Efficacy and tolerance of LV5FU2-carboplatin chemotherapy in patients with advanced pancreatic ductal adenocarcinoma after failure of standard regimens.

Background: Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. Objectives: We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. Design: We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2-carboplatin between 2009 and 2021 in an expert center. Methods: We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. Results: In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2-carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0-6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4-3.0). At multivariable analysis, no extrahepatic metastases (p = 0.083), no ascites or opioid-requiring pain (p = 0.023), <2 prior treatment lines (p < 0.001), full dose of carboplatin (p = 0.004), and treatment initiation >18 months after initial diagnosis (p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48-4.92) and was influenced by the presence of extrahepatic metastases (p = 0.058), opioid-requiring pain or ascites (p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3-4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Conclusion: Although the efficacy of LV5FU2-carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients.

Physiological response to the weaning in two pig lines divergently selected for residual feed intake.

Breeding efficient pigs is a way to reduce dietary costs and environmental waste. However, optimization of feed efficiency must not be linked to a decrease of the ability of animals to cope with stress, such as the weaning. This study characterizes the response after weaning of pigs from two lines divergently selected for residual feed intake (RFI) during growth. Animals of the low (L) RFI line are more efficient than animals from the high (H) RFI line. Thirty-six piglets from each line weaned at 28 days of age were individually housed and fed a conventional dietary sequence. Their performance, behaviour, health and oxidative status, immune and nutritional parameters were followed during three weeks. Daily feed intake and growth rate of pigs from the LRFI line were 35% and 40% lower compared with HRFI (p < 0.001). Pigs from the LRFI-line had lower total tract apparent digestibility (-6% for OM) and suffered more from undernutrition with a 167 and 55% higher plasmatic concentration of NEFA and urea compared with HRFI (p < 0.01). In the first week after the weaning, they had more diarrhoea and had a higher inflammatory status with concentration of haptoglobin 52% higher (p < 0.001). These piglets then seemed to adapt to the weaning conditions and to recover during the second and third weeks. Both lines had similar zootechnical performance and physiological characteristics at the end of the post-weaning period. To conclude, the physiological responses to the weaning differed between lines. Pigs from the LRFI line, selected for greater feed efficiency, were more sensitive to the weaning stress. They were also more resilient as they finally adapted to the new condition and recovered to show similar performance results as pigs of the HRFI line.

Natural history of SPINK1 germline mutation related-pancreatitis.

BACKGROUND: The aim was to describe genetic, clinical and morphological features in a large, multicentre European cohort of patients with SPINK1 related pancreatitis, in comparison with patients with idiopathic pancreatitis (IP). METHODS: All SPINK1 mutation carriers with pancreatic symptoms from two French and one English centers were included. Patients with IP were included in a control group. Genetic, clinical, radiological and biochemical data were collected. FINDINGS: 209 and 302 patients were included in the SPINK1 and control groups (median follow-up: 8.3 years (3.7-17.4) vs 5.3 (2.5-8.8)). The median age at onset of symptoms was 20.1 years (17.5-22.8) in the SPINK1 group versus 41.2 (35.2-45.2). The age of exocrine pancreatic insufficiency (EPI) onset in the SPINK1 group was 49.5 (44.5-54.6) years vs. 65.2 (62.1-68.3), p < 0.001. SPINK1 patients with EPI were 5.3%, 14.7%, 28.3% and 52.4% at 20, 30, 40 and 50 years. Diabetes occurred 37.7 (33.3-42.1) years following the onset of symptoms in the SPINK1 group vs. 30.6 (17.3-43.8) (p = 0.002). SPINK1 patients with diabetes were 7.8%, 13.4%, 26.3% and 43.4% at 30, 40, 50 and 60 years. Seven patients (3.3%) developed pancreatic cancer in the SPINK1 group (versus 3 (0.99%), p = 0.1), at a median age of 60 vs 66 years. The cancer risk was 0.8% before 50 years, 11.9%, 27.7%, 51.8% at 60, 70 and 80 years and was 12 times higher than in controls (Cox HR 12.0 (3.0-47.8), p < 0.001). INTERPRETATION: SPINK1 related pancreatitis is associated with earlier onset and pancreatic insufficiencies. p.N34S SPINK1 may well be associated with cancer.

Responses to weaning in two pig lines divergently selected for residual feed intake depending on diet.

Weaning is a stress every piglet has to face. It is a main cause of antibiotic uses due to digestive disorders. In this study, response to weaning was analyzed in pigs from two lines divergently selected for residual feed intake (RFI) during growth. A total of 132 pigs from each line, housed per line and diet in conventional postweaning units of 12 castrated males and 12 females, were fed either a conventional control (two successive diets) or a complex (three successive diets) dietary sequence during the postweaning period (4 to 10 wk of age). BWs were recorded at weaning (days 0 and 28 of age), days 1, 2, 6, 12, 19, 26, and 42 (10 wk of age), and at 23 wk of age. Feces texture was examined before weaning (day -1), at day 1, 2, 6, 12, and 19. Feed intake was recorded at pen level from days 0 to 42 after weaning, and individually thereafter. Plasma was collected after blood samplings at days -1, 6, 19, and 42 on half of the piglets: all piglets of a given sex in each pen were sampled, to achieve a balanced number across factors. Pigs of the low RFI (LRFI) line were heavier at weaning, had greater glucose concentration, and lower levels of diarrhea at days 1 and 2 than pigs from the high RFI (HRFI) line (P < 0.01). At day 42, there was no BW difference between lines, and G:F ratio did not differ between lines (P = 0.40). The LRFI pigs had lower feed intake and growth rate from day 0 to day 19 (P < 0.005), and greater plasma concentration of non-esterified fatty acid (P < 0.001), indicating an increased mobilization of body lipids and proteins immediately after weaning compared with HRFI pigs. They also had greater levels of diarrhea at day 6 (22% for LRFI vs. 14% for HRFI, P = 0.002), but the concentration of plasma haptoglobin did not indicate acute inflammation. The complex diet sequence improved feed intake and growth, and reduced diarrhea, mainly in the LRFI line (P < 0.001). To conclude, pigs from the LRFI line were more negatively affected by weaning stress, but managed to recover afterwards. The complex diet sequence ameliorated some of the negative effects that weaning had on the LRFI pigs, but limited effects of nursery period feeding sequence on growth performance were observed during the growing-finishing period.

Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) are a heterogeneous subgroup of rare neoplasms that represent about a third of all poorly differentiated neuroendocrine carcinomas (PDNEC). MiNEN combine a neuroendocrine component, usually a PDNEC, and a non-neuroendocrine component, generally an adenocarcinoma, both accounting for at least 30% of the neoplasm. MiNEN are classified as high-, intermediate-, or low-grade malignancies depending on the metastatic potential of the tumour components. High-grade malignant component should be considered even if it represents <30% of the tumour. The prognosis of MiNEN is generally intermediate between those of the two "pure" components composing it. The aim of this comprehensive review of the literature is to suggest a standardized management of MiNEN. An increasing body of evidence suggests that PDNEC components share molecular abnormalities with their adenocarcinoma counterparts, but also display additional alterations. This advocates for a common origin, and that the presence of a PDNEC component in an adenocarcinoma could indicate a turning point in carcinogenesis.

Epidemiology of pancreatic cancer in France: descriptive study from the French national hospital database.

INTRODUCTION: Although indirect evidence suggests that the incidence of pancreatic adenocarcinoma has increased in the last decade, few data are available in European countries. The aim of the present study was to update the epidemiology of pancreatic cancer in France in 2014 from the French national hospital database (Programme de Médicalisation des Systèmes d'Information). PATIENTS AND METHODS: All patients hospitalized for pancreatic cancer in France in 2014 in public or private institutions were included. Patient and stays (length, type of support, institutions) characteristics were studied. The results were compared with those observed in 2010. RESULTS: A total of 13 346 (52% men, median age 71 years) new patients were treated for pancreatic cancer in 2014, accounting for a 12.5% increase compared with 2010. Overall, 22% of patients were operated on. Liver metastases were present in 60% of cases. The disease accounted for 146 680 hospital stays (+24.8% compared with 2010), 76% of which were related to chemotherapy (+32%). The average annual number and length of stay were 7 and 2.6 days, respectively. In 2014, 11 052 deaths were reported (+15.8%). CONCLUSION: Approximately 13 350 new cases of pancreatic cancer were observed in France in 2014. The increase in incidence was associated with a marked increase in hospital stays for chemotherapy.

Rescue therapy with bismuth-containing quadruple therapy in patients infected with metronidazole-resistant Helicobacter pylori strains.

BACKGROUND: The emergence of H. pylori strains that are resistant to clarithromycin, metronidazole and fluoroquinolone requires the evaluation of new and effective salvage therapies. AIMS: To test the efficacy of a new formulation of a bismuth-containing quadruple therapy as a rescue therapy in patients who were infected with a H. pylori strain resistant to metronidazole, clarithromycin and fluoroquinolone or who failed multiple lines of treatment using these three antibiotics. METHODS: A total of 103 patients with confirmed H. pylori infection with a resistance profile described above were treated with Pylera(®) (3-in-1 capsules containing bismuth subcitrate potassium 140mg, metronidazole 125mg and tetracycline 125mg) 3 capsules four times a day plus omeprazole 20mg two times a day for 10 days in a named patient program. Eradication was confirmed using a urea breath test at least 28 days after the end of treatment. Efficacy and safety were studied. RESULTS: A total of 103 patients were prospectively included from June 2010 to October 2011. The eradication rate for the intent-to-treat analysis was 83% (CI95%[75-89%]); an 87% eradication rate (CI95%[80-94%]) was found for the per-protocol analysis and 81% (CI95%[80-82%]) for the intent-to-treat analysis in patients with proven resistance to metronidazole. Nine patients discontinued treatment, all due to adverse events. Two serious adverse events (AEs) were reported (memory disorders of unknown significance). Fifty-six (54%) patients reported at least one AE. CONCLUSION: This bismuth-containing quadruple therapy achieved a remarkable eradication rate as a salvage therapy in patients infected with metronidazole-resistant H. pylori strain, despite the frequent occurrence of mild-to-moderate adverse events.

[Inadequate involvement of general practitioners in end-of-life's decisions in an intensive care unit]. / Implication insuffisante des médecins généralistes lors des décisions de limitation et/ou d'arrêt des traitements au sein d'un service de réanimation.

INTERESTS AND OBJECTIVES: Patients' general practitioners (GPs) could be relevant consultants for collegial decisions of withholding or withdrawing treatment (WWT) defined by the Leonetti law. We therefore studied their implication by intensivists in end-of-life decisions and collected their feelings. Their wishes for the coming law revision were also investigated. METHODS: Retrospective descriptive study conducted in the polyvalent intensive care unit (ICU) of Longjumeau's hospital (France) using a distributed questionnaire to GPs of patients who benefited from collegial decisions of WWT in 2012. RESULTS: The response rate was 60.4% (32/53) and only 18.8% of the respondents participated as a consultant in WWT's decision for their patient. Two GPs out of three reported that they never participate in such decisions for their others patients. All uninvolved GPs did not contribute because intensivists did not consult them. Only 43.7% of GPs were contacted by intensivists during the stay and 21.9% at the discharge or death of their patient. GPs took news about their patient during ICU hospitalization in 37.5% of cases. Regarding uninvolved GPs, their participation could have changed WWT's decisions made for two patients (7.7%). Most respondents felt available (78.1%) and skilled (81.2 %) to participate in this kind of decision. A third was also questioned by the patient's family about it. Only 21.7% of GPs report to be familiar with the French end-of-life legislation. In case of a next revision, two thirds considered important to make the use of GPs obligatory in such decisions. CONCLUSION: Despite an undeniable interest, GPs are rarely involved in collegial processes of WWT in ICUs, partially related to an insufficient knowledge of the law by the healthcare providers. At the dawn of end-of-life law's revision, their share could however improve our practices in this field.

A genome-wide association study of production traits in a commercial population of Large White pigs: evidence of haplotypes affecting meat quality.

BACKGROUND: Numerous quantitative trait loci (QTL) have been detected in pigs over the past 20 years using microsatellite markers. However, due to the low density of these markers, the accuracy of QTL location has generally been poor. Since 2009, the dense genome coverage provided by the Illumina PorcineSNP60 BeadChip has made it possible to more accurately map QTL using genome-wide association studies (GWAS). Our objective was to perform high-density GWAS in order to identify genomic regions and corresponding haplotypes associated with production traits in a French Large White population of pigs. METHODS: Animals (385 Large White pigs from 106 sires) were genotyped using the PorcineSNP60 BeadChip and evaluated for 19 traits related to feed intake, growth, carcass composition and meat quality. Of the 64,432 SNPs on the chip, 44,412 were used for GWAS with an animal mixed model that included a regression coefficient for the tested SNPs and a genomic kinship matrix. SNP haplotype effects in QTL regions were then tested for association with phenotypes following phase reconstruction based on the Sscrofa10.2 pig genome assembly. RESULTS: Twenty-three QTL regions were identified on autosomes and their effects ranged from 0.25 to 0.75 phenotypic standard deviation units for feed intake and feed efficiency (four QTL), carcass (12 QTL) and meat quality traits (seven QTL). The 10 most significant QTL regions had effects on carcass (chromosomes 7, 10, 16, 17 and 18) and meat quality traits (two regions on chromosome 1 and one region on chromosomes 8, 9 and 13). Thirteen of the 23 QTL regions had not been previously described. A haplotype block of 183 kb on chromosome 1 (six SNPs) was identified and displayed three distinct haplotypes with significant (0.0001 < P < 0.03) associations with all evaluated meat quality traits. CONCLUSIONS: GWAS analyses with the PorcineSNP60 BeadChip enabled the detection of 23 QTL regions that affect feed consumption, carcass and meat quality traits in a LW population, of which 13 were novel QTL. The proportionally larger number of QTL found for meat quality traits suggests a specific opportunity for improving these traits in the pig by genomic selection.