Specificities and challenges of imaging response in pancreatic neuroendocrine tumors treated with targeted therapies

Les tumeurs neuroendocrines pancréatiques bien différenciées (pNET) sont richement vascularisées et ont une imagerie caractéristique au scanner. Lorsque ces tumeurs sont traitées par une thérapie ciblée, en particulier un antiangiogénique tel que le sunitinib, ces lésions présentent peu de changement de taille, mais des modifications de la densité tumorale. Les faibles taux de réponse objective (< 10 %) rapportés dans les 2 études randomisées ayant permis l’AMM pour le sunitinib et l’évérolimus dans les pNET, confirment que les critères RECIST sont insuffisants à évaluer ces thérapies ciblées, nécessitant l’exploration de nouveaux critères tels que ceux de Choi, qui intègrent les variations de densité tumorale.Well-differentiated pancreatic neuroendocrine tumors (pNET) are highly vascularized and display specific imaging patterns on CT-scans. When treated with targeted therapies such as the VEGFR inhibitor sunitinib, target lesions show limited if any variation in dimensions, but modifications in tumor density. The low rates of objective response (< 10%) reported in the 2 randomized trials leading to the approval of sunitinib and everolimus in pNET highlight the limits of RECIST criteria to evaluate the effects of targeted therapies, warranting to explore new endpoints involving variation of tumor density, such as Choi criteria

Pharmacocinétique (PK) et pharmacodynamie (PD) de l'imatinib (Glivec

L'imatinib (Glivec®) est un inhibiteur spécifique de récepteur à la tyrosine kinase, en particulier du proto-oncogène c-kit. Ce proto-oncogène c-kit est exprimé ou muté dans les tumeurs stromales digestives (GIST). L'analyse pharmacocinétique (PK) montre que l'imatinib a une cinétique linéaire chez les patients porteurs de tumeurs stromales digestives. L'imatinib est essentiellement métabolisé par l'intermédiaire du cytochrome P450. L'acide α1 glycoprotéine (AAG), protéine intervenant dans la phase aiguë de l'inflammation, est impliquée dans la liaison protéique de l'imatinib et semble jouer un rôle clé dans la pharmacocinétqiue de l'imatinib

Plasminogen activation in melanocytic neoplasia

A large body of experimental evidence suggests that plasminogen activators provide tumoral cells with efficient means to degrade extracellular matrix constituents and thereby facilitate their dissemination to distant sites. Melanocytic neoplasia encompass a spectrum of lesions exhibiting diverse clinical behavior that remain difficult to predict with current histopathological evaluations. Little information concerning the contribution of plasminogen activation in diagnostic specimens of human melanocytic tumors is presently available. We thus analyzed biopsy specimens of pigmented skin lesions by histological techniques that identify the cellular sites of synthesis of plasminogen activators and of their inhibitors and that localize the sites of plasminogen activators-catalyzed enzymatic activities. We found that urokinase-type plasminogen activators (uPA) and plasminogen activator inhibitor type 1 mRNAs accumulate in atypical nevocytes and in melanoma cells, but not in benign nevocytes. However, uPA-catalyzed proteolytic activity was detected exclusively in melanomas. These observations suggest that up-regulation of the uPA gene is an early feature of melanocyte transformation and that unbalanced enzyme/inhibitor activity is associated with the malignant phenotype. By supporting a role for uPA in melanoma invasiveness, they provide a novel tool for the evaluation of atypia in nevi

Drug-induced epidermolysis bullosa acquisita with antibodies to type VII collagen

We describe a 73-year-old patient who had a subepidermal bullous eruption develop after a course of antibiotics, including vancomycin. The patient had deposits of IgA and IgG in the cutaneous basement membrane zone that were located on the dermal side of 1 M NaCl-treated autologous skin. By an enzyme-linked immunosorbent assay, the patient was found to have circulating IgG antibodies directed against type VII collagen, the target antigen of epidermolysis bullosa acquisita. Our observation expands the spectrum of immune-mediated subepidermal bullous skin eruptions precipitated by drugs and lends support to the idea that a subset of these cases represents an unusual variant of drug-triggered epidermolysis bullosa acquisita

Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients

International audienceIntroduction: Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB–IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting.Patients and Methods: Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease.Results: Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0–28, interquartile range 6.9–14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4–19.1) months. The 3-year overall survival rate was 62% (95% CI, 58–67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin.Discussion: Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial

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