The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

Pancreatic cancer is characterised by a hallmark desmoplastic response that includes upregulated expression of the extracellular matrix, and type I collagen in particular. Recent studies indicate that pancreatic cancer cells stimulate type I collagen synthesis in adjacent stellate cells, and that this upregulated type I collagen expression promotes the malignant phenotype in tumour cells as defined by increased proliferation, resistance to chemically induced apoptosis, and increased tumorigenesis. The integrin specificity of this interaction between type I collagen and tumour cells was not identified, however. In the present study, we examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration, on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. Our results indicate, for the overwhelming majority of cell lines, that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilising function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, we demonstrate further that the malignant phenotype on type I collagen is mediated specifically by the α2β1 integrin. These results identify α2β1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

BACKGROUND: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. METHODS: A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m(2 )twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m(2 )for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. RESULTS: Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. CONCLUSION: There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent

Laparoscopic management of appendicitis and symptomatic cholelithiasis during pregnancy

BACKGROUND: Laparoscopic surgery during pregnancy is a challenging procedure that most surgeons are reluctant to perform. The objective of this study was to evaluate whether laparoscopic appendectomy and cholecystectomy is safe in pregnant women. The management of these situations remains controversial. We report a single center study describing the successful management of 16 patients during pregnancy. METHODS: More than 3,356 laparoscopic procedures were performed in our institutions between May 1990 and June 2005. Sixteen of these patients were operated on in the second and third trimester between 22 and 32 weeks of estimated gestational age. We performed 11 laparoscopic appendectomies and 5 laparoscopic cholecystectomies. We also reviewed the management and operative technique used in these patients. RESULTS: In this study, the laparoscopic appendectomy or cholecystectomy was performed successfully in all patients. Three patients were in their second trimester, weeks 22, 23, and 25, and 13 were in the third trimester, weeks 27 (three patients), 28 (five patients), 31 (three patients), and 32 (two patients). No maternal or fetal morbidity occurred. Open laparoscopy was performed safely in all patients and all patients delivered healthy babies. CONCLUSION: From our experience laparoscopic management of appendicitis and biliary colic during pregnancy is safe, however the second trimester is preferable for laparoscopic cholecystectomy. Pregnancy is not a contraindication to the laparoscopic approach to appendicitis or symptomatic cholelithiasis. We believe that laparoscopic operations, when performed by experienced surgeons, are safe and even preferable for the mother and the fetu

Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: a multicenter study (vol 12, pg 1104, 2021)

Transplantation and immunomodulatio

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Chirurgie [Visceral surgery].

Visceral surgery has benefited from several significant therapeutical improvements in 2005. They involve more specifically endocrine surgery, obesity, ovarian cancer, rectocele and cystic pancreatic neoplasia. Minimal invasive surgery is increasingly used, for example in endocrine conditions and obesity treatment. New techniques also emerge, such as electrical gastric stimulation for obesity or Stapled Trans Anal Rectal Resection (STARR) for anterior rectocele. Accurate diagnosis criteria allow better management of cystic pancreatic neoplasia, especially to choose the best treatment of this condition

Nouveautés en médecine 2008: Chirurgie

More than the number of real novelties, trends and preliminary results characterise the annual development in surgery. The wealth and diversity of topics to be covered require arbitrary choices, therefore not necessarily complete. The constant development of choledocolithiasis management, dominated by minimal invasive technology, treatments of unusual nature of two frequent proctological conditions, fistulae and haemorrhoids, the increasing importance of metabolic bariatric surgery, as well as the strict rules of effective melanoma treatment, represent as many directions in which the operating procedure, although unseen, continue to gain quality and security

Pediatric Patients with Eosinophilic Esophagitis and Their Parents Identify Symptoms as the Most Important Treatment Outcome.

Given the lack of data, we aimed to explore which therapeutic endpoints pediatric patients with eosinophilic esophagitis (EoE) and their parents consider to be relevant. We created an educational brochure on EoE and a questionnaire, both of which were content-validated by pediatric patients and parents. Validated documents were sent to 112 patients and parents. They ranked the importance (5 levels) of short (during next 3 months) and long-term (≥1 year) treatment effect on symptoms, quality of life, endoscopic inflammation, stricture formation, histological inflammation, and fibrosis. A total of 45 parents and 30 pediatric patients ≥11 years completed the questionnaires. Pediatric patients identified improvement in the following domains as most important in the short- and long-term, respectively: symptoms (73% vs. 77%), QoL (53% vs. 57%), histologic inflammation (47% vs. 50%), histologic fibrosis (40% vs. 33%), endoscopic inflammation (47% vs. 40%), and strictures (33% vs. 40%). Parents of children ≥11 years old classified improvement in the following domains as most important in the short- and long-term, respectively: symptoms (70% vs. 83%), QoL (63% vs. 80%), histologic inflammation (67% vs. 77%), histologic fibrosis (47% vs. 63%), endoscopic inflammation (77% vs. 80%), and strictures (40% vs. 53%). Agreement between caregiver and children on the short-term importance of treatment outcomes was as follows: symptoms (77%), QoL (40%), histologic inflammation and fibrosis (47% and 43%), endoscopic inflammation and strictures (50% and 40%). Pediatric patients and parents attributed most importance to improvement in symptoms and QoL. Agreement between parents and patients regarding therapy goals is limited

Supplementary Material for: Pediatric patients with eosinophilic esophagitis and their parents identify symptoms as the most important treatment outcome

Introduction: Given the lack of data, we aimed to explore which therapeutic endpoints pediatric patients with eosinophilic esophagitis (EoE) and their parents consider to be relevant. Methods: We created an educational brochure on EoE and a questionnaire, both of which were content-validated by pediatric patients and parents. Validated documents were sent to 112 patients and parents. They ranked the importance (5 levels) of short‐ (during next 3 months) and long‐term (≥1 year) treatment effect on symptoms, quality of life, endoscopic inflammation, stricture formation, histological inflammation and fibrosis. Results: A total of 45 parents and 30 pediatric patients ≥11 years completed the questionnaires. Pediatric patients identified improvement in the following domains as most important in short- and long-term, respectively: symptoms (73% vs. 77%), QoL (53% vs. 57%), histologic inflammation (47% vs. 50%), histologic fibrosis (40% vs. 33%), endoscopic inflammation (47% vs. 40%), and strictures (33% vs. 40%). Parents of children ≥11 years old classified improvement in the following domains as most important in short- and long-term, respectively: symptoms (70% vs. 83%), QoL (63% vs. 80%), histologic inflammation (67% vs. 77%), histologic fibrosis (47% vs. 63%), endoscopic inflammation (77% vs. 80%, and strictures (40% vs. 53%). Agreement between caregiver and children on the short-term importance of treatment outcomes was as follows: symptoms 77%, QoL 40%, histologic inflammation and fibrosis (47% and 43%), endoscopic inflammation and strictures (50% and 40%). Conclusion: Pediatric patients and parents attributed most importance to improvement in symptoms and QoL. Agreement between parents and patients regarding therapy goals is limited

Diagnostic yield of next-generation sequencing in very early-onset inflammatory bowel diseases: A multicentre study

Background and Aims An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: Predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD