Clinical Study A Reappraisal of Chemotherapy-Induced Liver Injury in Colorectal Liver Metastases before the Era of Antiangiogenics

Background and Aims. Chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. We describe these lesions and assess risk factors and impacts on postresection morbidity and mortality in naive patients to chemotherapy before the era of bevacizumab. Methods. Noncancerous liver tissue lesions were analysed according to tumour, chemotherapy, surgery, and patient characteristics. Results. Fifty patients aged 62 ± 9.3 years were included between 2003 and 2007. Thirty-three (66%) received chemotherapy, with Folfox (58%), Folfiri (21%), LV5FU2 (12%), or Xelox (9%) regimens. Hepatotoxicity consisted of 18 (36%) cases of severe sinusoidal dilatation (SD), 13 (26%) portal fibrosis, 7 (14%) perisinusoidal fibrosis (PSF), 6 (12%) nodular regenerative hyperplasia (NRH), 2 (4%) steatosis >30%, zero steatohepatitis, and 16 (32%) surgical hepatitis. PSF was more frequent after chemotherapy (21% versus 0%, = 0.04), especially LV5FU2 ( = 0.02). SD was associated with oxaliplatin (54.5% versus 23.5%, = 0.05) and low body mass index ( = 0.003). NRH was associated with oxaliplatin ( = 0.03) and extensive resection ( = 0.04). No impact on mortality and morbidity was observed, apart postoperative elevation of bilirubin levels in case of PSF ( = 0.03), longer hospitalization in case of surgical hepatitis ( = 0.03), and greater blood loss in case of portal fibrosis ( = 0.03). Conclusions. Chemotherapy of colorectal liver metastases induces sinusoidal dilatation related to oxaliplatin and perisinusoidal fibrosis related to 5FU, without any impact on postoperative mortality

Domestication of different varieties in the cheese-making fungus Geotrichum candidum

Domestication is an excellent model for studying adaptation processes, involving recent adaptation and diversification, convergence following adaptation to similar conditions, as well as degeneration of unused functions. Geotrichum candidum is a fungus used for cheese making and is also found in other environments such as soil and plants. By analyzing whole-genome data from 98 strains, we found that all strains isolated from cheese formed a monophyletic clade. Within the cheese clade, we identified three genetically differentiated populations and we detected footprints of recombination and admixture. The genetic diversity in the cheese clade was similar as that in the wild clade, suggesting the lack of strong bottlenecks. Commercial starter strains were scattered across the cheese clade, thus not constituting a single clonal lineage. The cheese populations were phenotypically differentiated from other populations, with a slower growth on all media, even cheese, a prominent production of typical cheese volatiles and a lower proteolytic activity. One of the cheese clusters encompassed all soft goat cheese strains, suggesting an effect of cheese-making practices on differentiation. Another of the cheese populations seemed to represent a more advanced stage of domestication, with stronger phenotypic differentiation from the wild clade, harboring much lower genetic diversity, and phenotypes more typical of cheese fungi, with denser and fluffier colonies and a greater ability of excluding cheese spoiler fungi. Cheese populations lacked two beta lactamase-like genes present in the wild clade, involved in xenobiotic clearance, and displayed higher contents of transposable elements, likely due to relaxed selection. Our findings suggest the existence of genuine domestication in G. candidum, which led to diversification into different varieties with contrasted phenotypes. Some of the traits acquired by cheese strains indicate convergence with other, distantly related fungi used for cheese maturation

Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Valeurs diagnostiques et pronostiques de la cytokératine 18 dans l'hépatite alcoolique aiguë sévère

Introduction : L hepatite alcoolique aigue (HAA) s accompagne de phenomenes d apoptose et de necrose. L anticorps M30 detecte un neoepitope de la cytokeratine 18 (CK18) apparaissant lors de l apoptose, M65 detectant la CK 18 entiere. Patients et méthodes : Les fragments de la CK18 ont ete doses chez 159 patients (76 HAA severes, 38 cirrhoses sans HAA, 45 temoins sains) avec les kits M30 ApoptosenseR ELISA et M65R ELISA (Peviva AB). L objectif principal a ete de rechercher les variables permettant le diagnostic d HAA. Résultats : Les moyennes de M30, M65 et de M30/M65 etaient differentes entre les 3 groupes (ANOVA, tous les p<0,0001). Parmi ces marqueurs, M30 avait la meilleure valeur diagnostique (AUROC=0,825). En analyse multivariee, la difference entre les groupes HAA et cirrhose etait significative pour M30 (OR=1,004), l uree (OR=0,64), le score de Child-Pugh (OR=2,72) et le score de Maddrey (OR=1,20). Un nouveau score developpe a partir des variables discriminantes (DF M30 = -19,04 + 0,179 x Score de Maddrey - 0,448 x Uree + 0,004426869 x M30 + 1,002 x Score de Child-Pugh) avait une AUROC a 0,985, superieure a celle du score de Maddrey (p=0,04) et du MELD (p=0,003). La valeur seuil de 0,617 pour le diagnostic d HAA severe avait une sensibilite de 96,7 % et une specificite de 94,4 %. Enfin, M30 et M65 n etaient pas correles a la survie a 6 mois. Conclusion : Le DF M30 presente de bonnes caracteristiques diagnostiques, et pourrait permettre de surseoir a la biopsie hepatique necessaire dans les formes severes d HAA mais doit etre confirmee dans une cohorte de validation.Background : Acute alcoholic hepatitis (AAH) is associated with both apoptosis and necrosis phenomena. M30 antibody detects a specific caspase-cleaved neoepitope of cytokeratin 18 (CK18) whereas M65 detects all forms of CK 18s. Patients and methods : CK18 fragments were assessed in 159 patients (76 severe AAH, 38 cirrhosis without AAH and 45 controls) with M30 ApoptosenseR ELISA and M65R ELISA kits (Peviva AB). Primary objective was to identify variables associated with the diagnosis of severe AAH. Results : Mean M30, M65 and M30/M65 ratio were significantly different between the three groups (ANOVA, all p<0,0001). Among these markers, M30 had the best diagnostic value (AUROC=0,825). Multivariate analysis between severe AAH and cirrhosis group was significant for M30 (OR=1,004), uremia (OR=0,64), Child-Pugh score (OR=2,72) and discriminant function (OR=1,20). A new score including the discriminant variables (DF M30 = -19,04 + 0,179 x Discriminant function - 0,448 x Uremia + 0,004426869 x M30 + 1,002 x Child-Pugh score) had an AUROC of 0,985 and was significantly higher than Discriminant function (p=0,04) and MELD score (p=0,003). The best cut-off for the diagnosis of severe AAH was 0,617 with a sensitivity of 96,7 % and a specificity of 94,4 %. Finally, M30 and M65 were not correlated with the 6 month survival. Conclusion : The DF M30 is accurate for the diagnosis of severe AAH, and could therefore allow to avoid liver biopsy that is needed before treatment, but has to be confirmed in a validation cohort.AMIENS-BU Santé (800212102) / SudocSudocFranceF

Generalized pruritus in dysmetabolic hyperferritinemia treated by phlebotomy

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies.A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative.In spite of the dietary measures, the ferritin level was still high (853ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia.Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy wasinitiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels

Generalized pruritus in dysmetabolic hyperferritinemia treated by phlebotomy

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies.A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative.In spite of the dietary measures, the ferritin level was still high (853ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia.Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy wasinitiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels

Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB

Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-damaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (P < 0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE

Value of a patient-reported-outcome measure of carcinoid syndrome symptoms

International audienceObjective Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score. Methods Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020. Results In total, 147 patients with metastatic ileal ( n =126), lung ( n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level ( n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden. Conclusions PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS

FOLFIRINEC: a randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin

International audienceBackgroundPoorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen.MethodsThe primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled.Main inclusion criteria areNEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6–8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype.This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events