Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

Temporary successful results of ventral rectopexy for enterocele surgical correction, about 138 patients.

PURPOSE: This work aimed to analyse short- and long-term results of enterocele surgical treatment by ventral rectopexy. METHODS: All females who underwent ventral rectopexy for enterocele in our department were included. All patients underwent standardized preoperative evaluation. Data was retrospectively collected, after examination of patients or by telephone survey. Postoperative evaluation was performed by an independent observer. RESULTS: One hundred thirty-eight females (median age = 63 years [21-86 years]) were included. They were postmenopausal and multiparous in 94 and 70% of cases, respectively. Pelvic pressure, vaginal prolapse, or the both were observed in 28, 16 or 56% of the patients, respectively. The most frequent associated symptoms were dyschezia (63%) and faecal incontinence (30%). On preoperative workup, enterocele was isolated in two cases. Rectocele, internal rectal prolapse and cervicocystoptosis were the most frequently associated pelvic floor disorders. Ventral rectopexy was performed through laparoscopy in 128 patients (93%). In the short term, all pelvic symptoms were significantly improved, except urinary incontinence. At the end of follow-up (56 months [7-125]), specific symptoms and dyschezia were still significantly improved. Secondary failure was reported in 31% of patients. By multivariate analysis, two predictive factors for long-term failure were found: diagnosis of rectocele on preoperative MRI (odd ratio = 15; 95% CI 1.4-163; p = 0.03) and conversion into open surgery (odd ratio = 8; 95% CI 1.4-43; p = 0.02). CONCLUSION: This study suggests that ventral rectopexy is an effective treatment of enterocele, but secondary failure can be observed. Patients should be informed of the potential risk of long-term degradation.

Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts.

c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.

Implications of SDHB genetic testing in patients with sporadic pheochromocytoma.

PURPOSE: Succinate dehydrogenase B (SDHB) associated pheochromocytomas (PHEOs) are associated with a higher risk of tumor aggressiveness and malignancy. The aim of the present study was to evaluate (1) the frequency of germline SDHB mutations in apparently sporadic patients with PHEO who undergo preoperative genetic testing and (2) the ability to predict pathogenic mutations. METHODS: From 2012 to 2016, 82 patients underwent a PHEO surgical resection. Sixteen were operated in the context of hereditary PHEO and were excluded from analysis. Among the 66 remaining cases, 48 were preoperatively screened for an SDHB mutation. In addition to imaging studies with specific radiopharmaceuticals (123I-MIBG or 18F-FDOPA) for exclusion of multifocality/metastases, 36 patients underwent 18F-FDG PET/CT. RESULTS: From the 48 genetically screened patients, genetic testing found a germline SDHB variant in two (4.2%) cases: a variant of unknown significance, exon 1, c.14T>G (p.Val5Gly), and a most likely pathogenic mutation, exon 5, c.440A>G (p.Tyr147Cys), according to in silico analysis. Structural and functional analyses of the protein predicted that p.Tyr147Cys mutant was pathogenic. Both tumors exhibited moderate 18F-FDG PET uptake with similar uptake patterns to non-SDHB mutated PHEOs. The two patients underwent total laparoscopic adrenalectomies. Of the remaining patients, 44 underwent a laparoscopic adrenalectomy, and two had an open approach. Pathological analysis of the tumors from patients bearing two germline SDHB variants revealed a typical PHEO (PASS 0 and 2). Ex-vivo analyses (metabolomics, SDHB immunohistochemistry, loss of heterozygosity analysis) allowed a reclassification of the two SDHB variants as probably non-pathogenic variants. CONCLUSIONS: This study illustrates that SDHx mutational analysis can be misleading, even if structural and functional analyses are done. Surgeons should be aware of the difficulty of classifying new SDHB variants prior to implementing SDHB mutation status into a tailored surgical management strategy of a patient.

A pancreatic ductal adenocarcinoma subpopulation is sensitive to FK866, an inhibitor of NAMPT.

Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.

New anatomical data on the drainage patterns of the uncinate process of the pancreas.

PURPOSE: Recently, progress has been made in the surgical management of benign pancreatic tumors sparing as much of the pancreatic parenchyma and pancreatic function as possible. However, the main complication of partial pancreatectomy is the disruption of pancreatic ducts ensuing leak of pancreatic secretion leading to the formation of pancreatic fistulae. In this study, we attempt to precisely define the anatomy of the branch duct draining the uncinate process which is of interest to the surgeons. METHODS: Seventeen formalin-fixed pancreases were taken and ducts were injected with a colored gelatin solution. Within the uncinate process of the pancreases, the branch duct was localized, measured and its anatomical drainage defined. Statistics were performed using Spearman's correlation test. RESULTS: The uncinate process was drained exclusively by the main pancreatic duct in ten cases, by the accessory pancreatic duct in three cases, and by both the ducts in four cases. All of the branches drained into the main pancreatic duct downstream to the junction between the main and the accessory pancreatic duct, except for one. CONCLUSIONS: We have precised the possibility of double drainage of the uncinate process, but this could not be correlated with simple anatomical or radiological landmarks such as the length of the main pancreatic duct or the patency of the minor duodenal papilla.