F., Birner, P., Preusser, M., Lenz, H., Curtis, C. 2019

  Abstract

  Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118biopsies from 23patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01cm3). We validated the association between early drivers and metastasis in an independent cohort of 2,751colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.

  View details for DOI 10.1038/s41588-019-0423-x

  View details for PubMedID 31209394

• Tumor heterogeneity and testing discrepancy confound ROS1 detection in NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Sun, T. Y., Stehr, H., Suarez, C. J., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.jtho.2019.03.011

  View details for PubMedID 30914313

• A Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors: ATrial of the ECOG-ACRIN Cancer Research Group (E2211) Kunz, P. L., Catalano, P., Nimeiri, H. S., Fisher, G. A., Longacre, T. A., Suarez, C. J., Yao, J. C., Kulke, M. H., Hendifar, A., Shanks, J. C., Shah, M. H., Zalupski, M. M., Schmulbach, E., Reidy-Lagunes, D. L., Strosberg, J. R., O'Dwyer, P. J., Benson, A. B. LIPPINCOTT WILLIAMS & WILKINS. 2019: 443

  View details for Web of Science ID 000462541800082

• Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy NATURE COMMUNICATIONS Caswell-Jin, J. L., McNamara, K., Reiter, J. G., Sun, R., Hu, Z., Ma, Z., Ding, J., Suarez, C. J., Tilk, S., Raghavendra, A., Forte, V., Chin, S., Bardwell, H., Provenzano, E., Caldas, C., Lang, J., West, R., Tripathy, D., Press, M. F., Curtis, C. 2019; 10

  View details for DOI 10.1038/s41467-019-08593-4

  View details for Web of Science ID 000458175300006

• Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I. Nature communications Gomez-Ospina, N. n., Scharenberg, S. G., Mostrel, N. n., Bak, R. O., Mantri, S. n., Quadros, R. M., Gurumurthy, C. B., Lee, C. n., Bao, G. n., Suarez, C. J., Khan, S. n., Sawamoto, K. n., Tomatsu, S. n., Raj, N. n., Attardi, L. D., Aurelian, L. n., Porteus, M. H. 2019; 10 (1): 4045

  Abstract

  Lysosomal enzyme deficiencies comprise a large group of genetic disorders that generally lack effective treatments. A potential treatment approach is to engineer the patient's own hematopoietic system to express high levels of the deficient enzyme, thereby correcting the biochemical defect and halting disease progression. Here, we present an efficient ex vivo genome editing approach using CRISPR-Cas9 that targets the lysosomal enzyme iduronidase to the CCR5 safe harbor locus in human CD34+ hematopoietic stem and progenitor cells. The modified cells secrete supra-endogenous enzyme levels, maintain long-term repopulation and multi-lineage differentiation potential, and can improve biochemical and phenotypic abnormalities in an immunocompromised mouse model of Mucopolysaccharidosis type I. These studies provide support for the development of genome-edited CD34+ hematopoietic stem and progenitor cells as a potential treatment for Mucopolysaccharidosis type I. The safe harbor approach constitutes a flexible platform for the expression of lysosomal enzymes making it applicable to other lysosomal storage disorders.

  View details for DOI 10.1038/s41467-019-11962-8

  View details for PubMedID 31492863

• Pharma-Oncogenomics in theEra of Personal Genomics: A Quick Guide to Online Resources and Tools. Advances in experimental medicine and biology Joshi, R. P., Steiner, D. F., Konnick, E. Q., Suarez, C. J. 2019; 1168: 103–15

  Abstract

  The past two decades have seen unprecedented advances in the field of oncogenomics. The ongoing characterization of neoplastic tissues through genomic techniques has transformed many aspects of cancer research, diagnosis, and treatment. However, identifying sequence variants with biological and clinical significance is a challenging endeavor. In order to accomplish this task, variants must be annotated and interpreted using various online resources. Data on protein structure, functional prediction, variant frequency in relevant populations, and multipleother factors have beencompiled in usefuldatabasesfor this purpose.Thus, understanding the available online resourcesfor the annotation and interpretationof sequencevariantsis critical to aid molecular pathologistsand researchers working in this space.

  View details for DOI 10.1007/978-3-030-24100-1_7

  View details for PubMedID 31713167

• Multi-Institutional Evaluation of Inter-rater Agreement of Variant Classification Based on the 2017 AMP, ASCO and CAP Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer. The Journal of molecular diagnostics : JMD Sirohi, D. n., Schmidt, R. L., Aisner, D. L., Behdad, A. n., Betz, B. L., Brown, N. n., Coleman, J. F., Corless, C. L., Deftereos, G. n., Ewalt, M. D., Fernandes, H. n., Hsiao, S. J., Mansukhani, M. M., Murray, S. S., Niu, N. n., Ritterhouse, L. L., Suarez, C. J., Tafe, L. J., Thorson, J. A., Segal, J. P., Furtado, L. V. 2019

  Abstract

  This multi-institutional study was undertaken to evaluate inter-rater reliability of the 2017 AMP/ASCO/CAP guidelines for interpretation and reporting of oncology sequence variants and to assess current practices and perceptions surrounding these guidelines. Fifty-one variants were distributed to 20 participants from 10 institutions for classification using the new guidelines. Agreement was assessed using chance corrected agreement (Cohen's kappa). Overall chance corrected agreement (kappa) was 0.35. In order to evaluate if data sharing could help resolve disagreements, a summary of variant classifications and additional information about each variant were distributed to all participants. Chance corrected agreement improved to 0.7 after the original classifications were revised. Participants were invited to take a web-based survey regarding their perceptions of the guidelines. Only 20% (n=3) of the survey respondents had prior experience with the guidelines in clinical practice. The main perceived barriers to guideline implementation included the complexity of the guidelines, discordance between clinical actionability and pathobiologic relevance, lack of familiarity with the new classifications, and uncertainty when applying criteria to potential germline variants. This study demonstrates noteworthy discordances between pathologists for variant classification in solid tumors when using the 2017 AMP/ASCO/CAP guidelines. These findings highlight potential areas for clarification/refinement prior to mainstream clinical adoption.

  View details for DOI 10.1016/j.jmoldx.2019.10.010

  View details for PubMedID 31837433

• Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nature communications Caswell-Jin, J. L., McNamara, K. n., Reiter, J. G., Sun, R. n., Hu, Z. n., Ma, Z. n., Ding, J. n., Suarez, C. J., Tilk, S. n., Raghavendra, A. n., Forte, V. n., Chin, S. F., Bardwell, H. n., Provenzano, E. n., Caldas, C. n., Lang, J. n., West, R. n., Tripathy, D. n., Press, M. F., Curtis, C. n. 2019; 10 (1): 657

  Abstract

  Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.

  View details for PubMedID 30737380

• Publisher Correction: Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy. Nature communications Caswell-Jin, J. L., McNamara, K. n., Reiter, J. G., Sun, R. n., Hu, Z. n., Ma, Z. n., Ding, J. n., Suarez, C. J., Tilk, S. n., Raghavendra, A. n., Forte, V. n., Chin, S. F., Bardwell, H. n., Provenzano, E. n., Caldas, C. n., Lang, J. n., West, R. n., Tripathy, D. n., Press, M. F., Curtis, C. n. 2019; 10 (1): 2433

  Abstract

  The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.

  View details for DOI 10.1038/s41467-019-10456-x

  View details for PubMedID 31147552

• Tumor Molecular Profiling Aids in Determining Tissue of Origin and Therapy for Metastatic Adenocarcinoma in a Patient With Multiple Primary Malignancies. JCO precision oncology Costa, H. A., Reyes, R., Mills, M., Zehnder, J. L., Sledge, G., Curtis, C., Ford, J. M., Suarez, C. J. 2018; 2: 1-4

  View details for DOI 10.1200/PO.18.00177

  View details for PubMedID 35135146

• Tumor Molecular Profiling Aids in Determining Tissue of Origin and Therapy for Metastatic Adenocarcinoma in a Patient With Multiple Primary Malignancies JCO PRECISION ONCOLOGY Costa, H. A., Reyes, R., Mills, M., Zehnder, J. L., Sledge, G., Curtis, C., Ford, J. M., Suarez, C. J. 2018; 2

  View details for DOI 10.1200/PO.18.00177

  View details for Web of Science ID 000462187500001

• Patient and provider perspectives on the development of personalized medicine: a mixed-methods approach JOURNAL OF COMMUNITY GENETICS Puryear, L., Downs, N., Nevedal, A., Lewis, E. T., Ormond, K. E., Bregendahl, M., Suarez, C. J., David, S. P., Charlap, S., Chu, I., Asch, S. M., Pakdaman, N., Chang, S., Cullen, M. R., Palaniappan, L. 2018; 9 (3): 283–91

  View details for DOI 10.1007/s12687-017-0349-x

  View details for Web of Science ID 000435437400011

• A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211). Kunz, P. L., Catalano, P. J., Nimeiri, H., Fisher, G. A., Longacre, T. A., Suarez, C. J., Yao, J. C., Kulke, M. H., Hendifar, A., Shanks, J., Shah, M. H., Zalupski, M., Schmulbach, E. L., Reidy, D., Strosberg, J. R., O'Dwyer, P. J., Benson, A. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.4004

  View details for Web of Science ID 000442916001583

• Molecular Characterization of Aggressive Estrogen Receptor Positive Breast Cancer Resistant to Palbociclib Therapy Lei, L., Lin, C., Steiner, D., Ford, J. M., Zehnder, J. L., Suarez, C. J. NATURE PUBLISHING GROUP. 2018: 703

  View details for Web of Science ID 000459341003278

• Molecular Characterization of Aggressive Estrogen Receptor Positive Breast Cancer Resistant to Palbociclib Therapy Lei, L., Lin, C., Steiner, D., Ford, J. M., Zehnder, J. L., Suarez, C. J. NATURE PUBLISHING GROUP. 2018: 703

  View details for Web of Science ID 000429308604325

• IDH2 Mutation in a Patient with Metastatic Colon Cancer NEW ENGLAND JOURNAL OF MEDICINE Zhang, B. M., Zehnder, J. L., Suarez, C. J. 2017; 376 (20): 1991-1992

  View details for DOI 10.1056/NEJMc1701072

  View details for PubMedID 28514606

• Promoting appropriate genetic testing: the impact of a combined test review and consultative service. Genetics in medicine Suarez, C. J., Yu, L., Downs, N., Costa, H. A., Stevenson, D. A. 2017

  Abstract

  Genetic test misorders can adversely affect patient care. However, little is known about the types of misorders and the overall impact of a utilization management (UM) program on curbing misorders. This study aimed to identify different types of misorders and analyze the impact of a combined test review and consultative service on reducing misorders over time.Selected genetic tests were systematically reviewed between January and December 2015 at Stanford Health Care. Misorders were categorized into five types: clerical errors, redundant testing, better alternatives, controversial, and uncategorized. Moreover, consultations were offered to help clinicians with test selection.Of the 629 molecular test orders reviewed, 13% were classified as misorders, and 7% were modified or canceled. Controversial misorders constitute the most common type (42%); however, unlike the other misorder types, they were negligibly affected by test review. Simultaneously, 71 consults were received. With the introduction of the UM program, genetic test misorders went from 22% at baseline to 3% at the end of the year.Our results show that the combined approach of test review and consultative service effectively reduced misorders over time and suggest that a UM program focused on eliminating misorders can positively influence health-care providers' behaviors.Genet Med advance online publication 26 January 2017Genetics in Medicine (2017); doi:10.1038/gim.2016.219.

  View details for DOI 10.1038/gim.2016.219

  View details for PubMedID 28125079

• Patient and provider perspectives on the development of personalized medicine: a mixed-methods approach. Journal of community genetics Puryear, L. n., Downs, N. n., Nevedal, A. n., Lewis, E. T., Ormond, K. E., Bregendahl, M. n., Suarez, C. J., David, S. P., Charlap, S. n., Chu, I. n., Asch, S. M., Pakdaman, N. n., Chang, S. I., Cullen, M. R., Palaniappan, L. n. 2017

  Abstract

  While genetic testing gains adoption in specialty services such as oncology, neurology, and cardiology, use of genetic and genomic testing has yet to be adopted as widely in primary care. The purpose of this study is to identify and compare patient and primary care provider (PCP) expectations of genetics services in primary care. Patient and PCP perspectives were assessed through a mixed-method approach combining an online survey and semi-structured interviews in a primary care department of a large academic medical institution. A convenience sample of 100 adult primary care patients and 26 PCPs was gathered. The survey and interview questions focused on perceptions of genetic testing, experience with genetic testing, and expectations of genetic services in primary care. Patients felt that their PCP was knowledgeable about genetic testing and expected their PCP to be the first to recognize a need for genetic testing based on family history. Nonetheless, patients reported that PCPs rarely used family history information to discuss genetic risks or order testing. In contrast, PCPs felt uncertain about the clinical utility and scientific value of genetic testing. PCPs were concerned that genetic testing could cause anxiety, frustration, discrimination, and reduced insurability, and that there was unequal access to testing. PCPs described themselves as being "gatekeepers" to genetic testing but did not feel confident or have the desire to become experts in genetic testing. However, PCPs were open to increasing their working knowledge of genetic testing. Within this academic medical center, there is a gap between what patients expect and what primary care providers feel they are adequately prepared to provide in terms of genetic testing services.

  View details for PubMedID 29280052

• Synchronous immunophenotypically and clonally distinct follicular lymphoma and marginal zone lymphoma with massive amyloid deposition HUMAN PATHOLOGY: CASE REPORTS Frost, A. S., Suarez, C. J., Kieckbusch, M. E., Burtelow, M., Natkunam, Y. 2016; 5: 10-17

  View details for DOI 10.1016/j.ehpc.2015.12.003

• Next-Generation Sequencing for Infectious Disease Diagnosis and Management A Report of the Association for Molecular Pathology JOURNAL OF MOLECULAR DIAGNOSTICS Lefterova, M. I., Suarez, C. J., Banaei, N., Pinsky, B. A. 2015; 17 (6): 623-634

  Abstract

  Next-generation sequencing (NGS) technologies are increasingly being used for diagnosis and monitoring of infectious diseases. Herein, we review the application of NGS in clinical microbiology, focusing on genotypic resistance testing, direct detection of unknown disease-associated pathogens in clinical specimens, investigation of microbial population diversity in the human host, and strain typing. We have organized the review into three main sections: i) applications in clinical virology, ii) applications in clinical bacteriology, mycobacteriology, and mycology, and iii) validation, quality control, and maintenance of proficiency. Although NGS holds enormous promise for clinical infectious disease testing, many challenges remain, including automation, standardizing technical protocols and bioinformatics pipelines, improving reference databases, establishing proficiency testing and quality control measures, and reducing cost and turnaround time, all of which would be necessary for widespread adoption of NGS in clinical microbiology laboratories.

  View details for DOI 10.1016/j.jmoldx.2015.07.004

  View details for Web of Science ID 000363830000001

  View details for PubMedID 26433313

• Lymph node involvement by mycosis fungoides and Sezary syndrome mimicking angioimmunoblastic T-cell Lymphoma HUMAN PATHOLOGY LeBlanc, R. E., Lefterova, M. I., Suarez, C. J., Tavallaee, M., Kim, Y. H., Schrijver, I., Kim, J., Gratzinger, D. 2015; 46 (9): 1382-1389

  Abstract

  Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

  View details for DOI 10.1016/j.humpath.2015.05.024

  View details for Web of Science ID 000360779200017

• Lymph node involvement by mycosis fungoides and Sézary syndrome mimicking angioimmunoblastic T-cell lymphoma. Human pathology LeBlanc, R. E., Lefterova, M. I., Suarez, C. J., Tavallaee, M., Kim, Y. H., Schrijver, I., Kim, J., Gratzinger, D. 2015; 46 (9): 1382-9

  Abstract

  Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

  View details for DOI 10.1016/j.humpath.2015.05.024

  View details for PubMedID 26193796

• Mycotic aneurysm of the abdominal aorta caused by Haemophilus influenzae type f JOURNAL OF MEDICAL MICROBIOLOGY Suarez, C. J., Glover, W. A., Cowan, J., Smith, A., Clarridge, J. E. 2013; 62: 658-660

  Abstract

  Prior to the advent of the Haemophilus influenzae type b vaccine, invasive infections due to H. influenzae type f were rarely described. However, the epidemiology of H. influenzae is changing. While the incidence of invasive infections due to H. influenzae is declining in children, such infections are becoming more common in adults, particularly in the elderly. Here, we report an unusual case of infective aortic aneurysm caused by H. influenzae type f that underlines the emerging clinical relevance and pathogenic capability of this organism.

  View details for DOI 10.1099/jmm.0.055228-0

  View details for Web of Science ID 000318203100023

  View details for PubMedID 23355310

• Actions and consequences: characterization of a deletion in the cftr gene that encompasses a splice site Grand Rounds Suarez, C. J., Boyle, T., Chiang, T., Schrijver, I. 2013; 12: 36-39

  View details for DOI 10.1102/1470-5206.2012.0009

• Genotypic and phenotypic characterization and clinical significance of 'Haemophilus quentini' isolated from the urinary tract of adult men JOURNAL OF MEDICAL MICROBIOLOGY Glover, W. A., Suarez, C. J., Clarridge, J. E. 2011; 60 (11): 1689-1692

  Abstract

  'Haemophilus quentini' has been proposed as the name for a distinct and homogeneous Haemophilus genospecies associated with urogenital tract and neonatal-related infections. Reports of 'H. quentini' isolation from adult men are rare and the disease potential in this population is unknown. We report six cases where 'H. quentini' was isolated from the genito-urinary tract in males. The isolation of 'H. quentini' during routine urine and urethral culture in adult men may aid in the determination of unresolved urethritis and possible urinary tract infections.

  View details for DOI 10.1099/jmm.0.031591-0

  View details for Web of Science ID 000296547900017

  View details for PubMedID 21737543

• Genetic biomarkers in colorectal cancer Clinical Laboratory International Suarez, C. J., Konnick, E. Q., Pritchard, C. 2011; 35: 26-28
• Respiratory Comparative anatomy and histology: A mouse and human atlas Suarez, C. J., Frevert, C. W., Dintzis, S. M. Elsevier. 2011; 1st: 121–134
• Surfactant Protein D-Mediated Decrease of Allergen-Induced Inflammation Is Dependent upon CTLA4 JOURNAL OF IMMUNOLOGY Lin, K., Jen, K. Y., Suarez, C. J., Crouch, E. C., Perkins, D. L., Finn, P. W. 2010; 184 (11): 6343-6349

  Abstract

  Pulmonary surfactant protein D (SP-D), a member of the collectin family, is an innate immune molecule critical for defense that can also modulate adaptive immune responses. We previously showed that SP-D-deficient mice exhibit enhanced allergic responses and that SP-D induction requires lymphocytes. Thus, we postulated that SP-D may decrease adaptive allergic responses through interaction with T cells. In this study, we used two forms of SP-D, a dodecamer and a shorter fragment containing the trimeric neck and carbohydrate recognition domains (SP-D NCRD). Both forms decreased immune responses in vitro and in a murine model of pulmonary inflammation. SP-D NCRD increased transcription of CTLA4, a negative regulator of T cell activation, in T cells. SP-D NCRD no longer decreased lymphoproliferation and IL-2 cytokine production when CTLA4 signals were abrogated. Administration of SP-D NCRD in vivo no longer decreased allergen induced responses when CTLA4 was inhibited. Our results indicate that SP-D decreases allergen responses, an effect that may be mediated by increase of CTLA4 in T cells.

  View details for DOI 10.4049/jimmunol.0901947

  View details for Web of Science ID 000278439600049

  View details for PubMedID 20435925

• T Cell Pathways Involving CTLA4 Contribute To a Model of Acute Lung Injury JOURNAL OF IMMUNOLOGY Nakajima, T., Suarez, C. J., Lin, K., Jen, K. Y., Schnitzer, J. E., Makani, S. S., Parker, N., Perkins, D. L., Finn, P. W. 2010; 184 (10): 5835-5841

  Abstract

  Acute lung injury (ALI) is a frequent pulmonary complication in critically ill patients. We characterized a murine model of LPS-induced ALI, focusing on Th cells. Following LPS administration, bronchoalveolar lavage lymphocytes, neutrophils, IL-6, TNF-alpha, and albumin were increased. Analysis of LPS-induced T cells revealed increased Th cell-associated cytokines (IL-17A, -17F, and -22), as well as increased expression of CD69 (a cell activation marker), Foxp3, and CTLA4 in CD4(+) T cells. Administration of anti-CTLA4 Ab decreased LPS-induced bronchoalveolar lavage albumin and IL-17A, while increasing CD4(+)Foxp3(+) cell number and Foxp3 expression in CD4(+)Foxp3(+) cells. These data suggest that pulmonary LPS administration promotes CD4(+) T cells and that T cell pathways involving CTLA4 contribute to ALI.

  View details for DOI 10.4049/jimmunol.0903238

  View details for Web of Science ID 000277530700047

  View details for PubMedID 20385880

• Innate immune mechanism in allergic asthma CURRENT ALLERGY AND ASTHMA REPORTS Suarez, C. J., Parker, N. J., Finn, P. W. 2008; 8 (5): 451-459

  Abstract

  Allergic asthma is a chronic inflammatory disorder of the airways characterized by eosinophilic inflammation, airway hyperresponsiveness, and mucus hypersecretion. Adaptive, antigen-dependent immunity is critical for asthma pathogenesis. Allergic asthma may involve adaptive and innate, antigen-independent immune responses. This review discusses the current evidence that associates innate immunity with allergic asthma pathogenesis. In particular, we focus on the role of innate immune cells (eg, bronchial epithelial cells, alveolar macrophages, and dendritic cells) and molecules (Toll-like and nucleotide-binding oligomerization domain-like receptors) in modifying allergic immune responses.

  View details for Web of Science ID 000258547500013

  View details for PubMedID 18682113

• First detection of the plasmid-mediated class A carbapenemase KPC-2 in clinical isolates of Klebsiella pneumoniae from South America ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Villegas, M. V., Lolans, K., Correa, A., Suarez, C. J., Lopez, J. A., Vallejo, M., Quinn, J. P. 2006; 50 (8): 2880-2882

  Abstract

  The plasmid-mediated class A carbapenemase KPC-2 was isolated from unrelated Klebsiella pneumoniae isolates in Medellin, Colombia. These KPC enzymes are the first from South America and the second isolation outside of the United States. The expanding geographic spread of KPC carbapenemases underscores the importance of clinical recognition of these enzymes.

  View details for DOI 10.1128/AAC.00186-06

  View details for Web of Science ID 000239640400047

  View details for PubMedID 16870793

• Mechanism of resistance to Carbapenems in Enterobacteriaceae, P.aeruginosa and A.baumannii, and some strategies for containment Infectio Suarez, C. J., Kattan, J. N., Villegas, M. V. 2006; 10 (2): 69-77
• First detection of metallo-beta-lactamase VIM-2 in Pseudomonas aeruginosa isolates from Colombia ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Villegas, M. V., Lolans, K., Olivera, M. D., Suarez, C. J., Correa, A., Queenan, A. M., Quinn, J. P. 2006; 50 (1): 226-229

  Abstract

  Carbapenem resistance rates in Pseudomonas aeruginosa isolates in Colombia, as in many South American countries, are high for reasons that remain unclear. From our nationwide network, we describe the first detection of the metallo-beta-lactamase VIM-2 in clinical isolates of P. aeruginosa from multiple cities within Colombia. Metallo-beta-lactamases were not detected in the two centers with the highest imipenem resistance rates. Clonality was noted in five of the eight centers with strains meeting the criteria for molecular typing. The high carbapenem resistance in P. aeruginosa in Colombia may be attributable to a combination of factors, including the presence of metallo-beta-lactamases and nosocomial transmission.

  View details for DOI 10.1128/AAC.50.1.226-229.2006

  View details for Web of Science ID 000234988000029

  View details for PubMedID 16377690

• Mechanisms of resistance to beta-lactams in some common Gram-negative bacteria causing nosocomial infections. Expert review of anti-infective therapy Suárez, C. J., Lolans, K., Villegas, M. V., Quinn, J. P. 2005; 3 (6): 915-922

  Abstract

  Gram-negative bacilli remain major killers of hospitalized patients and continue to evolve new resistance mechanisms. This review describes the mechanisms of resistance to beta-lactam antibiotics from those Gram-negative pathogens most often isolated from nosocomial infections.

  View details for PubMedID 16307504