Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators

Pimecrolimus in atopic dermatitis: Consensus on safety and the need to allow use in infants

Atopic dermatitis (AD) is a distressing dermatological disease, which is highly prevalent during infancy, can persist into later life and requires long-term management with anti-inflammatory compounds. The introduction of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, more than 10 yr ago was a major breakthrough for the topical anti-inflammatory treatment of AD. Pimecrolimus 1% is approved for second-line use in children (≥2 yr old) and adults with mild-to-moderate AD. The age restriction was emphasized in a boxed warning added by the FDA in January 2006, which also highlights the lack of long-term safety data and the theoretical risk of skin malignancy and lymphoma. Since then, pimecrolimus has been extensively investigated in short- and long-term studies including over 4000 infants (<2 yr old). These studies showed that pimecrolimus effectively treats AD in infants, with sustained improvement with long-term intermittent use. Unlike topical corticosteroids, long-term TCI use does not carry the risks of skin atrophy, impaired epidermal barrier function or enhanced percutaneous absorption, and so is suitable for AD treatment especially in sensitive skin areas. Most importantly, the studies of pimecrolimus in infants provided no evidence for systemic immunosuppression, and a comprehensive body of evidence from clinical studies, post-marketing surveillance and epidemiological investigations does not support potential safety concerns. In conclusion, the authors consider that the labelling restrictions regarding the use of pimecrolimus in infants are no longer justified and recommend that the validity of the boxed warning for TCIs should be reconsidered

FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review

BackgroundPancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.MethodsWe performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.ResultsA total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p &lt; 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p &lt; 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.ConclusionsIn patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting

ASO Visual Abstract: FOLFIRINOX or Gemcitabine Based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-Institutional, Patient-Level Meta-Analysis and Systematic Review

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Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer : An International Multicenter Cohort Study

Background. Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.Methods. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.Results. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.Conclusions. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.Peer reviewe

Relations entre la dermatite atopique et la taille du thymus chez le nourisson (étude de cas-témoins)

FORT-DE-FRANCE-CHRU-BU (972332102) / SudocBORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Barrière cutanée et dermatite atopique

La pathogénie de la dermatite atopique (DA) intègre des facteurs génétiques, immunologiques et environnementaux. Nos hypothèses étaient qu'une anomalie de la barrière cutanée favorise le passage percutané d'allergènes, et que la colonisation staphylococcique favorise l'activation TH2. Méthodes: Nous avons étudié le rôle de la barrière épidermique dans la survenue de sensibilisations aux atopènes, puis nous avons étudié le polymorphisme des gènes de la filagrine, kLK7 et LEKTI dans une cohorte de DA. Nous avons ensuite étudié l'effet des toxines SEB et SEA et du LPS de S aureus sur la sécrétion de cytokines (IL-5, IL-6, IL10, IL-12, TNF-a) et de chimiokines (IL-8, IP-10) par les monocytes isolés du sang de DA et de témoins, en fonction de la présence des mutations R753Q de TLR2 et D299g de TLR4. Résultats : Il existe une corrélation entre TEWL et positivité des patch-tests aux aéroallergènes, et l'application cutanée précoce d'un extrait protéique d'avoine peut induire une sensibilisation à ce produit. Les mutations R501X et 2282del4 de filaggrine sont associes à la DA, avec un risque relatif respectif de 3,2 et 11,7. La stimulation par SEB de monocytes circulants diminue la production de TNF-a et IP-10 dans la DA. La sécrétion d'IL-12 après stimulation par le LPS diminue chez l'adulte et non chez l'enfant. La production de TNF-a diminue sous l'effet de SEB chez les mutants TLR2 et sous l'effet de LPS chez les mutants TLR4. Conclusion : Notre travail conforte le rôle déterminant et inaugural de l'anomalie de la barrière cutanée dans la prédisposition à la DA, et montre que les toxines staphylococciques favorisent le déséquilibre TH1 < TH2 observé dans la DA.The pathophysiology of atopic dermatitis (AD) involves genetic, immunological and environmental factors. We hypothesize that constitutive epidermal barrier impairment may facilitate the percutaneous penetration of allergens, and that staphylococcal colonization may drive TH2 polarization. Methods : We assessed whether trans epidermal water loss correlates with atopen sensitization, and we investigated the filaggrin, KLK7 and SPINK5 polymorphisms in a French AD cohort. Then, we studied the cytokine (IL-5, IL-6, IL-10, IL-12, TNFa) and chemokine (IL-8, IP10) production by circulating monocytes upon staphylococcus aureus toxins (SEA, SEB) and LPS stimulation, according to their TLR2 and TLR4 genotype. Results : We found that the higher the prevalence of sensitization to aeroallergens, and that repeated applications of protein extracts on the skin of infants may lead to sensitization. R501X and 2282del4 filaggrin mutants were associated with AD (Odds Ratio were 3.2 and 11.7, respectively). SEB-induced TNFa and IP-10 secretion by monocytes decreased significantly in AD. LPS-induced IL-12 production decreased significantly in adults but not in children. SEB-induced TNF-a production decreased in TLR2 variants, confirming SEB as a putative TLR2 ligand, and that and LPS-induced TNF-a production decreased in TLR4 variants. Conclusion : Our data are in favour of a major role of a constitutive epidermal barrier impairment in determining early atopen sensitization in AD infants, and showed that staphylococcal toxins may enhance TH2 profile in AD.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF