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Author(s): Ling Huang [1]; Audrey Holtzinger [1, 2]; Ishaan Jagan [1]; Michael BeGora [1]; Ines Lohse [1]; Nicholas Ngai [1]; Cristina Nostro [1, 2]; Rennian Wang [3, 4]; Lakshmi B [...], There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53[sup.R175H] induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

The study attempts to evaluate the data derived from the RNA sequencing of 18 ovarian carcinomas to identify variants in ARID1A mutations. The results indicate that ARIDIA mutations are present in ovarian carcinomas and that it is indicative of an early event in the transformation of endometriosis into cancer.

The study aims to investigate four adult-type granulosa-cell tumors (GCTs) of the ovary and the role of FOXL2 mutation in the pathogenesis of GCTs. The results indicate that mutant FOXL2 is responsible for adult-type GCTs of the ovary.

Introduction Ovarian carcinoma is a heterogeneous disease. On the basis of histopathological examination, pathologists classify ovarian carcinoma into serous, clear cell, endometrioid, and mucinous subtypes. Each of theses subtypes is [...], Background Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis. Methods and Findings In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a populationbased cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%-2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%-2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%-0.8%). Conclusions The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma. The Editors' Summary of this article follows the references.

Gastric carcinoma contributes to 10% of cancer deaths worldwide with a case to fatality ratio of 70%. (1) Despite recent advances in cancer treatment, the overall 5-year survival for patients [...], Context.--Immunohistochemical (IHC) testing for HER2/neu is becoming the standard of care for guiding adjuvant treatment of gastric carcinoma with trastuzumab. Objective.--To assess interlaboratory variation in IHC staining and interpretation across multiple laboratories. Design.--A tissue microarray consisting of 45 cores from 28 gastric cancers was distributed to 37 laboratories for HER2/neu assessment. The IHC results were compared against expert scores at an academic institution and correlated with in situ hybridization results from the originating specimen. Interlaboratory agreement was calculated using Cohen k statistic. Results.--The survey demonstrated several variations in IHC methods, including the primary antibodies in use. There was excellent agreement among laboratories in HER2/[neu.sup.+] (IHC [3.sup.+]) cases ([kappa] = 0.80 [+ or -] 6 0.01) and very good agreement among laboratories in HER2/[neu.sup.-] (IHC 0 or [1.sup.+]) cases ([kappa] = 0.58 [+ or -] 0.01). Less agreement was observed among laboratories when scoring equivocal (IHC [2.sup.+]) cases ([kappa] = 0.22 [+ or -] 0.01). Sensitivity and specificity of HER2/neu IHC were 99% and 100%, respectively, when measured against expert review and consensus score as a reference standard. Conclusions.--There is substantial interlaboratory agreement in the interpretation of HER2/neu IHC despite variability in protocols. Although HER2/neu IHC is a highly sensitive and specific test, primary antibody selection may significantly affect IHC results. Furthermore, gastric tumors require a unique scoring system and expertise in interpretation. Intratumoral heterogeneity has a significant effect on HER2/neu scoring by IHC. Ongoing quality assurance exercises among laboratories will help ensure optimized HER2/neu testing. (Arch Pathol Lab Med. 2014; 138:1495-1502; doi: 10.5858/arpa.2013-0604-OA)