Kristin Jensen

All Publications

• Clinicopathologic Characteristics of HER2 FISH-ambiguous Breast Cancer at a Single Institution AMERICAN JOURNAL OF SURGICAL PATHOLOGY Clay, M. R., Iberri, D. J., Bangs, C. D., Cherry, A., Jensen, K. C. 2013; 37 (1): 120-127

  Abstract

  : The typical algorithm for human epidermal growth factor-2 (HER2) testing is immunohistochemistry (IHC), followed by reflex HER2 fluorescence in situ hybridization (FISH) for HER2 IHC-ambiguous (2+) cases. At our institution, HER2 FISH testing is initially performed as part of routine breast cancer testing, with HER2 FISH-ambiguous (HER2:CEP17 ratio, 1.8 to 2.2) cases reflexed to HER2 IHC. This provides a unique dataset for lesions that may not routinely undergo FISH testing. The clinicopathologic characteristics of HER2 FISH-ambiguous cases are described.: The electronic pathology database in our institution was searched for HER2 FISH-ambiguous cases from 2007 to December 2011. Review of clinical and pathologic characteristics was performed.: Sixty cases from 60 patients were reported as HER2 FISH ambiguous. Reflex HER2 IHC testing was performed on all 60 cases, of which 26 were HER2 IHC negative (0 to 1+), 18 were HER2 IHC ambiguous (2+), and 16 were HER2 IHC positive (3+). Of the 46 HER2 FISH-ambiguous patients with available clinical records, 13 (32%) pursued anti-HER2 treatment (10 IHC 3+, 1 IHC 2+, 2 IHC 0 to 1+). All were grade II or III ductal carcinomas, with 1 grade III metaplastic carcinoma.: Reflex HER2 IHC testing after initially ambiguous HER2 FISH testing provides definitive HER2 status in a majority of cases (70%). However, a substantial percentage (30%) of HER2 FISH-ambiguous cases is also HER2 IHC ambiguous, suggesting an intermediate HER2 biology. Most HER2 FISH-ambiguous patients who received trastuzumab were HER2 IHC 3+, grade III, and had associated high-grade ductal carcinoma in situ. Although not statistically significant and with only minimal follow-up, no recurrences have occurred in those patients treated with trastuzumab (P=0.5754).

  View details for DOI 10.1097/PAS.0b013e31826ab19d

  View details for Web of Science ID 000312486700015

  View details for PubMedID 23108020

• Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo. Hormones & cancer Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Peng, L., Albertelli, M. A., Feldman, D. 2011; 2 (3): 190-202

  Abstract

  Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.

  View details for DOI 10.1007/s12672-011-0073-7

  View details for PubMedID 21686077

  View details for PubMedCentralID PMC3114631

• Variations in stromal signatures in breast and colorectal cancer metastases JOURNAL OF PATHOLOGY Webster, J. A., Beck, A. H., Sharma, M., Espinosa, I., Weigelt, B., Schreuder, M., Montgomery, K. D., Jensen, K. C., van de Rijn, M., West, R. 2010; 222 (2): 158-165

  Abstract

  The tumour microenvironment (TME) plays an important role in tumour survival and growth, but little is known about the degree of preservation between different stromal response patterns found in primary tumours and their metastases. We have previously identified gene expression profiles for two distinct stromal signatures in breast carcinoma of fibroblast (aka DTF) and macrophage (aka CSF1) response and found them to be correlated with clinicopathological features, including outcome. In this study, we compare the DTF fibroblast and CSF1 macrophage stromal response patterns in primary breast and colorectal cancers to their matched lymph node metastases. In both breast and colorectal cancer, there was a significant positive correlation between the CSF1 macrophage signature in the primary tumours and the matched lymph node metastases, as assessed by immunohistochemical markers. No such correlation was observed for the DTF fibroblast signature. A similar result was seen in independent analysis of two published gene expression microarray datasets. The variations of these stromal reaction patterns from the primary to the metastasis shed light on the relationship between the neoplastic cells and the non-neoplastic cells in the TME. The preservation of the CSF1 macrophage response pattern in metastases lends support to targeting the CSF1 pathway in cancer.

  View details for DOI 10.1002/path.2738

  View details for PubMedID 20593409

• Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ BREAST CANCER RESEARCH AND TREATMENT Sharma, M., Beck, A. H., Webster, J. A., Espinosa, I., Montgomery, K., Varma, S., van de Rijn, M., Jensen, K. C., West, R. B. 2010; 123 (2): 397-404

  Abstract

  Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.

  View details for DOI 10.1007/s10549-009-0654-0

  View details for Web of Science ID 000280807900008

  View details for PubMedID 19949854

  View details for PubMedCentralID PMC2976659

• New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up BREAST CANCER RESEARCH AND TREATMENT Jensen, K. C., Turbin, D. A., Leung, S., Miller, M. A., Johnson, K., Norris, B., Hastie, T., McKinney, S., Nielsen, T. O., Huntsman, D. G., Gilks, C. B., West, R. B. 2008; 112 (3): 453-459

  Abstract

  HER2 gene amplification and/or protein overexpression in breast cancer is associated with a poor prognosis and predicts response to anti-HER2 therapy. We examine the natural history of breast cancers in relationship to increased HER2 copy numbers in a large population-based study.HER2 status was measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in approximately 1,400 breast cancer cases with greater than 15 years of follow-up. Protein expression was evaluated with two different commercially-available antibodies.We looked for subgroups of breast cancer with different clinical outcomes, based on HER2 FISH amplification ratio. The current HER2 ratio cut point for classifying HER2 positive and negative cases is 2.2. However, we found an increased risk of disease-specific death associated with FISH ratios of >1.5. An 'intermediate' group of cases with HER2 ratios between 1.5 and 2.2 was found to have a significantly better outcome than the conventional 'amplified' group (HER2 ratio >2.2) but a significantly worse outcome than groups with FISH ratios less than 1.5.Breast cancers with increased HER2 copy numbers (low level HER2 amplification), below the currently accepted positive threshold ratio of 2.2, showed a distinct, intermediate outcome when compared to HER2 unamplified tumors and tumors with HER2 ratios greater than 2.2. These findings suggest that a new cut point to determine HER2 positivity, at a ratio of 1.5 (well below the current recommended cut point of 2.2), should be evaluated.

  View details for DOI 10.1007/s10549-007-9887-y

  View details for Web of Science ID 000261951000007

  View details for PubMedID 18193353

• Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K. C., Schaeffer, D. F., Cheang, M., Montgomery, K., West, R. B., Gilks, C. B., Ross, D., Turashvili, G., Schnitt, S., van de Rijn, M. NATURE PUBLISHING GROUP. 2008: 1413–20

  Abstract

  Fatty acid synthase (FASN) expression has been reported in many different tumors, including breast cancer. In gene microarray studies, the fatty acid synthase gene co-clustered with cytokeratins 5 and 17 and other genes that defined the basal-like subset of breast cancers. To define the use of this marker in breast pathology, a rabbit polyclonal antiserum (S143) to a peptide fragment of this gene was produced and compared with a commercially available monoclonal antibody by immunohistochemistry on various tissue microarrays and whole tissue sections. The tissue microarrays included 1090 breast cancers and 244 normal breast tissues. Whole tissue sections consisted of benign and malignant tissues from breast resection specimens. In contrast to other 'basal' markers identified by gene expression profiling data, the fatty acid synthase (FASN) expression pattern in normal breast was notable for its expression in only a small subset of basal and suprabasal cells. Dual staining experiments revealed that the subpopulation of cells labeling with FASN did not coexpress myoepithelial markers CK5/6 or p63, but did coexpress e-cadherin. In addition to staining a subset of basal and suprabasal cells, the antiserum highlighted apocrine differentiation, and stained 106/144 (74%) cases of columnar cell lesions and five of five cases of flat epithelial atypia. Despite its association with basal keratins in gene array studies, FASN expression did not correlate significantly with the outcome in breast cancer. We describe an expression pattern that highlights only a subset of basal and suprabasal cells in normal breast ducts and we show by dual expression studies that this subset of cells is different from myoepithelial and basal cytokeratin-positive cells. In addition, FASN expression is described in apocrine metaplasia, columnar cell lesions, and flat epithelial atypia.

  View details for DOI 10.1038/modpathol.2008.163

  View details for PubMedID 18820672

• Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger 95th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K. C., Mariappan, M. R., Putcha, G. V., Husain, A., Chun, N., Ford, J. M., Schrijver, I., Longacre, T. A. LIPPINCOTT WILLIAMS & WILKINS. 2008: 1029–37

  Abstract

  Ovarian malignancies occurring in the setting of hereditary nonpolyposis colorectal carcinoma syndrome typically present in young women, often as the first or "sentinel" cancer, but the frequency of microsatellite instability (MSI) and mismatch repair (MMR) defects in ovarian surface epithelial malignancies in women

  View details for PubMedID 18469706

• The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms MODERN PATHOLOGY Jensen, K. C., Higgins, J. P., Montgomery, K., Kaygusuz, G., van de Rijn, M., Natkunam, Y. 2007; 20 (8): 871-877

  Abstract

  PAX5 is a B-cell transcription factor whose expression at the protein level is reliably detected by immunohistochemistry in routine biopsies. The purpose of this study was to investigate whether PAX5 immunohistochemistry has diagnostic benefit as a B-cell marker in the work-up of undifferentiated malignant neoplasms. Twenty-five cases previously diagnosed as undifferentiated malignant neoplasms were selected. In addition, 59 hematolymphoid and 884 non-hematolymphoid malignancies were studied such that the specificity of PAX5 immunohistochemistry could be addressed. Two of the 25 (8%) undifferentiated neoplasms showed diffuse staining for PAX5, which indicated a B-cell derivation for these neoplasms that was not appreciated at the time of initial diagnosis. PAX5 staining was detected in the vast majority of hematolymphoid tumors of B-cell derivation but only in 5 of 884 (less than 1%) non-hematolymphoid tumors. Our results further show that PAX5 may be the only detectable marker of B lineage in lymphomas that lack or show equivocal CD45RB and CD20 expression. We conclude that the addition of PAX5 to a panel of immunohistologic markers used in the interrogation of undifferentiated neoplasms is of diagnostic benefit. Its expression can also facilitate the diagnosis of classical and nodular lymphocyte-predominant Hodgkin lymphoma with atypical morphologic and immunohistologic features. Lastly, we have shown that the lack of its expression at the protein level in many epithelial and mesenchymal neoplasms renders PAX5 expression an extremely specific marker of the B lineage.

  View details for PubMedID 17529924

• Cytologic diagnosis of columnar-cell lesions of the breast 52nd Annual Scientific Meeting of the American-Society-of-Cytopathology Jensen, K. C., Kong, C. S. WILEY-LISS. 2007: 73–79

  Abstract

  This study describes the cytologic features of breast columnar-cell lesions (CCLs) and determines whether these lesions can be diagnosed by fine-needle aspiration. We present ten cases of biopsy-proven CCL with prior fine-needle aspiration material and discuss the spectrum of changes, as well as features important in the cytologic distinction of CCL from diagnostic mimics. CCLs were characterized by flat sheets of cells with enlarged nuclei, distinct cell borders, and finely granular cytoplasm. Cytologic atypia ranged from minimal to severe, and many cases (8/10) exhibited a paucity of myoepithelial cells. CCL showed significant cytologic overlap with papillary neoplasms and well-differentiated adenocarcinomas. The prospective diagnosis of CCL cannot reliably be made by fine-needle aspiration. However, it is important to recognize the range of cytologic atypia that can be seen with CCL to avoid an overdiagnosis of malignancy.

  View details for DOI 10.1002/dc.20601

  View details for PubMedID 17230565

• Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma Clin Cancer Res Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM 2004; 10 (16): 5367-5374
• A magnetic hydrogel for the efficient retrieval of kidney stone fragments during ureteroscopy. Nature communications Ge, T. J., Roquero, D. M., Holton, G. H., Mach, K. E., Prado, K., Lau, H., Jensen, K., Chang, T. C., Conti, S., Sheth, K., Wang, S. X., Liao, J. C. 2023; 14 (1): 3711

  Abstract

  Only 60-75% of conventional kidney stone surgeries achieve complete stone-free status. Up to 30% of patients with residual fragments <2 mm in size experience subsequent stone-related complications. Here we demonstrate a stone retrieval technology in which fragments are rendered magnetizable with a magnetic hydrogel so that they can be easily retrieved with a simple magnetic tool. The magnetic hydrogel facilitates robust in vitro capture of stone fragments of clinically relevant sizes and compositions. The hydrogel components exhibit no cytotoxicity in cell culture and only superficial effects on ex vivo human urothelium and in vivo mouse bladders. Furthermore, the hydrogel demonstrates antimicrobial activity against common uropathogens on par with that of common antibiotics. By enabling the efficient retrieval of kidney stone fragments, our method can lead to improved stone-free rates and patient outcomes.

  View details for DOI 10.1038/s41467-023-38936-1

  View details for PubMedID 37349287

  View details for PubMedCentralID 5853829

• Randomized controlled trial investigating use of submucosal injection of EverLift in rates of complete resection of non-pedunculated 4-9mm polyps. International journal of colorectal disease Wei, M. T., Louie, C. Y., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. 2022

  Abstract

  INTRODUCTION: Currently, cold snare polypectomy (CSP) without submucosal injection is recommended for removing polyps<10mm. Use of viscous submucosal agents has not been previously evaluated in CSP. We investigate the potential role of EverLift (GI Supply, Pennsylvania) in CSP.METHODS: The study is a single-center prospective randomized non-inferiority clinical trial evaluating CSP of non-pedunculated 4-9mm polyps, with or without submucosal injection of EverLift. Patients 18-80years of age presenting for colonoscopy were recruited. Eligible polyps underwent block randomization to CSP with or without EverLift. Following CSP, two biopsies were performed at the CSP site margin. The primary non-inferiority outcome was complete resection rate, defined by absence of residual polyp in the margin biopsies (non-inferiority margin-10%).RESULTS: A total of 291 eligible polyps underwent CSP, with 142 removed using EverLift. There was similar polyp size and distribution of pathology between the two groups. Overall, there was a low rate of positive margins with (1.4%) or without submucosal injection (2.8%), with no significant difference in complete resection (difference 1.28%, 95% CI:-2.66 to 5.42%), demonstrating non-inferiority of EverLift injection. Use of EverLift significantly increased CSP time (109.8 vs 38.8s, p<0.0001) and frequency of use of hemostatic clips (13.4 vs 3.6%, p=0.002).CONCLUSION: Submucosal injection of EverLift was non-inferior to CSP of 4-9mm polyps without injection and increased time for resection as well as use of hemostatic clips to control acute bleeding. Our results suggest that polypectomy of 4-9mm polyps can be safely performed without submucosal injection of EverLift.

  View details for DOI 10.1007/s00384-022-04136-4

  View details for PubMedID 35507047

• RANDOMIZED CONTROLLED TRIAL INVESTIGATING COLD SNARE AND FORCEPS POLYPECTOMY AMONG SMALL POLYPS IN RATES OF COMPLETE RESECTION: THE TINYPOLYP TRIAL Wei, M., Louie, C., Chen, Y., Pan, J. Y., Quan, S., Wong, R., Brown, R., Clark, M., Jensen, K. C., Lau, H. D., Friedland, S. W B SAUNDERS CO-ELSEVIER INC. 2022: S142-S143

  View details for Web of Science ID 000826446200345

• Randomized controlled Trial Investigating cold snare aNd forceps polypectomY among small POLYPs in rates of complete resection: the TINYPOLYP Trial. The American journal of gastroenterology Wei, M. T., Louie, C. Y., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. 2022

  Abstract

  BACKGROUND: Optimizing complete resection during colonoscopy is important as residual neoplastic tissue may play a role in interval cancers. The United States Multi-Society Task Force recommends diminutive (<5mm) and small (6-9mm) polyps be removed by cold snare polypectomy (CSP). However, evidence is less clear whether CSP retains significant advantage over cold forceps polypectomy (CFP) for polyps <3mm.METHODS: This study is a single-center prospective non-inferiority randomized clinical trial evaluating CFP and CSP for nonpedunculated polyps <3mm. Patients >18 years of age undergoing colonoscopy for any indication were recruited. During each colonoscopy, polyps underwent block randomization to removal with CFP or CSP. Following polypectomy, two biopsies were taken from the polypectomy margin. The primary non-inferiority outcome was complete resection rate, defined by absence of residual polyp in the margin biopsies.RESULTS: A total of 179 patients were included. Patients had similar distribution in age, sex, race/ethnicity, as well as indication of procedure. A total of 279 polyps <3mm were identified, with 138 in the CSP group and 141 in the CFP group. Mean polypectomy time was longer for CSP compared to CFP (42.3 vs 23.2 seconds, p<0.001), though a higher proportion of polyps removed by CFP were removed in more than one piece compared to CSP (15.6 vs 3.6%, p<0.001). There were positive margin biopsies in 2 cases per cohort, with complete resection rate of 98.3% in both groups. There was no significant difference in cohorts in complete resection rates (difference in complete resection rates was 0.057%, 95% CI: -4.30 to 4.53%), demonstrating non-inferiority of CFP compared to CSP.CONCLUSIONS: Use of CFP was non-inferior to CSP in the complete resection of nonpedunculated polyps <3mm. CSP required significantly more time to perform compared to CFP. CFP should be considered an acceptable alternative to CSP for removal of polyps <3mm.

  View details for DOI 10.14309/ajg.0000000000001799

  View details for PubMedID 35467557

• Towards high reliability in national pathology education: Evaluating the United States and Canadian Academy of Pathology educational product. Academic pathology Harris, C. K., Chen, Y., Jensen, K. C., Hornick, J. L., Kilfoyle, C., Lamps, L. W., Heher, Y. K. 2022; 9 (1): 100048

  Abstract

  The United States and Canadian Academy of Pathology (USCAP) leadership undertook a high level, global review of educational product outcomes data using high reliability organization (HRO) principles: preoccupation with failure; reluctance to simplify; sensitivity to operations; commitment to resilience; and deference to expertise. HRO principles have long been applied to fields such as aviation, nuclear power, and more recently to healthcare, yet they are rarely applied to the field that underpins these-and many other-complex systems: education. While errors in education are less calamitous than in air travel or healthcare delivery, USCAP's educational products impact over 15,000 learners a year, and thus have important implications for the future practice of pathology. Here we report USCAP's experiences using HRO principles to evaluate our keystone educational product, the "USCAP Short Course." Following this novel method of data review, USCAP leadership was able to better understand diverse learner needs based on practice venue, training level, and course topic. Unexpected lessons included the identification of specifically challenging educational topics, such as molecular pathology, and a need to focus more resources on emerging fields such as quality and patient safety. The results allow USCAP to assess educational product performance using HRO tools, and provide strong data-driven decision support for future national pathology education strategy.

  View details for DOI 10.1016/j.acpath.2022.100048

  View details for PubMedID 36061265

• Evaluation of EverLift in the Performance of Cold Snare Polypectomy (CSP) for 4-9mm Polyps Wei, M. T., Louie, C., Chen, Y., Pan, J. Y., Quan, S. Y., Wong, R., Brown, R., Clark, M., Jensen, K., Lau, H., Friedland, S. LIPPINCOTT WILLIAMS & WILKINS. 2021: S130-S131

  View details for Web of Science ID 000717526100297

• Molecular profiling of a primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid. Journal of cutaneous pathology Raghavan, S., Clark, M., Louie, C., Jensen, K. C., Dietrich, B., Beadle, B. M., El-Sawy, T., Baik, F., Kunder, C. A., Brown, R. A. 2020

  Abstract

  Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/cup.13733

  View details for PubMedID 32358805

• 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

  Abstract

  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

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

  View details for Web of Science ID 000521531000011

• Androgen Receptor is Frequently Expressed by ER and HER2-Positive Breast Cancers but is Largely Restricted to Carcinomas with Apocrine Features among Triple-Negative/Basal-Like Breast Cancers Limiting its Predictive Value Thomason, J., Dhungana, N., Jensen, K. C., Bellizzi, A. NATURE PUBLISHING GROUP. 2018: 109

  View details for Web of Science ID 000429308600305

• The clinicopathologic and genomic features of fibrotic foci in breast cancer - results from the TCGA cohort Beca, F., Tsang, J., Jensen, K. C., Allison, K., Tse, G. NATURE PUBLISHING GROUP. 2018: 50

  View details for Web of Science ID 000429308600145

• Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast cancer research and treatment Telli, M. L., Hellyer, J. n., Audeh, W. n., Jensen, K. C., Bose, S. n., Timms, K. M., Gutin, A. n., Abkevich, V. n., Peterson, R. N., Neff, C. n., Hughes, E. n., Sangale, Z. n., Jones, J. n., Hartman, A. R., Chang, P. J., Vinayak, S. n., Wenstrup, R. n., Ford, J. M. 2018; 168 (3): 625–30

  Abstract

  Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52-11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65-160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%).HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.

  View details for PubMedID 29275435

• 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

  Abstract

  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

• Characteristics and clinical outcomes of pleomorphic lobular carcinoma in situ of the breast BREAST JOURNAL Fasola, C. E., Chen, J., Jensen, K. C., Allison, K. H., Horst, K. C. 2018; 24 (1): 66–69

  Abstract

  Pleomorphic lobular carcinoma in situ (PLCIS) of the breast is a rare variant of lobular carcinoma in situ (LCIS). We reviewed 78 cases of PLCIS diagnosed at our institution from 1998 to 2012. Among all cases, 47 (60%) were associated with invasive carcinoma and/or ductal carcinoma in situ (DCIS) after final surgical excision. Of the 20 cases with PLCIS alone on core needle biopsy (CNB), 6 (30%) were upgraded to invasive carcinoma or DCIS after final surgical excision. Our findings support a recommendation for complete surgical excision of PLCIS when diagnosed on CNB.

  View details for PubMedID 28929550

• Comparison of Estrogen and Progesterone Receptor Antibody Reagents Using Proficiency Testing Data ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Troxell, M. L., Long, T., Hornick, J. L., Ambaye, A. B., Jensen, K. C. 2017; 141 (10): 1402–12

  Abstract

  - Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PgR) expression in breast cancer is the current standard of care and directly determines therapy. In 2010 the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) published guidelines for ER and PgR predictive testing, encompassing preanalytic, analytic, postanalytic factors; antibody validation; and proficiency testing.- To compare the performance of different antibody reagents for ER and PgR immunohistochemical analysis by using CAP proficiency testing data.- The CAP PM2 survey uses tissue microarrays of ten 2-mm cores per slide. We analyzed survey data from 80 ER and 80 PgR cores by antibody clone from more than 1200 laboratories.- Laboratories used the ER antibodies SP1 (72%), 6F11 (17%), 1D5 (3%), and the PgR antibodies 1E2 (61%), 16 (12%), PgR-636 (13%), PgR-1294 (8%) in 2015. While 63 of 80 ER cores (79%) were scored similarly using each of the 3 antibodies, there were significant differences for others, with SP1 yielding more positive interpretations. Four cores were scored as ER negative by more than half of the laboratories using 1D5 or 6F11, while SP1 produced positive results in more than 70% of laboratories using that antibody. Despite the greater variety of PgR antibody reagents and greater PgR tumor heterogeneity, 61 of 80 cores (76%) were scored similarly across the 4 PgR antibodies.- Accurate ER and PgR testing in breast cancer is crucial for appropriate treatment. The CAP proficiency testing data demonstrate differences in staining results by ER clone, with SP1 yielding more positive results.

  View details for DOI 10.5858/arpa.2016-0497-OA

  View details for Web of Science ID 000417030000010

  View details for PubMedID 28714765

• Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics. Clinical cancer research : an official journal of the American Association for Cancer Research Sin, M. L., Mach, K. E., Sinha, R., Wu, F., Trivedi, D., Altobelli, E., Jensen, K. C., Sahoo, D., Lu, Y., Liao, J. C. 2017

  Abstract

  The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance.RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients (n=13) and controls (n=10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines.418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (PBC) based on expression of 3-markers (ROBO1, WNT5A, and CDC42BPB). Setting PBC=0.45 as the cutoff for a positive test, urine testing using the 3-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the 3-marker panel in the independent validation cohort yielded an area under the curve of 0.87 and overall 83% sensitivity and 89% specificity.Urine-based molecular diagnostics using this 3-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis.

  View details for DOI 10.1158/1078-0432.CCR-16-2610

  View details for PubMedID 28193625

• 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study MODERN PATHOLOGY Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2017; 30 (2): 227-235

  Abstract

  The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

  View details for DOI 10.1038/modpathol.2016.175

  View details for Web of Science ID 000393257400007

• The molecular basis of breast cancer pathological phenotypes. journal of pathology Heng, Y. J., Lester, S. C., Tse, G. M., Factor, R. E., Allison, K. H., Collins, L. C., Chen, Y., Jensen, K. C., Johnson, N. B., Jeong, J. C., Punjabi, R., Shin, S. J., Singh, K., Krings, G., Eberhard, D. A., Tan, P. H., Korski, K., Waldman, F. M., Gutman, D. A., Sanders, M., Reis-Filho, J. S., Flanagan, S. R., Gendoo, D. M., Chen, G. M., Haibe-Kains, B., Ciriello, G., Hoadley, K. A., Perou, C. M., Beck, A. H. 2017; 241 (3): 375-391

  Abstract

  The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  View details for DOI 10.1002/path.4847

  View details for PubMedID 27861902

• Tumor BRCA1 Reversion Mutation Arising During Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research Afghahi, A., Timms, K. M., Vinayak, S., Jensen, K. C., Kurian, A. W., Carlson, R. W., Chang, P., Schackmann, E. A., Hartman, A., Ford, J. M., Telli, M. L. 2017

  Abstract

  In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy.PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was re-sequenced in the residual surgical breast tumor tissue.Nineteen patients had a deleterious germline BRCA1/2 mutation and 4 had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA and W1712X mutations, respectively, with loss of heterozygosity at these loci in the pre-treatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14 amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy four months later revealed the identical reversion mutation, and the patient subsequently died of metastatic breast cancer.We report a BRCA1 reversion mutation in a newly diagnosed triple-negative breast cancer patient that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse and death.

  View details for DOI 10.1158/1078-0432.CCR-16-2174

  View details for PubMedID 28087643

• Spectroscopic Photoacoustic Molecular Imaging of Breast Cancer using a B7-H3-targeted ICG Contrast Agent THERANOSTICS Wilson, K. E., Bachawal, S. V., Abou-Elkacem, L., Jensen, K., Machtaler, S., Tian, L., Willmann, J. K. 2017; 7 (6): 1463-1476

  Abstract

  Purpose: Breast cancer imaging methods lack diagnostic accuracy, in particular for patients with dense breast tissue, and improved techniques are critically needed. The purpose of this study was to evaluate antibody-indocyanine green (ICG) conjugates, which undergo dynamic absorption spectrum shifts after cellular endocytosis and degradation, and spectroscopic photoacoustic (sPA) imaging to differentiate normal breast tissue from breast cancer by imaging B7-H3, a novel breast cancer associated molecular target. Methods: Quantitative immunohistochemical staining of endothelial and epithelial B7-H3 expression was assessed in 279 human breast tissue samples, including normal (n=53), benign lesions (11 subtypes, n=129), and breast cancers (4 subtypes, n=97). After absorption spectra of intracellular and degraded B7-H3-ICG and Isotype control-ICG (Iso-ICG) were characterized, sPA imaging in a transgenic murine breast cancer model (FVB/N-Tg(MMTVPyMT)634Mul) was performed and compared to imaging of control conditions [B7-H3-ICG in tumor negative animals (n=60), Iso-ICG (n=30), blocking B7-H3+B7-H3-ICG (n=20), and free ICG (n=20)] and validated with ex vivo histological analysis. Results: Immunostaining showed differential B7-H3 expression on both the endothelium and tumor epithelium in human breast cancer with an area under the ROC curve of 0.93 to differentiate breast cancer vs non-cancer. Combined in vitro/in vivo imaging showed that sPA allowed specific B7-H3-ICG detection down to the 13 nM concentration and differentiation from Iso-ICG. sPA molecular imaging of B7-H3-ICG showed a 3.01-fold (P<0.01) increase in molecular B7-H3-ICG signal in tumors compared to control conditions. Conclusions: B7-H3 is a promising target for both vascular and epithelial sPA imaging of breast cancer. Leveraging antibody-ICG contrast agents and their dynamic optical absorption spectra allows for highly specific sPA imaging of breast cancer.

  View details for DOI 10.7150/thno.18217

  View details for Web of Science ID 000398783200005

  View details for PubMedID 28529630

• Regional Variability in Percentage of Breast Cancers Reported as Positive for HER2 in California: Implications of Patient Demographics on Laboratory Benchmarks. American journal of clinical pathology Lin, C. Y., Carneal, E. E., Lichtensztajn, D. Y., Gomez, S. L., Clarke, C. A., Jensen, K. C., Kurian, A. W., Allison, K. H. 2017; 148 (3): 199–207

  Abstract

  The expected regional variability in percent human epidermal growth factor receptor 2 (HER2)-positive breast cancers is not currently clear.Data from the 2006 to 2011 California Cancer Registry were examined by county and health service area. The influence of demographic and pathologic features was used in a multivariable logistic regression model to compare expected with observed HER2-positive percentages by region.There was significant geographic variation by California counties (11.6%-26%). The reported HER2-positive percentage was higher when the population had higher stage, tumor size, grade, percent estrogen receptor negative, younger age, or lower socioeconomic status. Ethnic distribution of the population also influenced HER2-positive percentages. Using a multivariable logistic regression model, most regions had expected values based on their population characteristics; however, "outlier" regions were identified.These results deepen our understanding of population characteristics' influence on the distribution of HER2-positive breast cancers. Taking these factors into account can be useful when setting laboratory benchmarks and assessing test quality.

  View details for PubMedID 28821197

• 'Non-classical' HER2 FISH results in breast cancer: a multi-institutional study. Modern pathology Ballard, M., Jalikis, F., Krings, G., Schmidt, R. A., Chen, Y., Rendi, M. H., Dintzis, S. M., Jensen, K. C., West, R. B., Sibley, R. K., Troxell, M. L., Allison, K. H. 2016

  Abstract

  The 2013 CAP/ASCO HER2 Testing Guidelines Update modified HER2 FISH categories such that some cases with 'monosomy', 'co-amplification/polysomy', low-level increased HER2 signals or clustered heterogeneity now are considered amplified or equivocal. This study examines the frequency and clinico-pathologic characteristics of breast cancers with equivocal or 'non-classical' HER2 FISH results. Breast cancers (2001-2014) with HER2 FISH results, HER2 immunohistochemistry, ER, grade, and age from three institutions (Stanford, UCSF, UWMC) were collected. HER2 FISH was interpreted using the updated recommendations. Amplified cases with non-classical results were grouped into the following categories: (1) 'monosomy' (ratio ≥2.0, mean HER2/cell<4.0); (2) 'co-amplified' (ratio<2.0, mean HER2/cell ≥6.0); (3) 'low amplified' (ratio ≥2.0, mean HER2/cell 4.0-5.9). Heterogeneous cases with clustered HER2-positive cells were also included. Of 8068 cases, 5.2% were equivocal and 4.6% had a 'non-classical' HER2 amplified result; 1.4% 'monosomy', 0.8% 'co-amplified', 2.1% 'low amplified', and 0.3% clustered heterogeneity. These cancers had a high frequency of ER positive (80.4%), Nottingham grade 3 (52.1%) results. The highest percentage of grade 3 cancers (66.7%) and positive HER2 immunohistochemistry (31.7%) was in the 'co-amplified' group. The 'monosomy' group had the highest percent grade 1 cancers (13.3%) and was most frequently HER2 immunohistochemistry negative (30.1%). Equivocal cases had very similar characteristics to the 'low-amplified' category. Cases with non-classical HER2 amplification or equivocal results are typically ER positive, higher grade cancers. 'Co-amplified' cases have the highest frequencies of aggressive characteristics and 'monosomy' cases the highest frequencies of lower risk features. With little clinical outcomes data currently available on these non-classical HER2 results, these results support the current classification scheme for HER2 FISH, with case-by-case correlation with additional clinical-pathologic factors when evaluating whether to offer HER2-targeted therapies in these non-classical cases.Modern Pathology advance online publication, 14 October 2016; doi:10.1038/modpathol.2016.175.

  View details for DOI 10.1038/modpathol.2016.175

  View details for PubMedID 27739440

• Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clinical cancer research Telli, M. L., Timms, K. M., Reid, J., Hennessy, B., Mills, G. B., Jensen, K. C., Szallasi, Z., Barry, W. T., Winer, E. P., Tung, N. M., Isakoff, S. J., Ryan, P. D., Greene-Colozzi, A., Gutin, A., Sangale, Z., Iliev, D., Neff, C., Abkevich, V., Jones, J. T., Lanchbury, J. S., Hartman, A., Garber, J. E., Ford, J. M., Silver, D. P., Richardson, A. L. 2016; 22 (15): 3764-3773

  Abstract

  BRCA1/2 mutated and some sporadic triple negative breast cancers (TNBCs) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed based on loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score {greater than or equal to}42 or BRCA1/2 mutation, with response to platinum-based therapy.In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted Residual Cancer Burden score of 0 or 1 (RCB 0/1) and pathologic complete response (pCR) (OR=4.96, p=0.0036; OR=6.52, p=0.0058). HR deficiency remained a significant predictor of RCB 0/1 when adjusted for clinical variables (OR=5.86, p=0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/1 and pCR (OR=10.18, p=0.0011; OR=17.00, p=0.0066). In a multivariable model of RCB 0/1, HR deficiency retained significance when clinical variables were included (OR=12.08, p=0.0017). When restricted to BRCA1/2 non-mutated tumors, response was higher in patients with high HRD scores: RCB 0/1 p=0.062, pCR p=0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/1 p=0.0039, pCR p=0.018 in the neoadjuvant cisplatin trials.HR deficiency identifies TNBC tumors, including BRCA1/2 non-mutated tumors more likely to respond to platinum-containing therapy.

  View details for DOI 10.1158/1078-0432.CCR-15-2477

  View details for PubMedID 26957554

• How Good Is Good Enough? Lymph Node Metastasis After Endoscopic Resection of a Rectosigmoid Polyp. Digestive diseases and sciences Holmes, I., Triadafilopoulos, G., Jensen, K., Friedland, S. 2016; 61 (3): 704-707

  View details for DOI 10.1007/s10620-015-3785-7

  View details for PubMedID 26134989

• Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer CELL Ciriello, G., Gatza, M. L., Beck, A. H., Wilkerson, M. D., Rhie, S. K., Pastore, A., Zhang, H., McLellan, M., Yau, C., Kandoth, C., Bowlby, R., Shen, H., Hayat, S., Fieldhouse, R., Lester, S. C., Tse, G. M., Factor, R. E., Collins, L. C., Allison, K. H., Chen, Y., Jensen, K., Johnson, N. B., Oesterreich, S., Mills, G. B., Cherniack, A. D., Robertson, G., Benz, C., Sander, C., Laird, P. W., Hoadley, K. A., King, T. A., Perou, C. M. 2015; 163 (2): 506-519

  Abstract

  Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

  View details for DOI 10.1016/j.cell.2015.09.033

  View details for Web of Science ID 000362952700023

  View details for PubMedID 26451490

  View details for PubMedCentralID PMC4603750

• Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer BREAST CANCER RESEARCH Afghahi, A., Forgo, E., Mitani, A. A., Desai, M., Varma, S., Seto, T., Rigdon, J., Jensen, K. C., Troxell, M. L., Gomez, S. L., Das, A. K., Beck, A. H., Kurian, A. W., West, R. B. 2015; 17

  Abstract

  Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

  View details for DOI 10.1186/s13058-015-0623-y

  View details for Web of Science ID 000359348400001

  View details for PubMedID 26265211

  View details for PubMedCentralID PMC4534146

• Breast Cancer Detection by B7-H3-Targeted Ultrasound Molecular Imaging. Cancer research Bachawal, S. V., Jensen, K. C., Wilson, K. E., Tian, L., Lutz, A. M., Willmann, J. K. 2015; 75 (12): 2501-2509

  Abstract

  Ultrasound complements mammography as an imaging modality for breast cancer detection, especially in patients with dense breast tissue, but its utility is limited by low diagnostic accuracy. One emerging molecular tool to address this limitation involves contrast-enhanced ultrasound using microbubbles targeted to molecular signatures on tumor neovasculature. In this study, we illustrate how tumor vascular expression of B7-H3 (CD276), a member of the B7 family of ligands for T-cell coregulatory receptors, can be incorporated into an ultrasound method that can distinguish normal, benign, precursor, and malignant breast pathologies for diagnostic purposes. Through an IHC analysis of 248 human breast specimens, we found that vascular expression of B7-H3 was selectively and significantly higher in breast cancer tissues. B7-H3 immunostaining on blood vessels distinguished benign/precursors from malignant lesions with high diagnostic accuracy in human specimens. In a transgenic mouse model of cancer, the B7-H3-targeted ultrasound imaging signal was increased significantly in breast cancer tissues and highly correlated with ex vivo expression levels of B7-H3 on quantitative immunofluorescence. Our findings offer a preclinical proof of concept for the use of B7-H3-targeted ultrasound molecular imaging as a tool to improve the diagnostic accuracy of breast cancer detection in patients. Cancer Res; 75(12); 2501-9. ©2015 AACR.

  View details for DOI 10.1158/0008-5472.CAN-14-3361

  View details for PubMedID 25899053

  View details for PubMedCentralID PMC4470725

• Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. Journal of clinical oncology Telli, M. L., Jensen, K. C., Vinayak, S., Kurian, A. W., Lipson, J. A., Flaherty, P. J., Timms, K., Abkevich, V., Schackmann, E. A., Wapnir, I. L., Carlson, R. W., Chang, P., Sparano, J. A., Head, B., Goldstein, L. J., Haley, B., Dakhil, S. R., Reid, J. E., Hartman, A., Manola, J., Ford, J. M. 2015; 33 (17): 1895-1901

  Abstract

  This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

  View details for DOI 10.1200/JCO.2014.57.0085

  View details for PubMedID 25847929

• Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105 JOURNAL OF CLINICAL ONCOLOGY Telli, M. L., Jensen, K. C., Vinayak, S., Kurian, A. W., Lipson, J. A., Flaherty, P. J., Timms, K., Abkevich, V., Schackmann, E. A., Wapnir, I. L., Carlson, R. W., Chang, P., Sparano, J. A., Head, B., Goldstein, L. J., Haley, B., Dakhil, S. R., Reid, J. E., Hartman, A., Manola, J., Ford, J. M. 2015; 33 (17): 1895-U57

  Abstract

  This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

  View details for DOI 10.1200/JCO.2014.57.0085

  View details for Web of Science ID 000355999800009

  View details for PubMedID 25847929

• Initial results with preoperative tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast cancer patients. Annals of surgical oncology Choy, N., Lipson, J., Porter, C., Ozawa, M., Kieryn, A., Pal, S., Kao, J., Trinh, L., Wheeler, A., Ikeda, D., Jensen, K., Allison, K., Wapnir, I. 2015; 22 (2): 377-382

  Abstract

  Pretreatment evaluation of axillary lymph nodes (ALNs) and marking of biopsied nodes in patients with newly diagnosed breast cancer is becoming routine practice. We sought to test tattooing of biopsied ALNs with a sterile black carbon suspension (Spot™). The intraoperative success of identifying tattooed ALNs and their concordance to sentinel nodes was determined.Women with suspicious ALNs and newly diagnosed breast cancer underwent palpation and/or ultrasound-guided fine needle aspiration or core needle biopsy, followed by injection of 0.1 to 0.5 ml of Spot™ ink into the cortex of ALNs and adjacent soft tissue. Group I underwent surgery first, and group II underwent neoadjuvant therapy followed by surgery. Identification of black pigment and concordance between sentinel and tattooed nodes was evaluated.Twenty-eight patients were tattooed, 16 in group I and 12 in group II. Seventeen cases had evidence of atypia or metastases, 8 (50 %) in group I and 9 (75 %) in group II. Average number of days from tattooing to surgery was 22.9 (group I) and 130 (group II). Black tattoo ink was visualized intraoperatively in all cases, except one case with microscopic black pigment only. Fourteen group I and 10 group II patients had black pigment on histological examination of ALNs. Sentinel nodes corresponded to tattooed nodes in all except one group I patient with a tattooed non-sentinel node.Tattooed nodes are visible intraoperatively, even months later. This approach obviates the need for additional localization procedures during axillary staging.

  View details for DOI 10.1245/s10434-014-4034-6

  View details for PubMedID 25164040

• Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer. Breast cancer research Afghahi, A., Forgó, E., Mitani, A. A., Desai, M., Varma, S., Seto, T., Rigdon, J., Jensen, K. C., Troxell, M. L., Gomez, S. L., Das, A. K., Beck, A. H., Kurian, A. W., West, R. B. 2015; 17: 108-?

  Abstract

  Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.

  View details for DOI 10.1186/s13058-015-0623-y

  View details for PubMedID 26265211

• Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III. Cancer research Emlet, D. R., Gupta, P., Holgado-Madruga, M., Del Vecchio, C. A., Mitra, S. S., Han, S., Li, G., Jensen, K. C., Vogel, H., Xu, L. W., Skirboll, S. S., Wong, A. J. 2014; 74 (4): 1238-1249

  Abstract

  The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII- cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

  View details for DOI 10.1158/0008-5472.CAN-13-1407

  View details for PubMedID 24366881

• A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. Breast cancer research and treatment Vinayak, S., Schwartz, E. J., Jensen, K., Lipson, J., Alli, E., McPherson, L., Fernandez, A. M., Sharma, V. B., Staton, A., Mills, M. A., Schackmann, E. A., Telli, M. L., Kardashian, A., Ford, J. M., Kurian, A. W. 2013; 142 (2): 389-398

  Abstract

  Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

  View details for DOI 10.1007/s10549-013-2739-z

  View details for PubMedID 24166281

• Radiologic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status. Radiotherapy and oncology Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Le, Q. 2013; 109 (2): 293-296

  Abstract

  Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, ⩾3 involved cervical LN, and ⩾1 involved contralateral LN, or lateral/posterior subsites.

  View details for DOI 10.1016/j.radonc.2013.09.001

  View details for PubMedID 24103114

• Radio logic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status RADIOTHERAPY AND ONCOLOGY Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Quynh-Thu Le, Q. T. 2013; 109 (2): 293-296

  Abstract

  Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, ⩾3 involved cervical LN, and ⩾1 involved contralateral LN, or lateral/posterior subsites.

  View details for DOI 10.1016/j.radonc.2013.09.001

  View details for Web of Science ID 000329019900020

• EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene Del Vecchio, C. A., Giacomini, C. P., Vogel, H., Jensen, K. C., Florio, T., Merlo, A., Pollack, J. R., Wong, A. J. 2013; 32 (21): 2670-2681

  Abstract

  Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.

  View details for DOI 10.1038/onc.2012.280

  View details for PubMedID 22797070

• Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model CANCER RESEARCH Bachawal, S. V., Jensen, K. C., Lutz, A. M., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 73 (6): 1689-1698

  Abstract

  While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.

  View details for DOI 10.1158/0008-5472.CAN-12-3391

  View details for Web of Science ID 000316187500006

  View details for PubMedID 23328585

  View details for PubMedCentralID PMC3602408

• Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma CANCER CELL Kopp, J. L., von Figura, G., Mayes, E., Liu, F., Dubois, C. L., Morris, J. P., Pan, F. C., Akiyama, H., Wright, C. V., Jensen, K., Hebrok, M., Sander, M. 2012; 22 (6): 737-750

  Abstract

  Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

  View details for DOI 10.1016/j.ccr.2012.10.025

  View details for Web of Science ID 000312467000007

  View details for PubMedID 23201164

• Radiologic Assessment of Lymph Node Involvement in HPV/p16+Oropharyngeal Cancers 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Tang, C., Komakula, S., Chan, C., Murphy, J., Kong, C., Jensen, K., Le, Q. ELSEVIER SCIENCE INC. 2012: S473–S473

  View details for Web of Science ID 000310542901391

• Chest Wall Leiomyosarcoma After Breast-Conservative Therapy for Early-Stage Breast Cancer in a Young Woman With Li-Fraumeni Syndrome JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Henry, E., Villalobos, V., Million, L., Jensen, K. C., West, R., Ganjoo, K., Lebensohn, A., Ford, J. M., Telli, M. L. 2012; 10 (8): 939-942

  Abstract

  Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

  View details for PubMedID 22878818

• Methods for registration of magnetic resonance images of ex vivo prostate specimens with histology JOURNAL OF MAGNETIC RESONANCE IMAGING Kimm, S. Y., Tarin, T. V., Lee, J. H., Hu, B., Jensen, K., Nishimura, D., Brooks, J. D. 2012; 36 (1): 206-212

  Abstract

  To evaluate two methods of scanning and tissue processing to achieve accurate magnetic resonance (MR)-histologic correlation in human prostate specimens.Two prostates had acrylic paint markers injected to define the plane of imaging and serve as internal fiducials. Each was placed on a polycarbonate plane-finder device (PFD), which was adjusted to align the imaging and cutting planes. Three prostates were aligned by use of a plane finder key (PFK), a polycarbonate plate that locks the specimen in a cylindrical carrier. Markers were injected for registration analysis. Prostates were imaged, then sectioned. Imaging software was used to create registration maps of the MR and histology images. Measurements between control points were made and compared.Accurate correlation was achieved between MR and histologic images. The mean displacement (MD) between the corresponding registration points using the PFD technique ranged from 1.11-1.38 mm for each section. The MD for all sections was 1.24 mm. The MD using the PFK technique ranged from 0.79-1.01 mm for each section, and the MD across all sections for the PFK was 0.92 mm.We describe two methods that can achieve accurate, reproducible correlation between MR imaging and histologic sections in human prostatectomy specimens.

  View details for DOI 10.1002/jmri.23614

  View details for PubMedID 22359365

• Dietary Vitamin D-3 and 1,25-Dihydroxyvitamin D-3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer ENDOCRINOLOGY Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Horst, R., Albertelli, M. A., Feldman, D. 2012; 153 (6): 2576-2587

  Abstract

  1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1α-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 μg/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 μg and 0.1 μg caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D(3). Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

  View details for DOI 10.1210/en.2011-1600

  View details for Web of Science ID 000304370700010

  View details for PubMedID 22454149

  View details for PubMedCentralID PMC3359605

• Epidermal Growth Factor Receptor Variant III Contributes to Cancer Stem Cell Phenotypes in Invasive Breast Carcinoma CANCER RESEARCH Del Vecchio, C. A., Jensen, K. C., Nitta, R. T., Shain, A. H., Giacomini, C. P., Wong, A. J. 2012; 72 (10): 2657-2671

  Abstract

  EGFRvIII is a tumor-specific variant of the epidermal growth factor receptor (EGFR). Although EGFRvIII is most commonly found in glioblastoma, its expression in other tumor types remains controversial. In this study, we investigated EGFRvIII expression and amplification in primary breast carcinoma. Our analyses confirmed the presence of EGFRvIII, but in the absence of amplification or rearrangement of the EGFR locus. Nested reverse transcriptase PCR and flow cytometry were used to detect a higher percentage of positive cases. EGFRvIII-positive cells showed increased expression of genes associated with self-renewal and epithelial-mesenchymal transition along with a higher percentage of stem-like cells. EGFRvIII also increased in vitro sphere formation and in vivo tumor formation. Mechanistically, EGFRvIII mediated its effects through the Wnt/β-catenin pathway, leading to increased β-catenin target gene expression. Inhibition of this pathway reversed the observed effects on cancer stem cell (CSC) phenotypes. Together, our findings show that EGFRvIII is expressed in primary breast tumors and contributes to CSC phenotypes in breast cancer cell lines through the Wnt pathway. These data suggest a novel function for EGFRvIII in breast tumorigenesis.

  View details for DOI 10.1158/0008-5472.CAN-11-2656

  View details for Web of Science ID 000307346800020

  View details for PubMedID 22419663

• Next generation of optical diagnostics for bladder cancer using probe-based confocal laser endomicroscopy Conference on Photonic Therapeutics and Diagnostics VIII Liu, J., Chang, T. C., Pan, Y., Hsiao, S. T., Mach, K. E., Jensen, K. C., Liao, J. C. SPIE-INT SOC OPTICAL ENGINEERING. 2012

  View details for DOI 10.1117/12.907623

  View details for Web of Science ID 000302580900030

• A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272

  Abstract

  To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

  View details for DOI 10.1158/1078-0432.CCR-11-0179

  View details for PubMedID 21998334

• Dynamic Real-time Microscopy of the Urinary Tract Using Confocal Laser Endomicroscopy UROLOGY Wu, K., Liu, J., Adams, W., Sonn, G. A., Mach, K. E., Pan, Y., Beck, A. H., Jensen, K. C., Liao, J. C. 2011; 78 (1): 225-231

  Abstract

  To develop the diagnostic criteria for benign and neoplastic conditions of the urinary tract using probe-based confocal laser endomicroscopy (pCLE), a new technology for dynamic, in vivo imaging with micron-scale resolution. The suggested diagnostic criteria will formulate a guide for pCLE image interpretation in urology.Patients scheduled for transurethral resection of bladder tumor (TURBT) or nephrectomy were recruited. After white-light cystoscopy (WLC), fluorescein was administered as contrast. Different areas of the urinary tract were imaged with pCLE via direct contact between the confocal probe and the area of interest. Confocal images were subsequently compared with standard hematoxylin and eosin analysis.pCLE images were collected from 66 participants, including 2 patients who underwent nephrectomy. We identified key features associated with different anatomic landmarks of the urinary tract, including the kidney, ureter, bladder, prostate, and urethra. In vivo pCLE of the bladder demonstrated distinct differences between normal mucosa and neoplastic tissue. Using mosaicing, a post hoc image-processing algorithm, individual image frames were juxtaposed to form wide-angle views to better evaluate tissue microarchitecture.In contrast to standard pathologic analysis of fixed tissue with hematoxylin and eosin, pCLE provides real time microscopy of the urinary tract to enable dynamic interrogation of benign and neoplastic tissues in vivo. The diagnostic criteria developed in this study will facilitate adaptation of pCLE for use in conjunction with WLC to expedite diagnosis of urinary tract pathology, particularly bladder cancer.

  View details for DOI 10.1016/j.urology.2011.02.057

  View details for Web of Science ID 000292080300062

  View details for PubMedID 21601243

  View details for PubMedCentralID PMC4038103

• Comparison of 2.6-and 1.4-mm Imaging Probes for Confocal Laser Endomicroscopy of the Urinary Tract JOURNAL OF ENDOUROLOGY Adams, W., Wu, K., Liu, J., Hsiao, S. T., Jensen, K. C., Liao, J. C. 2011; 25 (6): 917-921

  Abstract

  Probe-based confocal laser endomicroscopy (pCLE) is an emerging technology for dynamic, in vivo imaging of the urinary tract with micron-scale resolution. We conducted a comparative analysis of pCLE with a 2.6-mm probe and a 1.4-mm probe that is compatible with flexible endoscopes.Sixty-seven patients scheduled for bladder tumor resection were recruited. pCLE imaging was performed using 2.6- and 1.4-mm probes. Image quality with the different probes was examined and further compared with standard histopathology.Images with the 2.6-mm probe have better resolution of cell morphology. The 1.4-mm probe has a wider field of view and better view of microarchitecture. While image quality with the 2.6-mm probe is superior, the 1.4-mm probe is compatible with flexible cystoscopy and maneuverability is maintained, enabling imaging of areas of the bladder that were previously challenging to access with the larger probe.The optical specifications of the 2.6-mm probe are more suitable for distinguishing urinary tract histopathology. Further design optimization to improve resolution and additional validation of the diagnostic accuracy of the smaller probe are needed to help extend application of pCLE for optical biopsy of the upper and lower urinary tract.

  View details for DOI 10.1089/end.2010.0686

  View details for Web of Science ID 000291553500004

  View details for PubMedID 21568756

• Real Time Diagnosis of Bladder Cancer with Probe-Based Confocal Laser Endomicroscopy Conference on Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues IX Liu, J., Wu, K., Adams, W., Hsiao, S. T., Mach, K. E., Beck, A. H., Jensen, K. C., Liao, J. C. SPIE-INT SOC OPTICAL ENGINEERING. 2011

  View details for DOI 10.1117/12.874243

  View details for Web of Science ID 000297677500045

• DYNAMIC REAL TIME MICROSCOPY OF THE URINARY TRACT: AN IMAGING ATLAS BASED ON CONFOCAL LASER ENDOMICROSCOPY Adams, W., Wu, K., Sonn, G., Jensen, K., Liao, J. C. MARY ANN LIEBERT INC. 2010: A278–A278

  View details for Web of Science ID 000283864901225

• Variations in Stromal Signatures in Breast Cancer Metastases 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Webster, J. A., Beck, A. H., Sharma, M., Espinosa, I., Schreuder, M., Montgomery, K. D., Jensen, K. C., van de Rijn, M., West, R. B. NATURE PUBLISHING GROUP. 2010: 77A–77A

  View details for Web of Science ID 000274582500335

• HER2 Intermediate Breast Cancers AMERICAN JOURNAL OF SURGICAL PATHOLOGY Jensen, K. C., Nielsen, T. O., Gilks, C. B., West, R. B. 2009; 33 (11): 1739-1739

  View details for Web of Science ID 000271795800022

  View details for PubMedID 19745698

• Modulation of Vitamin D Receptor Activity by the Corepressor Hairless: Differential Effects of Hairless Isoforms ENDOCRINOLOGY Malloy, P. J., Wang, J., Jensen, K., Feldman, D. 2009; 150 (11): 4950-4957

  Abstract

  The vitamin D receptor (VDR) and its corepressor Hairless (HR) are thought to regulate key steps in the hair cycle because mutations in VDR or HR cause alopecia in humans and mice. Many mammalian cells express two major HR isoforms due to alternative splicing of exon 17. HR isoform-a encodes an 1189-amino acid protein (full-length HR), and isoform-b encodes an 1134-amino acid protein (HRDelta1072-1126). We demonstrated that both HR isoforms are expressed in primary human keratinocytes and in the human keratinocyte cell line HaCaT. In transfected COS-7 cells, the full-length HR repressed VDR-mediated transactivation. In contrast, HRDelta1072-1126 failed to suppress and even stimulated VDR-mediated transactivation. In coimmunoprecipitation, both HR isoforms interacted with the VDR, but only the full-length HR interacted with histone deacetylase 1 (HDAC1). Alanine mutagenesis of two conserved glutamic acids residues (E1100A/E1101A) encoded by exon 17 completely eliminated HR corepressor activity and interactions with HDAC1. When the two HR isoforms were coexpressed in COS-7 cells, the corepressor activity of the full-length HR was not antagonized by the HRDelta1072-1126 isoform. When transfected into HaCaT cells, the full-length HR inhibited endogenous CYP24A1 basal gene expression as well as 1,25-dihydroxyvitamin D3-stimulated CYP24A1 expression. HRDelta1072-1126 failed to suppress basal or 1,25-dihydroxyvitamin D3-stimulated CYP24A1 gene expression. In conclusion, we have demonstrated that both HR isoforms are expressed in keratinocytes and that the HRDelta1072-1126 isoform lacks corepressor activity and is unable to bind HDACs. HRDelta1072-1126 may function as a coactivator in some settings by inhibiting HDAC recruitment to the VDR transcriptional complex.

  View details for DOI 10.1210/en.2009-0358

  View details for Web of Science ID 000271007700015

  View details for PubMedID 19819974

  View details for PubMedCentralID PMC2775984

• Optical Biopsy of Human Bladder Neoplasia With In Vivo Confocal Laser Endomicroscopy JOURNAL OF UROLOGY Sonn, G. A., Jones, S. E., Tarin, T. V., Du, C. B., Mach, K. E., Jensen, K. C., Liao, J. C. 2009; 182 (4): 1299-1305

  Abstract

  Confocal laser endomicroscopy is a new endoscopic imaging technology that could complement white light cystoscopy by providing in vivo bladder histopathology. We evaluated confocal laser endomicroscopy by imaging normal, malignant appearing and indeterminate bladder mucosa in a pilot study.Patients scheduled to undergo transurethral resection of bladder tumors were recruited during a 3-month period. After standard cystoscopy fluorescein was administered intravesically and/or intravenously as a contrast dye. A 2.6 mm probe based confocal laser endomicroscope was passed through a 26 Fr resectoscope to image normal and abnormal appearing areas. The images were collected with 488 nm excitation at 8 to 12 frames per second. The endomicroscopic images were compared with standard hematoxylin and eosin analysis of transurethral resection of bladder tumor specimens.Of the 27 recruited patients 8 had no cancer, 9 had low grade tumors, 9 had high grade tumors and 1 had a low grade tumor with a high grade focus. Endomicroscopic images demonstrated clear differences between normal mucosa, and low and high grade tumors. In normal urothelium larger umbrella cells are seen most superficially followed by smaller intermediate cells and the less cellular lamina propria. In contrast, low grade papillary tumors demonstrate densely arranged but normal-shaped small cells extending outward from fibrovascular cores. High grade tumors show markedly irregular architecture and cellular pleomorphism.We report the first study to our knowledge of in vivo confocal laser endomicroscopy in the urinary tract. Marked differences among normal urothelium, low grade tumors and high grade tumors were visualized. Pending further clinical investigation and technological improvement, confocal laser endomicroscopy may become a useful adjunct to conventional cystoscopy.

  View details for DOI 10.1016/j.juro.2009.06.039

  View details for Web of Science ID 000269764100016

  View details for PubMedID 19683270

• OPTICAL BIOPSY OF HUMAN BLADDER NEOPLASIA WITH IN VIVO CONFOCAL LASER ENDOMICROSCOPY 104th Annual Meeting of the American-Urological-Association Sonn, G. A., Jones, S., Mach, K. E., Du, C. B., Jensen, K., Liao, J. C. ELSEVIER SCIENCE INC. 2009: 414–15

  View details for Web of Science ID 000264448501254

• Fibered Confocal Microscopy of Bladder Tumors: An ex Vivo Study JOURNAL OF ENDOUROLOGY Sonn, G. A., Mach, K. E., Jensen, K., Hsiung, P., Jones, S., Contag, C. H., Wang, T. D., Liao, J. C. 2009; 23 (2): 197-201

  Abstract

  The inadequacy of white-light cystoscopy to detect flat bladder tumors is well recognized. Great interest exists in developing other imaging technologies to augment or supplant conventional cystoscopy. Fibered confocal microscopy offers the promise of providing in vivo histopathologic information to help distinguish malignant from benign bladder lesions. We report the initial use of this technology to visualize tumors in the human bladder.We performed ex vivo fibered confocal imaging of fresh radical cystectomy specimens using the Mauna Kea Technologies Cellvizio system. The findings were compared with results from standard histopathology.The bladders of four patients were imaged using the fibered confocal microscope. Normal and neoplastic urothelium manifested differences in cellular and vascular density.This study demonstrates the feasibility of using fibered confocal microscopy to detect histologic differences between normal and neoplastic urothelium, and establishes a foundation for the use of fiber-based confocal microscopy in clinical studies.

  View details for DOI 10.1089/end.2008.0524

  View details for Web of Science ID 000263355500005

  View details for PubMedID 19196063

• CSF-1 and Fibromatosis Expression in Stroma of Ductal Carcinoma In Situ 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Sharma, M., Espinosa, I., Beck, A. H., Webster, J. A., Montgomery, K. D., van de Rijn, M., Jensen, K. C., West, R. B. NATURE PUBLISHING GROUP. 2009: 67A–67A

  View details for Web of Science ID 000262486300290

• Gene expression profiling identifies p63 as a diagnostic marker for giant cell tumor of the bone MODERN PATHOLOGY Lee, C., Espinosa, I., Jensen, K. C., Subramanian, S., Zhu, S. X., Varma, S., Montgomery, K. D., Nielsen, T. O., van de Rijn, M., West, R. B. 2008; 21 (5): 531-539

  Abstract

  Giant cell tumor of the bone (GCTOB) is a primary bone tumor that occurs mainly in young adults and is capable of locally aggressive growth. Its histologic appearance can resemble a number of benign and malignant tumors but no useful diagnostic marker is known currently. To identify diagnostic markers for this tumor, global gene expression profiling using cDNA microarray was performed on 6 fresh-frozen GCTOB, 3 aneurysmal bone cysts, 4 fibrous dysplasias and 12 giant cell tumors of tendon sheath/diffuse-type giant cell tumors. Unsupervised hierarchical clustering separated the tumors based on their histopathologic types, and significance analysis of microarray identified several genes including TP73L (encoding the p63 protein) that are significantly highly expressed in GCTOB relative to these other tumors. The diagnostic utility of p63 was subsequently confirmed using anti-p63 antibody on a series of 26 GCTOB, 25 aneurysmal bone cysts, 15 chondroblastomas, 13 giant cell reparative granulomas, 13 chondromyxoid fibromas, 4 brown tumors, 4 fibrous dysplasias, 53 giant cell tumors of tendon sheath/diffuse-type giant cell tumors and 385 additional mesenchymal tumors in tissue microarrays. Strong p63 nuclear staining was present in 18 of 26 (69%) GCTOB, 3 of 15 (20%) chondroblastomas and in 1 of 25 (4%) aneurysmal bone cysts while none of the other tumors commonly considered in the differential diagnosis of GCTOB showed any detectable p63 staining. Strong p63 staining is rare in bone and soft-tissue tumors in general. In contrast to the pattern of p63 staining, the majority of the chondroblastomas (70%) demonstrated S-100 immunoreactivity while only a minority of the GCTOB (8%) was immunoreactive for S-100. These findings altogether show that p63 can be used as a diagnostic marker to aid the clinical diagnosis of GCTOB.

  View details for DOI 10.1038/modpathol.3801023

  View details for PubMedID 18192965

• A case of prostatic adenocarcinoma recurrence presenting as ductal carcinoma of the prostate NATURE CLINICAL PRACTICE UROLOGY Tu, W. H., Jensen, K., Freiha, F., Liao, J. C. 2008; 5 (1): 55-58

  Abstract

  A 61-year-old man with a history of recurrent prostate cancer presented with obstructive urinary symptoms. He had been diagnosed with locally invasive adenocarcinoma of the prostate 10 years previously and treated with neoadjuvant hormonal and external beam radiation therapies. Because of the patient's rising PSA level, he had been started on goserelin 6 years after this diagnosis and bicalutamide 6 months before the current presentation. The patient presented to the urology clinic with worsening lower urinary tract symptoms consisting of nocturia, urgency, and weak stream.Physical examination revealed a largely normal digital rectal examination, although there was slight asymmetry. The post-void residual urine volume was approximately 200 ml. Laboratory tests showed no evidence of urinary tract infection, but confirmed a rising PSA level despite low serum testosterone levels. Cystoscopic examination revealed hypervascular, large lateral prostatic lobes obstructing the bladder neck. The bladder was normal.The patient underwent transurethral resection of the prostate. Soon after the resection started, bilateral papillary tumors arising from the stroma of both prostatic lobes were uncovered. Owing to the diffuse nature of the papillary tumors, complete resection was not possible. Pathologic analysis confirmed the presence of ductal carcinoma of the prostate.The patient had an uneventful postoperative course and reported improvement of voiding symptoms. Staging with bone scan and CT of the abdomen and pelvis demonstrated multi-focal bony metastasis. The patient was started on docetaxel-based chemotherapy for hormone refractory recurrence of prostate cancer as ductal carcinoma of the prostate. He remains under close surveillance for clinical response and progression of disease.

  View details for DOI 10.1038/ncpuro0994

  View details for Web of Science ID 000252111100013

  View details for PubMedID 18185514

• HER2 status in a large, population-based cohort: Analysis of distinct HER2 subgroups 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K. C., Turbin, D. A., Leung, S., Miller, M. A., Johnson, K., Norris, B., Hastie, T., McKinney, S., Nielsen, T. O., Huntsman, D. G., Gilks, C. B., West, R. B. NATURE PUBLISHING GROUP. 2008: 39A–39A

  View details for Web of Science ID 000252181100167

• Expression of fatty acid synthase (FAS) in columnar cell lesions of the breast 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology TURASHVILI, G. A., Watson, P. H., Gilks, C. B., Schaeffer, D. F., Jensen, K. C., Montgomery, K. D., van de Ryn, J. M., Aparicio, S. A. NATURE PUBLISHING GROUP. 2008: 57A–57A

  View details for Web of Science ID 000252180200251

• Nonfunctioning parathyroid carcinoma: case report and review of literature. Endocrine practice Fernandez-Ranvier, G. G., Jensen, K., Khanafshar, E., Quivey, J. M., Glastonbury, C., Kebebew, E., Duh, Q., Clark, O. H. 2007; 13 (7): 750-757

  Abstract

  To report a case of nonfunctioning parathyroid carcinoma that was incidentally found during a thyroidectomy for multinodular goiter.We present a case report, detailing the clinical course and histologic findings in a patient with a nonfunctional parathyroid carcinoma. The related literature is also reviewed.A 67-year-old woman presented with a 30-year history of a multinodular goiter that was symptomatic. A total thyroidectomy was performed. Histologic examination revealed not only a multinodular thyroid but also a mass in the left lobe, which was diagnostic of a parathyroid carcinoma. Serum calcium and parathyroid hormone levels were normal postoperatively. Eleven months after the initial operation, a suprasternal mass developed, and she underwent neck reexploration and subtotal resection of an invasive recurrent nonfunctioning parathyroid carcinoma. The serum parathyroid hormone and calcium levels were normal before and after the operation. Postoperatively, the patient underwent radiation therapy. Twenty-three months after the initial operation, a computed tomographic scan of the chest revealed an interval increase in size of a nodule in the left lower lobe of the lung, and 30 months after her initial operation, she underwent resection of an isolated, 1-cm (greatest diameter), metastatic parathyroid carcinoma in the left lower lobe of the lung. The patient is currently doing well without evidence of recurrent disease.Nonfunctioning parathyroid carcinomas are difficult to diagnose and to treat. Recurrent disease after operation is common, and radiation therapy may help stabilize tumor growth. Patients with nonfunctioning parathyroid carcinomas appear to have a poorer prognosis than do those with functioning parathyroid cancers.

  View details for PubMedID 18194932

• Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? CANCER Fernandez-Ranvier, G. G., Khanafshar, E., Jensen, K., Zarnegar, R., Lee, J., Kebebew, E., Duh, Q., Clark, O. H. 2007; 110 (2): 255-264

  Abstract

  Parathyroid carcinoma, atypical parathyroid adenoma, and parathyromatosis can be differentiated relatively easily from typical parathyroid adenomas, but distinguishing them from each other is more difficult.A retrospective study of 28 consecutive patients with parathyroid carcinoma, 7 patients with atypical parathyroid adenoma, and 13 patients with parathyromatosis who were treated at the University of California at San Francisco Medical Center between 1966 and 2005 was performed. Patient demographics and clinical characteristics, indication for surgery, intraoperative findings, histopathologic characteristics, disease recurrence or persistence, site of invasion/metastases, and survival were compared in the 3 groups.Parathyroid carcinoma (19 of 28 patients) and atypical adenoma (4 of 7 patients) were significantly more common in men, whereas parathyromatosis was more common in women (10 of 13 patients) (P = .02). A palpable neck mass and hoarseness were almost exclusively present in patients with parathyroid carcinoma. Prior to the first parathyroid surgery, patients with parathyroid carcinoma were found to have higher blood calcium levels (>/=14 mg/dL in 16 of 26 patients [62%]), whereas only 1 of 6 patients with atypical adenoma (17%) and no patients with parathyromatosis were found to have profound hypercalcemia (P < .01). Intraoperatively, patients with parathyroid carcinoma and atypical adenoma presented with single lesions, whereas patients with parathyromatosis had multiple small lesions. Histopathologic findings were well defined in parathyroid carcinoma, but some findings overlapped in the 3 tumors studied.Patients with parathyroid carcinoma often differ from those with atypical parathyroid adenoma or parathyromatosis at the time of presentation because patients with parathyroid carcinoma have more profound hypercalcemia as well as invasive tumors. However, at times it is difficult to distinguish between these conditions both clinically and by final histologic examination.

  View details for DOI 10.1002/cncr.22790

  View details for Web of Science ID 000247985600004

  View details for PubMedID 17559137

• Comparison of a new mouse monoclonal Anti-HER2/neu antibody to a rabbit polyclonal antibody 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Turbin, D. A., Jensen, K., Leung, S., McKinney, S. E., Huntsman, D. G., Gilks, C. B., West, R. B. NATURE PUBLISHING GROUP. 2007: 52A–52A

  View details for Web of Science ID 000244935300217

• Pancreatic intraepithelial neoplasia: Analysis of apomucin and tumor suppressor gene expression by tissue microarray 95th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Pai, R. K., Jensen, K. C., Fischer, E. G., Kim, G. E., Kong, C. S. NATURE PUBLISHING GROUP. 2006: 279A–279A

  View details for Web of Science ID 000234207602141

• Pancreatic mucinous neoplasms: Analysis of apomucin and tumor suppressor gene expression by tissue microarray 95th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Pai, R. K., Jensen, K. C., Fischer, E. G., Kim, G. E., Kong, C. S. NATURE PUBLISHING GROUP. 2006: 278A–278A

  View details for Web of Science ID 000234094502235

• Characterization of anti-fatty acid synthase expression in normal breast and breast cancer. 28th Annual San Antonio Breast Cancer Symposium Jensen, K. C., Montgomery, K., West, R. B., van de Rijn, J. M. SPRINGER. 2005: S282–S282

  View details for Web of Science ID 000233407100765

• PAX5 protein expression in bladder tumors by tissue microarray immunohistochemistry 94th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K. C., Kaygusuz, G., Montgomery, K., van de Rijn, M., Higgins, J. NATURE PUBLISHING GROUP. 2005: 148A–148A

  View details for Web of Science ID 000226117900683

• Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma CLINICAL CANCER RESEARCH Nielsen, T. O., Hsu, F. D., Jensen, K., Cheang, M., Karaca, G., Hu, Z. Y., Hernandez-Boussard, T., Livasy, C., Cowan, D., Dressler, L., Akslen, L. A., Ragaz, J., GOWN, A. M., Gilks, C. B., van de Rijn, M. V., Perou, C. M. 2004; 10 (16): 5367-5374

  Abstract

  Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors.To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings.Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis.A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.

  View details for Web of Science ID 000223454600011

  View details for PubMedID 15328174

• Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis 31st Annual Meeting of the Western-Association-of-Gynecologic-Oncologists Juretzka, M. M., Jensen, K. C., Longacre, T. A., Teng, N. N., Husain, A. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2004: 107–11

  Abstract

  The objectives of this study were to (1) determine the incidence of lymph node micrometastasis in cervical cancer by immunohistochemical analysis and (2) determine if the presence of micrometastasis is a poor prognostic feature in early cervical cancer.We retrospectively reviewed the medical records of 62 patients who underwent radical hysterectomy and lymphadenectomy for FIGO stage IA2-IB2 cervical cancer at Stanford University Hospital from 1990 to 2000. Forty-nine patients with negative lymph nodes were identified. A total of 976 formalin-fixed paraffin-embedded pelvic lymphadenectomy specimens were serially sectioned and stained with anti-cytokeratin antibodies AE1 and AE1/CAM5.2.Six patients had stage IA2 disease, 37 had stage IB1, and 6 had IB2. The mean age of the patients was 44 years (range, 24-76). Seventy-one percent had squamous cell carcinomas, 22% had adenocarcinomas, and 6% had other types. Lymph node micrometastases were immunohistochemically detected in 4 of the 49 (8.1%) patients, comprising 4 of 976 (0.41%) pelvic lymph nodes examined. Twelve of 45 (15.6%) patients with negative nodes had lymph-vascular space invasion (LVSI) whereas 3 of 4 (75%) patients with micrometastases had LVSI. At a mean follow-up time of 39.4 months, 2 of 4 (50%) patients with micrometastasis had recurrent disease, while 3 of 45 (6.7%) patients without micrometastasis developed recurrent disease.These preliminary data suggest that immunohistochemical detection of pelvic lymph nodes is more frequent in patients with LVSI and may identify patients needing adjuvant chemoradiation.

  View details for DOI 10.1016/j.ygyno.2003.11.033

  View details for Web of Science ID 000220850800016

  View details for PubMedID 15047221

• Procollagen 1 expression in atypical fibroxanthoma and other tumors JOURNAL OF CUTANEOUS PATHOLOGY Jensen, K., Wilkinson, B., Wines, N., Kossard, S. 2004; 31 (1): 57-61

  Abstract

  Procollagen (PC) is secreted by fibroblasts into the extracellular matrix, where it is cleaved to form collagen. The rat anti-human PC-1 monoclonal antibody has been reported to react with atypical fibroxanthoma (AFX), a poorly differentiated but usually benign skin lesion common in elderly patients. We have studied PC-1 staining in 50 tumors with AFX histological features (four of which were subsequently reclassified as non-AFX tumors) to confirm this prior observation. In addition, we have investigated PC-1 in other skin tumors, particularly those with spindled cell or sclerosing/desmoplastic morphologies.Archival material was retrieved and sections were prepared and immunostained with PC-1 as well as a panel of antibodies, including S-100 and MNF-116 (cytokeratins 5, 6, 7, 8, 17, and 19).PC-1 staining was strongly positive in 40 of 46 (87%) AFXs. Three AFXs displayed weak staining with PC-1 even after repeat staining of 10 tumors that were initially weak. Three additional tumors stained with both PC-1 and MNF-116 and were classified as AFX-like squamous cell carcinoma (SCC). One tumor with AFX-like histology was PC-1 negative and S-100 positive and was classified as an AFX-like melanoma. Positive staining in tumor cells was observed in three of nine (33%) desmoplastic malignant melanomas, three of eight (38%) desmoplastic SCCs, zero of 10 (0%) desmoplastic trichoepitheliomas, zero of 10 (0%) morpheic basal cell carcinomas, and zero of 10 (0%) sclerosing sweat duct carcinomas.PC-1 is a useful antibody in a diagnostic immunohistochemical panel when investigating AFX and AFX-like tumors; however, good technical quality and careful interpretation are necessary when using a panel of antibodies, particularly to keratin and S-100 protein, for optimal accuracy.

  View details for Web of Science ID 000187275100009

  View details for PubMedID 14675286

• Array-based comparative genomic hybridization (ACGH) of dermatofibrosarcoma protuberans (DFSP) on cDNA micorarrays using DNA isolated from fresh frozen and paraffin embedded tissue 92nd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K., West, R. B., Zhu, S. X., Linn, S. C., Nielsen, T. O., Goldblum, J. R., Patel, R., Rubin, B. P., Botstein, D., BROWN, P., Pollack, J., Gilks, B., van de Rijn, M. NATURE PUBLISHING GROUP. 2003: 15A–15A

  View details for Web of Science ID 000180732500067

• Array-based comparative genomic hybridization (ACGH) of dermatofibrosarconta protuberans (DFSP) on cDNA micorarrays using DNA isolated from fresh frozen and paraffin embedded tissue 92nd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Jensen, K., West, R. B., Zhu, S. X., Linn, S. C., Nielsen, T. O., Goldblum, J. R., Patel, R., Rubin, B. P., Botstein, D., BROWN, P., Pollack, J., Gilks, B., van de Rijn, M. NATURE PUBLISHING GROUP. 2003: 15A–15A

  View details for Web of Science ID 000180720100066

• Cytokeratin staining in Merkel cell carcinoma: An immunohistochemical study of cytokeratins 5/6, 7, 17, and 20 APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Jensen, K., Kohler, S., Rouse, R. V. 2000; 8 (4): 310-315

  Abstract

  Merkel cell carcinoma is an aggressive cutaneous neoplasm with neuroendocrine differentiation that carries a poor prognosis. Its homogeneous morphology is easily confused with lymphoma, leukemia, metastatic small cell carcinoma, and poorly differentiated cutaneous malignancies. Histopathologic diagnosis frequently requires support by immunohistochemistry. The authors investigated cytokeratins (CKs) 5/6, 7, 17, and 20 staining in paraffin sections of 26 Merkel cell carcinomas to expand the knowledge of the CK staining profile of this entity. Reactivity with anti-CK 20 was demonstrated in 23 of 26 Merkel cell carcinomas (88%). All three CK 20-negative tumors showed punctate staining with anti-keratin CAM5.2. Six of 26 tumors (23%) were positive for CK 7, a finding not previously reported. The staining patterns for both CKs 20 and 7 ranged from punctate (perinuclear) to localized (confined to half of the cytoplasm) to diffuse. Punctate CK 20 staining was seen in 17 of 26 cases but was the predominant pattern in only 10 cases. Antibodies to CKs 5/6 and 17 were each negative in the 13 cases for which these stains were performed. Both the positive and negative elements of the CK profile of this distinctive neoplasm provide additional useful diagnostic information for the differential diagnosis between Merkel cell carcinoma and other carcinomas that may simulate it. The authors note that the classically described perinuclear dotlike keratin staining pattern is not universally seen with CK 20 and that CK 7 staining may be seen in a subset of Merkel cell carcinomas.

  View details for Web of Science ID 000165547800008

  View details for PubMedID 11127923