DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes.

Funder: addenbrooke's charitable trust, cambridge university hospital

Advanced Hodgkin lymphoma in the East of England: a 10-year comparative analysis of outcomes for real-world patients treated with ABVD or escalated-BEACOPP, aged less than 60 years, compared with 5-year extended follow-up from the RATHL trial.

Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or escalated(e)-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone) remains the international standard of care for advanced-stage classical Hodgkin lymphoma (HL). We performed a retrospective, multicentre analysis of 221 non-trial ("real-world") patients, aged 16-59 years, diagnosed with advanced-stage HL in the Anglia Cancer Network between 2004 and 2014, treated with ABVD or eBEACOPP, and compared outcomes with 1088 patients in the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma (RATHL) trial, aged 18-59 years, with median follow-up of 87.0 and 69.5 months, respectively. Real-world ABVD patients (n=177) had highly similar 5-year progression-free survival (PFS) and overall survival (OS) compared with RATHL (PFS 79.2% vs 81.4%; OS 92.9% vs 95.2%), despite interim positron-emission tomography-computed tomography (PET/CT)-guided dose-escalation being predominantly restricted to trial patients. Real-world eBEACOPP patients (n=44) had superior PFS (95.5%) compared with real-world ABVD (HR 0.20, p=0.027) and RATHL (HR 0.21, p=0.015), and superior OS for higher-risk (international prognostic score ≥3 [IPS 3+]) patients compared with real-world IPS 3+ ABVD (100% vs 84.5%, p=0.045), but not IPS 3+ RATHL patients. Our data support a PFS, but not OS, advantage for patients with advanced-stage HL treated with eBEACOPP compared with ABVD and suggest higher-risk patients may benefit disproportionately from more intensive therapy. However, increased access to effective salvage therapies might minimise any OS benefit from reduced relapse rates after frontline therapy

Infliximab for Diabetic Macular Edema Refractory to Laser Photocoagulation A randomized, double-blind, placebo-controlled, crossover, 32-week study

OBJECTIVE - Because many patients with diabetic macular edema (DME) do not respond to focal/grid laser photocoagulation, the only currently approved treatment, alternatives are needed. Based on encouraging preliminary findings, we aimed to assess efficacy and safety of the anti tumor necrosis factor (TNF) monoclonal antibody infliximab in this condition. RESEARCH DESIGN AND METHODS - This was a single-center, double-blind, randomized, placebo-controlled, crossover study. Eleven patients with sight-threatening DME persisting after two sessions of laser photocoagulation received infliximab (5 mg/kg) intravenously at weeks 0, 2, 6, and 14, followed by placebo at weeks 16, 18, 22, and 30, or vice versa. Blinding was maintained to week 32, when the final assessments were performed. Best corrected visual acuity evaluated by a mixed-models approach for imbalanced crossover design using the percentage difference as the outcome variable was the primary study end point. Data were analyzed on an intention-to-treat basis. RESULTS - Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 +/- 5.1 (mean +/- SD) letters read at baseline to 28.8 +/- 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 +/- 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 +/- 10.3 at baseline to 30.4 +/- 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 +/- 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8-43.7; P = 0.017). Infliximab treatment was well tolerated. CONCLUSIONS - The positive results of this small phase Ill study suggest that larger and longer term trials should be conducted to assess the efficacy of systemic or intravitreal anti-TNF agent administration for primary treatment of DME

A phase 2 study of carfilzomib, cyclophosphamide and dexamethasone as frontline treatment for transplant-eligible MM with high-risk features (SGH-MM1)

10.1038/s41408-021-00544-xBLOOD CANCER JOURNAL11

Evolving therapeutic landscape of diffuse large B-cell lymphoma: challenges and aspirations

Abstract Diffuse large B-cell lymphoma (DLBCL) represents the commonest subtype of non-Hodgkin lymphoma and encompasses a group of diverse disease entities, each harboring unique molecular and clinico-pathological features. The understanding of the molecular landscape of DLBCL has improved significantly over the past decade, highlighting unique genomic subtypes with implications on targeted therapy. At the same time, several new treatment modalities have been recently approved both in the frontline and relapsed settings, ending a dearth of negative clinical trials that plagued the past decade. Despite that, in the real-world setting, issues like drug accessibility, reimbursement policies, physician and patient preference, as well as questions regarding optimal sequencing of treatment options present difficulties and challenges in day-to-day oncology practice. Here, we review the recent advances in the therapeutic armamentarium of DLBCL and discuss implications on the practice landscape, with a particular emphasis on the context of the healthcare system in Singapore

Obstacles for T-lymphocytes in the tumour microenvironment: therapeutic challenges, advances and opportunities beyond immune checkpoint

The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms - elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.Ministry of Education (MOE)Ministry of Health (MOH)Nanyang Technological UniversityNational Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThis research was supported, in part, by the Singapore Ministry of Education (MOE) under its MOE Academic Research Fund (AcRF) Tier 2 (MOE2017-T2-2-004) and Tier 1 (2020-T1-001-062) grants, and the National Research Foundation Singapore under its Open Fund - Large Collaborative Grant (OFLCG18May-0028) and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). N.F.G. acknowledges funding support from the NMRC Transition Award (NMRC/TA/0051/2016) and the NMRC Centre Grant (TETRAD 2). B.H.S.W. and Z.S.P. were provided with PhD fellowship by HealthTech NTU and Lee Kong Chian School of Medicine, Nanyang Technological University Singapore

High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma

10.1038/s41408-021-00535-yBLOOD CANCER JOURNAL11

DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes

10.1186/s12943-021-01437-0MOLECULAR CANCER20