Peripheral Innate Lymphoid Cells Are Increased in First Line Metastatic Colorectal Carcinoma Patients: A Negative Correlation With Th1 Immune Responses

Several distinct innate lymphoid cell (ILC) populations have been recently identified and shown to play a critical role in the immediate immune defense. In the context of tumors, there is evidence to support a dual role for ILCs with pro-or antitumor effects, depending on the ILC subset and the type of cancer. This ambivalent role has been particularly well-described in colorectal cancer models (CRC), but the presence and the evolution of ILCs in the peripheral blood of metastatic CRC (mCRC) patients have not yet been explored. Here, we investigated the distribution of ILC subsets in 96 mCRC patients who were prospectively included in the "Epitopes-CRCO2" trial. Peripheral bloodmononuclear cells (PBMCs) were analyzed by flow cytometry at metastatic diagnosis and after 3-months of treatment. The treatments consisted of Oxaliplatin-based chemotherapies for 76% of the patients or Folfiri (5FU, Irinotecan) chemotherapies for 14% of patients. Compared to healthy donors, the frequency of total ILCs was dramatically increased at metastatic diagnosis. CD56(+) ILC1-like cells were expanded, whereas ILC2, NCR- ILCP and NCR+ ILCP subsets were decreased. Combined analysis with the systemic anti-telomerase hTERT Th1 CD4 response revealed that patients with low anti-TERT Th1 CD4 responses had the highest frequencies of total ILCs at diagnosis. Of those, 91% had synchronous metastases, and their median progression-free survival was 7.43 months (vs. 9.17 months for the other patients). In these patients, ILC1 and ILC2 were significantly decreased, whereas CD56(+) ILC1-like cells were significantly increased compared to patients with low frequency of total ILCs and high anti-TERT responses. After treatment, the NCR+ ILCP were further decreased irrespective of the chemotherapy regimen, whereas the balance between ILC1 and CD56(+) ILC1-like cells was modulated mainly by the Folfiri regimen in favor of ILC1. Altogether our results describe the effects of different chemotherapies on ILCs in mCRC patients. We also establish for the first time a link between frequency of ILCs and anti-tumor CD4 T cell responses in cancer patients. Thus, our study supports an interest in monitoring ILCs during cancer therapy to possibly identify predictive biomarkers in mCRC

Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels.

International audienceBACKGROUND: Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients. METHODS: We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline. RESULTS: Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002). CONCLUSIONS: As front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2

Study of the microenvironment and oncogenesis of Angiopoietin 2 expressing colorectal cancers

Le cancer colorectal est une maladie grave et fréquente, pour laquelle la survie s'est considérablement améliorée du fait de l'essor des thérapeutiques et des stratégies de combinaisons médico-chirurgicales, même en situation métastatique. C'est également une entité hétérogène, pour laquelle la personnalisation de la prise en charge reste réduite, de par l'absence de scores pronostiques ou prédictifs utilisés en routine et guidant les pratiques. Les classifications moléculaires établies n'ont pas de caractère prédictif et semblent inadaptées au stade métastatique, mais elles peuvent apporter de l'aide à la meilleure compréhension de la biologie des cancers colorectaux et de leur microenvironnement. L'utilisation de tests sériques récapitulant les caractéristiques de la tumeur serait probablement plus simple et moins couteux. La recherche de biomarqueurs résumant les caractéristiques de la tumeur, et guidant les traitements, est donc un enjeu majeur.Ce travail de thèse a porté sur l'étude de l'Angiopoietine 2, de la signature génique et protéique qui lui est associée, et sur l'analyse du microenvironnement et de la réponse immunitaire périphérique Th1 chez des patients atteints d'un cancer colorectal.La première partie du travail a consisté à étudier la valeur pronostique de l'Angiopoietine 2 au sein d'une cohorte de patients atteints d'un cancer colorectal métastatique. Un seuil discriminant de l'Angiopoietine 2 a été établi, définissant les patients de mauvais pronostic, indépendamment associé à la survie globale. Ce dosage améliorait la capacité discriminante de scores pronostiques classiques. La seconde partie du travail a consisté à identifier, à partir de bases de données transcriptomiques, les caractéristiques des patients porteurs de cancer colorectaux et surexprimant l'Angiopoietine 2. Les voies de signalisation et les gènes associés à cette entité de tumeur ont été analysés, pour mieux comprendre les éléments qui confèrent un mauvais pronostic, et pour définir des candidats, protéines sécrétées, pouvant être dosées chez les patients. Une signature génique puis sérique a été élaborée, reflétant le stroma l'angiogenèse l'invasion et la chimiorésistance. Le dosage des marqueurs ANGPT2, CD138 et STC1 sur une cohorte de patients a confirmé l'association de ces biomarqueurs au caractère de chimiorésistance. Cette signature associée aux tumeurs surexprimant l'Angiopoietine 2 est inversement corrélée à la réponse immunitaire dans les premières approches réalisées. Ceci nous a incité à étudier l'effet de la réponse immunitaire périphérique CD4 de type Th1 anti télomérase, COA1 et mésothéline, sur la survie globale des patients atteints de cancers colorectaux métastatiques. L'étude sérique de l'Angiopoietine 2 y a été associée. Nous avons ainsi validé des données récemment publiées dans d'autres localisations tumorales, attestant de la valeur pronostique de la réponse immunitaire périphérique, sur la survie globale pour les cancers du côlon métastatiques (étude prospective Epitopes-CRC02). Une corrélation inverse entre réponse immunitaire CD4 de type Th1 et l'ANGPT2 a été confirmée.Ces travaux ouvrent la voie sur le ciblage spécifique des tumeurs présentant la signature Angiopoietine 2 de chimiorésistance et de stroma abondant, par une approche combinatoire associant des thérapeutiques ciblant le microenvironnement tumoral. Un monitoring est également réalisable pour accompagner ces futurs projets de recherche, et les modèles pronostiques à venir intégreront ces données au sein des tests de survie multi-paramétriques.Colorectal cancer (CRC) is a severe and frequent disease, with important survival improvement due to therapeutic new approaches and surgical methods, even in metastatic setting. It is an heterogeneous entity, and personalized strategies are mandated, whereas few predictive and prognostic biomarkers are available in practical care. Molecular classifications are useful to better understand CRC biological characteristics, but they do not have predictive values, and seem to be inadequate for metastatic setting. Seric biomarkers are attractive since they could recapitulate tumor features, while being simpler and less expansive. There is a need to investigate surrogacy biomarkers illustrating intra tumoral microenvironment, in order to adapt treatment strategies.This thesis is about the clinical and molecular characterization of Angiopoietin 2 (ANGPT2) associated colorectal cancer. Assessment of microenvironment and peripheral immune Th1 response are performed and correlated with this entity.Prognostic value of ANGPT2 in metastatic colorectal cancer was studied in the first part of the manuscript. We described that ANGPT2 plasmatic levels were associated with a worst overall survival in metastatic setting. In the second part, using the open source transcriptomic tools, we decided to define the specific molecular signaling pathways correlated to ANGPT2 expression in CRC and its prognostic value in localized CRC. A specific signature was drawn, combining genes associated with stroma, invasion, angiogenesis, and chemo-resistance. Looking for associated secreted proteins, we could identify a seric signature (combining STC1, CD138 and ANGPT2), predictive for chemo-resistance. An negative correlation was observed between ANGPT2 signature and immune response. The last part of the thesis then explored the prognostic value of anti TERT peripheral immune Th1 response in metastatic colorectal cancer (Epitopes-CRC02 study), and validated its beneficial role for predicting OS. A negative correlation was confirmed, in seric measurement between CD4 immune response and ANGPT2.This work paves the way for individualized treatments in tumors harboring ANGPT2 associated characteristics', targeting the stromal and immune microenvironment. This immune and stromal biomonitoring is feasible and have to be associated to futures clinical studies. Future prognostic scores should probably assess the place of these biomarkers in order to improve their discriminant values

Efficacité, tolérance et analyse du coût de la Trabectédine chez des patients présentant un sarcome des tissus mous (Une étude rétrospective bicentrique)

BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

Self-Medication during and after Cancer: A French Nation-Wide Cross-Sectional Study

(1) Background: Little data are available in Western countries regarding self-medication practices in the context of cancer. The aim of this study was to describe the prevalence of self-medication practices during (cancer patients) and after cancer (cancer survivors). (2) Methods: This multicenter, cross-sectional, and online study was designed to assess self-medication prevalence. Other objectives were explored, notably the medication types, the perceived risks, and the relation with symptoms and quality of life. (3) Results: Among the 518 patients analyzed, 56.4% declared they practiced self-medication. Dietary supplements and pain medications were used by more than half of the patients. Self-medication was practiced in order to manage the adverse effects of anticancer therapies (63.8%), for which pain was the leading indication (39%), and to improve the efficacy of anticancer therapies (43.8%, cancer patients). Patients believed that self-medication could not lead to drug interactions with anticancer therapies (84.9%, cancer patients), or to adverse effects (84.6%, cancer patients and survivors). Self-medication practices were associated with altered social functioning, pain, insomnia, and financial difficulties. (4) Conclusions: Self-medication was performed by more than half of the responders (ongoing or past cancer) and could be a marker of the undermanagement of cancer and treatment-related adverse effects

Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients: Resistance to HIV capsid inhibitors

International audienceBackground: GS-6207 is a first-in-class HIV capsid inhibitor, targeting several functions of the HIV capsid in the viral cycle, including viral particle assembly, capsid formation and nuclear entry. GS-6207 has demonstrated picomolar potency in vitro, activity confirmed by high potency in a Phase 1 clinical study, with a long-acting antiretroviral profile with potential dosing every 6 months. In vitro resistance selections previously conducted with increasing doses of GS-6207 have identified capsid variants with reduced susceptibility to GS-6207.Objectives: To study the prevalence of capsid mutations associated with in vitro resistance to GS-6207 in people living with HIV (PLWH).Methods: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.Results: Among the samples from the 1500 patients studied, none of the seven GS-6207 resistance mutations identified during in vitro selection experiments was detected, regardless of HIV subtype or PLWH treatment history.Conclusions: Out of the seven HIV capsid substitutions previously selected in vitro and shown to confer phenotypic resistance to GS-6207, none of these seven mutations was observed in this large dataset, suggesting that neither PLWH with previous PI failure nor PLWH with emergence of PI resistance mutations are anticipated to impact GS-6207 activity in these diverse HIV-infected populations

Efficacy, Safety and Cost of Regorafenib in Patients with Metastatic Colorectal Cancer in French Clinical Practice

Background Regorafenib is an orally administered multikinase inhibitor that has been approved for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Even though regorafenib significantly improved survival in two international phase 3 trials (CORRECT and CONCUR), a high rate of treatment-related toxic effects and dose modifications were observed with a modest benefit. The aim of this study was to provide information concerning the efficacy, safety, and cost of regorafenib in patients with mCRC in clinical practice. Material and Methods We retrospectively reviewed patients treated with regorafenib monotherapy for unresectable mCRC in five Franche-Comté cancer hospitals (France). The primary end point was overall survival. Secondary end points were safety and descriptive cost analyses of patients treated with regorafenib in clinical practice. Another aim of this study was to assess the impact of regorafenib prescription on the risk of hospitalization in real-life practice. Results From January 2014 to August 2014, 29 consecutive patients were enrolled. Patients were heavily pretreated and were refractory to standard chemotherapies. The primary tumor sites were the colon and the rectum for 55% and 45% of patients, respectively. Fifteen patients (51%) harbored an RAS mutation. Eastern Cooperative Oncology Group - Performance Status (PS) was 0–1 for 86% of patients and 2 for 14% of patients. Nineteen patients (66%) initially received reduced doses of 120 or 80 mg/day. The median duration of treatment was 2.5 months (range, 0.13–11.4 months). Treatment-related adverse events occurred in 86% of patients. The most frequent adverse events of any grade were fatigue (35%), diarrhea (20%), and hand-foot skin reaction (20%). Grade 3 or 4 treatment-related adverse events occurred in 10 patients (35%). Three patients (10%) were admitted to hospital due to drug-related severe adverse events. The mean cost of patient management with regorafenib for the duration of treatment was 9908 ± 8191€, and median cost was 7917€ (Interquartile range (IQR) 4469-13,042). The median overall survival was six months (95% confidence interval, five to eight months). Conclusions The safety and efficacy of regorafenib in heavily pretreated mCRC patients was comparable, in our study, to prospective and retrospective trials. Toxic effects were mostly manageable in an outpatient setting. Regorafenib itself represented the most important (93%) part of supported costs. Even though most side effects were manageable in an outpatient setting, severe adverse events occurred from hospitalization in 10% of patients. These data should be confirmed in a larger real-life-based cohort. Identification of predictive biomarkers is needed for mCRC patient selection for regorafenib treatment

A systematic review of economic evaluation in pancreatic ductal adenocarcinoma

International audienceObjectives: The economic evaluation (EE) of healthcare interventions has become a necessity. However, high quality needs to be ensured in order to achieve validated results and help making informed decisions. Thus, the objective of the present study was to systematically identify and review published pancreatic ductal adenocarcinoma-related EEs and to assess their quality. Methods: Systematic literature research was conducted in PubMed and Cochrane to identify published EEs between 2000 and 2015. The quality of each selected EE was assessed by two independent reviewers, using the Drummond's checklist. Results: Our systematic review was based on 32 EEs and showed a wide variety of methodo-logical approaches, including different perspectives, time horizon, and cost effectiveness analyses. Nearly two-thirds of EEs are full EEs (n Z 21), and about one-third of EEs had a Drummond score 7, synonymous with 'high quality'. Close to 50% of full EEs had a Drum-mond score 7, whereas all of partial EEs had a Drummond score <7 (n Z 11). Conclusions: Over the past 15 years, a lot of interest has been evinced over the EE of pancre-atic ductal adenocarcinoma (PDAC) and its direct impact on therapeutic advances in PDAC. To provide a framework for health care decision-making, to facilitate transferability and to lend credibility to health EEs, their quality must be improved. For the last 4 years, a tendency towards a quality improvement of these studies has been observed, probably coupled with a context of rational decision-making in health care, a better and wider spread of recommendations and thus, medical practitioners' full endorsement.