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 (LAMIS
) 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). LAMIS
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.
OBJECTIVE To evaluate the association between recurrent subthreshold depressive episodes and functioning in a prospective community sample of people with type 2 diabetes. RESEARCH DESIGN AND METHODS ...A prospective community study in Quebec, Canada, was carried out between 2008 and 2013 (n = 1,064). Five yearly follow-up assessments (telephone interviews) were conducted. Baseline and the first three follow-up assessments were used to identify recurrent subthreshold depressive episodes (Patient Health Questionnaire PHQ-9). Functioning (World Health Organization Disability Assessment Schedule II WHODAS-II) and health-related quality of life (Centers for Disease Control and Prevention CDC unhealthy days) at 4- and 5-year follow-up assessments were the outcome measures. RESULTS Nearly half of the participants suffered from at least one episode of subthreshold depressive symptoms. After adjusting for potentially confounding factors, the risk of poor functioning/impaired health-related quality of life was nearly three times higher (relative risk = 2.86) for participants with four subthreshold depressive episodes compared with participants with no/minimal depression. Results suggest a dose-response relationship: the risk of poor functioning/impaired health-related quality of life increased with the number of recurrent subthreshold depressive episodes even after controlling for potentially confounding variables (significant linear trend, P < 0.001). CONCLUSIONS Recurrent subthreshold depressive symptoms might be an important risk factor for poor health outcomes in type 2 diabetes. Early identification, monitoring, and treatment of recurrent subthreshold depressive symptoms might improve functioning and quality of life in people with type 2 diabetes.
The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose ...chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL).
Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM).
From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio HR, 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance.
Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.
To study pharmacokinetics, toxicity, and efficacy of prolonged rituximab exposure in elderly patients with diffuse large B-cell lymphoma (DLBCL).
In the SMARTE-R-CHOP-14 trial, rituximab 375 mg/m(2) ...was administered, together with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone on a 14-day schedule (6×R-CHOP-14), on days -4, 0, 10, 29, 57, 99, 155, and 239. Pharmacokinetics and outcome were to be compared with those of patients who had received 6×R-CHOP-14 in combination with eight 2-week applications of rituximab in the RICOVER-60 (Rituximab With CHOP Over Age 60 Years) trial.
The complete response (CR)/unconfirmed CR rate was 85% in 189 evaluable patients, 90% for 90 good-prognosis patients (International Prognostic Index IPI, 1 or 2), and 81% for 99 poor-prognosis patients (IPI, 3 to 5); 3-year event-free survival (EFS) was 71%, 75%, and 67%, respectively; and 3-year overall survival (OS) was 84%, 88%, and 80%, respectively, with no differences between men and women. The preplanned historical comparison with 306 RICOVER-60 patients (good prognosis, n = 183; poor prognosis, n = 123) revealed no outcome differences for all and good-prognosis patients; however, the longer exposure time in SMARTE-R-CHOP-14 compared with RICOVER-60 was associated with better 3-year EFS (67% v 54%) and OS (80% v 67%) in poor-prognosis patients.
Extended rituximab exposure compared with eight 2-week applications in combination with 6×R-CHOP-14 significantly improved outcome of elderly poor-prognosis patients without increasing toxicity. To our knowledge, results obtained with the SMARTE-R-CHOP-14 rituximab schedule are the best reported for elderly patients with DLBCL to date. In the subgroup of poor-prognosis patients treated with extended rituximab exposure, the outcome seemed superior to that of a similar historical cohort of patients treated with 6×R-CHOP-14 plus 2-week rituximab, with similar toxicity. A randomized comparison of the two schedules is warranted.
High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment ...needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy.
Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points.
From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001).
Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.
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.
Summary
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.
•High risk people are likely to overestimate their risk of developing depression.•Inaccurate depression risk perception is related to people's health status.•Sex differences in depression risk ...perception exist.•Perceived risk is an important factor that influences health behavior change.
Prevention and early detection of depression is a top public health priority. Accurate perception of depression risk may play an important role in health behavior change and prevention of depression. However, the way in which people in the community perceive their risk of developing depression is currently unknown.
We analyzed the baseline data from a randomized controlled trial in 358 men and 356 women who are at high risk of having a major depressive episode (MDE). The predicted risk was assessed by sex-specific multivariable risk predictive algorithms for MDE. We compared participants’ perceived risk and their predicted risk. Accurate risk perception was defined as perceived risk is in the range of predicted risk ± 10%.
In men, 29.7% perceived their risk accurately; 47.5% overestimated their risk; 22.8% underestimated their risk. In women, the proportions were 21.7%, 59.6% and 18.7%, respectively. Compared to men, women were more likely to overestimate their risk and less likely to be accurate. Regression modeling revealed that poor self-rated health and higher predicted depression risk were associated with inaccuracy of risk perception in men; a family history of MDE, higher psychological distress and lower predicted risk were associated with inaccuracy of risk perception in women.
Individuals who are at high risk of developing depression tend to overestimate their risk, especially women. Inaccurate depression risk perception is related to people's health status. Educational interventions are needed to enhance the accuracy of risk perception to encourage positive behavior change and uptake of preventive strategies.
To compare the clinical outcome in terms of nonrelapse mortality (NRM), relapse rate (RR), overall survival (OS), and progression-free survival (PFS) in patients with relapsed Hodgkin's lymphoma (HL) ...treated with reduced-intensity conditioning (RIC) or myeloablative conditioning followed by allogeneic stem-cell transplantation (alloSCT).
A total of 168 patients with HL undergoing a first alloSCT (RIC, n = 89; myeloablative conditioning, n = 79) between January 1997 and December 2001 and registered in the European Group for Blood and Marrow Transplantation database were analyzed.
NRM was significantly decreased in the RIC group (hazard ratio HR, 2.85; 95% CI, 1.62 to 5.02; P < .001). OS was better in the RIC group (HR, 2.05; 95% CI, 1.27 to 3.29; P = .04) and there was a trend for better PFS in the RIC group (HR, 1.53; 95% CI, 0.97 to 2.40; P = .07). RR was higher in the RIC group in univariate but not in multivariate analysis. The development of chronic graft-versus-host disease (GVHD) significantly decreased the incidence of relapse, which translated into a trend for a better PFS.
The lower incidence of NRM in the RIC group is encouraging, particularly because these patients experienced adverse pretransplantation characteristics more frequently. This analysis also indicates the existence of a graft-versus-HL effect correlated to the development of GVHD. Additional efforts to reduce the high RR seen in both groups of patients will be necessary to improve the modest PFS (31% v 27%) and OS (59% v 36%) for patients prepared with RIC or myeloablative conditioning.
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