Long-term excess mortality and net survival among elderly diffuse large B-cell lymphoma patients after front-line R-CHOP treatment.

In the era of immunochemotherapy, data on the long-term prognosis of elderly patients diagnosed with a diffuse large B-cell lymphoma (DLBCL) are scarce. In this population and on the longer term, other-cause mortality is an important competing risk that needs to be accounted for. Using clinical trial data and relative survival approaches, we estimated the 10-year net survival (NS) and we described the excess mortality hazard (EMH) due (directly or indirectly) to the DLBCL, over time and according to main prognosis factors using flexible regression modelling. The 10-year NS was 65% [59; 71]. Using the flexible modelling, we showed that the EMH decreases steeply after diagnosis. The variables 'performance status', 'number of extra-nodal sites' and the serum 'lactate dehydrogenase' were strongly associated with the EMH, even after adjustment on other important variables. EMH is very close to zero at 10 years for the whole population, so DLBCL patients do not experience an increased mortality compared to the general population in the long term. The number of extra-nodal sites was an important prognostic factor shortly after diagnosis, suggesting that it is correlated with an important but unmeasured prognostic factor that would lead to this selection effect over time.

Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA.

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.

Positron emission tomography-imaging assessment for guiding strategy in patients with relapsed/refractory large B-cell lymphoma receiving CAR T cells.

The aim of this study was to evaluate the prognostic impact of the F-fluorodeoxyglucose positron emission tomography response at 1 month (M1) and 3 months (M3) after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in a multicenter cohort of 160 patients with relapsed/refractory large B-cell lymphomas (R/R LBCL). In total, 119 (75%) patients reached M1 evaluation; 64 (53%, 64/119) had a complete response (CR); 91% were Deauville Score (DS) 1-3. Progressionfree survival (PFS) and overall survival (OS) were significantly worse in patients with DS-5 at M1, than in patients with DS 1-3 (PFS hazard ratio [HR]=6.37, 95% confidence interval [CI]: 3.5-11.5 vs. OS HR=3.79, 95% CI: 1.7-8.5) and DS-4 (PFS HR=11.99, 95% CI: 5.0-28.9 vs. OS HR=12.49, 95% CI: 2.8-55.8). The 1-year PFS rates were 78.9% (95% CI: 58.9-89.9) for DS-4 at M1, similar to 67.3% (95% CI: 51.8-78.8) for patients with DS 1-3 at M1, very different to 8.6% (95% CI: 1.8-22.4) for DS-5, respectively. Only eight of 30 (26%) patients with DS-4 progressed. Response at M3 evaluated in 90 (57%) patients was prognostic for PFS with lower discrimination (HR=3.28, 95% CI: 1.5-7.0; P=0.003) but did not predict OS (HR=0.61, 95% CI: 0.2-2.3; P=0.45). Patients with a high baseline total metabolic tumor volume (TMTV) >80 mL had worse PFS (HR=2.05, 95% CI: 1.2-3.5; P=0.009) and OS (HR=4.52, 95% CI: 2.5-8.1; P<0.001) than patients with low TMTV. Multivariable analyses identified baseline elevated lactate dehydrogenase, DS-5, CAR T cells at M1 for PFS and baseline elevated lactate dehydrogenase, TMTV >80 mL, and DS-5 at M1 for OS. In conclusion, baseline TMTV and response at M1 strongly predicts outcomes of patients with R/R LBCL undergoing CAR T-cell therapy.

High total metabolic tumor volume at baseline predicts survival independent of response to therapy.

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.

A French multicentric prospective prognostic cohort with epidemiological, clinical, biological and treatment information to improve knowledge on lymphoma patients: study protocol of the "REal world dAta in LYmphoma and survival in adults" (REALYSA) cohort.

BACKGROUND: Age-adjusted lymphoma incidence rates continue to rise in France since the early 80's, although rates have slowed since 2010 and vary across subtypes. Recent improvements in patient survival in major lymphoma subtypes at population level raise new questions about patient outcomes (i.e. quality of life, long-term sequelae). Epidemiological studies have investigated factors related to lymphoma risk, but few have addressed the extent to which socioeconomic status, social institutional context (i.e. healthcare system), social relationships, environmental context (exposures), individual behaviours (lifestyle) or genetic determinants influence lymphoma outcomes, especially in the general population. Moreover, the knowledge of the disease behaviour mainly obtained from clinical trials data is partly biased because of patient selection. METHODS: The REALYSA ("REal world dAta in LYmphoma and Survival in Adults") study is a real-life multicentric cohort set up in French areas covered by population-based cancer registries to study the prognostic value of epidemiological, clinical and biological factors with a prospective 9-year follow-up. We aim to include 6000 patients over 4 to 5 years. Adult patients without lymphoma history and newly diagnosed with one of the following 7 lymphoma subtypes (diffuse large B-cell, follicular, marginal zone, mantle cell, Burkitt, Hodgkin, mature T-cell) are invited to participate during a medical consultation with their hematologist. Exclusion criteria are: having already received anti-lymphoma treatment (except pre-phase) and having a documented HIV infection. Patients are treated according to the standard practice in their center. Clinical data, including treatment received, are extracted from patients' medical records. Patients' risk factors exposures and other epidemiological data are obtained at baseline by filling out a questionnaire during an interview led by a clinical research assistant. Biological samples are collected at baseline and during treatment. A virtual tumor biobank is constituted for baseline tumor samples. Follow-up data, both clinical and epidemiological, are collected every 6 months in the first 3 years and every year thereafter. DISCUSSION: This cohort constitutes an innovative platform for clinical, biological, epidemiological and socio-economic research projects and provides an opportunity to improve knowledge on factors associated to outcome of lymphoma patients in real life. TRIAL REGISTRATION: 2018-A01332-53, ClinicalTrials.gov identifier: NCT03869619 .

Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study.

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.

Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial.

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 cm3) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d'Etude des Lymphomes de l'Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+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.

Drawing optical fibers from three-dimensional printers.

The temperature distribution within extrusion nozzles of three low-cost desktop 3D printers is characterized using fiber Bragg gratings (FBGs) to assess their compatibility as micro-furnaces for optical fiber and taper production. These profiles show remarkably consistent distributions suitable for direct drawing of optical fiber. As proof of principle, coreless optical fibers (φ=30 µm) made from fluorinated acrylonitrile butadiene styrene (ABS) and polyethylene terephthalate glycol (PETG) are drawn. Cutback measurements demonstrate propagation losses as low as α=0.26 dB/cm, which are comparable with standard optical fiber losses with some room for improvement. This work points toward direct optical fiber manufacture of any material from 3D printers.

Step-index optical fiber drawn from 3D printed preforms.

Optical fiber is drawn from a dual-head 3D printer fabricated preform made of two optically transparent plastics with a high-index core (NA∼0.25, V>60). The asymmetry observed in the fiber arises from asymmetry in the 3D printing process. The highly multimode optical fiber has losses measured by cut-back as low as α∼0.44 dB/cm in the near IR.

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway.

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.

HBV immunization and vaccine coverage among hospitalized children in Cameroon, Central African Republic and Senegal: a cross-sectional study.

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 < 0,001). The immunization rate based on maternal recall was 91 %, 17 % and 88 % in Cameroon, CAR and Senegal, respectively (p < 0,001). According to serology (anti-HBs titer ≥ 10 mUI/mL and anti-HBc-), the coverage rate was 68 %, 13 % and 46 % in Cameroon, CAR and Senegal, respectively (p < 0,001). In Senegal and Cameroon, factors associated with having been vaccinated were: mother's higher education (OR = 2.2; 95 % CI [1.5-3.2]), no malnutrition (OR = 1.6; 95 % CI [1.1-2.2]), access to flushing toilets (OR = 1.6; 95 % CI [1.1-2.3]), and < 24 months old (OR = 2.1; 95 % CI [1.3-3.4] between 12 and 23 months and OR = 2.7; 95 % CI [1.6-4.4] < 12 months). The prevalence of HBV-infected children (HBsAg+) were 0.7 %, 5.1 %, and 0.2 % in Cameroon, CAR and Senegal, respectively (p < 0.001). CONCLUSIONS: Assessing immunization coverage based on immunization cards, maternal recall or administrative data could be usefully reinforced by epidemiological data combined with immunological profiles. Serology-based studies should be implemented regularly in African countries, as recommended by the WHO. Malnutrition, lack of maternal education and poverty are factors associated with vaccine non-compliance. The countries' vaccination programs should actively address these problems.

Short-term spontaneous fluctuations of HBV DNA levels in a Senegalese population with chronic hepatitis B.

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 <1.1 to 7 log10 IU/mL and 55 (63%) had HBV DNA fluctuations≥0.5 log10 IU/mL between two visits. Patients in whom HBV DNA fluctuated ≥0.5 log10 IU/mL between M0 and M2 also had significant fluctuations between M2 and M4, while patients with stable HBV DNA between M0 and M2 showed a stable viral load between M2 and M4. The only factor found to be associated with HBV DNA fluctuations≥0.5 log10 IU/mL was a low BMI (<21 kg/ m2). HBsAg levels were not correlated with HBV DNA levels. CONCLUSION: Sixty-three percent of the enrolled Senegalese population showed a large, short-term fluctuation of HBV DNA levels. Such fluctuations may have an impact on therapeutic management, requiring closer monitoring.

Case presentation and management of Lyme disease patients: a 9-year retrospective analysis in France.

Introduction: Lyme borreliosis (LB) is the most common vector disease in temperate countries of the northern hemisphere. It is caused by Borrelia burgdorferi sensu lato complex. Methods: To study the case presentation of LB in France, we contacted about 700 physicians every year between 2003 and 2011. An anonymous questionnaire was established allowing the collection of 3,509 cases. The information collected was imported or directly entered into databases and allowed identifying variables that were validated in a multiple correspondence analysis (MCA). Results: Sixty percent of the cases were confirmed, 10% were probable, 13.5% doubtful, 10.2% asymptomatic seropositive and 6.3% were negative. The clinical manifestations reported were cutaneous (63%), neurological (26%), articular (7%), ocular (1.9%) and cardiac (1.3%). Almost all patients were treated. When focusing more particularly on confirmed cases, our studies confirm that children have a distinct clinical presentation from adults. There is a gender effect on clinical presentation, with females presenting more often with erythema migrans or acrodermatitis chronica atrophicans than males, while males present more often with neurological signs or arthritis than females. Discussion: This is the first time that a comprehensive study of suspected Lyme borreliosis cases has been conducted over several years in France. Although we were not able to follow the clinical course of patients after treatment, these results suggest the interest of refining the questionnaire and of following up a cohort of patients over a sufficiently long period to obtain more information on their fate according to different parameters.

Central nervous system relapse in younger patients with diffuse large B-cell lymphoma: a LYSA and GLA/DSHNHL analysis.

Most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients with progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in frontline therapy has not been systematically investigated in this context. To this end, we analyzed a large cohort of 2203 younger patients with DLBCL treated on 10 German (German Lymphoma Alliance [GLA]/The German High Grade Non-Hodgkin's Lymphoma Study Group [DSHNHL]) and French (The Lymphoma Study Association [LYSA]) prospective phase 2 and 3 trials after first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, and prednisone) followed by consolidation including multiple drugs crossing the blood-brain barrier (BBB). Patients with DLBCL with an age-adjusted International Prognostic Index (aaIPI) of 0 to 1 showed very low cumulative incidence rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year cumulative incidences 0%-1%). Younger high-risk patients with aaIPI of 2 to 3 had 3-year cumulative incidence rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (hazard ratio 2.4; 95% confidence interval: 0.8-7.4; P = .118). Thus, for younger high-risk patients, frontline regimens incorporating agents crossing the BBB may reduce often fatal CNS relapse.

Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA group.

Patients with relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) have a poor prognosis. Bendamustine (B) and brentuximab-vedotin (Bv) have shown interesting results in this setting. However, little information is available about their efficacy in combination. This multicenter and retrospective study aimed to evaluate the efficacy and safety of the combination of BBv in patients with noncutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was the overall response rate. A total of 82 patients with R/R PTCL were included. The best overall response rate (ORR) was 68%, with 49% of patients in complete response (CR). In multivariable analysis, only the disease status after the last regimen (relapse vs refractory) was associated with the response with an ORR of 83% vs 57%. Median duration of response was 15.4 months for patients in CR. With a median follow-up of 22 months, the median progression free survival (PFS) and overall survival (OS) were 8.3 and 26.3 months respectively. Moreover, patients in CR, who underwent an allogeneic transplant, had a better outcome than patients who did not with a median PFS and OS of 19.3 vs 4.8 months and not reached vs 12.4 months, respectively. Fifty-nine percent of patients experienced grade 3/4 adverse events that were mainly hematologic. BBv is highly active in patients with R/R PTCL and should be considered as a one of the best options of immunochemotherapy salvage combination in this setting and particularly as a bridge to allogeneic transplant for eligible patients.

A tumor volume and performance status model to predict outcome before treatment in diffuse large B-cell lymphoma.

Aggressive large B-cell lymphoma (LBCL) has variable outcomes. Current prognostic tools use factors for risk stratification that inadequately identify patients at high risk of refractory disease or relapse before initial treatment. A model associating 2 risk factors, total metabolic tumor volume (TMTV) >220 cm3 (determined by fluorine-18 fluorodeoxyglucose positron emission tomography coupled with computed tomography) and performance status (PS) ≥2, identified as prognostic in 301 older patients in the REMARC trial (#NCT01122472), was validated in 2174 patients of all ages treated in 2 clinical trials, PETAL (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas; N = 510) and GOYA (N = 1315), and in real-world clinics (N = 349) across Europe and the United States. Three risk categories, low (no factors), intermediate (1 risk factor), and high (2 risk factors), significantly discriminated outcome in most of the series. Patients with 2 risk factors had worse outcomes than patients with no risk factors in the PETAL, GOYA, and real-world series. Patients with intermediate risk also had significantly worse outcomes than patients with no risk factors. The TMTV/Eastern Cooperative Oncology Group-PS combination outperformed the International Prognostic Index with a positive C-index for progression-free survival and overall survival in most series. The combination of high TMTV > 220 cm3 and ECOG-PS ≥ 2 is a simple clinical model to identify aggressive LBCL risk categories before treatment. This combination addresses the unmet need to better predict before treatment initiation for aggressive LBCL the patients likely to benefit the most or not at all from therapy.

New Approaches in Characterization of Lesions Dissemination in DLBCL Patients on Baseline PET/CT.

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 < 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.

Baseline Total Metabolic Tumor Volume Measured with Fixed or Different Adaptive Thresholding Methods Equally Predicts Outcome in Peripheral T Cell Lymphoma.

The purpose of this study was to compare in a large series of peripheral T cell lymphoma, as a model of diffuse disease, the prognostic value of baseline total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT with adaptive thresholding methods with TMTV measured with a fixed 41% SUVmax threshold method. METHODS: One hundred six patients with peripheral T cell lymphoma, staged with PET/CT, were enrolled from 5 Lymphoma Study Association centers. In this series, TMTV computed with the 41% SUVmax threshold is a strong predictor of outcome. On a dedicated workstation, we measured the TMTV with 4 adaptive thresholding methods based on characteristic image parameters: Daisne (Da) modified, based on signal-to-background ratio; Nestle (Ns), based on tumor and background intensities; Fit, including a 3-dimensional geometric model based on spatial resolution (Fit); and Black (Bl), based on mean SUVmax The TMTV values obtained with each adaptive method were compared with those obtained with the 41% SUVmax method. Their respective prognostic impacts on outcome prediction were compared using receiver-operating-characteristic (ROC) curve analysis and Kaplan-Meier survival curves. RESULTS: The median value of TMTV41%, TMTVDa, TMTVNs, TMTVFit, and TMTVBl were, respectively, 231 cm3 (range, 5-3,824), 175 cm3 (range, 8-3,510), 198 cm3 (range, 3-3,934), 175 cm3 (range, 8-3,512), and 333 cm3 (range, 3-5,113). The intraclass correlation coefficients were excellent, from 0.972 to 0.988, for TMTVDa, TMTVFit, and TMTVNs, and less good for TMTVBl (0.856). The mean differences obtained from the Bland-Altman plots were 48.5, 47.2, 19.5, and -253.3 cm3, respectively. Except for Black, there was no significant difference within the methods between the ROC curves (P > 0.4) for progression-free survival and overall survival. Survival curves with the ROC optimal cutoff for each method separated the same groups of low-risk (volume ≤ cutoff) from high-risk patients (volume > cutoff), with similar 2-y progression-free survival (range, 66%-72% vs. 26%-29%; hazard ratio, 3.7-4.1) and 2-y overall survival (79%-83% vs. 50%-53%; hazard ratio, 3.0-3.5). CONCLUSION: The prognostic value of TMTV remained quite similar whatever the methods, adaptive or 41% SUVmax, supporting its use as a strong prognosticator in lymphoma. However, for implementation of TMTV in clinical trials 1 single method easily applicable in a multicentric PET review must be selected and kept all along the trial.