Second-line treatment and prognostic factors in neuroendocrine carcinoma: the RBNEC study.

Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an 'adenocarcinoma-like' or a 'neuroendocrine-like' 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum-etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum-etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.

Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity.

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

Quantification of steatosis in alcoholic and nonalcoholic fatty liver disease: Evaluation of four MR techniques versus biopsy.

PURPOSE: Given the growing prevalence of obesity and metabolic syndrome, the management of hepatic steatosis, especially its quantification, is a major issue. We assessed the quantification of liver steatosis using four different MR methods, in order to determine the one that is best correlated with the reference method which consists of histological measurement by liver biopsy. METHOD: Seventy-one successive patients requiring liver biopsy for acute or chronic liver disease were enrolled prospectively between March 2017 and March 2018, 11 were excluded and 60 were reported. Liver MR (1.5 T) was organised in order to be performed the same day, using four different steatosis quantification techniques (3-echo MRI, 6-echo MRI, 11-echo MRI and MR Spectroscopy). Quantitative histological and imaging data were compared. In a secondary analysis, we studied the possible influence of alcohol drinking, hepatic iron overload, and the presence of liver fibrosis. RESULTS: All four MR techniques were found to have excellent correlations with the histological measurements: 3-echo MRI (r = 0.852, p < 0.001), 6-echo MRI (r = 0.819, p < 0.001), 11-echo MRI (r = 0.818, p < 0.001) and MR Spectroscopy (r = 0,812, p < 0,001). Interestingly, we also found that the presence of alcohol consumption, iron overload and fibrosis did not interfere with measurements, whichever technique was used. CONCLUSION: In the evaluation of hepatic steatosis, our study showed very good correlations of all four MR techniques with the histological standard. There was no confounding factor in a representative group of patients with associated liver conditions such as alcohol consumption, fibrosis and iron overload, for each technique. All four MR techniques may be used in daily practice.

Specificities of Human Hepatocellular Carcinoma Developed on Non-Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue Extracts ¹H-NMR Spectroscopy.

There is a rising incidence of non-alcoholic fatty liver disease (NAFLD) as well as of the frequency of Hepato-Cellular Carcinoma (HCC) associated with NAFLD. To seek for putative metabolic pathways specific of the NAFLD etiology, we performed comparative metabolomics between HCC associated with NAFLD and HCC associated with cirrhosis. The study included 28 pairs of HCC tissue versus distant Non-Tumoral Tissue (NTT) collected from patients undergoing hepatectomy. HCC was associated with cirrhosis (n = 9), normal liver (n = 6) and NAFLD (n = 13). Metabolomics was performed using 1H-NMR Spectroscopy on tissue extracts and combined to multivariate statistical analysis. In HCC compared to NTT, statistical models showed high levels of lactate and phosphocholine, and low level of glucose. Shared and Unique Structures (SUS) plots were performed to remove the impact of underlying disease on the metabolic profile of HCC. HCC-cirrhosis was characterized by high levels of ß-hydroxybutyrate, tyrosine, phenylalanine and histidine whereas HCC-NAFLD was characterized by high levels of glutamine/glutamate. In addition, the overexpression glutamine/glutamate on HCC-NAFLD was confirmed by both Glutamine Synthetase (GS) immuno-staining and NMR-spectroscopy glutamine quantification. This study provides evidence of metabolic specificities of HCC associated with non-cirrhotic NAFLD versus HCC associated with cirrhosis. These alterations could suggest activation of glutamine synthetase pathway in HCC-NAFLD and mitochondrial dysfunction in HCC-cirrhosis, that may be part of specific carcinogenic processes.

The prognostic influence of the proliferative discordance in metastatic pancreatic neuroendocrine carcinoma revealed by peptide receptor radionuclide therapy: Case report and review of literature.

RATIONALE: Pancreatic neuroendocrine tumors (pNET) are rare slowly growing tumors with a high metastatic potential. Peptide receptor radionuclide therapy (PRRT) with radiolabeled analogues has been developed as a new tool for the management of metastatic well-differentiated (grade 1 and 2) neuroendocrine tumors expressing somatostatin receptor (SSTR2). Chemotherapy is the mainstay in the management of grade 3 (G3) unresectable pancreatic neuroendocrine carcinoma (pNEC). To date, no study has evaluated the efficacy of PRRT in such tumors. DIAGNOSES AND INTERVENTIONS: We describe a case of a progressive G3 pNEC with huge liver metastases successfully treated with PRRT (Lu DOTATATE). OUTCOMES: Complete remission was obtained for 3 years. Indeed, the mitotic index was low (as G2 tumors) but with a very high Ki-67 index (45%-70%). Such discordance between the proliferative markers should consider the use of PRRT before chemotherapy in unresectable metastatic G3 tumors expressing SSTR2. LESSONS: This case supports the hypotheses highlighting the heterogeneity of G3 pNEC. The latter should be subdivided into 2 distinct categories: proliferation-discordant (well differentiated) and concordant (poorly differentiated) NEC. PRRT could be suggested for the former group before the conventional chemotherapy.

Dietary Supplementation with a Low Dose of Polyphenol-Rich Grape Pomace Extract Prevents Dextran Sulfate Sodium-Induced Colitis in Rats.

Evidence from several epidemiological and experimental studies points to a beneficial role of dietary polyphenols in inflammatory bowel disease. In this study, we investigate the protective effect of dietary supplementation with various amounts of a polyphenol-rich grape pomace extract (GPE) on the development of dextran sulfate sodium (DSS)-induced colitis in rats. Rats were fed 21 days on a semisynthetic diet enriched with GPE (0.1%, 0.5%, and 1%), and acute colitis was induced by DSS (40 g/L in the drinking water) administration during the last 7 days. The low GPE content in the diet (0.1%) attenuated clinical signs and colon shortening and limited DSS-induced histological lesions. GPE 0.1% also attenuated the DSS-induced increase in myeloperoxidase activity and improved superoxide dismutase activity. Higher amounts of GPE in the diet induced only weak and nonsignificant protective effects. These results suggest that consumption of a low amount of polyphenol-rich GPE helps protect against colitis development.

Polyphenol-rich grape pomace extracts protect against dextran sulfate sodium-induced colitis in rats.

BACKGROUND: Several studies have reported that polyphenols may exert beneficial effects on inflammatory bowel disease. This study aimed to evaluate the effects of preventive consumption of polyphenol-rich red grape pomace extracts (GPEs) on dextran sulfate sodium (DSS)-induced colitis in rats. Rats were fed for 21 days with a semi-synthetic diet enriched with a GPE (Alicante-S, Alicante-P or Pinot-S) and colitis was induced by DSS administration in drinking water (40 g L(-1) ) during the last 7 days of experimentation. RESULTS: GPEs attenuated clinical signs and colon shortening and Alicante GPEs limited histological lesions induced by DSS. GPEs curbed the increase in myeloperoxidase activity and modulated antioxidant enzyme activities. Moreover, GPEs prevented the DSS-induced increase in pro-inflammatory cytokine levels and the up-regulation of various genes implicated in colitis such as intercellular adhesion molecule 1 (ICAM-1) and matrix metalloproteinase 9 (MMP-9). CONCLUSION: These results suggest that polyphenol-rich red GPEs could provide prevention against colon inflammation.

Impact of basal diet on dextran sodium sulphate (DSS)-induced colitis in rats.

PURPOSE: Dextran sodium sulphate (DSS)-induced colitis is a widely used model for inflammatory bowel disease. However, various factors including nutrition may affect the development of this colitis. This study aimed to compare and characterize the impact of purified and non-purified basal diets on the development of DSS-induced colitis in the rat. METHODS: Wistar rats were fed a non-purified or a semi-synthetic purified diet for 21 days. Colitis was then induced in half of the rats by administration of DSS in drinking water (4% w/v) during the last 7 days of experimentation. At the end of the experimental period, colon sections were taken for histopathological examination, determination of various markers of inflammation (myeloperoxidase: MPO, cytokines) and oxidative stress (superoxide dismutase: SOD, catalase: CAT, glutathione peroxidase: GPx and glutathione reductase: GRed activities), and evaluation of the expression of various genes implicated in this disorder. RESULTS: DSS ingestion induced a more marked colitis in animals receiving the purified diet, as reflected by higher histological score and increased MPO activity. A significant decrease in SOD and CAT activities was also observed in rats fed the purified diet. Also, in these animals, administration of DSS induced a significant increase in interleukin (IL)-1α, IL-1ß and IL-6. In addition, various genes implicated in inflammation were over-expressed after ingestion of DSS by rats fed the purified diet. CONCLUSIONS: These results show that a purified diet promotes the onset of a more severe induced colitis than a non-purified one, highlighting the influence of basal diet in colitis development.

Annexin A1 in primary tumors promotes melanoma dissemination.

Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.

Aloysia triphylla infusion protects rats against dextran sulfate sodium-induced colonic damage.

BACKGROUND: Inflammatory bowel diseases consist of uncontrolled intestinal inflammation leading to mucosal disruption. Polyphenols are micronutrients with antioxidant and anti-inflammatory properties and may play an interesting role in the prevention of intestinal inflammation. Lemon verbena (Aloysia triphylla (L'Herit.) Britton, Verbenaceae) infusion is a popular herbal drink rich in polyphenols. This study evaluated the protective effects of lemon verbena infusion consumption on the development of dextran sulfate sodium (DSS)-induced colitis in rats. The infusion was given to rats as a drink providing 82 µmol polyphenols day(-1) for 21 days. Colitis was induced with 40 g l(-1) DSS in the drink for the last 7 days. RESULTS: Lemon verbena infusion treatment restored body weight gain and prevented colonic shortening. Despite no protective effect on myeloperoxidase activity, A. triphylla infusion limited histological colonic alterations. CONCLUSION: The results suggest that lemon verbena infusion partially protects rats against DSS-induced inflammation.

Lemon verbena infusion consumption attenuates oxidative stress in dextran sulfate sodium-induced colitis in the rat.

BACKGROUND: Inflammatory bowel diseases (IBD) consist of an uncontrolled intestinal inflammation leading to mucosal disruption. This inflammation is accompanied by an excessive production of reactive oxygen species (ROS). Polyphenols are micronutrients with antioxidative and anti-inflammatory properties, and may play an interesting role in the prevention of intestinal inflammation. Lemon verbena (Aloysia triphylla) infusion is a popular herbal infusion rich in polyphenols (flavones and verbascoside). AIMS: This study evaluated the preventive effects of lemon verbena infusion consumption against mild-to-moderate dextran sulfate sodium (DSS)-induced colitis in rats. METHODS: Wistar rats drank water or lemon verbena infusion for 14 days. On day 15, half of the rats received DSS (4%) in their drink for 7 days. At the end of the experimental period, the colon was taken for histopathological examination and determination of myeloperoxidase (MPO) activity, antioxidant enzyme activities (superoxide dismutase [SOD], glutathione peroxidase [GPx], glutathione reductase [GR], catalase [CAT]), glutathione and lipid peroxidation. Lymphocyte populations were determined in blood, mesenteric nodes and Peyer's patches. RESULTS: Rats ingested daily 5.6 µmol of polyphenols. DSS reduced food intake and induced colitis, as reflected by histological lesions and increased MPO activity. Although these alterations were not significantly counteracted by lemon verbena consumption, the herbal infusion increased colonic SOD activity and decreased lipid peroxidation (malondialdehyde). Other oxidative stress markers (GPx, GR, CAT, glutathione) were not significantly modified. CONCLUSION: Our study shows that the preventive consumption of lemon verbena infusion offered some antioxidative protection during experimental colitis by stimulating SOD activity and decreasing lipid peroxidation.

Epithelioid hemangioendothelioma of the liver with metastatic coeliac lymph nodes in an 11-year-old boy.

Epithelioid hemangioendothelioma of the liver is a very rare vascular tumour in children with intermediate malignant potential. We present a case in which the typical imaging appearances of coalescent peripheral hepatic masses with capsular retraction contributed to the diagnosis. A positron emission tomography-CT (PET-CT) procedure was performed in staging the disease with a strong suspicion of coeliac nodal involvement confirmed after laparotomy and histological analysis. Our case is unique because of the rarity of the disease, the young age of the child, and proven nodal metastases at initial diagnosis. The use of PET-CT allows better staging at initial diagnosis and thus better management with improved follow-up in these patients.

[Peritoneal serous borderline tumors: report of two cases]. / Tumeurs séreuses borderline du péritoine: à propos de deux cas.

Two cases of serous borderline tumors of the peritoneum are reported. These rare tumors may show variable histological features. The lack of peritoneal invasion, which may be difficult to assess, with minimal or no ovarian involvement are major features for the diagnosis. These tumors should be distinguished from other peritoneal neoplasms such as serous carcinomas because of their good prognosis after surgical therapy alone.