MDM2 amplification is rare in gastric cancer.

The MDM2 proto-oncogene (MDM2) is a primary negative regulator of p53. The latter is frequently mutated in gastric cancer (GC). In the present study, we aimed to validate gene amplification, protein expression, and the putative tumor biological function of MDM2 in a well-characterized Western GC cohort. MDM2 amplification and protein expression were studied in a cohort of 327 GCs by fluorescence in situ hybridization (FISH) and immunohistochemistry. Gene amplification and protein expression were correlated with diverse clinicopathological patient characteristics including patient outcome. Immunohistochemically, 97 GCs (29.7%) were categorized as MDM2 positive and 230 GCs (70.3%) as negative. An amplification of MDM2 was found in 11 (3.4%) cases without evidence of intratumoral heterogeneity. Nine of these eleven (81.8%) cases showed MDM2 protein expression. MDM2 amplification correlated significantly with MDM2 protein expression (p < 0.001). On a case-by-case analysis, MDM2-amplified cases showed varied histological phenotypes and were most commonly microsatellite stable; EBV, HER2, and MET negative; and FGFR2 positive. A single case harbored both, MDM2 amplification and TP53 mutation. MDM2 amplification and MDM2 expression, respectively, did not correlate with overall or tumor-specific survival. Our targeted analysis of MDM2 in a well-characterized cohort of GC patients showed that MDM2 amplification is rare, of no specific histological phenotype, and may not be always mutually exclusive with TP53 mutations. Given the low number of cases, currently, no diagnostic or therapeutic recommendation related to MDM2 amplification can be given for GC of Western origin.

Insulin Receptor in Pancreatic Cancer-Crown Witness in Cross Examination.

BACKGROUND: The proximity of pancreatic cancer (PDAC) to the physiological source of the growth promoting hormone insulin might be exploited by this highly malignant cancer entity. We investigated if (I) PDACs express the insulin receptor (IR) in cancer cells and cancer vasculature, (II) if IR correlates with clinicopathological patient characteristics, including survival, and hence is involved in PDAC biology, (III) if IR is already expressed in precursor lesions, if (IV) the IGF1 receptor (IGF1R) is associated with clinicopathological patient characteristics and survival and (V) is linked to IR expression. METHODS: 160 PDAC samples were examined for IR and IGF1R expression by immunohistochemistry. A modified HistoScore was correlated with clinicopathological characteristics and survival. RESULTS: IR overexpression was already observed in pancreatic intraepithelial neoplasia. Furthermore, it was more frequently observed in advanced disease and associated with distant metastasis, UICC stage, lymphatic invasion and an increased lymph node ratio, but without impacting survival in the end. IGF1R expression was not associated with clinicopathological parameters or survival, in contrast to former paradigms. CONCLUSIONS: We hypothesize that the close proximity to the pancreatic islets might be advantageous for cancer growth at first, but it experiences self-limitation due to surgical removal or local destruction following accelerated cancer growth.

Programmed Death-Ligand 1 (PD-L1) Expression Is Induced by Insulin in Pancreatic Ductal Adenocarcinoma Cells Pointing to Its Role in Immune Checkpoint Control.

Type-2 diabetes (T2DM) is a risk factor for the development of pancreatic ductal adenocarcinoma (PDAC) and is characterized by insulin resistance and hyperinsulinemia. Besides the well-known growth-promoting activity of insulin or the other members of the Insulin/Insulin-like Growth factor (IGF) axis, we here describe an inducing effect of insulin on PD-L1 expression in PDAC cells. Treatment of the PDAC cell lines BxPc3, A818-6, and T3M4 with insulin increased PD-L1 expression in a time- and dose dependent fashion, as shown by Western blot and qPCR analysis. siRNA mediated knock-down showed that the effects of insulin on PD-L1 depend on the insulin and IGF receptors (InsR and IGFR, respectively). In addition, a crosstalk of insulin-induced ERK activation and Epidermal Growth Factor (EGF) triggered PD-L1 expression. This involves different mechanisms in the three cell lines including upregulation of InsR-A expression in A818-6 and modulation of the adaptor protein Gab1 in BxPc3 cells. As a consequence of the insulin-induced PD-L1 expression, PDAC cells suppress the proliferation of activated human CD8+ T-cells in coculture experiments. The suppression of CD8+ cell proliferation by insulin-pretreated PDAC cells was reversed by PD-1 blockade with Pembrolizumab or by PD-L1 siRNA. Furthermore, the clinical relevance of these observations was supported by detecting a coexpression of cytoplasmic InsR (characteristic for its activation) and PD-L1 in tumor tissues from PDAC patients. Our findings provide a novel insight into the protumorigenic role of insulin in PDAC. Recognizing the impact of insulin on PD-L1 expression as part of the immune privilege, strategies to interfere with this mechanism could pave the way towards a more efficient immunotherapy of PDAC.

Mucinous Cystic Neoplasm of Pancreas in a Pregnant Woman Presenting with Severe Anemia and Gastric Bleeding: Case Report and Review of the Literature.

Mucinous cystic neoplasms of the pancreas are uncommon and especially their occurrence during pregnancy is an extremely rare event which necessitates an individualized and interdisciplinary management. A 33-year old woman was referred to our department during her third trimester of pregnancy (34th week of gestation) with severe anemia and tarry stools. Based on gastroscopic findings, our interdisciplinary team suspected a gastrointestinal stromal tumor and therefore indicated a prompt delivery via cesarean section completed with an oncological resection of the neoplasm. Histological examination subsequently showed a mucinous cystic neoplasm of the pancreas with no evidence of malignancy. To review the prevalence of mucinous cystic neoplasms and to discuss diagnosis and treatment during pregnancy. Moreover, we critically value the indication of preterm delivery and the oncological procedure in the perspective of outcome for mother and infant. A bleeding gastrointestinal tumor during pregnancy represents a life-threatening risk for mother and infant and requires an immediate interdisciplinary treatment. The urgency and radicality of the therapy should be adapted according to individual findings. As our patient's tumor was suspected of having a malignant progression, an extensive surgical intervention was necessary.

The Contribution of Additional Sampling in Cholecystectomy Materials: A Multicenter Prospective Study.

OBJECTIVE: Cholecystectomy materials are frequently encountered in routine practice. The aim of this study was to determine the true frequency of gallbladder lesions, the diagnostic consistency, and standardization of reports after macroscopic sampling and microscopic evaluation based on previously defined criteria. MATERIAL AND METHOD: 14 institutions participated in the study within the Hepato-Pancreato-Biliary Pathology Study Group. Routinely examined cholecystectomies within the last year were included in the study in these institutions. Additional sampling was performed according to the indications and criteria. The number of blocks and samples taken in the first macroscopic examination and the number of blocks and samples taken in the additional sampling were determined and the rate of diagnostic contribution of the additional examination was determined. RESULTS: A total of 5,244 cholecystectomy materials from 14 institutions were included in the study. Additional sampling was found to be necessary in 576 cases (10.98%) from all institutions. In the first macroscopic sampling, the mean of the numbers of samples was approximately 4 and the number of blocks was 2. The mean of the numbers of additional samples and blocks was approximately 8 and 4, respectively. The diagnosis was changed in 144 of the 576 new sampled cases while the remaining 432 stayed unaltered. CONCLUSION: In this study, it was observed that new sampling after the first microscopic examination of cholecystectomy materials contributed to the diagnosis. It was also shown that the necessity of having standard criteria for macroscopic and microscopic examination plays an important role in making the correct diagnosis.

Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma.

The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T>C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.

A Retrospective Evaluation of the Epithelial Changes/Lesions and Neoplasms of the Gallbladder in Turkey and a Review of the Existing Sampling Methods: A Multicentre Study.

OBJECTIVE: As there is continuing disagreement among the observers on the differential diagnosis between the epithelial changes/lesions and neoplasms of the gallbladder, this multicentre study was planned in order to assess the rate of the epithelial gallbladder lesions in Turkey and to propose microscopy and macroscopy protocols. MATERIAL AND METHOD: With the participation of 22 institutions around Turkey that were included in the Hepato-Pancreato-Biliary Study Group, 89,324 cholecystectomy specimens sampled from 2003 to 2016 were retrospectively evaluated. The numbers of adenocarcinomas, dysplasias, intracholecystic neoplasms/adenomas, intestinal metaplasias and reactive atypia were identified with the review of pathology reports and the regional and countrywide incidence rates were presented in percentages. RESULTS: Epithelial changes/lesions were reported in 6% of cholecystectomy materials. Of these epithelial lesions, 7% were reported as adenocarcinoma, 0.9% as high-grade dysplasia, 4% as low-grade dysplasia, 7.8% as reactive/regenerative atypia, 1.7% as neoplastic polyp, and 15.6% as intestinal metaplasia. The remaining lesions (63%) primarily included non-neoplastic polypoids/hyperplastic lesions and antral/pyloric metaplasia. There were also differences between pathology laboratories. CONCLUSION: The major causes of the difference in reporting these epithelial changes/lesions and neoplasms include the differences related to the institute's oncological surgery frequency, sampling protocols, geographical dissimilarities, and differences in the diagnoses/interpretations of the pathologists. It seems that the diagnosis may change if new sections are taken from the specimen when any epithelial abnormality is seen during microscopic examination of the cholecystectomy materials.

Mature cystic teratoma of the ovary: a cutting edge overview on imaging features.

Mature cystic teratoma (MCT) is the most common neoplasm of the ovary and includes at least two well- differentiated germ cell layers. Different combinations of mature tissue derivatives with varying arrangements in the tumour cause a wide spectrum of radiological presentation ranging from a purely cystic mass to a complex cystic mass with a considerable solid component. In different imaging modalities, each radiological feature reflects a specific pathologic equivalent that forms because of diverse compositions of histological components. Understanding uncommon findings as well as the classic signs with basic knowledge of pathological equivalents permits a more accurate diagnosis and guides adequate treatment. In this review, radiological features of MCT in different imaging modalities (US, CT, MR imaging) including specific signs and useful radiological artefacts with brief emphasis on pathological basics are discussed. Teaching points • Ovarian mature cystic teratomas (MCTs) have a wide spectrum of radiological presentation.• Each radiological feature of MCT reflects a specific pathologic equivalent.• Understanding radiological signs with basic knowledge of pathology can permit a more accurate diagnosis.

Jejunum/DIEP Composite Flap: A Novel Rat Model of Viscerocutaneous Flap Prefabrication.

Background Reconstruction of complex pharyngoesophageal defects presents a major challenge, particularly in soft tissue deficient and previously scarred surgical sites. In recent years, the free jejunum flap method has emerged as a reliable means of esophageal reconstruction. However, it may require cutaneous coverage with an additional flap in extensively scarred, secondary reconstructions. Prefabrication of an intestinal/cutaneous composite flap can potentially solve this problem. Materials and Methods Total 28 Sprague Dawley rats were used in the study protocol. A vascularized jejunal segment was transposed beneath the deep inferior epigastric perforator (DIEP) flap. Contact with underlying abdominal fascia was prevented using a silicone sheet. Animals were distributed into five groups based on the timing of deep inferior epigastric vessel ligation to determine the time required for successful revascularization. The viability and the vascular anatomy of the prefabricated structures were analyzed using histology and microangiography. Results A jejunum/DIEP composite flap was successfully prefabricated based on mesenteric vessels. The skin component survived intact after 5 days of contact with serosal surface of the jejunal segment. Conclusion The clinical application of this technique can provide an alternative means of single-stage esophageal reconstruction, especially in patients with soft tissue deficiency and donor vessel unavailability.

Effect of irinotecan on liver regeneration: an experimental study in rats.

BACKGROUND/AIMS: The aim of this study was to determine the histopathological changes caused by irinotecan and show the effect of these changes on liver regeneration. METHODOLOGY: In this experimental study 96 Winstar-Albino breed female rats were used. The animals were divided into two groups. Study group received intraperitoneal irinotecan weekly for four weeks. Control group received normal saline. One week after the last injection all animals had undergone 70% hepatectomy. Following 70% hepatectomy rats were sacrificed and liver tissue samples were obtained at 0, 24, 48, 72, 96 and 120 hours. Specimens were evaluated for steatosis, lobular inflammation and cellular swelling with hematoxylin and eosin staining. Liver regeneration was evaluated im munohistochemically using proliferating cell nuclear antigen activity index. RESULTS: Hepatic steatosis was significantly more in the irinotecan group. Although lobular inflammation and cellular swelling were more prominent in the irinotecan group these values were not statistically significant. In both groups, regeneration reached to peak at 48th hour and returned to baseline at 120th hour. Liver regeneration indices were not different between the groups. CONCLUSION: It was shown that irinotecan did not affect the liver regeneration adversely. In order to show the effects of irinotecan on liver regeneration in humans further clinical studies are needed.

Primary low grade intratesticular leiomyosarcoma: case report and review of the literature.

A 49-year-old male presented with a painful mass in the left scrotum. An inguinal orchiectomy was performed. Pathological examination revealed a well-differentiated leiomyosarcoma completely located inside the testicular parenchyma. We report this unusual case because primary leiomyosarcoma of the testis proper is extremely rare; our patient being the 19th case recorded thus far in the medical literature. It can lead to significant clinical and diagnostic difficulty due to its wide differential diagnosis and extreme rarity.

The presence of Epstein-Barr virus (EBV) in diffuse large B-cell lymphomas (DLBCLs) in Turkey: special emphasis on 'EBV-positive DLBCL of the elderly'.

Accumulated evidence has shown the importance of Epstein-Barr virus in the pathogenesis of various lymphomas. This study aimed to determine the prevalence of Epstein-Barr virus expression and its effect on survival amongst diffuse large B-cell lymphoma (DLBCL) cases from two large tertiary care centres in Turkey with a particular interest in identifying cases of 'Epstein-Barr virus-positive DLBCL of the elderly'. Diffuse large B-cell lymphoma cases diagnosed between 1999 and 2009 were retrieved and 340 cases were used to construct tissue microarrays. The presence of Epstein-Barr virus small ribonucleic acids was examined by in situ hybridization using Epstein-Barr virus (EBV)-encoded small RNA (EBER) oligonucleotides. A total of 18 cases (5.3%) showed Epstein-Barr virus expression. Twelve cases were classified as Epstein-Barr virus-positive DLBCL of the elderly. Epstein-Barr virus-positive DLBCL cases showed a significantly inferior overall survival as compared with Epstein-Barr virus-negative cases (p < 0.001). In our study group Epstein-Barr virus expression is not prevalent in DLBCLs. Epstein-Barr virus-positive DLBCL of the elderly is also rare in the Turkish population. The presence of Epstein-Barr virus, however, is associated with poor prognosis.

Uterine tumors resembling ovarian sex cord-stromal tumors: synchronous uterine tumors resembling ovarian sex cord-stromal tumors and ovarian sex cord tumor.

Uterine tumors resembling ovarian sex cord-stromal tumors (UTROSCTs) are very rare. In this article, we present 3 cases that manifest classical histomorphological features alongside diverse immunohistochemical findings. As a distinctive finding, one of the patients had UTROSCT in the uterus and an ovarian sex cord tumor, called granulosa cell tumor, in the left ovary, simultaneously. Problems in diagnosing such pathologic condition generally arise because of the variable histologic picture of UTROSCT and may cause problems for general and other nongynecologic surgical pathologists. Immunohistochemically, these tumors express different markers that indicate their polyphenotypic origins.