Person: Hirsch, Michelle
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Hirsch
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Michelle
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Hirsch, Michelle
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Publication Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry(Public Library of Science, 2013) Kluk, Michael J.; Ashworth, Todd; Wang, Hongfang; Knoechel, Birgit; Mason, Emily F.; Morgan, Elizabeth; Dorfman, David; Pinkus, Geraldine; Weigert, Oliver; Hornick, Jason; Chirieac, Lucian; Hirsch, Michelle; Oh, David J.; South, Andrew P.; Leigh, Irene M.; Pourreyron, Celine; Cassidy, Andrew J.; DeAngelo, Daniel J.; Weinstock, David M.; Krop, Ian E.; Dillon, Deborah; Brock, Jane; Lazar, Alexander J. F.; Peto, Myron; Cho, Raymond J.; Stoeck, Alexander; Haines, Brian B.; Sathayanrayanan, Sriram; Rodig, Scott; Aster, JonFixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials.Publication Early-stage clear cell tubulopapillary renal cell carcinoma: imaging features and distinction from clear cell and papillary subtypes(Springer Nature, 2016) Mnatzakanian, Gevork Nshan; Shinagare, Atul; Sahni, Vikram; Hirsch, Michelle; Silverman, StuartPurpose: Clear cell tubulopapillary renal cell carcinoma (CCTPRCC) is a recently described, low grade subtype of renal cancer. We determined if imaging features could be used to distinguish early-stage CCTPRCC from stage-matched clear cell RCC (ccRCC) and papillary RCC (pRCC). Subjects and Methods: This IRB-approved retrospective study included 54 stage-Ia patients with pathologically-confirmed CCTPRCC (n=18), ccRCC (n=18), and pRCC (n=18). CT (n=48) and MRI (n=27) exams were reviewed and imaging features compared. Continuous variables were evaluated using ANOVA and Tukey's multiple comparison tests. Categorical variables were compared using Chi square test or Fisher's exact test. Results: Compared to pRCC, CCTPRCC had a lower mean attenuation value on unenhanced CT (p<0.017), was more often hyperintense on T2-weighted images (p<0.0001), showed an ill-defined margin (p=0.003), and demonstrated nonenhancing areas (p=0.0003). The presence of all three of these statistically significant features (hypoattenuation [unenhanced attenuation < 25HU], ill-defined margin, nonenhancing areas) yielded an area under the Receiver Operator Curve (ROC) of 0.92 (95% CI: 0.83-0.99) for differentiating CCTPRCC from pRCC. There were no significant differences in the imaging features of CCTPRCC and ccRCC. Conclusions: Early stage clear cell tubulopapillary renal cell carcinoma can be distinguished from papillary RCC based on low attenuation on unenhanced CT, high intensity on T2-weighted images, an ill-defined margin, and presence of nonenhancing areas, but cannot be distinguished from clear cell RCC.Publication FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder(BlackWell Publishing Ltd, 2014) Guancial, Elizabeth A; Werner, Lillian; Bellmunt, Joaquim; Bamias, Aristotle; Choueiri, Toni K; Ross, Robert; Schutz, Fabio A; Park, Rachel S; O'Brien, Robert J; Hirsch, Michelle; Barletta, Justine; Berman, David M; Lis, Rosina; Loda, Massimo; Stack, Edward C; Garraway, Levi A; Riester, Markus; Michor, Franziska; Kantoff, Philip W; Rosenberg, Jonathan EWhile fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.Publication FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis(2014) Levanon, Keren; Sapoznik, Stav; Bahar-Shany, Keren; Brand, Hadar; Shapira-Frommer, Ronnie; Korach, Jacob; Hirsch, Michelle; Roh, Michael H.; Miron, Alexander; Liu, Joyce F.; Vena, Natalie; Ligon, Azra; Fotheringham, Susan; Bailey, Dyane; Flavin, Richard J.; Birrer, Michael J.; Drapkin, RonnySerous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here, we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high grade serous ovarian carcinomas (HGSOCs). We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.Publication PAX8 Distinguishes Diffuse Large B-Cell Lymphoma Mimicking Sarcoma(Hindawi, 2017) Hirsch, Michelle; Nascimento, Alessandra F.PAX8 is important for embryogenesis of the thyroid, Müllerian system, and upper urinary/renal tract, and expression of PAX8 has been described in carcinomas from each of these sites. The sensitivity and specificity of the polyclonal PAX8 antibody in a large cohort of epithelial tumors as well as lymphomas have been previously determined, the latter because polyclonal PAX8 is known to be immunoreactive in nonneoplastic B-cell lymphocytes which are often used as the positive internal control for immunohistochemistry. In this case report, PAX8 was a diagnostic clue for revising a previous diagnosis of unclassified high grade sarcoma to diffuse large B-cell lymphoma. This case report demonstrates a pitfall for PAX8 immunoreactivity and acts as a reminder that lymphoma should be included in the differential diagnosis of a PAX8 positive, epithelial cell marker negative tumor of unknown primary origin.Publication Mucinous tubular and spindle cell carcinoma of the kidney: imaging features(E-MED LTD, 2012) Sahni, Vibhu; Hirsch, Michelle; Sadow, Cheryl; Silverman, StuartThis article describes the features on sonography, computed tomography (CT) and magnetic resonance imaging (MRI) of mucinous tubular and spindle cell carcinoma of the kidney. Six pathologically proven cases of mucinous tubular and spindle cell carcinoma of the kidney were identified (5 females, 1 male); all patients underwent preoperative imaging. The mean age of the patients was 58.5 years. Thirteen imaging studies were available for review: 2 sonograms, 1 unenhanced CT scan, 5 contrast-enhanced CT scans, 1 unenhanced magnetic resonance imaging (MRI) examination, and 4 contrast-enhanced MRI examinations. Two abdominal radiologists evaluated all images retrospectively on a PACS workstation using a standardized data collection sheet until consensus was reached. All mucinous tubular and spindle cell carcinomas presented as well-marginated, small (mean 2.6 cm, range 1.9–3.2 cm) predominantly solid masses. No intratumoral fat or calcification was identified. Unenhanced CT and MRI appearances were variable as was the degree of enhancement following intravenous contrast material administration. There was no evidence of perinephric extension, renal vein involvement or metastatic disease in any of the cases. The radiological appearance of mucinous tubular and spindle cell carcinoma is diverse and therefore indistinguishable from the more common subtypes of renal cell carcinoma.Publication Prior appendectomy does not protect against subsequent development of malignant or borderline mucinous ovarian neoplasms(Elsevier BV, 2014) Elias, Kevin; Labidi-Galy, S. Intidhar; Vitonis, Allison F.; Hornick, Jason; Doyle, Leona; Hirsch, Michelle; Cramer, Daniel; Drapkin, RonnyBackground Due to concern that mucinous malignant or borderline ovarian neoplasms (MON) may represent metastatic deposits from appendiceal primaries, gynecologic oncologists routinely perform appendectomy in these cases. However, a multidisciplinary critique of this practice is lacking. Methods The New England Case-Control study database was utilized to compare the effect of prior appendectomy against known risk factors for MON. Pathology and operative reports of local cases of MON were reviewed to estimate the frequency of microscopic mucinous lesions in the appendix. Protein expression patterns among mucinous ovarian, colorectal, and appendiceal cancers were compared by immunohistochemistry. Results From the New England Case-Control study, 287 cases of MON were compared against 2,339 age-matched controls. Prior appendectomy did not reduce the risk of MON (OR 1.28, 95% CI 0.83–1.92, p=0.23), while prior tubal ligation, parity, and breastfeeding were each protective against MON. Active smoking (OR 2.04, 95% CI 1.48–2.80, p<0.001) was associated with an increased risk of MON. Among 196 mucinous adnexal tumors, appendectomy did not reclassify any MON as appendiceal in origin. By immunohistochemistry, mucinous ovarian carcinomas tended to be CK7+/CK20-/MUC2-/CDX2-, whereas mucinous colorectal and appendiceal adenocarcinomas were typically CK7-/CK20+/MUC2+/CDX2+, although with some overlap in immunophenotype. Additionally, PAX8 was positive in a subset of MOC and negative in all appendiceal carcinomas. Conclusion Prior appendectomy is not protective against development of malignant or borderline MON. Routine appendectomy during surgery for MON seldom reveals an unsuspected GI primary in early stage tumors but may aid in final diagnosis in advanced stage cases.Publication Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer(Public Library of Science, 2012) Risch, Thomas; Fan, Jian-Bing; Holton, Kristina; Rubio, Renee; April, Craig; Wickham-Garcia, Eliza; Bentink, Stefan; Haibe-Kains, Benjamin; Hirsch, Michelle; Chen, Jing; Liu, Joyce; Culhane, Aedin; Drapkin, Ronny; Quackenbush, John; Matulonis, UrsulaOvarian cancer is the fifth leading cause of cancer death for women in the U.S. and the seventh most fatal worldwide. Although ovarian cancer is notable for its initial sensitivity to platinum-based therapies, the vast majority of patients eventually develop recurrent cancer and succumb to increasingly platinum-resistant disease. Modern, targeted cancer drugs intervene in cell signaling, and identifying key disease mechanisms and pathways would greatly advance our treatment abilities. In order to shed light on the molecular diversity of ovarian cancer, we performed comprehensive transcriptional profiling on 129 advanced stage, high grade serous ovarian cancers. We implemented a, re-sampling based version of the ISIS class discovery algorithm (rISIS: robust ISIS) and applied it to the entire set of ovarian cancer transcriptional profiles. rISIS identified a previously undescribed patient stratification, further supported by micro-RNA expression profiles, and gene set enrichment analysis found strong biological support for the stratification by extracellular matrix, cell adhesion, and angiogenesis genes. The corresponding “angiogenesis signature” was validated in ten published independent ovarian cancer gene expression datasets and is significantly associated with overall survival. The subtypes we have defined are of potential translational interest as they may be relevant for identifying patients who may benefit from the addition of anti-angiogenic therapies that are now being tested in clinical trials.Publication High grade serous ovarian carcinomas originate in the fallopian tube(Nature Publishing Group UK, 2017) Labidi-Galy, S. Intidhar; Papp, Eniko; Hallberg, Dorothy; Niknafs, Noushin; Adleff, Vilmos; Noe, Michael; Bhattacharya, Rohit; Novak, Marian; Jones, Siân; Phallen, Jillian; Hruban, Carolyn A.; Hirsch, Michelle; Lin, Douglas; Schwartz, Lauren; Maire, Cecile L.; Tille, Jean-Christophe; Bowden, Michaela; Ayhan, Ayse; Wood, Laura D.; Scharpf, Robert B.; Kurman, Robert; Wang, Tian-Li; Shih, Ie-Ming; Karchin, Rachel; Drapkin, Ronny; Velculescu, Victor E.High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.