The biology of classical Hodgkin lymphoma.

Classical Hodgkin lymphoma (cHL) is distinguished by several important biological characteristics. The presence of Hodgkin Reed Sternberg (HRS) cells is a defining feature of this disease. The tumor microenvironment with relatively few HRS cells in an expansive infiltrate of immune cells is another key feature. Numerous cell-cell mediated interactions and a plethora of cytokines in the tumor microenvironment collectively work to promote HRS cell growth and survival. Aberrancy and constitutive activation of core signal transduction pathways are a hallmark trait of cHL. Genetic lesions contribute to these dysregulated pathways and evasion of the immune system through a variety of mechanisms is another notable feature of cHL. While substantial elucidation of the biology of cHL has enabled advancements in therapy, increased understanding in the future of additional mechanisms driving cHL may lead to new treatment opportunities.

Richter Transformation of Chronic Lymphocytic Leukemia-Are We Making Progress?

PURPOSE OF REVIEW: The treatment paradigm of chronic lymphocytic leukemia (CLL) has dramatically changed with the advent of novel targeted agents over the past decade. Richter transformation (RT), or the development of an aggressive lymphoma from a background of CLL, is a well-recognized complication of CLL and carries significantly poor clinical outcomes. Here, we provide an update on current diagnostics, prognostication, and contemporary treatment of RT. RECENT FINDINGS: Several genetic, biologic, and laboratory markers have been proposed as candidate risk factors for the development of RT. Although a diagnosis of RT is typically suspected based on clinical and laboratory findings, tissue biopsy is essential for histopathologic confirmation of diagnosis. The standard of care for RT treatment at this time remains chemoimmunotherapy with the goal of proceeding to allogeneic stem cell transplantation in eligible patients. Several newer treatment modalities are being studied for use in the management of RT, including small molecules, immunotherapy, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy. The management of patients with RT remains a challenge. Ongoing trials show enormous promise for newer classes of therapy in RT, with the hope being that these agents can synergize, and perhaps supersede, the current standard of care in the near future.

Long-term outcomes for patients with Hodgkin lymphoma at increased risk of progression or relapse.

Although advancements in the treatment of Hodgkin lymphoma have enabled many patients to be cured of their disease, about half of patients who relapse or experience refractory disease ultimately fail treatment, even after autologous stem cell transplant. Risk stratification is crucial to enable escalation of therapy in patients at increased risk for progression while allowing for less intensive therapy in lower risk groups. Utilization of clinical factors to inform risk scores was common practice, but this historical approach has been supplemented by PET/CT risk adapted management. Long-term outcomes of high-risk patients have improved over the decades with advancements in therapy and emergence of novel agents including antibody-drug conjugates and immune checkpoint inhibitors, yet further research is urgently needed. Herein, we review long-term outcomes of patients with Hodgkin lymphoma at increased risk for progression or relapse and discuss limitations of current risk strategies.

Radiographic Response of Solitary Plasmacytomas After Conformal Radiotherapy May Be Delayed: Outcomes in the 3D Era.

OBJECTIVE: Although recurrence rates after radiotherapy for solitary plasmacytoma (SP) are well established, little is known about how SP responds radiographically, as most historical patients were treated in the 2D era. We evaluated the response to radiotherapy among SP patients staged and treated with 3D techniques, including proton therapy, which has not yet been previously reported. METHODS AND MATERIALS: Between 2007 and 2021, 15 SP patients (4 extramedullary, 11 bone) staged with 3D imaging and bone marrow evaluation were consecutively treated with definitive radiotherapy. The best response was categorized in 9 evaluable patients according to response evaluation criteria in solid tumors (RECIST) and positron emission tomography response criteria in solid tumors (PERCIST). RESULTS: With a median follow-up of 34 months, 4 patients relapsed. The median time to the best response was ~2 years (26.6 mo RECIST, 25.4 mo PERCIST). Response rates differed based on response assessment criteria. PERCIST was associated with higher rates of complete (85.7%) or partial response (14.3%) compared with RECIST (16.7% complete, 33.3% partial). Two-year and 4-year PFS for extramedullary SP were 100% and 75%, compared with 91% and 55% for bone ( P =0.75). Patients treated with proton therapy (n=5) did not appear to have different patterns of relapse (1 marginal, 1 distant) compared with those treated with photons or electrons (n=10; 2 distant). CONCLUSIONS: More conformal dose distribution with proton therapy does not appear to alter patterns of recurrence. Although response rates differ based on criteria by both RECIST and PERCIST assessments, the radiographic response may be slow and requires validation in other cohorts.

The Impact of COVID-19 on US Radiation Oncology Residents.

The purpose of our study is to assess the impact of COVID-19 on the clinical responsibilities, training, and wellness of US radiation oncology residents. An anonymous cross-sectional survey was sent to all 91 radiation oncology residency programs in the USA. The survey included questions related to demographics, changes in clinical duties and training, job prospects, and wellness indicators. Univariate and multivariate logistic regression analyses were used to evaluate factors associated with residents endorsing high satisfaction with their departments' response to COVID-19. A total of 96 residents completed the survey from 67 US radiation oncology programs. In the multivariate logistic regression model, remote contouring (OR: 3.91 (95% CI: 1.11, 13.80), p = 0.03) and belief that one will be adequately trained to independently practice after completing residency (OR: 4.68 (1.12, 19.47), p = 0.03) were significantly associated with high resident satisfaction with their department's response to COVID-19. Most residents indicated that hypofractionation was encouraged to a greater extent (n = 79, 82.3%), patients were triaged by disease risk (n = 67, 69.8%), and most agreed/strongly agreed that they have been provided with adequate personal protective equipment (PPE) (n = 85, 88.5%). The COVID-19 pandemic has affected the training and wellness of radiation oncology residents. Our analysis suggests that radiation oncology programs might increase resident satisfaction with their department's response to COVID-19 by enabling remote contouring and working with residents to identity and remedy possible concerns regarding their ability to independently practice post residency.

Systematic Review and Meta-Analysis on the Use of Photon-based Stereotactic Radiosurgery Versus Fractionated Stereotactic Radiotherapy for the Treatment of Uveal Melanoma.

PURPOSE: The purpose of this report is to assess the efficacy and adverse event profile of photon-based stereotactic radiosurgery (SRS) compared with fractionated stereotactic radiotherapy (fSRT) for the treatment of uveal melanoma. Primary outcomes include incidence proportions of local control, enucleation, metastatic progression, disease-specific, and overall mortality. Treatment-related toxicities such as incidence proportions of radiation retinopathy, neovascular glaucoma, optic neuropathy, and cataract formation were examined as secondary outcomes. Five-year survival and 5-year local control rates were also assessed. MATERIALS AND METHODS: PubMed, Embase, Web of Science, Scopus, and 2 Cochrane databases were searched up to December 31, 2018. Random effects models were used to calculate pooled incidence proportions of outcome measures. Meta-regression was carried out to explore the potential impact of dose per fraction on local control. RESULTS: Twenty-four articles with a total of 1745 patients were included in the meta-analysis. There were no statistically significant differences between photon-based fSRT and SRS for all primary, secondary and 5-year outcome measures, including local control (P=0.28), enucleation (P=0.51), and neovascular glaucoma (P=0.40). The 5-year local control rate was 90% (95% confidence interval: 76%, 96%) for fSRT and 89% (70%, 97%) for SRS. CONCLUSIONS: Our meta-analysis showed no difference in tumor control, survival and toxicities, as defined in this paper, between SRS and fSRT for uveal melanoma. Confounding biases remain an expected limitation in this study of novel treatment modalities deployed in rare tumors. Further investigation is needed to validate outcomes and compare stereotactic treatment techniques.

Attitudes about smoking cessation treatment, intention to quit, and cessation treatment utilization among young adult smokers with severe mental illnesses.

SIGNIFICANCE: Young adults with schizophrenia, bipolar disorder and other severe mental illnesses (SMI) have high rates of smoking, but little research has evaluated predictors of cessation activity and treatment utilization in this group. METHODS: We assessed attitudes, beliefs, social norms, perceived behavioral control, intention, quit attempts, treatment utilization, and cessation among 58 smokers with SMI, age 18-30, enrolled in a randomized pilot study comparing a brief interactive/motivational vs. a static/educational computerized intervention. Subjects were assessed at baseline, post intervention, and 3-month follow-up. RESULTS: Over follow-up, one-third of participants self-reported quit attempts. Baseline measures indicating lower breath CO, greater intention to quit, higher perceptions of stigma, higher perceptions of psychological benefits of smoking, and greater symptom distress were associated with quit attempts, whereas gender, diagnosis, social support, attitudes about smoking, and use of cessation treatment were not. In the multivariate analysis, lower breath CO, higher intention to quit and symptom distress were significantly related to quit attempts. Only 5% of participants utilized verified cessation treatment during follow-up. Consistent with the Theory of Planned Behavior, attitudes, social norms and perceived behavioral control regarding cessation treatments correlated significantly with intention to use treatment. Norms and beliefs about treatment were somewhat positive and some improved after intervention, with a pattern significantly favoring the interactive intervention, but intentions to use treatments remained low, consistent with low treatment utilization. CONCLUSIONS: Perceptions of traditional cessation treatments improved somewhat after brief interventions, but most young adult smokers with SMI did not use cessation treatment. Instead, interventions led to quit attempts without treatment.

Randomized Trial of Interventions for Smoking Cessation Among Medicaid Beneficiaries With Mental Illness.

OBJECTIVE: Medicaid beneficiaries with severe mental illnesses are a financially disadvantaged group with high rates of smoking and poor cessation outcomes. This study examined whether abstinence-contingent monetary incentives improved outcomes when added to cessation treatments at community mental health centers: prescriber visit for pharmacotherapy only (PV only), prescriber visit and facilitated quitline (PV+Q), and prescriber visit and telephone cognitive-behavioral therapy (PV+CBT). METHODS: During 2012-2015, a total of 1,468 adult, daily smoking Medicaid beneficiaries with mental illnesses received Web-based motivational tobacco education. Eligible participants who wanted cessation treatment (N=661) were randomly assigned to treatment with or without abstinence-contingent incentives for four weeks after a quit attempt and assessed for biologically verified abstinence at three, six, nine, and 12 months. To examine intervention effect on abstinence over time, logistic generalized linear models estimated with generalized estimating equations were used, with missing observations imputed as smoking. RESULTS: Participants included smokers with schizophrenia disorders (N=148), bipolar disorder (N=150), major depressive disorder (N=158), and anxiety and other disorders (N=205). There was no significant effect of intervention (PV only, PV+Q, and PV+CBT). However, participants who received monetary incentives were more likely to be abstinent from smoking over time (adjusted odds ratio [AOR]=1.77, p=.009). Post hoc comparisons indicated greater abstinence at 12 months in PV+Q with incentives than in PV+Q without incentives (14% versus 4% abstinent, AOR=3.94, p=.014). Treatment participation and cessation outcomes did not differ significantly between diagnostic groups. CONCLUSIONS: Abstinence-contingent incentives improved cessation outcomes among financially disadvantaged smokers with mental illness receiving tobacco treatment at community mental health centers.

Purinergic control of lysenin's transport and voltage-gating properties.

Lysenin, a pore-forming protein extracted from the coelomic fluid of the earthworm Eisenia foetida, manifests cytolytic activity by inserting large conductance pores in host membranes containing sphingomyelin. In the present study, we found that adenosine phosphates control the biological activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least. ATP removal from the bulk solutions by buffer exchange quickly reinstated the macroscopic conductance and demonstrated reversibility. Single-channel experiments pointed to an inhibition mechanism that most probably relies on electrostatic binding and partial occlusion of the channel-conducting pathway, rather than ligand gating induced by the highly charged phosphates. The Hill analysis of the changes in macroscopic conduction as a function of the inhibitor concentration suggested cooperative binding as descriptive of the inhibition process. Ionic screening significantly reduced the ATP inhibitory efficacy, in support of the electrostatic binding hypothesis. In addition to conductance modulation, purinergic control over the biological activity of lysenin channels has also been observed to manifest as changes of the voltage-induced gating profile. Our analysis strongly suggests that not only the inhibitor's charge but also its ability to adopt a folded conformation may explain the differences in the observed influence of ATP, ADP, and AMP on lysenin's biological activity.