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Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0–163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (

OBJECTIVES To evaluate the impact of providing personalized depression risk information on self-help and help-seeking behaviors among individuals who are at high risk of having a major depressive episode (MDE). MATERIALS AND METHODS In a mixed methods randomized controlled trial, participants who were at high risk of having a MDE, were recruited from across Canada, and were randomized into intervention (n = 358) and control (n = 354) groups. Participants in the intervention group received their personalized depression risk estimated by sex-specific risk prediction models for MDE. All participants were assessed at baseline, 6 and 12 months. RESULTS Repeated measure mixed effects modeling showed significant between group differences in self-help scores. In the complete case analysis, the between group difference in mean self-help change score was 1.13 at 12 months (effect size = 0.16). Among participants who reported "fair" or "poor health," the between group difference in mean self-help change score was 2.78 at 12 months (effect size = 0.35). The qualitative data revealed three themes and the findings are consistent with the quantitative results. CONCLUSIONS Providing personalized depression risk information has a positive impact on self-help in high-risk individuals, particularly in those with poor health.

Summary Background R-MegaCHOEP was the first phase 3 study comparing high-dose chemotherapy plus rituximab followed by autologous haematopoietic stem-cell transplantation (HSCT) with conventional chemotherapy plus rituximab in first-line therapy for patients aged 60 years or younger with high-risk aggressive B-cell lymphoma. Little is known about the long-term outcomes of these patients. We aimed to evaluate the long-term efficacy and safety of conventional chemotherapy versus high-dose chemotherapy after 10 years of follow-up in the R-MegaCHOEP trial. Methods In this open-label, randomised, phase 3 trial done across 61 centres in Germany, patients aged 18–60 years with newly diagnosed, high-risk (age-adjusted International Prognostic Index [IPI] 2 or 3) aggressive B-cell lymphoma were randomly assigned (1:1, using Pocock minimisation) to eight cycles of conventional chemotherapy (cyclosphosphamide, doxorubicin, vincristine, etoposide, and prednisolone) plus rituximab (R-CHOEP-14) or four cycles of high-dose chemotherapy plus rituximab followed by autologous HSCT (R-MegaCHOEP). The trial was unmasked. Patients were stratified by age-adjusted IPI factors, presence of bulky disease (tumour mass ≥7·5 cm diameter), and treatment centre. The primary endpoint was event-free survival, analysed here 10 years after randomisation. 10-year overall survival, progression-free survival, conditional survival, relapse patterns, secondary malignancies, and molecular characteristics were also analysed. All analyses were done on the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT00129090 . Findings Between March 3, 2003, and April 7, 2009, 275 patients were randomly assigned to R-CHOEP-14 (n=136) or R-MegaCHOEP (n=139). 130 patients in the R-CHOEP-14 group and 132 patients in the R-MegaCHOEP group were included in the intention-to-treat population. After a median follow-up of 9·3 years (IQR 5·1–11·1), 10-year event-free survival was 51% (95% CI 42–61) in the R-MegaCHOEP group and 57% (47–67) in the R-CHOEP-14 group (adjusted hazard ratio [HR] 1·3 [95% CI 0·9–1·8], p=0·23). 10-year progression-free survival was 59% (50–68) in the R-MegaCHOEP group and 60% (51–70) in the R-CHOEP-14 group (adjusted HR 1·1 [0·7–1·7], p=0·64). 10-year overall survival was 66% (57–76) in the R-MegaCHOEP group and 72% (63–81) in the R-CHOEP-14 group (adjusted HR 1·3 [0·8–2·1], p=0·26). Relapse occurred in 30 (16% [95% CI 11–22]) of 190 patients who had complete remission or unconfirmed complete remission; 17 (17%) of 100 patients in the R-CHOEP-14 group and 13 (14%) of 90 patients in the R-MegaCHOEP group. Seven (23%) of 30 patients had low-grade histology at relapse and had better outcomes compared with patients who relapsed with aggressive histologies. Lymphoma affected the CNS in 18 (28%) of 64 patients with treatment failure. 22 secondary malignancies were reported in the intention-to-treat population; in 12 (9%) of 127 patients in the R-CHOEP-14 group and ten (8%) of 126 patients in the R-MegaCHOEP group. Interpretation Event-free survival and overall survival were similar between groups after 10 years of follow-up; outcomes were not improved in the R-MegaCHOEP group by high-dose chemotherapy and autologous HSCT. Patients who relapsed with aggressive histology showed a high incidence of CNS involvement and poor prognosis. For these patients, novel therapies are greatly warranted. Funding Deutsche Krebshilfe (German Cancer Aid).

Purpose The purpose of this study was to estimate associations between distinct measures of depression and incident type 2 diabetes. Methods Our sample consisted of 30,360 community-dwelling adults aged 40 to 69 in Canada. Depression was defined as elevated depressive symptoms using the Patient Health Questionnaire 9, diagnoses of depression in administrative data, or antidepressant use from a medication inventory. Type 2 diabetes was ascertained in administrative data over up to 7 years of follow-up. Cox proportional hazards models were used to estimate associations between different measures of depression and incident diabetes. Results In separate models, elevated depressive symptoms were associated with a 17% increased risk of type 2 diabetes (hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.02–1.34), diagnoses of depression were associated with a 20% increased risk (HR 1.20, 95% CI 0.94–1.52), and antidepressant use was associated with a 19% increased risk (HR 1.19, 95% CI 1.01–1.41). When examining combinations of measures in the same model, depressive symptoms paired with antidepressant use and depressive symptoms paired with diagnoses of depression were associated with the highest risk of type 2 diabetes. Conclusions Various measures of depression and combinations of measures can be used to identify older adults at higher risk of type 2 diabetes in research and public health.

Background: Clinical, functional, and cost-effectiveness outcomes from early intervention services (EIS) for psychosis are significantly associated with the duration of untreated psychosis (DUP) for the patients they serve. However, most EIS patients continue to report long DUP, while a reduction of DUP may improve outcomes. An understanding of different components of DUP and the factors associated with them may assist in targeting interventions toward specific sources of DUP. Objectives: To examine the components of DUP and their respective determinants in order to inform strategies for reducing delay in treatment in the context of an EIS. Methods: Help-seeking (DUP-H), Referral (DUP-R), and Administrative (DUP-A) components of DUP, pathways to care, and patient characteristics were assessed in first episode psychosis ( N = 532) patients entering an EIS that focuses on systemic interventions to promote rapid access. Determinants of each component were identified in the present sample using multivariate analyses. Results: DUP-H (mean 25.64 ± 59.00) was longer than DUP-R (mean = 14.95 ± 45.67) and DUP-A (mean 1.48 ± 2.55). Multivariate analyses showed that DUP-H is modestly influenced by patient characteristics (diagnosis and premorbid adjustment; R 2 = 0.12) and DUP-R by a combination of personal characteristics (age of onset and education) and systemic factors (first health services contact and final source of referral; R 2 = 0.21). Comorbid substance abuse and referral from hospital emergency services have a modest influence on DUP-A ( R 2 = 0.08). Patients with health care contact prior to onset of psychosis had a shorter DUP-H and DUP-R than those whose first contact was after psychosis onset (F(1, 498) = 4.85, P < 0.03 and F(1, 492) = 3.34, P < 0.07). Conclusions: Although much of the variance in DUP is unexplained, especially for help-seeking component, the systemic portion of DUP may be partially determined by relatively malleable factors. Interventions directed at altering pathways to care and promote rapid access may be important targets for reducing DUP. Simplifying administrative procedures may further assist in reducing DUP.

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61–65 years, 66–70 years, 71–75 years, and 76–80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76–80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-020-04345-3.

Indications for autologous (auto-HCT) and allogeneic transplantation (allo-HCT) in relapsed/refractory Hodgkin lymphoma (rrHL) have been long established. The expectation is that long-term outcomes have significantly improved over time with increased experience in these procedures. The objective of this study was to assess whether this is the case and to identify further areas of improvement. A total of 13,639 adult patients receiving an auto-HCT or allo-HCT for rrHL were reported to the European Society for Blood and Marrow Transplantation (EBMT) over a 25-year period. Regarding auto-HCT, recipients are younger, interval between diagnosis and transplant shorter, peripheral blood has become the universal stem cell source and the use of total body irradiation is almost non-existent in recent years. Allo-HCT is currently mostly used as a second transplant; recipients are younger, fitter and less frequently, chemorefractory. Reduced intensity conditioning protocols have vastly replaced myeloablative protocols. Increasing numbers of haplo-HCT have been reported. Both in auto-HCT and allo-HCT, NRM, PFS and OS have significantly improved but relapse remains the main cause of treatment failure. A better selection of patients and improvements in the supportive care has resulted in a reduction in the NRM. Relapse after HCT remains unchanged and further research is needed.

OBJECTIVE: To investigate the association between newly developed type 2 diabetes (T2D) and incident psychopharmacological treatment and psychiatric hospital contact.METHODS: Via Danish registers, we identified all 56,640 individuals from the Central- and Northern Denmark Regions with newly developed T2D (defined by the first HbA1c measurement ≥6.5%) in 2000-2016 as well as 315,694 age and sex matched controls (without T2D). Those having received psychopharmacological treatment or having had a psychiatric hospital contact in the five years prior to the onset of T2D were not included. For this cohort, we first assessed the two-year incidence of psychopharmacological treatment and psychiatric hospital contact. Secondly, via Cox regression, we compared the incidence of psychopharmacological treatment/psychiatric hospital contact among individuals with T2D to propensity score matched controls - taking a wide range of potential confounders into account. Finally, via Cox proportional hazards regression, we assessed which baseline (T2D onset) characteristics were associated with subsequent psychopharmacological treatment and psychiatric hospital contact.RESULTS: A total of 8.3% of the individuals with T2D initiated psychopharmacological treatment compared to 4.6% of the age and sex matched controls. Individuals with T2D were at increased risk of initiating psychopharmacological treatment compared to the propensity score matched controls (HR=1.51, 95% CI=1.43-1.59), whereas their risk of psychiatric hospital contact was not increased to the same extent (HR=1.14, 95% CI=0.98-1.32). Older age, somatic comorbidity, and being divorced/widowed was associated with both psychopharmacological treatment and psychiatric hospital contact following T2D.CONCLUSION: Individuals with T2D are at elevated risk of requiring psychopharmacological treatment.

BackgroundPurported superior outcomes for treatment of psychosis in low- and middle-income (LMICs) compared with high-income (HICs) countries have not been examined in the context of early intervention services (EIS).AimsTo compare 2-year clinical outcomes in first-episode psychosis (FEP) treated in EIS in Chennai (LMIC) and Montreal (HIC) using a similar EIS treatment protocol and to identify factors associated with any outcome differences.MethodPatients with FEP treated in EIS in Chennai (n = 168) and Montreal (n = 165) were compared on change in level of symptoms and rate and duration of positive and negative symptom remission over a 2-year period. Repeated-measures analysis of variance, and logistic and linear regression analyses were conducted.ResultsFour patients died in Chennai compared with none in Montreal. Family support was higher for Chennai patients (F = 14.05, d.f. = 1, P < 0.001, ƞp2 = 0.061) and increased over time at both sites (F = 7.0, d.f. = 1.915, P < 0.001, ƞp2 = 0.03). Negative symptom outcomes were significantly better in Chennai for level of symptoms (time × site interaction F = 7.36, d.f. = 1.49, P = 0.002, ƞp2 = 0.03), duration of remission (mean 16.1 v. 9.78 months, t = −7.35, d.f. = 331, P < 0.001, Cohen's d = 0.80) and the proportion of patients in remission (81.5% v. 60.3%, χ2 = 16.12, d.f. = 1, P < 0.001). The site differences in outcome remained robust after adjusting for inter-site differences in other characteristics. Early remission and family support facilitated better outcome on negative symptoms. No significant differences were observed in positive symptom outcomes.ConclusionsPatients with FEP treated in EIS in LMIC contexts are likely to show better outcome on negative symptoms compared with those in HIC contexts. Early remission and family support may benefit patients across both contexts.

The conditional survival of patients after frontline therapy for diffuse large B-cell lymphoma (DLBCL) approaches that of the general population once patients have survived disease free for 2 years. We sought to determine the conditional survival of patients among patients with relapsed de novo DLBCL successfully undergoing an autologous stem-cell transplant (ASCT) after first relapse. A total of 478 patients with de novo DLBCL, relapsed after 1 treatment from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) and LY.12, were included. Patients were followed prospectively after ASCT for a median of 5.3 and 8.2 years, respectively. Individual patient data were analyzed for event-free survival (EFS) and overall survival. Standardized mortality ratios (SMRs) were estimated using French and Canadian life tables. The EFS estimates declined with each year of follow-up after ASCT and were 50.1% (95% confidence interval [CI]: 43.7% to 56.3%) and 43.4% (95% CI: 36.7% to 49.9%) at 5 years in CORAL and LY.12, respectively. The rate of death stabilized once patients achieved at least 4 years of EFS. Compared with the age- and sex-matched population, the SMR was significantly higher until 5 years after ASCT, when values were no longer statistically significant. Patients undergoing ASCT for relapsed DLBCL continue to have a higher rate of death at least until they have survived event free for 5 years. These observations can help to determine endpoints for future clinical trials in this population and for patient counseling. This trial was registered at www.clinicaltrials.gov as #NCT00078949.

Was ist neu? Molekulare Charakterisierung aggressiver Lymphome Die sogenannte „cell of origin“-Klassifikation von diffusen großzelligen B-Zell-Lymphomen (DLBCL) ist mittlerweile Bestandteil der revidierten WHO-Klassifikation von 2017. Dabei werden ABC- und GCB-DLBCL unterschieden. In der Praxis erfolgt diese Einteilung in der Regel unter Anwendung der Immunhistochemie, wobei meist der sogenannte Hans-Algorithmus eingesetzt wird. Erstlinientherapie von DLBCL-Patienten Die Hinzunahme verschiedener zielgerichteter Therapien konnte den Standard von 6–8 Zyklen R-CHOP-Chemoimmunotherapie bislang nicht verändern. Für junge Patienten bis 60 Jahre mit einem International Prognostic Index (IPI) von 0 kann die Therapie auf 4 Zyklen R-CHOP, gefolgt von 2 Applikationen Rituximab, reduziert werden. Prophylaxe von ZNS-Rezidiven bei DLBCL-Patienten Eine intrathekale Therapie mit chemotherapeutischen Substanzen hat keinen Einfluss auf die Verhinderung von Rezidiven im Bereich des zentralen Nervensystems (ZNS). Die Anwendung des ZNS-IPI zur Identifizierung von Patienten mit hohem Risiko für ein ZNS-Rezidiv erscheint sinnvoll, auch wenn es hierzu keine Daten aus randomisierten Studien gibt. Für Patienten mit einem hohen Risiko können 2 systemische Zyklen mit hochdosiertem Methotrexat zusätzlich zur Erstlinientherapie empfohlen werden. Behandlung von Patienten mit rezidiviertem oder therapierefraktärem DLBCL Patienten mit rezidiviertem und/oder refraktärem DLBCL erhalten eine Salvage-Chemotherapie, gefolgt von autologer oder allogener Stammzelltransplantation. Nach mindestens 2 Vortherapien sind aktuell 2 CAR-T-Zell-Produkte zugelassen. Dadurch erhalten auch ältere Patienten, die ggf. nicht für eine Transplantation infrage kommen, die Chance auf eine kurative Therapieoption. Ausblick Neue Substanzgruppen wie Antikörper-Medikamenten-Konjugate oder bispezifische Antikörper zeigen in Studien von Patienten mit rezidiviertem oder therapierefraktärem DLBCL sehr vielversprechende Ergebnisse. Aktuell laufende klinische Studien prüfen den Einsatz weiterer neuer Substanzen.

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Background Elevated depressive symptoms are associated with an increased risk for diabetes. Depression is a heterogeneous and chronic condition in which symptoms may remit, emerge, lessen, or intensify over time. Purpose The purpose of this study was to determine if trajectories of depressive symptoms measured at five time points over 8 years predicted incident diabetes over an 8-year follow-up in middle-aged and older adults. A secondary aim was to determine if trajectories of depressive symptoms predict incident diabetes, above and beyond depressive symptoms measured at a single time point. Methods Data came from the Health and Retirement Study (n = 9,233). Depressive symptoms were measured biennially from 1998 to 2006. Self-reported incident diabetes was measured during an 8-year follow-up. Results Five trajectories of depressive symptoms were identified (no depressive symptoms, low depressive symptoms, low-moderate depressive symptoms, moderate depressive symptoms, elevated and increasing depressive symptoms). Compared to the no depressive symptoms trajectory group (referent), all other trajectory groups were at higher risk of developing diabetes after adjusting for covariates. In most cases, trajectory group membership was associated with incident diabetes after controlling for depressive symptoms at a single time point. Conclusions Patterns of depressive symptoms over time were associated with incident diabetes. Patterns of depressive symptoms may be more predictive of diabetes incidence than depressive symptoms measured at a single time point.

This cohort study aimed to compare the incidence of type 2 diabetes in adults with depression-related weight gain, depression-related weight loss, depression with no weight change, and no depression. The study sample included 59,315 community-dwelling adults in Ontario, Canada. Depression-related weight change in the past 12 months was measured using the Composite International Diagnostic Interview—Short Form. Participants were followed for up to 20 years using administrative health data. Cox proportional hazards models compared the incidence of type 2 diabetes in adults with depression-related weight change and in adults with no depression. Adults with depression-related weight gain had an increased risk of type 2 diabetes compared to adults no depression (HR 1.70, 95% CI 1.32–2.20), adults with depression-related weight loss (HR 1.62, 95% CI 1.09–2.42), and adults with depression with no weight change (HR 1.39, 95% CI 1.03–1.86). Adults with depression with no weight change also had an increased risk of type 2 diabetes compared to those with no depression (HR 1.23, 95% CI 1.04–1.45). Associations were stronger among women and persisted after adjusting for attained overweight and obesity. Identifying symptoms of weight change in depression may aid in identifying adults at higher risk of type 2 diabetes and in developing tailored prevention strategies.

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2–2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2–2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3–2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL. peerReviewed

To test whether duration of untreated psychosis (DUP) 3 months, recommended by the World Health Organization/International Early Psychosis Association, enhances the effects of an extended early intervention service (EEIS) on symptom remission.We examined data from a randomized controlled trial in which patients who received 2 years of treatment in EIS for psychosis were subsequently randomized to either 3 years of EEIS or 3 years of regular care (RC). Using a DUP cut-off ≤ 12 weeks (approximately 3 months), patients were split into two groups. Length of positive, negative and total symptom remission were the outcomes.Patients (N = 217) were mostly male (68%) with schizophrenia spectrum disorder (65%); 108 (50%) received EEIS (58 had DUP ≤12 weeks; 50 had DUP12 weeks). Interaction between treatment condition (EEIS vs. RC) and DUP cut-off ≤ 12 weeks was only significant in multiple linear regression model examining length of negative symptom remission as the outcome (adjusted β = 36.88 [SE = 15.88], t = 2.32, P = 0.02). EEIS patients with DUP ≤12 weeks achieved 25 more weeks of negative symptom remission than EEIS patients with DUP12 weeks.Having a short DUP may be critical in deriving long-term benefits from EIS for psychosis, including EEIS settings. This work empirically supports policy recommendations of reducing DUP3 months.

Objectives This study describes associations between depressive symptoms and indices of obesity in a community sample of adults with prediabetes. The strengths of these associations were compared to those observed in individuals with normal blood glucose levels. Methods Cross-sectional data came from the baseline assessment of the Emotional Health and Wellbeing Study. Participants were classified as meeting the American Diabetes Association criteria for prediabetes (n=1,152) or normal blood glucose levels (n=1,567). Indices of obesity included body mass index, waist circumference and fat mass index. Results After adjusting for sociodemographic covariates, greater depressive symptoms were associated with greater body mass index, waist circumference and fat mass index. These associations were stronger in participants with prediabetes compared to participants with normal blood glucose levels. The pattern of results observed for body mass index and waist circumference held after controlling for self-reported fruit and vegetable consumption, physical activity and sedentary time, but the strength of the interaction was attenuated for fat mass index. Conclusions Depressive symptoms were more strongly associated with indices of obesity in people with prediabetes than in people with normal blood glucose levels. Depressive symptoms may be a barrier to weight management in people with prediabetes.

Standard first-line therapy for younger patients with peripheral T-cell lymphoma consists of six courses of CHOP or CHOEP consolidated by high-dose therapy and autologous stem cell transplantation (AutoSCT). We hypothesized that consolidative allogeneic transplantation (AlloSCT) could improve outcome. 104 patients with nodal peripheral T-cell lymphoma except ALK+ ALCL, 18 to 60 years of age, all stages and IPI scores except stage 1 and aaIPI 0, were randomized to receive 4 x CHOEP and 1 x DHAP followed by high-dose therapy and AutoSCT or myeloablative conditioning and AlloSCT. The primary endpoint was event-free survival (EFS) at three years. After a median follow-up of 42 months, 3-year EFS of patients undergoing AlloSCT was 43% (95% confidence interval [CI]: 29%; 57%) as compared to 38% (95% CI: 25%; 52%) after AutoSCT. Overall survival at 3 years was 57% (95% CI: 43%; 71%) versus 70% (95% CI: 57%; 82%) after AlloSCT or AutoSCT, without significant differences between treatment arms. None of 21 responding patients proceeding to AlloSCT as opposed to 13 of 36 patients (36%) proceeding to AutoSCT relapsed. Eight of 26 patients (31%) and none of 41 patients died due to transplant-related toxicity after allogeneic and autologous transplantation, respectively. In younger patients with T-cell lymphoma standard chemotherapy consolidated by autologous or allogeneic transplantation results in comparable survival. The strong graft-versus-lymphoma effect after AlloSCT was counterbalanced by transplant-related mortality. CHO(E)P followed by AutoSCT remains the preferred treatment option for transplant-eligible patients. AlloSCT is the treatment of choice for relapsing patients also after AutoSCT.

BackgroundThis study investigated potential psycho‐bio‐behavioral mediators of the association between adverse childhood experiences (ACEs) and the risk of coronary heart disease (CHD) in adulthood.Methods and ResultsParticipants were 5610 British civil servants (mean age, 55.5; 28% women) from the Whitehall II cohort study without CHD at baseline in 1997 to 1999 (wave 5) when retrospective data on the number of ACEs were collected via questionnaire (range, 0–8). Potential mediators assessed at wave 5 included depression and anxiety symptoms, health behaviors (smoking, alcohol dependence, sleep, and physical activity), and cardiometabolic dysregulations. New diagnoses of CHD (myocardial infarction, definite angina, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty) were assessed from wave 6 (2001) to wave 11 (2012–2013). Logistic regressions examined associations between ACEs, potential mediators, and CHD during the follow‐up period. Natural indirect effects were examined using mediation analysis. A total of 566 (10.1%) participants developed CHD during the follow‐up period. ACEs were associated with an increased likelihood of CHD (odds ratio per ACE, 1.09; 95% CI, 1.00–1.19). Controlling for age and sex, mediation analyses revealed an indirect effect of depression symptoms (natural indirect effects, 1.05; 95% CI, 1.03–1.07), anxiety symptoms (natural indirect effects, 1.12; 95% CI, 1.10–1.15), and a greater number of cardiometabolic dysregulations (natural indirect effects, 1.02; 95% CI, 1.01–1.03) in the association between ACEs and incident CHD. Behavioral factors were not statistically significant mediators.ConclusionsDepression symptoms, anxiety symptoms, and cardiometabolic dysregulations partially mediated the association between ACEs and CHD. Regular screening and treatment of symptoms of psychological disorders and cardiometabolic dysregulations may help mitigate the long‐term health burden of ACEs.

OBJECTIVE To investigate whether first-episode psychosis patients receiving extended early intervention had better functional outcomes than those in regular care and to examine the predictors of functional outcomes. METHODS This is a randomized controlled single-blind trial of 220 patients randomized after 2 years of early intervention to receive early intervention or regular care for the subsequent 3 years. Outcomes included cumulative time in functional recovery during the 3-year trial assessed using the Social and Occupational Functioning Assessment Scale (SOFAS); and employment/education at last assessment which were, respectively, analyzed using multiple linear regression and logistic regression, accounting for well-known predictors. Linear mixed and generalized linear models were also used to examine the course of SOFAS and employment/education over the 3-year period. RESULTS The extended early intervention and regular care groups did not differ on time in functional recovery (mean = 50.17 weeks, SD = 46.62 vs. mean = 46.18 weeks, SD = 51.54); percent employed/in school (60.4% vs. 68.8%) or change in SOFAS or employment/education status over time. SOFAS scores were stable between years 2 and 5. Individuals with longer periods of total symptom remission experienced significantly longer periods of functional recovery and were likelier to be employed/in school. Those who had completed high school were nine times likelier to be employed/studying. CONCLUSION Most individuals maintained functional gains accrued from 2 years of early intervention with no further improvement whether in extended early intervention or regular care. There was a gap between symptomatic and functional recovery, and one-third were unemployed/not in school at year 5. The lack of additional progress even in extended early intervention suggests that specific interventions addressing functional roles need to be provided beyond the first 2 years of early intervention. Sustaining symptom remission and high-school completion may be additional avenues for targeting functional recovery.

Disease progression after frontline therapy for Diffuse large B-cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time-dependent concordance indices (c-statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post-progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post-progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR-T therapy as well as trial designs. The model is available in smartphone-based point of care applications.

AIMS/HYPOTHESIS: We aimed to assess whether current antidepressant therapy or a history of hospital-diagnosed depression affects diabetes treatment initiation, adherence, and HbA1c and LDL-cholesterol target achievement.METHODS: In this register-based study, we included all individuals from Central and Northern Denmark with newly diagnosed type 2 diabetes, defined as a first-ever HbA1c measurement of ≥48 mmol/mol (6.5%), between 2000 and 2016. Individuals either diagnosed with depression at a psychiatric hospital in the 2 years prior to their diabetes diagnosis or currently receiving treatment with an antidepressant were compared with individuals with type 2 diabetes, but without depression treatment or previous history of depression. Outcome measures included initiation of glucose-lowering drugs and lipid-modifying agents, adherence to these medications (medication possession ratio >80%), and HbA1c (RESULTS: We included a total of 87,650 individuals with first-ever HbA1c-diagnosed type 2 diabetes, of whom 0.9% (n = 784) had hospital-diagnosed depression and 11.4% (n = 9963) currently received antidepressant treatment. Compared with those without depression treatment, treatment with an antidepressant was associated with increased likelihood of glucose-lowering drug initiation (HR 1.39 [95% CI 1.34, 1.44]) and adherence (OR 1.27 [95% CI 1.18, 1.36]), lipid-modifying agent initiation (HR 1.17 [95% CI 1.11, 1.23]) and adherence (OR 1.25 [95% CI 1.09, 1.43]), and achievement of LDL (OR 1.08 [95% CI 1.03, 1.14]) but not HbA1c target (OR 0.99 [95% CI 0.93, 1.06]). The findings were similar for individuals who had hospital-diagnosed depression.CONCLUSIONS/INTERPRETATION: In individuals with newly diagnosed type 2 diabetes, antidepressant treatment and depression were associated with improved diabetes treatment quality. Graphical abstract.

In order to differentiate prognostic subgroups of patients with aggressive B-cell lymphoma, we analyzed the expression of 800 miRNAs with the NanoString nCounter human miRNA assay on a cohort of 228 FFPE samples of patients enrolled in the RICOVER-60 and MegaCHOEP trials. We identified significant miRNA signatures for overall survival (OS) and progression-free survival (PFS) by LASSO-penalized linear Cox-regression. High expression levels of miR-130a-3p and miR-423-5p indicate a better prognosis, whereas high levels of miR-374b-5p, miR-590-5p, miR-186-5p, and miR-106b-5p increase patients' risk levels for OS. Regarding PFS high expression of miR-365a-5p in addition to the other two miRNAs improves the prognosis and high levels of miR374a-5p, miR-106b-5p, and miR-590-5p, connects with increased risk and poor prognosis. We identified miRNA signatures to subdivide patients into two different risk groups. These prognostic models may be used in risk stratification in future clinical trials and help making personalized therapy decisions.

Background: Disease progression (PD) after frontline IC therapy for DLBCL is a clinically significant event and only 20-40% of patients achieve durable remissions with salvage chemotherapy. Patients who experience early PD or have disease refractory to IC have especially poor outcomes. Chimeric antigen receptor T-cell therapy has emerged as a novel effective therapy for selected cases of relapsed or refractory (r/r) DLBCL, although its availability is limited by cost and logistic challenges. Simple, clinically applicable prognostic tools would be useful for selecting patients for consideration for novel therapies vs those who are more likely to be successfully managed by conventional therapies, but few have been developed for r/r DLBCL. Methods: Model building was performed in patients with PD after IC from 13 frontline, multicenter, randomized DLBCL clinical trials from the SEAL Consortium. All patients received rituximab and an anthracycline-based combination IC and were followed systematically; however therapy received, clinical, and laboratory data at progression were not available. OS was defined as time from first progression until death from any cause. Associations between variables and OS were evaluated using Cox models; splines were used to model functional forms. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish LYFO cohorts. Model performance was assessed using time-dependent concordance indices (c-stat), Brier scores, and calibration with metrics evaluated at two years from progression. Results: Model Development (SEAL): 1125 of 5112 patients had PD after IC. Median time to PD (TTP) was 11.8 months (IQR 6.6-23.5); median age at PD was 68 years (IQR 60-73). At a median follow-up of 21 months from PD (IQR 7-43), 732 patients (65%) had died and 24 month overall survival after PD (OS24) was 35% (95% CI: 32-38). TTP was strongly associated with post PD OS (spline p-value 36 months (Figure A). Additionally, age at PD (spline p-value External Validation (MER): The model was validated in 290 patients with DLBCL who initiated 2nd line therapy after PD to IC. Median age at PD was younger than the SEAL cohort at 62 years (IQR 57-70). Patients with biopsy proven indolent histology at relapse were excluded. Median TTP was 8.2 months (IQR 5.1-17.0). At a median follow-up of 87 months from PD, 201 patients (69%) had died. OS24 was 47% (95% CI: 41-53). The model showed similar concordance (c-stat=0.65), but underestimated OS24 (predicted =33% vs. 47% actual, Figure C). External Validation (LYFO): The model was validated in 599 patients with DLBCL and PD after frontline IC. Median age at PD was 67 years (IQR 60-73). Median TTP was 10.1 months (IQR 6.0-19.4). At a median follow-up of 82 months from PD, 435 patients (73%) had died. OS24 was 38% (95% CI: 34-42). The model showed similar concordance (c-stat=0.67) when applied to the LYFO cohort, but again underestimated OS24 (predicted =32% vs. 38% actual, Figure D). Case vignettes: A 74 year old patient who progressed 9 months after diagnosis would have a predicted OS24 of 20%. A 58 year old patient who progressed 32 months after diagnosis would have a predicted OS24 of 65% Conclusions: TTP to following IC is strongly associated with post-progression survival in DLBCL. We developed a model from the largest frontline clinical trial dataset in DLBCL and validated a simple to apply clinical prognostic tool in the r/r setting. The model allows better understanding of expected outcomes in r/r DLBCL and can aid design and interpretation of trial results in this setting. The model underestimated the actual survival probability when applied to non-trial validation cohorts. Recalibration of the model for transplant eligible patients and development of smartphone based point-of-care application of the model is ongoing. Figure Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Schmitz:Riemser: Consultancy, Honoraria; Celgene: Equity Ownership; Gilead: Honoraria; Novartis: Honoraria. Farooq:Kite Pharma: Research Funding; Celgene: Honoraria. Flowers:Optimum Rx: Consultancy; Burroughs Wellcome Fund: Research Funding; BeiGene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bayer: Consultancy; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Denovo Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding. Frederiksen:Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding. Cunningham:Eli Lilly: Research Funding; 4SC: Research Funding; Bayer: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Merrimack: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Merck: Research Funding; Clovis: Research Funding. Jørgensen:Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Poeschel:Amgen: Other: Travel, accommodations, expenses; Abbvie: Other: Travel, accomodations, expenses; Hexal: Speakers Bureau; Roche: Other: Travel, accomodations, expenses. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Seymour:Takeda: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Merli:Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Celgene: Consultancy, Research Funding; Roche: Consultancy. Salles:Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL. Electronic supplementary material The online version of this article (10.1007/s10637-020-00916-3) contains supplementary material, which is available to authorized users.

Cost-effectiveness studies of early intervention services (EIS) for psychosis have not included extension beyond the first 2 years. We sought to evaluate the cost-effectiveness of a 3-year extension of EIS compared to regular care (RC) from the public health care payer’s perspective. Following 2 years of EIS in a university setting in Montreal, Canada, patients were randomized to a 3-year extension of EIS (n = 110) or RC (n = 110). Months of total symptom remission served as the main outcome measure. Resource use and cost data for publicly covered health care services were derived mostly from administrative systems. The incremental cost-effectiveness ratio (ICER) and cost-effectiveness acceptability curve were produced. Relative cost-effectiveness was estimated for those with duration of untreated psychosis (DUP) of 12 weeks or less vs longer. Extended early intervention had higher costs for psychiatrist and nonphysician interventions, but total costs were not significantly different. The ICER was $1627 per month in total remission. For the intervention to have an 80% chance of being cost-effective, the decision-maker needs to be willing to pay $5942 per month of total symptom remission. DUP ≤ 12 weeks was associated with a reduction in costs of $12 276 even if no value is placed on additional months in total remission. Extending EIS for psychosis for people, such as those included in this study, may be cost-effective if the decision-maker is willing to pay a high price for additional months of total symptom remission, though one commensurate with currently funded interventions. Cost-effectiveness was much greater for people with DUP ≤12 weeks.

ObjectiveTo investigate the association between newly developed type 2 diabetes (T2D) and incident psychopharmacological treatment and psychiatric hospital contact.MethodsWe identified all individuals from the Central- and Northern Denmark Regions with newly developed T2D (defined by the first HbA1c measurement >6.5%) from 2000-2016 and up to five age and sex matched individuals without T2D (controls). Those having received psychopharmacological treatment or having had a psychiatric hospital contact in the five years prior to the onset of T2D were excluded. For this cohort, we first assessed the incidence of psychopharmacological treatment and psychiatric hospital contact among individuals with T2D and controls, respectively. Secondly, we compared the incidence of psychopharmacological/psychiatric hospital contact among individuals with T2D to propensity score matched controls. Finally, we assessed which baseline (T2D onset) characteristics that were associated with subsequent psychopharmacological treatment and psychiatric hospital contact.ResultsWe identified 56,640 individuals with newly developed T2D and 315,694 controls. A total of 8.3% of the individuals with T2D initiated psychopharmacological treatment within the 2 years following onset compared to 4.6% among the age and sex matched controls. Individuals with T2D were at increased risk of initiating psychopharmacological treatment compared to the propensity score matched controls (HR=1.51, 95% CI=1.43-1.59), whereas their risk of psychiatric hospital contact was not increased to the same extent (HR=1.14, 95% CI=0.98-1.32). Older age, somatic comorbidity, and being divorced/widowed was associated with both psychopharmacological treatment and psychiatric hospital contact following T2D.ConclusionIndividuals with T2D are at elevated risk of requiring psychopharmacological treatment.Significant outcomes8.3% of the individuals with T2D initiated psychopharmacological treatment within the 2 years following onset compared to 4.6% among the age and sex matched controlsIndividuals with newly developed T2D were at increased risk of initiating psychopharmacological treatment and of having psychiatric hospital contact compared to propensity score matched controls.Risk factors for psychopharmacological treatment/psychiatric hospital contact following development of T2D include older age, somatic comorbidity and being divorced or widowed.LimitationsIdentification of T2D (a HbA1c level >6.5%) itself might lead to the identification of mental illness and thereby psychopharmacological treatment initiation/psychiatric hospital contact.A proportion of the individuals with T2D will likely have initiated treatment with an antidepressant due to neuropathic pain developed as a complication to T2D

Background Self-help may reduce the risk of depression, and risk perception of depression may influence initiating self-help. It is unknown how risk perception is associated with self-help behaviours. The objectives of this study are to (1) describe the self-help strategies used by high-risk Canadians in relation to the accuracy of perceived depression risk, by sex, and (2) identify demographic and clinical factors associated with self-help behaviours. Methods Baseline data from a randomized controlled trial including 358 men and 356 women at high-risk of developing depression were used. Following methods used in cancer research, risk perception accuracy was determined by comparing the participant’s self-perceived and objective risk of developing depression and classifying as accurate, over-estimation and under-estimation based on a ± 10% threshold. The participant’s objective depression risk was assessed using sex-specific multivariable risk predictive algorithms. Frequency of using 14 self-help strategies was assessed. One-way ANOVA testing was used to detect if differences in risk perception accuracy groups existed, stratified by sex. Linear regression was used to investigate the clinical and demographic factors associated with self-help behaviours, also stratified. Results Compared to accurate-estimators, male over-estimators were less likely to “leave the house daily,” and “participate in activities they enjoy.” Male under-estimators were also less likely to “participate in activities they enjoy.” Both male ‘inaccurate’ perception groups were more likely to ‘create lists of strategies which have worked for feelings of depression in the past and use them’. There were no significant differences between self-help behaviours and risk perception accuracy in women. Regression modeling showed negative relationships between self-rated health and self-help scores, irrespective of sex. In women, self-help score was positively associated with age and educational attainment, and negatively associated with perceived risk. In men, a positive relationship with unemployment was also seen. Conclusions Sex differences exist in the factors associated with self-help. Risk perception accuracy, work status, and self-rated health is associated with self-help behaviours in high-risk men. In women, factors related to self-help included age, education, self-rated health status, and perceived risk. More research is needed to replicate findings. Trial registration Prospectively registered at ClinicalTrials.gov (NCT02943876) as of 10/21/16.

Access to affordable daycare might improve population mental health. However, evidence is sparse and restricted to middle- and high-income country settings. We conducted a cluster-randomized controlled trial in one low-income setting, rural Rajasthan, India. Communities lacking daycare facilities were identified (n = 160) and randomly selected for assistance in setting up a community-based daycare program (n = 80) or not (n = 80). Women eligible for the daycare program living in these communities completed structured interviews before the intervention (participation rate = 89%) and approximately one year after rollout of the intervention (participation rate = 96%), resulting in a final analytic sample of 3041. Mental distress was measured with the Hindi version of the 12-item General Health Questionnaire (score range: 0–12). We modeled the relation between access to daycare and number of mental distress symptoms (GHQ-12 score) with negative binomial regression using an intention-to-treat approach, which groups women according to if they lived in communities randomized to affordable daycare. We also evaluated the effect of access to daycare on secondary outcomes that may be related to mental distress, including women's work burden, agency, and intimate partner violence (IPV). We found that access to daycare resulted in modest reductions in symptoms of mental distress (mean difference = 0.21, 95% CI: −0.43, 0.02). We found some evidence that daycare reduced IPV, but virtually no change in women's work burden or agency. Our results provide some indication that access to affordable daycare might be one policy lever to improve population mental health.

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.

BACKGROUND Heavy alcohol consumption in individuals with type 2 diabetes mellitus (T2DM) is related to increased risks of diabetes-related micro- and macrovascular complications. Depressive symptoms may be relevant to this relationship, because high depressive symptoms are associated with an increased risk of complications. This study investigated whether the interaction between depressive symptoms and alcohol frequency was positively related to the development of neuropathy, retinopathy, nephropathy, and coronary artery disease (CAD), such that those with high depressive symptoms and high alcohol frequency will be at increased risk of complications. METHODS Data were from five waves of the Evaluation of Diabetes Treatment annual survey including 1413 adults with T2DM in Quebec. Data on alcohol frequency (number of drinking occasions), depressive symptoms, and complications were collected annually. The development of each complication was investigated using multiple logistic regression analysis with generalized estimating equations. RESULTS After adjusting for sociodemographic, lifestyle, and diabetes-related covariates, the interaction between alcohol frequency and depressive symptoms was positively related to the incidence of neuropathy and CAD, such that those with high depressive symptoms who drank the most frequently had the highest risk of neuropathy (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04; P = 0.04) and CAD (OR 1.02, 95% CI 1.00-1.04; P = 0.04). This interaction was not significantly related to retinopathy or nephropathy. CONCLUSION Individuals with high depressive symptoms and high alcohol frequency may have a particularly high risk of neuropathy and CAD. Future prevention efforts should examine both alcohol frequency and depressive symptoms when evaluating the risk of complications.

Mature T- and natural killer (NK)–cell neoplasms comprise a group of morphologically, immunophenotypically, molecularly, and clinically heterogeneous disorders with generally unfavorable outcome. Results of first-line chemotherapy are unsatisfactory for the most common T-cell lymphomas (peripheral T-cell lymphoma, not otherwise specified; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphomas; anaplastic lymphoma tyrosine kinase–negative) as well as for many other entities. High-dose therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is widely recommended for consolidation after a complete or partial remission is achieved. However, about one-third of patients never reach transplantation because of early relapse or refractoriness. Targeted therapies have recently been developed; combinations with chemotherapy may improve outcomes, but long-term results from prospective studies are largely missing. In this situation, allogeneic HSCT remains a valuable treatment option inducing long-lived remissions in about 30% to 50% of patients with relapsed and refractory T-cell lymphoma able to proceed to transplantation. Results of allogeneic transplantation for consolidation in first remission are less defined and its indications remain controversial. With growing evidence that haploidentical HSCT also works in lymphoma, more patients can be brought to transplantation. Decreasing the morbidity and mortality of allogeneic transplantation is a continuous challenge. Integrating new drugs into transplant concepts and setting up prospective studies involving allogeneic transplantation remain unmet needs that warrant urgent study in a group of disorders in which classical chemotherapy and new drugs have generated results, which are far from optimal until today.

Background: In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined. Patients and methods: Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18-86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT+RT; RT+CT) and concurrent modalities (CCRT; CCRT+CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated. Results: For CR, stage (P=0.027), prognostic index for NK/T-cell lymphoma (PINK) (P=0.026) and types of initial treatment (P=0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P=0.021) and PINK-EBV DNA (PINK-E) (P=0.002) significantly impacted on PFS; whereas ECOG performance score (P=0.008) and stage (P

Background Trajectories of anxiety symptoms in people with type 2 diabetes (T2D) and their associations with diabetes health outcomes have not been investigated. This study examined latent longitudinal trajectories of anxiety symptoms in adults with T2D and their associations with incident cardiovascular disease (CVD). Methods Data were from the Evaluation of Diabetes Treatment Study, a community-based cohort study of adults aged 40–76 years with T2D. Anxiety and CVD were assessed by self-report at baseline and at four annual follow-up assessments. N = 832 participants without cardiovascular disease at baseline and 12-month follow-up were included in the present study. Group-based trajectories of anxiety at baseline, 12-month follow-up, and 24-month follow-up were modelled using latent class growth modeling. Associations between anxiety trajectories and CVD reported at 24-, 36-, or 48-month follow-ups were examined with logistic regression analysis adjusted for sociodemographic and lifestyle characteristics. Results Four distinct anxiety trajectories were identified, reflecting chronically low (39.4%), chronically moderate-low (47.4%), chronically moderate-high (11.1%), and chronically high (2.2%) anxiety. The likelihood of CVD was greater for the chronically moderate-low (OR = 2.23, 95% CI = 1.36–3.66), chronically moderate-high (OR = 3.05, 95% CI = 1.54–6.02), and chronically high (OR = 3.61, 95% CI = 1.09–12.00) anxiety trajectory groups compared to the chronically low anxiety group. Conclusion The identified latent trajectories reflected three groups with chronic courses of anxiety symptoms at different levels of severity and one group with chronically low levels of anxiety. Chronic anxiety, even at subthreshold levels, was associated with an increased risk of CVD among people with T2D.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

To study if obesity is a risk factor in elderly patients (>60 years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI

Although heavy alcohol consumption is associated with diabetes-related complications, little is known about patterns of alcohol use among people with diabetes. Moreover, heavy drinking is more common among individuals with major depressive disorder (MDD), bipolar disorder (BD), and generalized anxiety disorder (GAD) than in the general population, and these disorders are often comorbid with diabetes. The present study tested the hypothesis that mental disorders moderate the association between diabetes status and alcohol consumption. A total of 14,302 adult participants aged 40-79 were included from the cross-sectional 2012 Canadian Community Health Survey-Mental Health (1,698 with diabetes). Data were analyzed using hierarchical linear regression models. MDD and BD, but not GAD, significantly moderated the association between diabetes status and alcohol quantity, such that the presence of diabetes was strongly and negatively associated with alcohol quantity if individuals had MDD or BD. There was no interaction between diabetes status and any of the mental disorders and alcohol frequency. This study suggests that among individuals with diabetes, those with comorbid MDD or BD drink less than those without MDD or BD. Further investigation of this association is needed and could help inform future alcohol-related interventions among individuals with diabetes.

Male sex is associated with unfavourable pharmacokinetics and prognosis in elderly patients with diffuse large B-cell lymphoma (DLBCL). We investigated higher rituximab doses for elderly male DLBCL patients. Elderly patients (61-80years) received 6 cycles CHOP-14 (cyclophosphamide, doxorubicin, vincristine and prednisone at 14-day intervals) and were randomized to 8 cycles rituximab (males 500 mg/m(2), females 375 mg/m(2)) every 2 weeks or according to an upfront dose-dense schedule. In 268 (120 females, 148 males) no difference between the standard and the upfront dose-dense rituximab schedule was found (3-year PFS 72% vs. 74%;OS 74% vs. 77%;P=0.651). The 500mg/m(2) dose of rituximab for male patients was associated with serum levels and exposure times slightly better than in females and a male/female hazard ratio of 0.9 for progression-free survival (PFS) and 0.8 for overall survival. For elderly males, 500 mg/m(2) was not more toxic than 375 mg/m(2) rituximab, but improved PFS by 32.5% (P=0.039), with a trend for a (30%) better overall survival (P=0.076) in a planned subgroup analysis adjusting for International Prognostic Index risk factors. We conclude that the higher rituximab dose for elderly male patients abrogated the adverse prognosis of male sex without increasing toxicity. In the era of personalized medicine, sex-specific pharmacokinetics and toxicities should be investigated for all drugs where these parameters impact on outcome.

The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age being patient age at diagnosis an adverse prognostic factor. However, elderly patients are often underrepresented in common studies. To investigate the effect between age and biological characteristics in DLBCL, we analyzed data of 1534 patients encompassing all adult age groups, enriched for the age ≥75 years. Follicular lymphoma (FL) grade 3B with histopathological characteristics of DLBCLs were included. Gender, centroblastic cytology, FL grade 3B morphology, CD10 expression, and ABC/non-GCB-subtype were significantly associated with age after correction for multiple testing and after adjusting for cohorts. Analysis of a subgroup points towards an association of MYC expression with age. Our data indicate that biological features of DLBCL and FL grade 3B are associated with increasing age among adult patients. The prevalence of the ABC/non-GCB-subtype in elderly patients suggests that therapies targeting this molecular subtype should be specifically explored in this subgroup.

OBJECTIVE Prospective studies testing the potential impact of diabetes complications on depression are limited. The present study examined the longitudinal associations between diabetes complications and the risk and recurrence/persistence of depressive symptoms. METHODS Data were from a prospective community cohort telephone survey of adults with diabetes (N = 1314). Diabetes complications and depressive symptoms were assessed via self-report (Diabetes Complications Index and Patient Health Questionnaire-9, respectively) at baseline and annually for 5 years. Statistical models adjusted for sociodemographic, lifestyle, and diabetes characteristics. RESULTS The number of diabetes complications at baseline was positively associated with a greater risk of elevated depressive symptoms, with the highest risk found for those with four to six complications at baseline (risk ratio = 2.73, 95% confidence interval = 1.64-4.56). Cerebrovascular disease was the complication most strongly associated with incident depressive symptoms (risk ratio = 2.22, 95% confidence interval = 1.59-3.10). Coronary artery disease, peripheral vascular disease, and neuropathy were also associated with the risk of depression, whereas foot problems and eye problems were not. In addition, a greater number of diabetes complications were associated with recurrent/persistent depression, though with a small effect size (Δr = .02). A parallel process latent growth curve model indicated that increases in diabetes complications were associated with increases in depressive symptoms during the course of the follow-up period (β = .74, p < .001). CONCLUSIONS This study demonstrates the temporal relation between diabetes complications and depressive symptoms and underscores the psychological burden of diabetes complications by prospectively demonstrating the increased risk and recurrence of depressive symptoms associated with diabetes complications.

Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

Objectives Evidence suggests that symptoms of depression and anxiety predict lower exercise behaviour and, inversely, that less exercise predicts higher symptomatology. The present longitudinal study examined this reciprocal association in adults with type 2 diabetes mellitus. We predicted that symptoms of anxiety or depression would intensify over time as a consequence of lower exercise frequency and, similarly, that exercise frequency would decrease as a consequence of greater symptoms of anxiety or depression. Methods We studied 1691 adults with type 2 diabetes who provided baseline measures in 2011 and 2 subsequent annual assessments (Follow-up 1 and Follow-up 2). Symptoms of depression and anxiety were measured using the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7, respectively. A single item assessed exercise frequency in the past month (in days). Results Separate 3-wave cross-lagged path models for symptoms of anxiety and depression tested the reciprocal associations. Contrary to our hypotheses, the reciprocal associations were not supported and, by extension, the predicted secondary associations were not tested. In sum, only depressive symptoms negatively predicted subsequent exercise frequency (Follow-up 1 and Follow-up 2). Conclusions Symptoms of depression were prospectively associated with lower exercise frequency, which is consistent with evidence from population-based studies that identify depressive symptoms as a barrier to exercise participation.

Introduction:Considering the increasing numbers of lymphoma patients (pts) surviving long-term, late effects of current treatment strategies such as secondary (sec) malignancies gain increasing importance. Many treatment regimens used in pts with lymphoma (R-CHOEP, DA-EPOCH-R, BEACOPP) include etoposide, a cytotoxic agent reported to increase sec leukemias. In order to further investigate the role of etoposide in inducing sec malignancies in pts with aggressive lymphoma we analyzed the R-MegaCHOEP trial (Schmitz et al., Lancet Oncology 2012) where young, high-risk pts with aggressive B-cell lymphomas had received R-CHOEP or R-MegaCHOEP, a regimen containing very high doses of etoposide (4g/m2). We compared rates of secondary tumors to incidences found in young patients treated with R-CHOP only. Methods:We analyzed 1536 pts aged 18-60 years with aggressive B-cell lymphoma treated in the prospective phase 3 trials FLYER (NCT00278421; n=588, median observation time (OT)=66 months), UNFOLDER (NCT00278408; n=695, median OT=72 months) and MegaCHOEP (NCT00129090; n=253, median OT=112 months) to compare the cumulative incidences of sec neoplasms. We performed a competing risk analysis for time from randomization to occurrence of sec malignancy (myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or other) according to first-line therapy with R-CHOP (n=1283) vs. R-CHOEP (n=127) vs. R-MegaCHOEP (n=126). We used a cause-specific hazard model adjusted for gender, age (>50 vs. Results:Adjusting for competing events, we found sec MDS/AML in 0.3% of pts treated with R-CHOP, in 1% of pts treated with R-CHOEP and in 2% of pts following treatment with R-MegaCHOEP. Cause-specific hazard ratios showed a trend for increased risk for sec AML following R-MegaCHOEP in comparison to R-CHOP (HR 5.2, 95%CI (1.0; 27.5), p=0.052) while R-CHOEP did not significantly increase the incidence of sec AML (HR 1.4, 95%CI (0.1; 14.0), p=0.777). Male gender and age >50 years showed a trend for increasing sec AML. We found very similar incidences of sec solid tumors (not MDS/AML) affecting 4% of pts treated with R-CHOP or R-MegaCHOEP and 6% of pts following R-CHOEP regimen. The only factor significantly increasing the risk of sec solid tumors was age >50 years (HR 2.6, 95%CI (1.5; 4.3), p Conclusions:This analysis shows that sec malignancies represent rare events in younger patients with aggressive B-cell lymphoma, even after extreme dose-escalation of etoposide. Compared to standard R-CHOP, 8 cycles of R-CHOEP were not associated with increased risk of sec AML or solid tumors thus remaining an attractive first-line treatment for young high-risk pts with DLBCL. Disclosures Haenel: Amgen, Novartis, Roche, Celgene, Takeda, Bayer:Honoraria.Truemper:Janssen:Consultancy;Mundipharma:Research Funding;Nordic Nanovector:Consultancy;Roche:Research Funding;Seattle Genetics:Research Funding;Takeda Europe:Consultancy, Research Funding.Held:MSD:Consultancy;Acrotech, Spectrum:Research Funding;Amgen:Research Funding;BMS:Consultancy, Other: Travel Grants, Research Funding;Roche:Consultancy, Other: travel grants, Research Funding.Borchmann:Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Dreyling:Celgene:Consultancy, Research Funding, Speakers Bureau;Roche:Consultancy, Research Funding, Speakers Bureau;Beigene:Consultancy;Janssen:Consultancy, Research Funding, Speakers Bureau;Novartis:Consultancy;Abbvie:Research Funding;Astra Zeneca:Consultancy;Bayer:Consultancy, Speakers Bureau;Gilead:Consultancy, Research Funding, Speakers Bureau.Viardot:Roche:Honoraria, Other: advisory board;Kite/Gilead:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;Gilead:Consultancy;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding.Ott:NIH:Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America..Lenz:Bayer:Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen:Consultancy, Honoraria, Research Funding, Speakers Bureau;Novartis:Consultancy;Gilead:Consultancy, Honoraria, Research Funding, Speakers Bureau;AQUINOX:Research Funding;AstraZeneca:Consultancy, Honoraria, Research Funding;Celgene:Consultancy, Honoraria, Speakers Bureau;Verastem:Research Funding;Morphosys:Consultancy, Honoraria, Research Funding;Roche:Consultancy, Honoraria, Research Funding, Speakers Bureau;Agios:Research Funding;BMS:Consultancy.Schmitz:Riemser:Honoraria;Takeda:Honoraria;Janssen:Research Funding;Bristol-Myers Squibb:Current equity holder in publicly-traded company.