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Proton pump inhibitors (PPI) may influence the gut microbiome and thus impact the effectiveness of immune checkpoint inhibitors (ICI). The effect of PPIs on the outcomes of ICI has not been fully explored and investigated in metastatic renal cell carcinoma (mRCC).This retrospective analysis used prospectively collected data from the GETUG-AFU 26 NIVOREN (NCT03013335) phase II study which enrolled 729 mRCC patients of whom 720 were treated with nivolumab. The main objective of this analysis was to evaluate the impact of PPI on the efficacy and safety outcomes of mRCC patients. PPI use was defined as PPI administration on the day of ICI initiation.Of the 707 patients with mRCC analyzed in this study, 196 (27.7%) were PPI users. The majority of PPI users were males (80.6%), had an ECOG performance status of 0-1 (78.9%) and a nephrectomy (82.1%). Almost two-thirds of the patients had a favorable and intermediate IMDC risk category and 52% received nivolumab in the third line and beyond. PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively). Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%).This real-world study suggests that PPI use in patients with mRCC does not impact the efficacy outcomes but may influence the safety of nivolumab which warrants further investigations.

Purpose:A minority of patients currently respond to single-agent immune-checkpoint blockade (ICB), and strategies to increase response rates are urgently needed. AXL is a receptor tyrosine kinase commonly associated with drug resistance and poor prognosis in many cancer types, including in clear-cell renal cell carcinoma (ccRCC). Recent experimental cues in breast, pancreatic, and lung cancer models have linked AXL with immune suppression and resistance to antitumor immunity. However, its role in intrinsic and acquired resistance to ICB remains largely unexplored.Experimental Design:In this study, tumoral expression of AXL was examined in ccRCC specimens from 316 patients who were metastatic receiving the PD-1 inhibitor nivolumab in the GETUG AFU 26 NIVOREN trial after failure of antiangiogenic therapy. We assessed associations between AXL and patient outcomes following PD-1 blockade, as well as the relationship with various markers, including PD-L1; VEGFA; the immune markers CD3, CD8, CD163, and CD20; and the mutational status of the tumor-suppressor gene von Hippel-Lindau (VHL).Results:Our results show that high AXL-expression level in tumor cells is associated with lower response rates and a trend to shorter progression-free survival following anti–PD-1 treatment. AXL expression was strongly associated with tumor–PD-L1 expression, especially in tumors with VHL inactivation. Moreover, patients with tumors displaying concomitant PD-L1 expression and high AXL expression had the worst overall survival.Conclusions:Our findings propose AXL as candidate factor of resistance to PD-1 blockade, and provide compelling support for screening both AXL and PD-L1 expression in the management of advanced ccRCC.See related commentary by Hahn et al., p. 6619

This file contains 6 supplementary figures and 5 supplementary Tables. Supplementary Figure S1 - Protein expression pattern of AXL in ccRCC specimens. Supplementary Figure S2 - Response rates, Survival and Biomarker analyses according to AXLneg, AXLlow and AXLhigh expression Supplementary Figure S3 - ORR and Progression-Free Survival according to PD-L1 Status alone or by grouping AXL expression plus PD-L1 status Supplementary Figure S4 - High AXL expression plus PD-L1 TC positivity is associated with worse OS in Nivolumab-treated patients in IMDC intermediate-risk/poor-risk group Supplementary Figure S5 - VHL status does not interfere with outcomes or AXL expression upon treatment with Nivolumab Supplementary Figure S6 - Biomarker distribution across AXL groups stratified based on VHL status

Introduction Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. Results RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. Conclusions Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov , number NCT01813136 .

Resistance of advanced hormone-dependent endometrial carcinoma to endocrine therapy remains a worldwide clinical issue. We recently reported that the combination of Vistusertib (V, mTOR inhibitor) and Anastrozole (A, aromatase inhibitor) improves the progression-free rate compared to Anastrozole alone. However, a better patient selection based on biomarkers would improve patient outcome. We evaluate for the first time the usage of ribosome biogenesis (RiBi) factors as a source of innovative markers. Using 47 FFPE tumours (A n = 18; V + A n = 29), 32 blood samples (A n = 13; V + A n = 19) and 30 samples of total RNAs (A n = 12; V + A n = 18) from the VICTORIA clinical trial, we observed an association between RiBi-associated markers and drug activity or prediction of treatment response. NOP10 and NHP2 mRNA levels were significantly higher in non-responders compared to responders in the Vistusertib + Anastrozole arm (P = 0.0194 and P = 0.0002 respectively; i.e. 8 weeks progression-free survival as endpoint). This study provides RiBi-based markers relevant for a better selection of patients with advanced endometrial carcinoma by predicting the response of endocrine therapy combined with mTOR inhibitor.

International audience; Simple Summary As patients with rare cancers face specific problems, reference networks have been developed in several European countries and then at the European level to improve their management. In some cases, the specialized centers belonging to reference networks provide remote services (specialized diagnosis review, discussion in the Multidisciplinary Tumour Board, etc.) to increase access to these services. Using data from the national sarcoma reference network implemented in France (NETSARC+), the IGeAS research program assesses the potential of its organization to address the geographical inequalities in cancer management. We analyze the individual, clinical, and geographical determinants of the overall survival of sarcoma patients in France. We found no association between the overall survival of sarcoma patients and variables measuring their social deprivation, remoteness from reference centers, and geographical context. Following previous results from the research program, this study suggests that reference network organization should be considered to reduce cancer inequalities. The national reference network NETSARC+ provides remote access to specialized diagnosis and the Multidisciplinary Tumour Board (MTB) to improve the management and survival of sarcoma patients in France. The IGeAS research program aims to assess the potential of this innovative organization to address geographical inequalities in cancer management. Using the IGeAS cohort built from the nationwide NETSARC+ database, the individual, clinical, and geographical determinants of the 3-year overall survival of sarcoma patients in France were analyzed. The survival analysis was focused on patients diagnosed in 2013 (n = 2281) to ensure sufficient hindsight to collect patient follow-up. Our study included patients with bone (16.8%), soft-tissue (69%), and visceral (14.2%) sarcomas, with a median age of 61.8 years. The overall survival was not associated with geographical variables after adjustment for individual and clinical factors. The lower survival in precarious population districts [HR 1.23, 95% CI 1.02 to 1.48] in comparison to wealthy metropolitan areas (HR = 1) found in univariable analysis was due to the worst clinical presentation at diagnosis of patients. The place of residence had no impact on sarcoma patients' survival, in the context of the national organization driven by the reference network. Following previous findings, this suggests the ability of this organization to go through geographical barriers usually impeding the optimal management of cancer patients.

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (

IMPORTANCE: Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy. OBJECTIVE: To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor−positive recurrent or metastatic endometrial cancer. DESIGN, SETTINGS, AND PARTICIPANTS: The VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor−positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021. INTERVENTIONS: Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm). MAIN OUTCOMES AND MEASURES: The primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)—assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events. RESULTS: Of the 75 patients who were randomized, 73 (median [range] age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade ≥2) adverse events associated with vistusertib. CONCLUSIONS AND RELEVANCE: This multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02730923

International audience; No abstract available

Primary tumour response may impact therapeutic strategies in metastatic renal cell carcinoma (mRCC) but remains unknown in the era of immune checkpoint inhibitors. We aimed to describe the response of the primary tumour in patients who did not undergo upfront cytoreductive nephrectomy (uCN) and were treated with nivolumab in the GETUG-AFU-26 NIVOREN phase 2 trial. Primary tumour response was prospectively assessed, as well as the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Among 720 patients, 111 did not undergo uCN, mainly patients with intermediate (45%) and poor (49%) International mRCC Database Consortium (IMDC) risk. In the 111 patients, nivolumab was used in the second line for 63% of patients and the third line or more for 37%, with an ORR of 16% (95% confidence interval [CI] 1025%); with a median follow-up of 24.5 mo (95% CI 21.6-27.1), median PFS was 2.7 mo (95% CI 2.5-4.0) and median OS was 15.9 mo (95% CI 9.5-19.8). A total of 67 patients had an evaluable primary renal lesion, four of whom (6%) experienced shrinkage of more than 30%. Overall, patients who did not undergo uCN had adverse baseline characteristics and nivolumab activity against the primary tumour was limited. PATIENT SUMMARY: In this report, we observed that nivolumab was associated with a limited response of the primary tumour in previously treated patients with metastatic kidney cancer.

4552 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes to nivolumab in mRCC pts. We previously identified on a training set (n = 80, 40 responders/40 progressors) several soluble factors significantly associated with worse overall survival (OS), progression-free survival (PFS) and response (IL-8 and VEGF), or with worse OS only (IL-6, IL-7) (Carril-Ajuria et al. ASCO GU. 2022). Our aim was to confirm these findings using an independent validation set. Methods: The remaining pts (n = 233) included in the translational-program of the NIVOREN study were included in this validation set. Based on previous results (training set), a panel of 7 different soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) were quantified for each plasma sample using the MSD electrochemiluminescence assay. The association between baseline soluble-factors levels and response, PFS and OS was evaluated using previously identified cut-off values. Results: Two hundred thirty-three pts were included in the validation set. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 17.7% good, 57.3% intermediate and 25.0% poor. With a median follow-up of 21.8 months (mo), the OS rate was 69.6% at 12 mo and median PFS was 3.0 mo. IL-8 (cut-off: 17.9 pg/ml) and IL-6 (cut-off: 8.7 pg/ml), involved in inflammation, confirmed an association with worse OS (IL8: HR = 2.57, p < 0.0001, IL-6: HR = 3.28,p < 0.0001) and worse PFS (IL-8: HR = 1.61,p = 0.0008, IL-6: HR = 1.68, p = 0.0021). VEGF (cut-off: 48.3 pg/ml) confirmed the association with worse OS (HR = 1.56, p = 0.0176), but not with PFS (p = 0.2068). IL-7, involved in T and B cells development, did not show a significant association with OS or PFS when using 8.6 pg/ml (training set) as cut-off (p = 0.0675 and p = 0.7818, respectively). IL-7 was the only cytokine to show an association with response (p = 0.044). Interestingly, circulating CXCL13 (cut-off: 106.4 pg/ml) and BAFF (cut-off: 1122.6 pg/ml), involved in B cell differentiation/survival, were significantly associated with worse OS (HR = 2.09, p = 0.0001 and HR = 2.34, p = 0.0001, respectively); BAFF showed a trend for worse PFS (HR = 1.29, p = 0.0920). Conclusions: Using the cut-off values previously identified in the training set, we confirmed a significant association between baseline blood concentration of IL-6/IL-8 and worse OS/PFS, and of VEGF with worse OS. Non-responders presented lower baseline circulating IL-7 concentrations. CXCL13 and BAFF were significantly associated with worse OS. Multivariate analyses are ongoing.

BackgroundThe phase II NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) in a ‘real-world setting’. We conducted a translational-research program to determine whether specific circulating immune-cell populations and/or soluble factors at baseline were predictive of clinical outcomes in patients with m-ccRCC treated with nivolumab within the NIVOREN study.MethodsAbsolute numbers of 106 circulating immune-cell populations were prospectively analyzed in patients treated at a single institution within the NIVOREN trial with available fresh-whole-blood, using dry formulation panels for multicolor flow cytometry. In addition, a panel of 14 predefined soluble factors was quantified for each baseline plasma sample using the Meso-Scale-Discovery immunoassay. The remaining patients with available plasma sample were used as a validation cohort for the soluble factor quantification analysis. Tumor immune microenvironment characterization of all patients included in the translational program of the study was available. The association of blood and tissue-based biomarkers, with overall survival (OS), progression-free survival (PFS) and response was analyzed.ResultsAmong the 44 patients, baseline unswitched memory B cells (NSwM B cells) were enriched in responders (p=0.006) and associated with improved OS (HR=0.08, p=0.002) and PFS (HR=0.54, p=0.048). Responders were enriched in circulating T follicular helper (Tfh) (p=0.027) and tertiary lymphoid structures (TLS) (p=0.043). Circulating NSwM B cells positively correlated with Tfh (r=0.70, pConclusionWe report the first fresh blood immune-monitoring of patients with m-ccRCC treated with nivolumab. Baseline blood concentration of NSwM B cells was associated to response, PFS and OS in patients with m-ccRCC treated with nivolumab. BCA-1/CXCL13 and BAFF, inversely correlated to NSwM B cells, were both associated with worse OS in discovery and validation cohorts. Our data confirms a role for B cell subsets in the response to immune checkpoint blockade therapy in patients with m-ccRCC. Further studies are needed to confirm these findings.

348 Background: Glandular metastases (GMs) (adrenal, pancreas, thyroid, ovary, breast, or prostate) are rare in mccRCC. Several studies have observed significantly longer overall survival (OS) for GM patients treated with anti-angiogenic therapy. This study assesses outcomes from mccRCC treated with nivolumab with or without GMs. Methods: The GETUG-AFU 26 NIVOREN, phase II trial assessed the activity and safety of nivolumab in pts with mccRCC who failed antiangiogenic therapies (NCT03013335). Pts were stratified in two subgroups according to the presence of at least one GM. Specific analyzes were performed for pancreatic and adrenal metastases. Primary endpoint was OS, secondary endpoint were progression free survival (PFS) and overall response rate (ORR). Results: Between February 2016 and July 2017, among 720 patients treated by nivolumab 217 patients had GM (151: adrenal and 86: pancreatic metastases). Clinical characteristics were comparable between the two subgroups except for IMDC poor subgroup (19% vs 28%) and for Furhman grade IV (13.5% vs 23.4%) for GM and non GM respectively. Median time between metastatic disease and nivolumab was 3.2 years (y) vs 2 y for GM and non GM respectively and 2.8 vs 2.1 y with or without adrenal metastasis. There was no statistical difference in outcomes between pts with or without GMs. However, pts with adrenal metastases had worse OS (12-months survival: 64% vs 71.1%; HR 1.51 (1.19-1.92)); shorter PFS (6-months survival: 27.2% vs 36.6%; HR 1.29 (1.07-1.57)) and lower ORR (12.5% [7.6%; 19.0%] vs 23.2% [19.8%; 27.0%]; p = 0.005) than non-adrenal metastases. Conversely, patients with pancreatic metastases had significantly longer overall survival (12-months survival: 82.3% vs 67.9%; HR 0.59 (0.40-0.85)) in univariate analysis compared to non-pancreatic metastases. In multivariate analysis, only adrenal metastasis remained associated with dismal prognosis (Table). Conclusions: Adrenal metastasis is an independent poor prognostic factor for response and survival in the GETUG-AFU 26 NIVOREN phase II trial. Limited activity with nivolumab is observed for patients with adrenal metastases from mccRCC without difference with previous anti angiogenic therapy. Molecular characterization could help to identify the angiogenic profile of adrenal metastases. Clinical trial information: NCT03013335. [Table: see text]

379 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with RCC in a “real world setting”. A translational research program was launched to quantify baseline cytokine levels and correlate them with outcomes to nivolumab. Methods: Extreme responder patients (pts) treated with nivolumab as part of the phase II NIVOREN GETUG-AFU 26 were included in this TRAINING cohort. A panel of 14 different plasma cytokines and proteins (VEGF, VCAM-1, IL-6, IL-7, IL-8, IL-10, APRIL, BAFF, 4-1BB, BCA, SDF-1, MDC, IFN-gamma and TNF-alpha) were quantified for each plasma sample using the Elisa-based Meso Scale Discovery electrochemiluminescence assay. The association between baseline cytokine levels and objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) was evaluated. Results: Overall, 80 pts, 40 responders and 40 progressors, were included for cytokine analysis. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 11.3% good, 56.3% intermediate and 32.5% poor. With a median follow-up of 21.2 months, mOS data was immature at data cut-off. Overall survival rate was 67.3% at 12 months and median PFS was 3.8 months. Increased levels of IL-6 (75th percentile=P75), IL-7 (P75), IL-8 (P50) and VEGF (P50) were significantly negatively associated with survival (IL-6: HR=2.44, p=0.0112; IL-7: HR=2.38, p=0.0123; IL-8: HR=2.80, p=0.0045, and VEGF: HR=2.43, p=0.0133). 4-1BB (P50) was associated with improved OS (HR=0.39, p=0.0375). Higher levels of IL-8 (P50) and VEGF (P50) were associated with worse PFS (IL-8: HR=2.50, p=0.0133, and VEGF: HR=1.96, p=0.0132) and worse ORR (IL-8: p=0.013, and VEGF: p=0.044). Except for IL-8 and VEGF, no other associations with response were observed. Conclusions: Higher baseline plasma levels of IL-6, IL-7, IL-8 and VEGF were significantly associated with worse survival outcomes in mRCC pts treated with nivolumab within TRAINING cohort of the NIVOREN trial. In contrast, 4-1BB was significantly associated with improved OS. IL-8 and VEGF were also associated with worse PFS and ORR. VALIDATION cohort within the entire NIVOREN study is ongoing.

342 Background: Bone metastases (BM) in renal cell carcinoma (RCC) are associated with a poor prognosis based on retrospective studies in which patients were treated with antiangiogenic agents. Since the development of immune checkpoint inhibitors, few data are available regarding the prognosis impact of BM or the efficacy and safety of checkpoint inhibitors in patients with bones metastatic RCC. GETUG-AFU26-NIVOREN (NIVOREN) is a French multicenter prospective study in which patients were treated with nivolumab after failure of one or more antiangiogenic tyrosine kinase inhibitors. We therefore aim to evaluate the impact of BM on prognosis, and the efficacy and safety of nivolumab in patients with BM enrolled in NIVOREN trial. Methods: All adult patients with BM at inclusion were included in our study. The primary endpoint of this ancillary study was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), safety, and skeletal-related events (SRE) in patients with BM. Clinical data were collected prospectively, except for SRE data which were collected retrospectively in a complementary consent report form. Results: Among 720 patients treated with nivolumab in the NIVOREN study, 194 had BM at inclusion. After a median follow-up of 23.9 months, the median OS was 17.9 months in patients with BM versus 26.1 months in patients without BM (HR = 1.42 CI95% [1.13-1.79], p = 0.0023). After adjustment on sex, age, IMDC group and line of treatments, the difference was not significant (HR = 1.24, CI95% [0.98-1.56], p = 0.0707). The median PFS was shorter in patients with BM even after adjustment (2.8 versus 4.6 months, HR = 1.30 CI95% [1.08-1.56]), as well as the ORR (14.8% versus 23.3%). The safety profile was similar between patients with or without BM at inclusion. The incidence of SRE in the BM population was 36% during the treatment period with nivolumab. A post-hoc analysis evaluating the impact of bone-targeting agents in association with nivolumab on SRE incidence was performed. There was a statistically significant benefit in patients treated with bone-targeting agents on the incidence of SRE (OR = 0.367, CI95% [0.151-0.895], p = 0.0276). Conclusions: Nivolumab is associated with shorter OS, PFS, and lower ORR in patients with BM. Our study confirms, in the era of immunotherapy that patients with BM are associated with poorer prognosis and suggests that association with bone-targeting agents decreases the incidence of SRE. Clinical trial information: 2015-004117-24.

e16566 Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p

5507 Background: Endometrial carcinoma is generally hormone dependent and aromatase inhibitors are used in routine practice before or after 1st line chemotherapy (CT) for HR positive patients. Deregulation of the Pi3K-Akt-mTOR signaling pathway is observed in many tumor types including endometroid carcinoma driven oncogenesis and hormonal resistance. Vistusertib (V) is a small-molecule ATP competitive inhibitor of both mTORC1 and mTORC2 complexes. Methods: Adult patients (pts) with recurrent oestrogen or progesterone (ER and/or PR) positive advanced/metastatic endometrial carcinoma, one previous line of chemotherapy (CT) allowed, with ECOG PS 0/1, were randomised (2:1, stratification according to prior CT line: 0 vs 1) to receive V (125 mg bid/2 days/week, orally) + Anastrozole (A, 1 mg/d, orally) or A alone. Treatments were given until progression, intolerable toxicity or patient willingness. Following a safety run in phase, a Simon’s 2-stage design was employed to explore the 8-week progression free rate (PFR-8W) according to central review (p1: 60%, p0: 40%, type I error rate of 5%, power of 80%). At the end of Stage II, if ≥24/46 evaluable pts are progression free at 8w in Arm A+V, the combination will be considered of interest for further investigation. Overall response rate (ORR) by RECIST v1.1, safety and progression-free survival (PFS) were key secondary endpoints. Results: Out of 75 patients (pts) enrolled, 73 were randomised and treated (Arm V+A: 49; Arm A: 24; median age: 69.5 y [36.8; 87.8]), BMI ≥30 kg/m²: 45%). PS ECOG was 0 (48%) and 44% of randomised pts were chemotherapy naïve; 12% previously received hormonal therapy. At the end of the safety run-in, no major safety concerns were reported. At the end of Simon’ Stage II, centrally assessed PFR-8W was 67.3% (33/49 [95% CI unilateral: 54.7; -]) for A + V arm and 39.1% (9/23 [[95% CI unilateral: 22.2; -[) for arm A. Median PFS was 5.2 months (95% CI: 3.4-8.9) and 1.9 months (95% CI: 1.6-8.9) for A+V and A arms, respectively. One complete response and 11 partial responses (PR) were observed (ORR: 24.5 % (CI 95% [13.3 – 38/9%]) in the combination arm and 4 PR in arm A (ORR: 17.4% [CI 95%: 5-38.8%]). Fatigue, lymphopenia, hyperglycaemia and diarrhoea were the main (≥10%) Grade ≥2 adverse events related to V. Overall survival and translational research are ongoing. Conclusions: The A+V combination demonstrated clinically and meaningful improvement in 8w-PFR and median PFS with manageable toxicity. PI3K pathway remains a key target for new therapies in endometrial cancer and translational research must help to better select pts benefiting from these targeted therapies. Clinical trial information: NCT02730923.

359 Background: Statins are HMG-CoA inhibitors that regulate several mechanisms involved in tumor growth, including mitochondrial metabolism, activation of oncogenic signaling pathways, and immune modulation. Population-based studies showed that statin intake may be negatively associated with RCC onset. The impact of statins on response to immunotherapy in mRCC is unknown. Herein we study the association between statin administration and outcomes in patients with mRCC treated with nivolumab in the NIVOREN-GETUG AFU 26 phase II trial (NCT03013335). Methods: Patients with mRCC who failed previous VEGFR inhibitors were included. We assessed nivolumab activity, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to statin intake at baseline. Toxicity was assessed using CTCAE v4.0. Results: Overall,133 patients were treated with statins at baseline among 702 evaluable for concomitant therapies (19%). Among them, median age was 68 (49-90), 84% were male, 85% had a performance status ≥ 80%, 42% were overweight and 20% obese. Patients treated with statins had mostly good (23%) or intermediate (58%) IMDC risk, 64% had grade 3 or 4 tumors, and nivolumab was given in a third line setting or more in 55%. Median follow-up was 23.9 months (95%CI 23.0-24.5) in the overall cohort. The ORR was 26% in patients treated with statins, PFS 5.0 months (CI95% 3.0 – 5.5), OS 27.9 months (CI95% 19.4-30.3). Outcomes of patients with or without statins did not differ significantly. Similar rates of grade 3-5 TRAE were reported in patients with (20%) or without (18%) statin intake. Conclusions: This is the first study to evaluate statin intake and outcomes with nivolumab in patients with mRCC. Despite numerically higher ORR, statins were not significantly associated with improved outcomes. These data require other analyzes considering other factors such as BMI and other comorbidities. Further studies may help better understand the interplay between immunity and metabolic reprogramming in RCC.

331 Background: NIVOREN GETUG AFU 26 study, is a french multicenter prospective study to evaluate safety and efficacy of Nivolumab (N) in a broad “real world setting” in mRCC after failure of 1 or 2 tyrosine kinase inhibitors. Methods: Between February 2016 and July 2017, 729 pts were enrolled across 27 institutions. Primary objective of the trial was safety assessed by grade ≥ 3 treatment related adverse event (TRAE). We report here results of older patients above 70 years old ([70;75[; [75;80[; ≥ 80) compared with their younger counterparts. Results: Overall, 720 patients were treated (median age 64 (22;90)). Among them 205 pts were ≥ 70 (28.5%) divided as follow: [70-75[:107 (14.9%) / [75-80[: 68 (9,4%) / ≥ 80: 30 (4,2%). Patients’ characteristics (Table) were similar in younger and older patients except for IMDC risk groups (IMDC) classification with less poor prognostic in pts ≥ 75 and fewer brain metastasis in pts ≥ 70. Treatment duration was similar across age groups despite a rate of discontinuation for TRAE increasing with age. Regarding efficacy, there was a non-significant trend toward improved response rate and progression free survival and lower specific survival with increasing age. Conclusions: In this large “real world” setting study a significant number of old pts were included. Prognostic profile appears better in older pts included. There is no signal for an excess of toxicity in this population and efficacy is comparable to younger patients. Age alone should not prevent prescribing N in mRCC. Clinical trial information: NCT03013335 . [Table: see text]

6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .

618 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of N in mccRCC pts in a “real world setting”. A translationnal research program was launched to characterize immune cell populations in the tumor by immunohistochemistry (IHC) and correlate them with outcome on N. Methods: All pts treated with N in the GETUG AFU 26 NIVOREN trial who consented for translational program and with available archived paraffin- embedded (FFPE) tumor tissue samples were eligible. Tumor were centrally reviewed. Using IHC we quantified main immune populations (B-cells, CD8 T-cells, macrophages), and immune checkpoints receptors (TIM-3, LAG-3, PD-1) at the invasive margin (IM) and at the core of the tumor (CT). We also identified AXL and PBRM1/BAP1 expression. Results: Overall 324 pts were included. Pts had similar baseline characteristics (IMDC Good, Intermediate, Poor in 18%, 60% and 22%, respectively) and comparable outcomes than overall trial population (PFS/OS = 4.5 / 25.4 months). PD-1 (IM) expression was associated with better PFS whereas AXL expression by tumor cells (TC) was associated with worse PFS (table). LAG-3 expression tend to be associated with worse OS. PBRM-1 loss (15%) was associated with better OS and PFS and with a higher density of CD8 T-cells (p = 0.001) and CD163-macrophages (p = 0.01) (CT) and a higher expression of LAG-3 (CT) (p = 0.01) and PD-1 (CT) (p = 0.02). BAP-1 loss was not associated with PFS (p = 0.6) nor OS (p = 0.9) in this cohort. Conclusions: We report the largest translational analysis supporting that PD-1 and AXL expression are associated with PFS in pts with mccRCC receiving N. We further confirm that PBRM-1 loss is a strong prognostic factor in this setting.[Table: see text]

The standard first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma combines Cisplatin, 5 Fluorouracil and Cetuximab, but many patients aren't eligible. We retrospectively evaluated the efficacy and the tolerability of Carboplatin and Paclitaxel in this indication, mostly in patients unfit to Cisplatin. Paclitaxel (80mg/m2) was administered at day 1, 8 and 15 and Carboplatin area under the curve 5 at day 1, repeated every 28 days, for 6 cycles. Carboplatin could be administered at area under the curve 2 at day 1, 8 and 15. 117 patients received this association at our institution, 94 of those were ineligible to cisplatin due to severe comorbidities, age >70years or Performance status >1. The overall response rate was 40%. The median progression free survival for patients ineligible to Cisplatin was 4.4 months [95% CI; 3.4; 5.0] and the median overall survival was 8 months [95% CI; 5.4-10.7]. The most frequent toxicities were hematologic, with 94 grade ≥ 3, mostly in patients who received monthly Carboplatin. Our study shows Carboplatin and Paclitaxel in first-line in recurrent/metastatic head and neck squamous cell carcinoma appear efficient for patients ineligible to Cisplatin and safe when both drugs are weekly administered.

Purpose To evaluate the prognostic value of F-fluorodeoxyglucose positron emission tomography (FDG PET) with quantitative analysis using metabolic parameters in metastatic differentiated thyroid cancer (DTC). Materials and methods The FDG-PET scans of 37 patients with metastatic DTC were studied retrospectively. The number of FDG-avid lesions, the SUVmax, the SULpeak of the lesion with the highest FDG uptake, the overall metabolic tumor volume (MTV), and the total lesion glycolysis (TLG) were measured. Curves of progression-free survival (Kaplan-Meier) and Cox univariate and multivariate analyses determined the prognostic factors for survival. Results Progression-free survival was better in patients with less than 10 FDG-avid lesions (P = 0.0089), the SUVmax less than 10 (P = 0.0026), the SULpeak less than 5 (P = 0.0004), and the TLG less than 154 (P = 0.0110).Cox analyses showed that only the result of the PET scan was predictive of survival (age, TNM stage, histology, and the I whole body radioiodine scan were not associated with prognosis). In the univariate analysis, prognostic factors for progression-free survival and overall survival were the SUVmax (P = 0.004; P = 0.018), the SULpeak (P = 0.001; P = 0.017), and the TLG (P = 0.014; P = 0.012). The number of FDG-avid lesions was significantly associated with progression-free survival (P = 0.012), but not the MTV. In the multivariate analysis, the number of FDG-avid lesions and the SULpeak were independent prognostic factors. Conclusions FDG PET using metabolic parameters is a prognostic factor in metastatic DTC. It could improve the therapeutic management and follow-up of patients.

Chemotherapy toxicity could be linked to decreased skeletal muscle (sarcopenia). We evaluated the effect of sarcopenia on chemotherapy toxicity among metastatic colorectal cancer (mCRC) patients. All consecutive mCRC patients in 3 hospitals were enrolled in this prospective, cross-sectional, multicenter study. Several nutritional indexes and scores were generated. Computed tomography (CT) images were analyzed to evaluate cross-sectional areas of muscle tissue (MT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT). Toxicities were evaluated in the 2 mo following clinical evaluation. Fifty-one mCRC patients were included in the study. Sarcopenia was observed in 71% of patients (39% of women and 82% of men) whereas only 4% and 18% were considered as underweight using body mass index (BMI) or severely malnourished using the Nutritional Risk Index (NRI), respectively. Grade 3-4 toxicities were observed in 28% of patients. In multivariate analysis including age, sex, BMI, sarcopenia, SAT, and VAT, the only factor associated with Grade 3-4 toxicities was sarcopenia (odds ratio = 13.55; 95% confidence interval [1.08; 169.31], P = 0.043). In mCRC patients undergoing chemotherapy, sarcopenia was much more frequently observed than visible malnutrition. Despite the small number of patients included in our study, we found sarcopenia to be significantly associated with severe chemotherapy toxicity.

Docetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC.Data were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks.Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %).TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.

Background End-of-life decision-making in Intensive care Units (ICUs) is difficult. The main problems encountered are the lack of a reliable prediction score for death and the fact that the opinion of patients is rarely taken into consideration. The Decision Curve Analysis (DCA) is a recent method developed to evaluate the prediction models and which takes into account the wishes of patients (or surrogates) to expose themselves to the risk of obtaining a false result. Our objective was to evaluate the clinical usefulness, with DCA, of the Simplified Acute Physiology Score II (SAPS II) to predict ICU mortality. Methods We conducted a retrospective cohort study from January 2011 to September 2015, in a medical-surgical 23-bed ICU at University Hospital. Performances of the SAPS II, a modified SAPS II (without AGE), and age to predict ICU mortality, were measured by a Receiver Operating Characteristic (ROC) analysis and DCA. Results Among the 4.370 patients admitted, 23.3% died in the ICU. Mean (standard deviation) age was 56.8 (16.7) years, and median (first-third quartile) SAPS II was 48 (34–65). Areas under ROC curves were 0.828 (0.813–0.843) for SAPS II, 0.814 (0.798–0.829) for modified SAPS II and of 0.627 (0.608–0.646) for age. DCA showed a net benefit whatever the probability threshold, especially under 0.5. Conclusion DCA shows the benefits of the SAPS II to predict ICU mortality, especially when the probability threshold is low. Complementary studies are needed to define the exact role that the SAPS II can play in end-of-life decision-making in ICUs.

577 Background: Nivolumab (N) has been approved for the treatment of mRCC after failure of 1 or 2 tyrosine kinase inhibitors (TKI) based on the results of Checkmate 025 study. Right after approval, we initiated the NIVOREN GETUG-AFU 26 study (NCT03013335), a French multicenter prospective study to evaluate safety and efficacy of N in a “real world setting”. Methods: Patients (pts) with clear cell mRCC could be enrolled if they had received at least one TKI. Compared with the pivotal trial, inclusion criteria allowed patients with more than 2 previous lines of treatment, including previous mTOR inhibitors, ECOG PS 2, asymptomatic brain metastases (BM) or impaired renal function. The primary objective of the study was the safety of N, efficacy being the main secondary objective. Between February 2016 and June 2017, 729 pts have been enrolled. We report the results from the first 528 pts. Results: All pts had clear cell mRCC, median age was 64, 77.2% were male. ECOG PS was > 1 in 73 pts (14.7%), 27.5% pts had received prior everolimus, 29.7% pts had received more than 2 previous lines, IMDC risk groups were 19%/54.9%/26.1% for good/intermediate and poor risk respectively; 69 (14%) pts had BM at screening. With a median follow up of 13.1 months, median duration of treatment was 4.1 months [0-15.6], with 31.4% of pts still on therapy. Treatment discontinuation due to adverse event (AE) occurred in (48) 13.3% pts . 64 serious related AE have been reported in 52 pts (9.9%) including 7 renal failures and 6 pneumonitis. Median PFS was 4.4 months 95%CI[3;4.6] . At the time of this analysis, 170 pts have died and 12 months OS rate was 66.4% 95%CI[ 61.7; 70.7]. In subgroups analysis, ECOG-PS > 1 (Hazard Ratio (HR) = 2.450 [1.704;3.523]), more than 2 previous lines (HR = 1.442 [1.059;1.963]) and prior use of everolimus (HR = 1.704 [1.250;2.322]) were associated with reduced OS in univariate analysis. Conclusions: We report the first analysis of the largest prospective real world setting study of N in mRCC. NIVOREN study demonstrates that N safety and efficacy in a “real world” prospective study are comparable to the pivotal study. Clinical trial information: NCT03013335.

Analysis of risk factors associated with severity in patients with confirmed leptospirosis.Retrospective study in 147 leptospirosis-confirmed patients at two tertiary nonteaching hospital in Reunion Island.138 men and 9 women, aged 36+/-14 years, 80 in the ICU and 67 in medical wards.We collected demographic, clinical, biological, and radiographic data and performed univariate and multivariate analysis to examine risk factors associated with admission in ICU and mortality. Pulmonary forms were more frequent (85%) than in previous reports, with 85 cases (65.3%) on abnormal chest radiography. Among the 38 patients who underwent bronchoalveolar lavage at admission 31 (81.5%) had alveolar hemorrhage. Independent factors related to ICU admission were: age over 46[Symbol: see text]years (OR 3.02), creatinine higher than 200[Symbol: see text]mumol/l (6.69), shock (13.87), and acute respiratory failure (20.69). Mortality was 12.9%. The only factor independently related to mortality was need for mechanical ventilation (OR 20.94). Icterohemorrhagiae serogroup was found in 62 cases (42.8%) but was not related to death.Pulmonary involvement is a major feature in leptospirosis disease but is not associated with poor outcome. Identification of clinical and laboratory findings on admission may help to better characterize severe cases.

Summary Objectives The sequence variability in the protease and in the 5 Gag cleavage sites (CS) were explored to look for eventual associations between the mutations. Moreover, we have evaluated associations between the Gag region sequence and the virological response to Protease Inhibitors (PI). Methods The protease and the 5 Gag CS sequences from 98 PI-experienced patients were sequenced and compared to the HXB2 reference sequence. Sixty patients, treated by Saquinavir plus Ritonavir, were studied to evaluate the clinical impact of the Gag region variability. Results The relationship between 63 protease mutations and 21 Gag CS mutations were explored. Two patterns of mutations in the protease were identified: (M46I/L, I54V, V82A/T/F) was associated to the A431V and (K20I/R/M, L89M/I) to the S373Q and L449P. None of the Gag CS mutations resulting from PI treatment was associated to the virological response to SQV/r. On the other hand, the S373P mutation had a negative impact on the virological response that remained statistically significant in a multivariate analysis after adjustment on the number of PI resistance mutations. Conclusions These results evoke the pertinence to introduce some mutations found in the Gag CS in the algorithms used for the interpretation of resistance testing.

This retrospective study evaluates the interest of CA 15-3 measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer we selected 117 patients without recurrence (WR) for 5 years or more, 33 with a local recurrence (LR) and 149 with at least one distant metastasis (DM). The sensitivity of CA 15-3 depends on the type of recurrence ([LR] or [DM]), the localization of unique DM, the presence and the number of metastatic sites, on hormonal receptor status and tumor subtypes. The number of metastatic sites and hormonal receptor status are independent predictive criteria of an elevation of CA 15-3. The analysis of ROC curve in order to separate patients with DM and patients WR shows an AUC of 0.87 (p0.0001). The optimal discriminative threshold is 26 kU/L. In conclusion, these data confirm that CA 15-3 increase depends on the kind of evolution and on initial tumor's hormonal status.

Objective To assess the effects of a peer support group therapy on HIV-infected adolescents. Design A prospective study of a cohort of HIV-infected adolescents participating or not participating in a psychodynamic oriented, emotional support group. Methods From a group of 30 perinatally HIV-infected adolescents who attended an outpatient clinic, 10 agreed to participate in the peer support group (group 1), 10 declined (group 2) and 10 others who lived too far from the clinic were not invited to participate (group 3). The three groups were compared at baseline and 2 years later using the outcome measures: perceived illness experience scale, perceived treatment inventory, self-esteem inventory. Results At baseline, the three groups had similar characteristics overall. The adolescents' self-esteem was in the normal range. After 2 years, worries about illness had decreased in group 1, whereas the scores had increased or remained the same for the other adolescents (P = 0.026). The adolescents in group 1 had less negative perception of treatment at 2 years than those in groups 2 and 3 (P = 0.030). After intervention, the percentage of adolescents with an undetectable viral load had increased in group 1 from 30 to 80% (P = 0.063) but was unchanged in groups 2 and 3. Considering the three groups altogether, the decrease in the viral load correlated with improvement of the perceived treatment inventory (Spearman R = 0.482 P = 0.015). Conclusions : This pilot study suggests that a peer support group intervention is associated with an improvement in adolescents' emotional well being, and that this can have a positive influence on medical outcomes.

It has been shown that virological protease inhibitor (PI) resistance mutations present at the initiation of saquinavir (SQV) plus ritonavir (RTV) therapy in PI-experienced patients are the strongest predictors of virological response. But most of the current resistance algorithms are adapted for unboosted SQV regimens. We applied a stepwise methodology for the development and validation of a clinically relevant genotypic resistance score for an SQV (800 mg twice per day [b.i.d.]) plus RTV (100 mg b.i.d.)-containing regimen. PI-experienced patients treated by this regimen achieved a human immunodeficiency virus plasma viral load (VL) of 10 and −1.23 log 10 copies/ml of VL reduction, respectively, while it was −0.27 log 10 copies/ml for those with at least two mutations, classifying the isolates as “no evidence of resistance” (0 or 1 mutation) or “resistance ” (≥2 mutations). The minimum concentration in plasma ( C min ) of SQV alone was not associated with the virological response. However, the combination of the SQV C min and the genotypic score, expressed as the genotypic inhibitory quotient, was predictive of the virological response, suggesting that the interpretation of SQV concentrations in plasma should be done only in the context of the resistance index provided by viral genotype for PI-experienced patients.

International audience; Background: While single nucleotide polymorphisms (SNP) in genes involved in DNA repair or drug metabolism have been shown to influence survival of metastatic colon cancer patients treated with FOLFOX, data on adjuvant setting are scarce.Methods: This study evaluated the correlation between disease-free survival (DFS) of 210 unselected stage III colon cancer patients receiving FOLFOX chemotherapy, and ERCC1-118 (rs11615, c.354T>C), XRCC1-399 (rs25487, c.1196G>A) and GSTP1-105 (rs1695, c.313A>G) polymorphisms. SNP were determined on tumor DNA using a PCR-based RFLP technique.Results: In univariate analysis, a trend towards longer DFS was observed for ERCC1 (C/T + T/T) versus (C/C) (HR=2.29; p=0.06), and XRCC1 (A/A) versus (G/G + G/A) (HR=1.61; p=0.16), but not for GSTP1 genotypes; a statistically significant p value was obtained when combining ERCC1 and XRCC1 favorable genotypes (0 versus ≥ 1 favorable genotypes, HR=2.42; p=0.02). After adjustment on tumor stage, lymph node ratio and differentiation grade, multivariate analysis showed that combining ERCC1 and XRCC1 genotypes gave a p value slightly above the threshold for statistical significance (HR=2.03; p=0.06), which was lower than for tumor stage, lymph node ratio or differentiation grade.Conclusion: The association of ERCC1 and XRCC1 polymorphisms may influence the prognosis of stage III colon cancer patients treated with FOLFOX adjuvant chemotherapy. Yet, these findings need to be confirmed in independent prospective studies.

International audience; BACKGROUND: The effectiveness of preventive measures depends on prevailing attitudes and mindsets within a population. Perceived risk is central to a shift in mindset and behaviour. The present study aims to investigate the perceived severity, vulnerability and precautionary behaviour adopted in response to the influenza A (H1N1) epidemic that broke out in 2009 on Reunion Island (Indian Ocean). As no H1N1 vaccination was available at the time, non-medical interventions appeared of crucial importance to the control of the epidemic. METHODS: A cross sectional survey was conducted in Reunion Island between November 2009 and April 2010 within 2 months of the passage of the influenza A (H1N1) epidemic wave. Individual contacts representing 725 households (one contact per household) were interviewed by telephone using validated questionnaires on perceived risks. Mean scores were calculated for perceived severity, vulnerability, efficacy of preventive measures and precautionary behaviour. Univariate analysis was applied to identify preventive measures and attitudes and multivariate analysis was used to study the determinants of precautionary behaviour. RESULTS: More than 95% of contacted persons accepted to participate to the survey. Eighty seven percent of respondents believed that prevention was possible. On average, three out of six preventive measures were deemed effective. Spontaneously, 57% of the respondents reported that they took one or more preventive measures. This percentage increased to 87% after the interviewer detailed possible precautions one by one. The main precautions taken were frequent hand washing (59%) and avoidance of crowded places (34%). In multivariate logistic regression analysis the following factors were significantly associated with taking one or more preventive measures: young age, previous vaccination against seasonal influenza, having had seasonal influenza in the last five years, effectiveness of the preventive measures taken and low standards of education. CONCLUSION: Inhabitants of Reunion Island have expressed a preventive approach adapted to the realities of the H1N1 pandemic, a feature that likely reflects some preparedness gained after the large and severe chikungunya epidemic that hit the island in 2006. The degree of severity was well assessed despite the initial alarmist messages disseminated by national and international media. Precautions that were undertaken matched the degree of severity of the epidemic and the recommendations issued by health authorities. Further qualitative studies are needed to help adapting public messages to the social and cultural realities of diverse communities and to prevent misconceptions.

Background Chemoradiation is the standard treatment for anal cancer. 3D conformal radiotherapy (3D-CRT) is usually split in 2 sequences with a therapeutic break (gap) in between. Intensity-modulated radiation therapy (IMRT) makes it possible to reduce treatment time by abandoning this gap. The purpose of this study was to compare outcomes and toxicities in patients treated with either IMRT or 3D-CRT. Methods Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6]. Results There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival, locoregional relapse-free survival and colostomy-free survival rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 acute toxicity. No grade 4 toxicity occurred. Conclusions Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to remove the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT.

Background: The possible impact of malnutrition on the tolerability and efficacy of modern chemotherapy regimens for metastatic colorectal cancer (mCRC) is unclear. Methods: In this prospective, cross-sectional, multicenter study, we collected demographic, oncological and nutritional data for all consecutive mCRC patients during a 14-day period in eight hospitals. Nutritional status was assessed with the nutritional risk index (NRI), and patients were classified as severely malnourished when NRI was Results: We enrolled 114 mCRC patients (median age: 65 years, range: 22–92; WHO performance status 0/1/2/3: 21/54/21/4%) of whom 88% had at least 2 metastatic sites and 49% were receiving chemotherapy as first-line treatment. Malnutrition was diagnosed in 65% of the patients and was severe in 19%. Severe malnutrition was associated with more adverse effects following chemotherapy (p = 0.01) and with shorter median overall survival (14.0 vs. 36.2 months in non-/moderately malnourished patients, p = 0.02). Conclusions: In mCRC patients, severe malnutrition is associated with greater chemotherapy toxicity and reduced overall survival.

Background & Aims Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. Methods Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. Results The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [ P P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant ( P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. Conclusions High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine.

In patients with extensive HIV resistance, one option is to delay salvage therapy until new drugs become available. We hypothesized that this delay period could be based on a simplified treatment, which would reduce drug toxicity, stabilize resistance, and prevent resurgence of wild-type virus.A prospective 24-week treatment simplification study in HIV-1-infected patients having failed several lines of antiretroviral therapy, with CD4+ T-cell countsor = 100 cells/ml, plasma HIV RNA (viral load [VL])or = 4 log10 copies/ml and a resistance genotype predicting less than two active drugs. Treatment associated ritonavir-boosted low-dose indinavir (200 mg twice daily) and lamivudine (150 mg twice daily). The primary endpoint was a decrease in CD4+ T-cell countsor = 25% or increase in VLor = 0.7 log copies/ml relative to baseline.Twenty-six patients were included. Baseline median VL was 4.5 log10 copies/ml and median CD4+ T-cell count was 290 cells/ml. During the study, 10/26 patients (38%, 95% confidence interval = 20.2-59.4) reached the primary endpoint. No patient had an AIDS-defining event. At week 24, the median change in plasma VL was +0.2 log10 copies/ml (interquartile range (IQR): 0-0.5; P = 0.003). The median change in CD4+ T-cell counts was -49 cells/ml (IQR: -14 to -93, P0.001), with a median decline slope of 10 cells/ml/month, which was not different from that measured under full highly active antiretroviral therapy during the 6 months preceding inclusion. There were no significant changes in HIV-1 protease and reverse transcriptase genotypes during the study.In patients with advanced resistance, treatment simplification prevented resurgence of wild-type HIV, reduced drug burden, but failed to stabilize progression of the immune deficiency.