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Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2−/PET4−) received immunochemotherapy. Responders after only cycle 4 (PET2+/4−) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2−/4− and PET2+/4− had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.

Early identification of ultra-risk diffuse large B-cell lymphoma (DLBCL) patients is needed to aid stratification to innovative treatment. Previous studies suggested high baseline total metabolic tumor volume (TMTV) negatively impacts survival of DLBCL patients. We analyzed the prognostic impact of TMTV and prognostic indices in DLBCL patients, aged 60 to 80 years, from the phase 3 REMARC study that randomized responding patients to R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) into maintenance lenalidomide or placebo. TMTV was computed on baseline positron emission tomography/computed tomography using the 41% maximum standardized uptake value method; the optimal TMTV cutoff for progression-free (PFS) and overall survival (OS) was determined and confirmed by a training validation method. There were 301 out of 650 evaluable patients, including 192 patients classified as germinal center B-cell–like (GCB)/non-GCB and MYC/BCL2 expressor. Median baseline TMTV was 238 cm3; optimal TMTV cutoff was 220 cm3. Patients with high vs low TMTV showed worse/higher Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, stage III or IV disease, >1 extranodal site, elevated lactate dehydrogenase, International Prognostic Index (IPI) 3-5, and age-adjusted IPI 2-3. High vs low TMTV significantly impacted PFS and OS, independent of maintenance treatment. Although the GCB/non-GCB profile and MYC expression did not correlate with TMTV/survival, BCL2 >70% impacted PFS and could be stratified by TMTV. Multivariate analysis identified baseline TMTV and ECOG PS as independently associated with PFS and OS. Even in responding patients, after R-CHOP, high baseline TMTV was a strong prognosticator of inferior PFS and OS. Moreover, TMTV combined with ECOG PS may identify an ultra-risk DLBCL population. This trial was registered at www.clinicaltrials.gov as #NCT01122472.

Dissemination, expressed recently by the largest Euclidian distance between lymphoma sites (SDmax), appeared a promising risk factor in DLBCL patients. We investigated alternative distance metrics to characterize the robustness of the dissemination information. In 290 patients from the REMARC trial (NCT01122472), the Euclidean (Euc), Manhattan (Man), and Tchebychev (Tch) distances between the furthest lesions, firstly based on the centroid of each lesion and then directly from the two most distant tumor voxels and the Travelling Salesman Problem distance (TSP) were calculated. For PFS, the areas under the ROC curves were between 0.63 and 0.64, and between 0.62 and 0.65 for OS. Patients with high SDmax whatever the method of calculation or high SD_TSP had a significantly poorer outcome than patients with low SDmax or SD_TSP (p &lt, 0.001 for both PFS and OS), with significance maintained in Ann Arbor advanced-stage patients. In multivariate analysis with total metabolic tumor volume and ECOG, each distance feature had an independent prognostic value for PFS. For OS, only SDmax_Tch, SDmax_Euc _Vox, and SDmax_Man _Vox reached significance. The spread of DLBCL lesions measured by the largest distance between lymphoma sites is a strong independent prognostic factor and could be measured directly from tumor voxels, allowing its development in the area of the deep learning segmentation methods.

Methods : This multicentric retrospective study aimed to evaluate the efficacy and the safety of the combination of BBV in patients with non-cutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was to evaluate the best overall response rate (ORR) (complete response (CR) and partial response (PR)). Secondary objectives were progression free survival (PFS), overall survival (OS), duration of response (DoR), impact of transplantation on outcome, and safety. Patients treated between January 2013 and October 2020 were reviewed and all the data were collected through an electronic questionnaire sent to all the physicians. Results : Eighty two patients with R/R PTCL (40 angioimmunoblastic lymphoma (AITL), 2 T-cell lymphoma with TFH phenotype ,13 PTCL not otherwise specified (PTCL NOS), 5 Alk+ anaplastic large cell lymphoma (ALCL), 17 Alk- ALCL, , 1 Extranodal NK-/T-cell lymphoma, 3 Enteropathy-associated T-cell lymphoma (EATL), 1 subcutaneous panniculitis) were included. Median age at beginning of BBV was 60 years, most of patients were male (61%), had advanced stage (88%) and an IPI ≥ 2 (79%). Half of patients were refractory to their last treatment. Median number of prior regimens was 1 (range 1 to 6). The best ORR was 71%, with 51% of patients in CR. In multivariable analysis, only the relapse status after the last regimen (relapse vs refractory) was associated with ORR, relapsed patients having a better ORR (83% vs 57% in refractory patients, p=.014, OR=3.70 (95%CI:1.3-10.5)). Median DoR was 15.4 months in patients with CR but differed significantly whether patients were transplanted or not (Not reached vs 8.4 months, p=.0055). Twenty-two patients (30% of patients ≤ 70 years of age) were transplanted (6 autologous and 16 allogenic). With a median follow-up of 9 months, the median PFS and OS were 8.3 and 26.3 months respectively. In multivariable analysis, only 2 factors had a significant impact on PFS and OS: best response (CR/PR vs SD/PD with a median PFS of 17.4 vs 1.9 months, p Fifty-nine percent of patients experienced a grade 3 to 4 adverse event which was mainly hematologic toxicity. Treatment had to be stopped in 11% of patients. Conclusion: To the best of our knowledge, this is the first study reporting on the combination of BBV in the treatment of R/R PTCL in such a large cohort. The results are very encouraging with a high response rate, long DoR in responding patients and a very good outcome. Furthermore, patients in CR who are eligible for transplant have the best outcome, making this combination a good candidate as salvage therapy before transplant consolidation in these high-risk lymphomas with limited treatment options. Figure 1 Figure 1. Disclosures Bouabdallah: Kite/Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Herbaux: Takeda: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Sibon: Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy; iQone: Consultancy; Takeda: Consultancy. Laribi: AstraZeneca: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Jansen: Research Funding. Damaj: roche: Consultancy, Honoraria; takeda: Consultancy, Honoraria. OffLabel Disclosure: Brentuximab Vedotin and Bendamustine

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

Purpose Identifying patients at high risk of progression and early death among those with high-tumor-burden follicular lymphoma (FL) is unsatisfactory with current prognostic models. This study aimed to determine the prognostic impact of the total metabolic tumor volume (TMTV) measured at baseline with [18F]fluorodeoxyglucose/positron emission tomography-computed tomography ([18F]FDG/PET-CT) scans and its added value to these models. Patients and Methods A pooled analysis was performed by using patient data and centrally reviewed baseline PET-CT scans for 185 patients with FL who were receiving immunochemotherapy within three prospective trials. TMTV was computed by using the 41% maximum standardized uptake value thresholding method, and the optimal cutoff for survival prediction was determined. Results Median age was 55 years, 92% of patients had stage III to IV disease, 37% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5, and 31% had a FLIPI2 score of 3 to 5. With a median follow-up of 64 months, overall 5-year progression-free survival (PFS) was 55% and overall survival (OS) was 92%. Median TMTV was 297 cm3 (quartile 1 through quartile 3, 135 to 567 cm3). The optimal cutoff identified was 510 cm3, with a markedly inferior survival in the 29% of patients with TMTV > 510 cm3. Five-year PFS was 33% versus 65% (hazard ratio [HR], 2.90; P < .001), and 5-year OS was 85% versus 95% (HR, 3.45; P = .010). On multivariable analysis, TMTV (HR, 2.3; P = .002) and FLIPI2 score (HR, 2.2; P = .002) were independent predictors of PFS. In combination, they identify three risk groups: high TMTV and intermediate-to-high FLIPI2 score with 5-year PFS of 20% (HR, 5.0; P < .001), high TMTV or intermediate-to-high FLIPI2 score with 5-year PFS of 46% (HR, 2.1; P = .007), and low TMTV and low FLIP2 with 5-year PFS of 69%. Conclusion Baseline TMTV is a strong independent predictor of outcome in FL. In combination with FLIPI2 score, it identifies patients at high risk of early progression. It warrants further validation as a biomarker for development of first-line PET-adapted approaches in FL.

International audience; Both total metabolic tumor volume (TMTV), computed on baseline positron emission tomography (PET), and end of induction (EOI) PET are imaging biomarkers showing promise for early risk stratification in patients with high-tumor-burden follicular lymphoma. A model was built incorporating these 2 factors in 159 patients from three prospective trials: 2 Lymphoma Study Association (LYSA) studies and 1 Fondazione Italiana Linfomi (FIL) trial. Median follow up was 64 months. High TMTV (>510 cm3) and positive EOI PET were independent, significant risk factors for progression. Their combination stratified the population into 3 risk groups: patients with no risk factors (n = 102; 64%) had a 5-year progression-free survival (PFS) of 67% vs 33% (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.8-4.9) for patients with 1 risk factor (n = 44; 27%) and only 23% (HR, 4.6; 95% CI, 2.3-9.2) for patients with both risk factors (n = 13; 8%). 2-year PFS was respectively 90% vs 61% (HR, 4.8; 95% CI, 2.2-10.4) and 46% (HR, 8.1; 95%CI, 3.1-21.3). This model enhances the prognostic value of PET staging and response assessment, identifying a subset of patients with a very high risk of progression and early treatment failure at 2 years.

Item does not contain fulltext We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P < .0001) and OS (P = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm(3)) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

More than 2 billion people worldwide have been exposed to hepatitis B virus (HBV). To prevent these infections, Senegal and Cameroon integrated the HBV vaccine into their Expanded Program on Immunization (EPI) in 2005, as did the Central African Republic (CAR) in 2008. We evaluated the prevalence of HBV exposure and infection after the integration of the HBV vaccine in the EPI.An observational cross-sectional study was conducted among the hospitalized children 3 months to 6 years of age in Cameroon, CAR and Senegal. Plasma was collected for the detection of anti-HBc, anti-HBs and hepatitis B surface antigen in children with anti-HBc and anti-HBs.Between April 2009 and May 2010, 1783 children were enrolled, 19.4% of whom were anti-HBc positive. The percentage of children with anti-HBc was 44.4% among the children younger than 6 months, decreasing after 6 months to reach 18.8% at 12 months. This decline was followed by a rapid increase in anti-HBc positivity rate in CAR observed as early as 12 months of age compared with Cameroon and Senegal, where the anti-HBc increased between 18 and 36 months of age, respectively. The prevalence of hepatitis B surface antigen-positive children was significantly higher in CAR than that in Cameroon and Senegal (5.1% versus 0.7% and 0.2%; P0.001). Socioeconomic level, age and country were factors associated with the presence of anti-HBc.Passive transfer of anti-HBc maternal antibodies versus HBV exposure could be differentiated as early as 12 months of age. The low prevalence of anti-HBc and hepatitis B surface antigen among children born after the integration of HBV vaccine in the EPI in Cameroon and Senegal suggests a positive impact of HBV vaccination.

602 Objectives To compare the prognostic value of baseline Total Metabolic Tumour Volume (TMTV) measured on FDG-PET/CT with different adaptive thresholding methods to a fixed 41% SUVmax threshold, in a large series of Peripheral T cell lymphoma (PTCL), as a model of diffuse disease, with a large range of tumor/background ratio. Methods 106 patients with PTCL from 5 LYSA centers, staged with a PET/CT were enrolled. It has been previously described in this series that TMTV computed with the 41% SUVmax threshold was a strong predictor of PFS and OS. On a dedicated workstation, we compared this fixed method to four adaptive thresholding methods depending on one or two characteristic image parameters: Daisne (Da) based on signal to background ratio, Nestle (Ns) based on tumor and background intensities, Fit including a 3D geometric model based on spatial resolution and Black (Bl) based on mean SUVmax. The prognostic relevance for each TMTV was pairwise comparison of ROC curves; survival functions were calculated using Kaplan Meier estimates. Results Tumor SUVmax/LiverSUVmax ratio ranged from 1 to 15. The median value of TMTV41%, TMTVDa, TMTVNs, TMTVFit, TMTVBl were respectively 231cm3 (CI 95% 145-361), 175 cm3 (129-311), 198 cm3 (137-343), 175 cm3 (134-313), 333 cm3 (260-652). There was an excellent concordance correlation between TMTV41%, and TMTVDa (ρ=0.99), TMTVNs (ρ=0.97), TMTVFi (ρ=0.99) but not with TMTVBl (ρ=0.85). Bland-Altman analysis showed that for high tumor burden, 41%SUVmax method slightly overestimated TMTV values compared to Da and Fit methods, whereas it underestimated TMTV values compared to Ns and Bl. There was no significant difference within the methods between TMTV ROC curves (p>0.4) for Progression free survival (PFS) and overall survival (OS), except for Black. Survival curves with the ROC optimal cut off for each method separated the same groups of low risk (volume≤cut-off) from high risk patients (volume>cut-off) with similar 2y-PFS (range 66-72% vs 26-29%; HR 3.7-3.9) and 2y-OS (79-83% vs 50-53%, HR 2.8-3.2). The positive predictive value for PFS and OS were 79%, 47% for TMTV41%, 70%, 47%, for TMTVDa, 70%, 47% for TMTVNs, 70%, 47% for TMTVFit, 69%, 48% for TMTVBl respectively. The negative predictive value for PFS and OS were 79%, 77% for TMTV41%, 69%, 82% for TMTVDa, 71%, 80% for TMTVNs, 69%, 81% for TMTVFit, 71%, 76%, for TMTVBl respectively. Conclusions Although each method produced some TMTV measurement differences, the prognostic value of TMTV remained quite similar. For implementation of TMTV in clinical trials one single method easily applicable in a multicentric PET review is mandatory.

Introduction : High total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT before R-CHOP has been shown to be significantly associated with worse progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL; Cottereau et al. Clin Cancer Res. 2016;22:3801-9) . The REMARC study (NCT01122472) is an international, multicenter, double-blind, randomized phase III trial that assessed lenalidomide (LEN) maintenance therapy versus placebo (PBO) in 650 patients responding to R-CHOP. With a median follow-up of ~40 months, independent review demonstrated that 2 years of LEN maintenance therapy significantly improved progression-free survival (PFS); median was not reached in the LEN arm vs 58.9 months in the PBO arm (HR=0.71 [95% CI, 0.54-0.93]; p=0.0135; Thieblemont et al. J Clin Oncol. 2017;35:2473-81). Methods: For these analyses, patients enrolled in the REMARC trial who had baseline PET/CT before R-CHOP (not mandatory per study protocol) with available fused images and end of treatment PET/CT were included. Total metabolic tumor volume (TMTV, defined as the sum of the regions of the local tumors with FDG uptake) was measured on baseline PET/CT with the 41% SUVmax thresholding method using the free semiautomatic software Beth Israel Fiji20 (http://petctviewer.org). The optimal TMTV cut-off to PFS (per FDA censoring rule) and overall survival (OS) was determined by Receiver Operating Curve (ROC) curves and X-tile analyses. Survival was estimated using Kaplan Meier (KM) curves. Multivariable analysis were performed with descending Cox model including TMTV, IPIaa, treatment arm and PET/CT response evaluated by Deauville criteria. Analyses were performed on the evaluable population and separate arms Results: 228 of 650 REMARC patients had TMTV data available for analysis, including n=108 in the PBO arm and n=120 in the LEN arm. Clinical characteristics were similar to the overall population. The median baseline TMTV was 295 cm3 (Q1-Q3, 99-702). After a median follow-up of 51.6 mo, 4y-PFS was 73% and 4y-OS was 85%. The optimal TMTV cut-off determined by ROC was 300 cm3 for PFS and OS. Patients with TMTV >300 vs ≤300 cm3 presented with worse ECOG performance status (ECOG ≥2: 19% vs 9%, p=0.034), higher Ann Arbor stage (stage III-IV: 95% vs 86%, p=0.042), more extra-nodal sites (>1: 65% vs 38%, p In all evaluated patients, a significant impact of TMTV for cut-offs of >300 vs ≤300 cm3 was observed for PFS (HR=2.09; 95% CI, 1.22-3.69) and OS (HR=2.99; 95% CI, 1.44-6.18). Patients with high TMTV >300 cm3 vs low TMTV ≤300 cm3, respectively, had a 4-year PFS of 57% vs 73% and OS of 70% vs 88%. These results were more disparate when a higher TMTV cut-off of >1000 was applied. In multivariate analysis, only TMTV maintained an independent prognostic value. The prognostic impact of TMTV >300 vs ≤300 cm3 on PFS (HR=2.4; 95% CI, 1.1-5.22) and OS (HR=5.0; 95% CI, 1.4-17.) was maintained in the PBO arm (Figure 1A). In contrast, when the analysis was focused on patients in LEN arm, TMTV >300 vs ≤300 cm3 lost its prognostic impact on PFS and OS. In the LEN arm, 4-year PFS and OS did not differ significantly between patients with high and low TMTV (Figure 1B). Conclusion: TMTV measured on baseline PET/CT is a strong prognosticator of outcome in DLBCL, even in patients in response after R-CHOP. High TMTV at baseline was significantly associated with worse PFS and OS in patients receiving PBO following a response to R-CHOP in the REMARC study. Interestingly, LEN maintenance reduces the negative impact of high baseline TMTV on survival in patients with DLBCL Disclosures Casasnovas: takeda: Consultancy; merck: Consultancy; MSD: Consultancy; Roche: Consultancy; Gilead Sciences: Research Funding; Roche: Honoraria; Takeda: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria; MSD: Honoraria; Roche: Research Funding; Gilead Sciences: Consultancy; Janssen: Consultancy. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ribrag:Infinity: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; MSD: Honoraria; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; argenX: Research Funding; pharmamar: Other: travel; Incyte Corporation: Consultancy. Macro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Morschhauser:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Beigene: Research Funding. Godmer:CELGENE: Other: Invitation to congress. Salles:Servier: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Acerta: Honoraria; Merck: Honoraria; Janssen: Honoraria, Other: Advisory Board; Pfizer: Honoraria; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Coiffier:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; CELLTRION: Membership on an entity's Board of Directors or advisory committees; MORPHOSYS: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Resume Les nouvelles technologies ont pris depuis quelques annees une place importante dans notre environnement quotidien, qu’il soit professionnel ou personnel. Le monde de la sante n’a pas echappe a cette mutation progressive, avec l’arrivee de l’informatique jusqu’au chevet du malade. La recherche clinique a aussi trouve un interet grandissant a tous ces nouveaux outils mis a la disposition aussi bien du medecin investigateur, du patient, que des services specialises qui contribuent au diagnostic et au suivi des patients, et aussi des differents metiers de la recherche clinique. Si l’usage des nouvelles technologies semble apporter des facilites, telles que la centralisation des informations ou la simplification des echanges de donnees entre differents intervenants, il n’en reste pas moins qu’il s’agit de donnees a caractere personnel, dont il faut assurer la fiabilite, la confidentialite et la securite, qu’elles soient utilisees dans le cadres des soins courants ou de celui de la recherche clinique academique ou industrielle. L’objectif de la table ronde etait d’evaluer l’impact des nouvelles technologies d’informations appliquees aux essais cliniques (y compris pour les donnees sources - dossier medical) et a la recherche sur la personne et le medicament. Dans un premier temps, un etat des lieux du developpement de ces nouvelles technologies dans l’environnement de la sante a ete realise. La recherche des benefices attendus pour emettre des recommandations de bon usage ou des precautions d’emploi lors de leur utilisation dans le cadre des essais cliniques a ete effectuee dans un second temps. Enfin, l’analyse de l’impact de ces nouvelles technologies tant du cote de l’investigateur, que de celui du promoteur, qu’il soit academique ou industriel a ete estimee.

Within the last few years, new technology has come to play an important part in our professional and private daily environment. Healthcare has not escaped this progressive mutation with computers reaching the bedside. Clinical research has also shown growing interest in these new tools available to the clinical investigator, the patient, as well as to specialist departments for diagnosis and follow-up of patients, and to the different professions in clinical research. If the use of new technology seems to make life easier, by centralizing data or by simplifying data-sharing between different teams, it is still a matter of private data which must remain reliable, confidential and secure, whether it is being used in ordinary healthcare or in academic or industrial research. The aim of the round table was to estimate the impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research. First, an inventory was made of the development of these new technologies in the healthcare system. The second point developed was identification of expected benefits in order to issue guidelines for their good use and hazard warnings in clinical trials. Finally, the impact of these new technologies on the investigator as well as the project manager was analysed.

Objectives: To identify predictors of Pneumocystis jiroveci pneumonia (PCP) or pulmonary tuberculosis (TB) in acid-fast bacillus smear-negative HIV-infected patients and to develop clinical prediction rules. Design: A cohort study conducted in consecutive hospitalized Asian patients. Methods: Multivariate analyses were performed on the Cambodian sample to determine clinical, radiological, and biological predictors of PCP or TB at hospital admission. The Vietnamese sample was kept for independent validation. Results: In Cambodia, the gold standard technique for TB and PCP were fulfilled in 172 (27 cases) and 160 (84 cases) patients, respectively. For TB, independent predictors included the following: headache [odds ratio (OR) 3.0; 95% confidence interval (CI) 1.04 to 8.6], localized radiological opacity (OR 5.8; 95% Cl 1.9-17.9), and mediastinal adenopathy (OR 10.1; 95% CI 3.5 to 29.0); and for PCP: resting oxygen saturation

Objectives: To determine the main causes of acid-fast bacillus sputum smear-negative pneumonia in Asian and African HIV-infected patients Design and setting: A prospective multicenter study (ANRS 1260) of consecutive hospitalized patients in tertiary hospitals in Phnom Penh Ho Chi Minh City Bangui and Dakar. Intervention: Use of the same clinical radiological and biological methods at the four sites; regular quality controls of participating laboratories; final review of medical records by experts. Similar criteria used to establish diagnoses. Results: In all 462 patients were enrolled 291 in Asia and 171 in Africa. The median CD4 cell count was 25 cells/microl. Radiological opacities were diffuse in 42% of patients and localized in 45%. Fiberoptic bronchoscopy was performed in 354 patients at similar rates in the four sites. A definite and/or probable diagnosis was obtained in 375 patients (81%). Pneumocystis jiroveci pneumonia bacterial pneumonia AFB sputum smear-negative tuberculosis andother infections (fungi parasites atypical mycobacteria) were diagnosed in respectively 47 30 17 and 12% of Asian patients and 3 48 26 and 5% of African patients. Conclusion: In South-east Asia acid-fast bacillus smear-negative pneumonia is caused by a wide variety of pathogens. When possible fiberoptic bronchoscopy must be performed rapidly if clinical data are not highly suggestive of bacterial pneumonia Pneumocystis jiroveci pneumonia or tuberculosis. In contrast in Africa bacterial pneumonia and tuberculosis are responsible for the large majority of cases. Fiberoptic bronchoscopy should be restricted to patients with clinical and/or radiological findings not suggestive of bacterial pneumonia or tuberculosis antibiotic failure and three consecutive negative sputum smears. (authors)

Background Hepatitis B is a major health concern in Africa. The vaccine against hepatitis B virus (HBV) was introduced into the Expanded Programme on Immunization (EPI) of Cameroon and Senegal in 2005, and of CAR (Central African Republic) in 2008. A cross-sectional study was conducted to assess HBV immunization coverage following the vaccine’s introduction into the EPI and factors associated with having been vaccinated. Methods All hospitalized children, regardless of the reasons for their hospitalization, between 3 months and 6 years of age, for whom a blood test was scheduled during their stay and whose condition allowed for an additional 2 mL blood sample to be taken, and who provided the parent’s written consent were included. All children anti-HBs- and anti-HBc + were tested for HBsAg. Vaccination coverage was assessed in three different ways: immunization card, maternal recall and serologic anti-HBs profile. Results 1783 children were enrolled between April 2009 and May 2010. An immunization card was only available for 24 % of the children. The median age was 21 months. Overall HBV immunization coverage based on immunization cards was 99 %, 49 % and 100 % in Cameroon, CAR and Senegal, respectively (p

To assess immunological parameters, including markers of immune activation, in highly HIV-1-exposed uninfected (EU) Vietnamese intravascular drug users (IDUs) in comparison with HIV-1-infected IDUs and HIVunexposed controls, we determined peripheral lymphocyte phenotypes in fresh whole blood samples from 32 EU IDUs, 28 HIV+ IDUs, and 26 blood donors. We found higher levels of activation markers (CD38, HLADR) on CD4+ and CD8+ T cells, lower percentages of naive CD4+ and CD8+ T cells, higher percentages of CD8+ T cells and of CD8+ T cells expressing CD25, and lower levels of CXCR4+CD4+ T cells in EU IDUs than in unexposed controls. Despite several differences in CD4+ and CD8+ T cell subset phenotypes, both EU and HIV+ IDUs exhibited a pattern of peripheral immune activation. Lymphocyte activation in EU IDUs may reflect immune stimulation driven by viral infections other than HIV-1 and/or allogeneic stimulation associated with needle sharing. Our results suggest that immune activation does not necessarily favor HIV-1 transmission, but, on the contrary, may alter the susceptibility of EUs to HIV-1 infection and contribute to their resistance.

Background We evaluated the short-term spontaneous fluctuations of HBV DNA and HBsAg levels in Senegalese patients with chronic infection with hepatitis B virus and normal ALT and determined factors related to these fluctuations. Method A total of 87 patients with persistent normal ALT values were enrolled in the study. Serum samples were obtained at three different visits, with an interval of 2 months (M0, M2, and M4), and without initiating anti HBV treatment. Levels of HBV DNA, quantitative HBsAg, ALT and AST, genotyping and viral DNA mutations were analyzed. Results Among the 87 patients, genotype E was predominant (75%). The median HBV DNA level was 2.9 log10 IU/mL [2.2-3.4], 2.7 log10 IU/mL [2.1-3.6] and 2.7 log10 IU/mL [2.1-3.4] at M0, M2 and M4, respectively. The values ranged from

We thank Pauls et al. for their comments (1) on our article describing that p21 restricts reverse transcription of HIV-1 in monocyte-derived macrophages (MDM) by blocking the synthesis of deoxynucleotides (dNTPs) through the repression of the transcription factor E2F1 and the subsequent inhibition of the expression of ribonucleotide reductase subunit R2 (RNR2) (2). Pauls et al. (1) confirm our finding that p21 blocks HIV replication in MDM, further show that p21 regulates the phosphorylation of SAM domain and HD domain-containing protein 1 (SAMHD1) in MDM, and suggest that p21-mediated restriction in these cells is dependent on SAMHD1. Indeed it has been recently reported that SAMHD1 viral restriction activity, but not its dNTPase activity, is inhibited by CDK1-mediated phosphorylation at residue T592 (3⇓–5). Like Pauls et al. (1), we have found that p21 does regulate SAMHD1 phosphorylation in MDM (Fig. 1). However, we believe that p21 restriction is, at least in MDM, mainly mediated by the block of dNTP synthesis because of RNR2 suppression, which is upstream … [↵][1]2To whom correspondence should be addressed. E-mail: gianfranco.pancino{at}pasteur.fr. [1]: #xref-corresp-1-1

Early identification of high risk patients is warranted in high tumor burden or advanced follicular lymphoma. In this regard post induction FDG-PET/CT and parameters obtained from quantitative baseline FDG-PET such as total metabolic tumor volume (TMTV) have been proposed as prognostic tools (J Clin Oncol, 2016, in press). It has been shown recently that the presence of large TMTV>510cm3 can help to early detect patients who relapse within two years of therapy but TMTV is not yet used routinely. The aim of this study was to assess the prognostic impact of SUVmax measured on baseline FDG-PET/CT as an index of tumor proliferation and its added value to other prognostic parameters in this population. Methods: A pooled analysis of patient data and centrally reviewed baseline PET/CT scan for 181 patients with high tumor burden follicular lymphoma receiving R-chemotherapy within three prospective trials was performed (PET-FOLL and PRIMA from the LYSA, FOLL05 from the FIL), (Lancet Haematol, 2014). 82% of patients received R-CHOP, 14% R-CVP, 4% R-FM and 16 patients received R maintenance. Baseline SUVmax was computed on quality controlled PET/CT scan and the optimal cut-off for survival prediction was determined by Receiver Operating Curves and X-tile analysis. Multivariate analysis stratified by study were performed between SUVmax and the different components of FLIPI2 and between SUVmax and baseline TMTV. Results: Median age was 55 years; 92% of patients had stage III/IV disease; 37% had FLIPI 3-5; 31% had FLIPI2 3-5. With a median follow up of 64 months, 5y-PFS was 55% and 5y-OS 92%. Only two patients had disease transformation. Median SUVmax was 10 (Q1-Q3:7-14). There was no correlation between the SUVmax and histological grade. The optimal SUVmax cut-off was 9.4. Surprisingly the 47% of patients with a SUVmax ≤9.4 had markedly inferior PFS. 5y PFS was 47.4% vs. 62.4% (HR= 1.62, p=0.032). On multivariate analysis between SUVmax, age, Longest diameter of Largest involved lymph node LodLin> 6cm, positive Bone marrow biopsy and β2 microglobulin, only SUVmax (HR=1.81, p=0.04) and β2 microglobulin (HR=2.48, p=0.006) were independent predictors of PFS (Table1). When SUVmax and β2 microglobulin were combined they identified three risk groups: low SUVmax and high β2 microglobulin with 5y-PFS 32% (HR=3.95, p=0.0005), low SUVmax or high β2 microglobulin with 5y-PFS 54% (HR=2.29, p=0.018) and high SUVmax and low β2 microglobulin with 5y-PFS 73 % (Fig1). In multivariate analysis TMTV>510cm3 remains the only significant predictor against SUVmax≤9.4. There was no difference in the SUVmax values in high or low TMTV groups and similar % of high and low TMTV in low and high SUVmax groups. Furthermore, the 17% of patients with SUVmax≤9.4 and TMTV>510cm3 had a 22% 5y PFS vs 67.4% for the 40% of patients with SUVmax>9.4 and TMTV≤510cm3 (HR=3.96, p Conclusions: SUVmax and β2 microglobulin are readily available parameters at staging. A low SUVmax observed on a baseline PET or an elevated β2 microglobulin is predictive of progression in patients with high tumor burden follicular lymphoma having received R-chemotherapy. The risk of progressive disease increases when patients have both these risk factors, and such patients deserve special consideration in treatment planning and follow-up. Figure 1. Figure 1. Disclosures Dupuis: janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Luminari:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.

International audience; Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.

Background Macrophages play crucial roles in HIV/AIDS pathogenesis as they are important targets for HIV-1 replication and contribute to viral spread and viral reservoir formation. We have previously reported that p21 inhibits HIV-1, HIV-2 and SIV replication in macrophages by a major block at the level of reverse transcription [1]. This study aimed at understanding the molecular mechanisms involved in p21-mediated restriction.

Background In Sub-Saharan Africa, infectious diarrhea is a major cause of morbidity and mortality. A case-control study was conducted to identify the etiology of diarrhea and to describe its main epidemiologic risk factors among hospitalized children under five years old in Bangui, Central African Republic. Methods All consecutive children under five years old hospitalized for diarrhea in the Pediatric Complex of Bangui for whom a parent’s written consent was provided were included. Controls matched by age, sex and neighborhood of residence of each case were included. For both cases and controls, demographic, socio-economic and anthropometric data were recorded. Stool samples were collected to identify enteropathogens at enrollment. Clinical examination data and blood samples were collected only for cases. Results A total of 333 cases and 333 controls was recruited between December 2011 and November 2013. The mean age of cases was 12.9 months, and 56% were male. The mean delay between the onset of first symptoms and hospital admission was 3.7 days. Blood was detected in 5% of stool samples from cases. Cases were significantly more severely or moderately malnourished than controls. One of the sought-for pathogens was identified in 78% and 40% of cases and controls, respectively. Most attributable cases of hospitalized diarrhea were due to rotavirus, with an attributable fraction of 39%. Four other pathogens were associated with hospitalized diarrhea: Shigella/EIEC, Cryptosporidium parvum/hominis, astrovirus and norovirus with attributable fraction of 9%, 10%, 7% and 7% respectively. Giardia intestinalis was found in more controls than cases, with a protective fraction of 6%. Conclusions Rotavirus, norovirus, astrovirus, Shigella/EIEC, Cryptosporidium parvum/hominis were found to be positively associated with severe diarrhea: while Giardia intestinalis was found negatively associated. Most attributable episodes of severe diarrhea were associated with rotavirus, highlighting the urgent need to introduce the rotavirus vaccine within the CAR’s Expanded Program on Immunization. The development of new medicines, vaccines and rapid diagnostic tests that can be conducted at the bedside should be high priority for low-resource countries., Author Summary Infectious diarrhea is a major cause of illness and death among children under five years from low-income country. In order to identify infectious agents associated with diarrhea, we conducted a case-control study in the Pediatric Complex of Bangui, the sole public pediatric hospital from Central African Republic (CAR). A total of 333 hospitalized children with diarrhea and 333 controls were included, controls being pair matched to the cases according to age, sex and neighborhood. At least one of the sought-for pathogens was identified in 80% of hospitalized children, and approximately one in ten cases presented mixed bacterial/viral co-infections. Five pathogens were positively associated with hospitalized diarrhea, namely rotavirus, norovirus, astrovirus, Shigella/EIEC and Cryptosporidium hominis/parvum. Giardia intestinalis was negatively associated with hospitalized diarrhea. A seasonality effect—viruses during the dry season, bacteria and parasites during the rainy season—but also an age effect, were observed, which may guide clinicians in the management of diarrhea. As rotavirus was the leading cause of severe diarrhea, the introduction of the rotavirus vaccine in CAR will certainly provide considerable direct health benefits in terms of reduced illness and deaths. New medicines, vaccines and rapid diagnostic tests that can be conducted bedside should be urgently developed for low-resource countries.

International audience; Limited data exist on Candida endocarditis (CE) outcome in the era of new antifungals. As early diagnosis of CE remains difficult, non-culture-based tools need to be evaluated. Through the French prospective MYCENDO study (2005-2007), the overall characteristics and risk factors for death from CE were analysed. The contribution of antigen detection (mannan/anti-mannan antibodies and (1,3)-β-d-glucans) and molecular tools was evaluated. Among 30 CE cases, 19 were caused by non-albicans species. Sixteen patients (53%) had a predisposing cardiac disease, which was a valvular prosthesis in ten (33%). Nine patients (30%) were intravenous drug users; none of them had right-sided CE. Among the 21 patients who were not intravenous drug users, 18 (86%) had healthcare-associated CE. Initial therapy consisted of a combination of antifungals in 12 of 30 patients (40%). Thirteen patients (43%) underwent valve replacement. The median follow-up was 1 year after discharge from hospital (range, 5 months to 4 years) and hospital mortality was 37%. On univariate analysis, patients aged ≥60 years had a higher mortality risk (OR 11, 95% CI 1.2-103.9; p 0.024), whereas intravenous drug use was associated with a lower risk of death (OR 0.12, 95% CI 0.02-0.7; p 0.03). Among 18 patients screened for both serum mannan/anti-mannan antibodies and (1,3)-β-d-glucans, all had a positive result with at least one of either test at CE diagnosis. Real-time PCR was performed on blood (SeptiFast) in 12 of 18, and this confirmed the blood culture results. In conclusion, CE prognosis remains poor, with a better outcome among younger patients and intravenous drug users. Detection of serum antigens and molecular tools may contribute to earlier CE diagnosis.

International audience; HBV vaccine was introduced into the Expanded Programme on Immunization (EPI) in Senegal and Cameroon in 2005. We conducted a cross-sectional study in both countries to assess the HBV immune protection among children. All consecutive children under 4 years old, hospitalized for any reason between May 2009 and May 2010, with an immunisation card and a complete HBV vaccination, were tested for anti-HBs and anti-HBc. A total of 242 anti-HBc-negative children (128 in Cameroon and 114 in Senegal) were considered in the analysis. The prevalence of children with anti-HBs ≥ 10 IU/L was higher in Cameroon with 92% (95% CI: 87%-97%) compared to Senegal with 58% (95% CI: 49%-67%), (p

International audience; BACKGROUND: Anopheles gambiae is a major vector of malaria and lymphatic filariasis. The arthropod-host interactions occurring at the skin interface are complex and dynamic. We used a global approach to describe the interaction between the mosquito (infected or uninfected) and the skin of mammals during blood feeding. METHODS: Intravital video microscopy was used to characterize several features during blood feeding. The deposition and movement of Plasmodium berghei sporozoites in the dermis were also observed. We also used histological techniques to analyze the impact of infected and uninfected feedings on the skin cell response in naive mice. RESULTS: The mouthparts were highly mobile within the skin during the probing phase. Probing time increased with mosquito age, with possible effects on pathogen transmission. Repletion was achieved by capillary feeding. The presence of sporozoites in the salivary glands modified the behavior of the mosquitoes, with infected females tending to probe more than uninfected females (86% versus 44%). A white area around the tip of the proboscis was observed when the mosquitoes fed on blood from the vessels of mice immunized with saliva. Mosquito feedings elicited an acute inflammatory response in naive mice that peaked three hours after the bite. Polynuclear and mast cells were associated with saliva deposits. We describe the first visualization of saliva in the skin by immunohistochemistry (IHC) with antibodies directed against saliva. Both saliva deposits and sporozoites were detected in the skin for up to 18 h after the bite. CONCLUSION: This study, in which we visualized the probing and engorgement phases of Anopheles gambiae blood meals, provides precise information about the behavior of the insect as a function of its infection status and the presence or absence of anti-saliva antibodies. It also provides insight into the possible consequences of the inflammatory reaction for blood feeding and pathogen transmission.

Introduction The prognosis for patients with high tumor burden follicular lymphoma (FL) continues to improve in the modern immunochemotherapy era. However there is still a subgroup of 20% of patients who progress within 2 years of first line R-CHOP, (rituximab, doxorubicin, vincristine, prednisone) and experience a poor outcome (Casulo JCO 2015). To date, early identification of these high risk patients has been unsatisfactory. FDG-PET-CT (PET) is now the recommended imaging technique for staging and response assessment in FL and central scan review in a pooled analysis from three prospective studies has shown that post induction PET identifies a population with a high risk of death (Trotman, Lancet Haematol 2014). From this new pooled analysis we aimed to determine the prognostic impact of the total metabolic tumour volume (TMTV) measured on baseline PET and its added value to existing clinical prognostic indexes. Material and Methods 161 FL patients who had measurable quantitative data on baseline PET were selected from PET-FL, n=84 (Dupuis, JCO 2012), PRIMA, n=36 (Trotman, JCO 2011) and FOLL05 studies, n=41 (Luminari, Ann Oncol 2014). All met criteria for treatment of symptomatic high tumour burden or advanced stage disease. They received R-CHOP (80%), R-CVP (17%) or R-FM (4%) induction therapy with 24% receiving Rituximab maintenance. TMTV was computed on baseline PET by summing the metabolic volumes of all nodal and extranodal lesions using the established 41% SUVmax thresholding method (Meignan, Eur J Nucl Med Mol Imaging 2013). Optimal cut-points for binary outcomes were determined using X-tile® and ROC analysis. Prognostic value was assessed using univariate analysis and Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) and compared to other prognostic factors. Results 156 patients with available survival data were analyzed. Median age was 56 years; 92% were stage III/IV; 38% had FLIPI 3-5; and 29% had FLIPI2 3-5. Median SUVmax was 10 (Q1-Q3: 7-14). Median TMTV was 260 cm3 (Q1-Q3: 131-513 cm3). With a median follow-up of 64 months, 5-yr PFS and OS were 56% and 92% respectively in the whole population. Using a cut-off of 510 cm3, 39 patients (25%) had a high TMTV (>510cm3). Patients with high TMTV (>510cm3) had a significantly shorter PFS (Figure 1) and OS (Figure 2) than those with low TMTV (≤510cm3), (5-yrs PFS was 37% vs 62% p=.0007, HR=2.3 and 5-yr OS 83% vs 95% p=.0045, HR=4.1). Median PFS was not reached for patients with low TMTV vs. 34.8 months for patients with high TMTV. Beta2 microglobulin (Β2Μ) >ULN and FLIPI2 3-5 were also predicted factor of poor PFS, whereas FLIPI and LDH were not. When combined, FLIPI2 and TMTV had a significant impact on PFS and OS . The 5-yr PFS was 67%, 45% and 27% respectively for patients with: low TMTV and FLIPI2 0-2, high TMTV or FLIPI2 3-5, and high TMTV and FLIPI2 3-5. Incorporating TMTV >510cm3 into the FLIPI2 instead of the longest diameter of the largest lymph node >6cm improved results for PFS and OS. Patients with 3-5 factors with this revised index had a significantly worse outcome than patients with 0-2 factors (5yr PFS 38% vs 66%, p=0.001, HR=2.62, 5yr OS 84% vs 97%, HR=4.98, p=0.013). Conclusions In this pooled analysis from three prospective studies baselineTMTV is a strong predictor of outcome in high tumor burden FL. It adds value to existing pre-treatment prognostic indices in identifying a population for whom FL can no longer be characterized as indolent. The prognostic value of TMTV in stratifying patient outcomes needs to be validated in other populations treated with both R-CHOP +/- maintenance and R-Bendamustine. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Dupuis: ABBVIE: Membership on an entity's Board of Directors or advisory committees; ROCHE: Speakers Bureau. Haioun:Roche: Honoraria. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

Background and aimsDespite the high prevalence of chronic hepatitis B (CHB) in Africa, few studies have been performed among African patients. We sought to evaluate liver stiffness measurement by FibroScan® (LSM) and two biochemical scores (FibroTest®, Fibrometer®) to diagnose liver fibrosis in Senegalese CHB patients with HBV plasma DNA load ≥3.2 log(10) IU/mL and normal alanine aminotransferase (ALT) values.MethodsLSM and liver fibrosis biochemical markers were performed on 225 consecutive HBV infected Senegalese patients with high viral load. Patients with an LSM range between 7 and 13 kPa underwent liver biopsy (LB). Two experienced liver pathologists performed histological grading using Metavir and Ishak scoring.Results225 patients were evaluated (84% male) and LB was performed in 69 patients, showing F2 and F3 fibrosis in 17% and 10% respectively. In these patients with a 7-13 kPa range of LSM, accuracy for diagnosis of significant fibrosis according to LB was unsatisfactory for all non-invasive markers with AUROCs below 0.70. For patients with LSM values below 7 kPa, FibroTest® (FT), and Fibrometer® (FM) using the cut-offs recommended by the test promoters suggested a fibrosis in 18% of cases for FT (8% severe fibrosis) and 8% for FM. For patients with LSM values greater than 13 kPa, FT, FM suggested a possible fibrosis in 73% and 70%, respectively.ConclusionIn highly replicative HBV-infected African patients with normal ALT and LSM value below 13 kPa, FibroScan®, FibroTest® or Fibrometer® were unsuitable to predict the histological liver status of fibrosis.

A prospective study was carried out in two tertiary hospitals in Dakar to determine the main causes of sputum acid-fast bacillus (AFB) smear-negative pneumonia in HIV-infected patients. All clinical and microbiological records were reviewed by experts. Seventy patients were finally enrolled. Most of them were hospitalized at an advanced stage of AIDS. The median CD4 cell count was 62/mm(3) and the median body mass index (BMC) was 18 kg/m(2). Thirty-one patients (44 %) were known as seropositive for HIV infection prior to admission. Radiological opacities were localized in 70 % of patients and diffuse in 21 %. Fiberoptic bronchoscopy was performed in 50 patients (71 %). A definite or probable diagnosis was obtained in 55 patients (79 %). Bacterial pneumonia (usually due to Enterobacteriaceae and Pseudomonas aeruginosa), tuberculosis, Pneumocystis pneumoniae and other causes (Kaposi's sarcoma, atypical mycobacteria) were diagnosed in 67 %, 24 %, 5 %, and 13 % of these patients respectively. In conclusion, pneumonia of bacterial origin and tuberculosis can be incriminated in the majority of cases of AFB negative pneumonia observed in HIV patients in Dakar.

International audience; BACKGROUND: Leptospirosis has long been a major public health concern in the southwestern Indian Ocean. However, in Madagascar, only a few, old studies have provided indirect serological evidence of the disease in humans or animals. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a large animal study focusing on small-mammal populations. Five field trapping surveys were carried out at five sites, from April 2008 to August 2009. Captures consisted of Rattus norvegicus (35.8%), R. rattus (35.1%), Mus musculus (20.5%) and Suncus murinus (8.6%). We used microbiological culture, serodiagnosis tests (MAT) and real-time PCR to assess Leptospira infection. Leptospira carriage was detected by PCR in 91 (33.9%) of the 268 small mammals, by MAT in 17 of the 151 (11.3%) animals for which serum samples were available and by culture in 9 of the 268 animals (3.3%). Rates of infection based on positive PCR results were significantly higher in Moramanga (54%), Toliara (48%) and Mahajanga (47.4%) than in Antsiranana (8.5%) and Toamasina (14%) (p = 0.001). The prevalence of Leptospira carriage was significantly higher in R. norvegicus (48.9%), S. murinus (43.5%) and R. rattus (30.8%) than in M. musculus (9.1%) (p

OBJECTIVES We conducted a comparison of the Abbott Molecular RealTime (Rungis, France) and Roche Diagnostics Cobas Taqman (Meylan, France) automated nucleic acid extraction and real-time polymerase chain reaction (PCR) amplification systems for their capacity to quantify HIV RNA of various subtypes. The systems were tested on culture supernatants belonging to HIV-1 group M (n = 29), HIV-1 group O (n = 8), and HIV-2 (n = 7). We also tested 88 plasma samples from patients infected with HIV-1 group M (B-D [n = 7], A-CRF01 [n = 16], CRF02 [n = 49], and other strains [n = 16]). RESULTS The Abbott RealTime system quantified all 29 HIV-1 group M supernatants. One of these samples was not detected by the Roche Cobas TaqMan system. The Abbott RealTime system quantified 7 HIV-1 group O strains. Neither technique cross-reacted with HIV-2. The 79% intraclass correlation coefficient for the 88 plasma samples was barely acceptable, but 4 plasma samples were underestimated by more than 1 log by the Roche Cobas TaqMan system. Similar values were obtained for subtype B and D strains with the tests, indicating that the primers and probes are suitable for these strains. In contrast, the large differences observed with other subtypes, particularly CRF02, show the importance of primer and probe selection. CONCLUSION The limitation of real-time PCR to span the entire diversity of HIV must be taken into account during treatment monitoring, resistance studies, and clinical trials.

Background Environmentally driven immune activation was suggested to contribute to high rates of HIV-1 infection in Africa. We report here a study of immune activation markers and susceptibility to HIV-1 infection in vitro of forty-five highly exposed uninfected partners (EUs) of HIV-1 infected individuals in Central African Republic, in comparison with forty-four low-risk blood donors (UCs). Results Analysis of T lymphocyte subsets and activation markers in whole blood showed that the absolute values and the percentage of HLA-DR+CD4 T cells and of CCR5+CD4 T cells were lower in the EUs than in the UCs (p = 0.0001). Mutations in the CCR5 coding region were not found in either group. Susceptibility to in vitro infection of unstimulated peripheral blood mononuclear cells, prior of PHA activation, was decreased in EUs compared to UCs, either using a CXCR4-tropic or a CCR5-tropic HIV-1 strain (p = 0.02 and p = 0.05, respectively). Levels of MIP-1β, but not of MIP-1α or RANTES, in the supernatants of PHA-activated PBMC, were higher in the EUs than in the UCs (p = 0.007). Conclusion We found low levels of CD4 T cell activation and reduced PBMC susceptibility to HIV-1 infection in Central African EUs, indicating that both may contribute to the resistance to HIV-1 infection.