Thymic function is a major determinant of onset of antibody-mediated rejection in heart transplantation.

Thymic function decreases progressively with age but may be boosted in certain circumstances. We questioned whether heart transplantation was such a situation and whether thymic function was related to the onset of rejection. Twenty-eight antithymocyte globulin-treated heart transplant recipients were included. Patients diagnosed for an antibody-mediated rejection on endomyocardial biopsy had a higher proportion of circulating recent thymic emigrant CD4+ T cells and T cell receptor excision circle levels than other transplanted subjects. Thymus volume and density, assessed by computed tomography in a subset of patients, was also higher in patients experiencing antibody-mediated rejection. We demonstrate that thymic function is a major determinant of onset of antibody-mediated rejection and question whether thymectomy could be a prophylactic strategy to prevent alloimmune humoral responses.

Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells.

OBJECTIVES: In obesity, while hyperleptinemia highly correlates with excess fat mass, the status of gastric leptin remains unknown. Here, we investigated the expression of leptin in stomach biopsies of obese humans and analyzed the temporal changes of gastric leptin expression in response to diet-induced obesity and its impact on 5-hydroxytryptamine (5HT)-producing cells. METHODS: Enterochromaffin (EC) cells and expression of leptin, PAX4 (critical factor for EC specification), tryptophane hydroxylase-1 (TPH1, the peripheral rate-limiting enzyme for 5HT) and 5HT were examined by immunofluorescence, quantitative real-time PCR, radioimmunoassay, respectively, in stomach and duodenum biopsies from 19 obese and 14 normo-weighed individuals, and in mucosa scrapings from C57Bl6/J diet-induced obese mice, leptin-deficient ob/ob mice and intestine-specific leptin receptor isoform B-deficient mice. RESULTS: Gastric mucosa of obese subjects displays an increased expression of leptin (LEP mRNA by fivefold and protein by twofold, P<0.01), TPH1 ((1.75-2.73, 95% confidence interval (CI)) vs (0.38-0.67, 95% CI); P<0.01) and PAX4 ((1.33-2.11, 95%CI) vs (0.62-0.81, 95% CI); P<0.01) as compared with normo-weighed individuals. In diet-induced obese mice, the overexpressions of gastric leptin, antral Pax4, Tph1 and increased EC cell number occurred before the onset of obesity and hyperleptinemia (reflect of adipocyte leptin production). In addition, leptin deficiency was associated with reduced Pax4 mRNA, whereas oral leptin treatment enhanced both Tph1 and Pax4 mRNA. Finally, mice with an intestine-specific deletion of leptin signaling exhibit significant decrease in duodenal mucosa 5HT content. CONCLUSIONS: These data demonstrate that gastric leptin is upregulated in obese individuals. RESULTS from high-fat diet mice showed that overexpression of gastric leptin that is linked to gut '5HT pathway' occurred before the onset of obesity and expansion of fat mass. This may be relevant in the pathophysiology of obesity.

NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms.

Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.

Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma.

BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-ß receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.

PD-L1 expression in the microenvironment and the response to checkpoint inhibitors in head and neck squamous cell carcinoma.

In head and neck squamous cell carcinoma (HNSCC), data from studies using checkpoint-inhibiting antibodies that target programmed death 1 (PD-1) or its ligand the programmed death ligand 1 (PD-L1) demonstrated outstanding clinical activity. Translational investigations also suggested some correlations between therapeutic response and PD-L1 expression in tumor tissue. We comprehensively summarize results that have evaluated PD-L1 expression in HNSCC. We discuss flaws and strength of current PD-1/PD-L1 detection, quantification methods and the evaluation of PD-L1 as a prognostic and theragnostic biomarker. Understanding tumor microenvironment may help understanding resistance to checkpoint inhibitors, designing clinical trials that can exploit drug combinations.

Morphological imaging and CT histogram analysis to differentiate pancreatic neuroendocrine tumor grade 3 from neuroendocrine carcinoma.

PURPOSE: To compare morphological imaging features and CT texture histogram parameters between grade 3 pancreatic neuroendocrine tumors (G3-NET) and neuroendocrine carcinomas (NEC). MATERIALS AND METHODS: Patients with pathologically proven G3-NET and NEC, according to the 2017 World Health Organization classification who had CT and MRI examinations between 2006-2017 were retrospectively included. CT and MRI examinations were reviewed by two radiologists in consensus and analyzed with respect to tumor size, enhancement patterns, hemorrhagic content, liver metastases and lymphadenopathies. Texture histogram analysis of tumors was performed on arterial and portal phase CT images. images. Morphological imaging features and CT texture histogram parameters of G3-NETs and NECs were compared. RESULTS: Thirty-seven patients (21 men, 16 women; mean age, 56±13 [SD] years [range: 28-82 years]) with 37 tumors (mean diameter, 60±46 [SD] mm) were included (CT available for all, MRI for 16/37, 43%). Twenty-three patients (23/37; 62%) had NEC and 14 patients (14/37; 38%) had G3-NET. NECs were larger than G3-NETs (mean, 70±51 [SD] mm [range: 18 - 196mm] vs. 42±24 [SD] mm [range: 8 - 94mm], respectively; P=0.039), with more tumor necrosis (75% vs. 33%, respectively; P=0.030) and lower attenuation on precontrast (30±4 [SD] HU [range: 25-39 HU] vs. 37±6 [SD] [range: 25-45 HU], respectively; P=0.002) and on portal venous phase CT images (75±18 [SD] HU [range: 43 - 108 HU] vs. 92±19 [SD] HU [range: 46 - 117 HU], respectively; P=0.014). Hemorrhagic content on MRI was only observed in NEC (P=0.007). The mean ADC value was lower in NEC ([1.1±0.1 (SD)]×10-3 mm2/s [range: (0.91 - 1.3)×10-3 mm2/s] vs. [1.4±0.2 (SD)]×10-3 mm2/s [range: (1.1 - 1.6)×10-3 mm2/s]; P=0.005). CT histogram analysis showed that NEC were more heterogeneous on portal venous phase images (Entropy-0: 4.7±0.2 [SD] [range: 4.2-5.1] vs. 4.5±0.4 [SD] [range: 3.7-4.9]; P=0.023). CONCLUSION: Pancreatic NECs are larger, more frequently hypoattenuating and more heterogeneous with hemorrhagic content than G3-NET on CT and MRI.

[Desmoplastic small round cell tumour of the pancreas with breast metastasis]. / Tumeur desmoplastique à petites cellules rondes du pancréas avec métastase mammaire.

Desmoplastic small round cell tumour (DSRCT) is a very rare, highly aggressive neoplasm. Most cases have been reported in adolescent and young male patients. These tumours occur mainly in the peritoneal cavity, with peritoneal and lymphatic dissemination. Their histologic features are unspecific and immunohistochemistry and cytogenetic or biomolecular techniques are required for their diagnosis. Involvement of the pancreas is exceptional and is difficult to differentiate from other pancreatic primary tumours. We report here the case of a 49-year-old woman who had a DSRCT of the pancreas with metastasis to the breast. She died within one year after the diagnosis despite an aggressive surgical strategy.

Cystic dystrophy in gastric heterotopic pancreas complicated by intracystic hemorrhage and fistulisation in the stomach - a pediatric case.

CONTEXT: Cystic dystrophy of the digestive wall, a rare but well-known complication of heterotopic pancreas when it is located in the duodenum, has been mainly described in adult series. Cystic dystrophy of the heterotopic pancreas within the gastric wall has been reported in only six adult cases. To our knowledge, no pediatric case has been described. CASE REPORT: We report a 15-year-old boy surgically treated for cystic dystrophy located in the antrum, complicated by an intracystic hemorrhage and fistulisation into the stomach. CONCLUSION: The diagnosis of heterotopic pancreas must be considered in case of submucosal cystic-gastric lesions, even in pediatric cases. Although the surgical approach is not systematic, it is recommended when cystic dystrophy is symptomatic (e.g., occlusion or hemorrhage).

[Verner-Morrison syndrome revealing a ganglioneuroblastoma in an adult]. / Syndrome de Verner-Morrison révélant un ganglioneuroblastome chez un adulte.

Most vasoactive intestinal peptide (VIP)-producing tumours are from epithelial origin. Tumours derived from the sympathetic nervous system can produce VIP as well. We report here the case of a Verner-Morrison syndrome in a 40-year-old woman revealing a metastatic ganglioneuroblastoma. The diarrhea resolved after the resection of primary tumour and liver metastases. Neuroblastic tumours occur extremely rarely in adults. Thus, the management of these tumours is poorly defined in adults.

[Limited pancreatic resections for intraductal papillary mucinous neoplasm]. / Résections limitées du pancréas pour tumeur intracanalaire papillaire et mucineuse non invasive.

INTRODUCTION: For non-invasive intraductal papillary and mucinous neoplasm (IPMN) with limited extent, pancreaticoduodenectomy (PD) or distal pancreatectomy (DP) seem excessive due to the risk of pancreatic insufficiency. Enucleation (EN) or medial pancreatectomy (MP) are not commonly performed for IPMN. The aim of this study was to evaluate the feasibility and results of EN and MP for non-invasive IPMN. PATIENTS AND METHODS: Of 249 patients with IPMN, we attempted a limited resection in 50 (20%) EN (n=31) or MP (n=20) with routine intra-operative frozen section pathology. One attempted EN was converted to MP. Indications for surgery were pain/pancreatitis (44%), suspicion of main duct involvement (28%), mural nodules in branch duct (14%), branch duct>30 mm (8%) or suspicion of mucinous cystadenoma (6%). Follow-up clinical assessment and MRI were performed on a yearly basis. RESULTS: Of the 31 attempted enucleations, 5 (13%) were immediately converted (4 PD, 1 MP) due to technical reasons (n=3) or due to findings on frozen section (n=2). At definitive pathological examination (accuracy of frozen sectioning=98%), branch ducts were involved by mild (n=21), moderate (n=7) or high grade dysplasia (n=2). One patient underwent a double EN. Of 20 attempted medial pancreatectomies, 8 (40%) required additional segmental resection due to significant IPMN lesions at pancreatic margins; 3 of the additional resection margins were tumor-free, and 5 were involved by IPMN (4 conversions to PD or DP, one contra-indication to PD). Overall, 49 pancreatic margins were analyzed by frozen sectioning with 98% accuracy. Resected specimens of 16 MP showed involvement by mild (n=7), moderate (n=7) or high grade dysplasia (n=2). There was no postoperative mortality. Median length of stay was 21 and 30 days respectively after EN and MP. Pancreatic fistula rate was 54% and 81% respectively after EN and MP. Three patients underwent early re-operation for hemorrhage. Overall median follow-up was 24 months (3-121). All patients are alive, 2 patients (5%) have presented with recurrent pain and 4 have developed tumor recurrence on imaging follow-up (4/33=12%). Two patients (5%) developed de novo diabetes (one after EN combined with DP) and a third patient developed worsening of pre-existing diabetes plus exocrine insufficiency. No patient had surgery for recurrence. CONCLUSIONS: EN and MP are feasible for non-invasive IPMN. Their significant early morbidity is counterbalanced by low rates of both long-term functional disorders and tumor recurrence.

Ectopic expression of OX1R in ulcerative colitis mediates anti-inflammatory effect of orexin-A.

Orexins (orexin-A and orexin-B) are hypothalamic peptides that are produced by the same precursor and are involved in sleep/wake control, which is mediated by two G protein-coupled receptor subtypes, OX1R and OX2R. Ulcerative colitis (UC) is an inflammatory bowel disease, (IBD) which is characterized by long-lasting inflammation and ulcers that affect the colon and rectum mucosa and is known to be a significant risk factor for colon cancer development. Based on our recent studies showing that OX1R is aberrantly expressed in colon cancer, we wondered whether orexin-A could play a role in UC. Immunohistochemistry studies revealed that OX1R is highly expressed in the affected colonic epithelium of most UC patients, but not in the non-affected colonic mucosa. Injection of exogenous orexin-A specifically improved the inflammatory symptoms in the two colitis murine models. Conversely, injection of inactive orexin-A analog, OxB7-28 or OX1R specific antagonist SB-408124 did not have anti-inflammatory effect. Moreover, treatment with orexin-A in DSS-colitis induced OX1R-/- knockout mice did not have any protective effect. The orexin-A anti-inflammatory effect was due to the decreased expression of pro-inflammatory cytokines in immune cells and specifically in T-cells isolated from colonic mucosa. Moreover, orexin-A inhibited canonical NFκB activation in an immune cell line and in intestinal epithelial cell line. These results suggest that orexin-A might represent a promising alternative to current UC therapies.

TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system.

Criteria for the staging and grading of neuroendocrine tumors (NETs) of midgut and hindgut origin were established at the second Consensus Conference in Frascati (Rome) organized by the European Neuroendocrine Tumor Society (ENETS). The proposed tumor-node-metastasis (TNM) classifications are based on the recently published ENETS Guidelines for the Diagnosis and Treatment of gastroenteropancreatic NETs and follow our previous proposal for foregut tumors. The new TNM classifications for NETs of the ileum, appendix, colon, and rectum, and the grading system were designed, discussed, and consensually approved by all conference participants. These proposals need to be validated and are meant to help clinicians in the stratification, treatment and follow-up of patients.

A new mRNA splice variant coding for the human EP3-I receptor isoform.

The cellular localization of prostaglandin E2 receptors (EP) and their corresponding transcripts were investigated in human gastric and vascular tissues. A strong staining of the EP3 receptor on the gastric glands, mucous cells, media of the mammary and pulmonary arteries was observed by immunohistochemistry. We identified a new mRNA splice variant of the EP3 gene in human gastric fundic mucosa, mammary artery and pulmonary vessels. This EP3-Ic transcript contains exons 1, 2, 3, 5 and 6 of the EP3 gene and should be translated in the EP3-I isoform. In addition, the EP3-Ib, EP3-II, EP3-III, EP3-IV and EP3-e mRNAs were detected in these tissues.

TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system.

The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.

[Non transplant-related constrictive bronchiolitis in adults]. / Bronchiolites constrictives de l'adulte, hors contexte de transplantation.

INTRODUCTION: The term bronchiolitis refers to inflammatory disorders of the bronchioles. Constrictive bronchiolitis is the type most frequently encountered. STATE OF THE ART/PERSPECTIVES: The main clinical manifestations include the development of exertional dyspnoea and fixed airflow obstruction. Chest x-ray findings are usually unhelpful, but CT scanning may reveal a mosaic pattern on expiration. Peripheral micronodules are less frequently seen. The causes of constrictive bronchiolitis are numerous. The diagnosis may be clear from the clinical context when a causative event or predisposing condition can be identified (lung or bone marrow transplantation, toxic fume or gas inhalation, rheumatoid arthritis); in other conditions, a stepwise approach to the diagnosis is usually recommended in order to exclude other causes of subacute or chronic obstructive disease. Formal diagnosis requires histological examination of surgical lung biopsies. Despite corticosteroid administration, respiratory failure usually develops. Specific inhibitors of pro-inflammatory cytokines may offer a new and promising therapeutic approach. CONCLUSIONS: If the clinical context or the radiology and clinical findings are not highly suggestive of a constrictive bronchiolitis, a surgical lung biopsy should be considered.

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

No evidence of somatic FGFR3 mutation in various types of carcinoma.

Germline specific point mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are associated with autosomal dominant human skeletal dysplasia and craniosynostosis syndromes. Mutations identical to the germinal activating mutations found in severe skeletal dysplasias have been identified in certain types of cancer: at low frequency in multiple myeloma and cervix carcinoma and at high frequency in bladder carcinoma. We analysed, by SSCP and sequencing, the prevalence of FGFR3 mutations in 116 primary tumours of various types (upper aerodigestive tract, oesophagus, stomach, lung and skin). The regions analysed encompassed all FGFR3 point mutations previously described in severe skeletal dysplasia and cancers. No mutations were detected in the tumour types examined, suggesting that FGFR3 mutations are restricted to a few tumour types, the evidence to date suggesting that they are very specific to bladder carcinomas.

[Intraductal papillary mucinous tumours of the pancreas: imaging features]. / Aspect radiologique des tumeurs intracanalaires pancréatiques mucineuses et papillaires.

IPMTP is a pancreatic duct disease that can better be diagnosed due to advances in imaging techniques. This probably explains the recent increased frequency of this disease. Enlargement of the main pancreatic duct and/or branch ducts is a typical feature. CT and MRI with MRCP are useful for diagnosis. Features of malignant degeneration are better known. Preoperative staging is performed at CT. Differential diagnosis includes main pancreatic duct dilatation and pancreatic cysts. Recent papers indicate that isolated side branch IPMTP is less frequently malignant. Surgery is indicated in the presence of acute pancreatitis or suspicion of malignant degeneration. Imaging is useful for the follow up of patients with isolated side branch IPMTP. In this paper, the diagnostic, staging and malignant features of IPMTP will be reviewed.

Parenchymal innervation of normal and cirrhotic human liver: a light and electron microscopic study using monoclonal antibodies against the neural cell-adhesion molecule.

Hepatic innervation participates in the control of sinusoidal blood flow and in the regulation of certain metabolic functions of the liver. The study of the distribution of hepatic nerves has been hampered by the lack of adequate markers. We therefore tested the value of the neural cell-adhesion molecule (NCAM) as a probe for the study of parenchymal nerves in the normal and cirrhotic human liver. Four antibodies against various epitopes of NCAM were tested by light and electron microscopic immunohistochemistry: Leu19, ERIC-1, VC1.1, and HNK-1. Their reactivity was compared with that of antibodies against the following neural cell markers: S100 protein, neurofilaments, and neuron-specific enolase (NSE). The tissue reactivity of anti-NCAM antibodies was variable, suggesting a microheterogeneity of the NCAM molecule in the normal liver. Clones Leu19 and ERIC-1 proved to be the most sensitive of the anti-NCAM antibodies. Their sensitivity was superior to that of the antibodies directed against the other neural cell markers tested. In the normal liver, both Leu19 and ERIC-1 demonstrated a heterogeneous distribution of nerve fibers inside the hepatic lobule. Intralobular nerve fibers predominated in Zone 1. This might contribute to the constitution of distinct zonal microenvironments inside the hepatic lobule. In cirrhosis, no nerve fiber was detected inside parenchymal nodules; no nerve plexus was visible at the contact of proliferating neoductules. These alterations might contribute to the pathogenesis of the hemodynamic and metabolic disorders observed in cirrhosis.