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Objective Chronic lymphocytic leukemia and small lymphocytic lymphoma remain the most prevalent adult leukemia in Western countries. Novel therapeutics have established long-term efficacy and have changed the landscape in patient management. In contrast, novel approaches pose opportunities for patients to be treated for finite durations. In this manuscript, we highlight long-term safety and efficacy data with Bruton's tyrosine kinase inhibitors and combination BCL2 + anti-CD20 therapies. We also offer key considerations for treatment selection and outline ongoing trials which may continue to expand therapeutic options and approaches. Data sources An electronic search of the PubMed database was performed to obtain key literature in chronic lymphocytic leukemia and small lymphocytic lymphoma published using the following search terms: chronic lymphocytic leukemia/small lymphocytic lymphoma, Richter syndrome, and histologic transformation. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. Data summary Chronic lymphocytic leukemia and small lymphocytic lymphoma are different manifestations of the same disease and are managed in much the same way. Bruton's tyrosine kinase inhibitors have demonstrated long and durable efficacy benefits in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma and in the relapsed/refractory setting. Despite these benefits, long terms adverse events have posed challenges for patients and have led to treatment discontinuations. Additionally, the use of monotherapy Bruton's tyrosine kinase inhibitor's requires chronic use of the medications leading to added financial implications. BCL2 inhibition with venetoclax in combination with anti-CD20 monoclonal antibodies has offered a novel and finite treatment approach in frontline and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Ongoing clinical trials are in investigating this modality further to enhance durable responses utilizing a combination Bruton's tyrosine kinase inhibitor's and BCL2 inhibitors. Conclusion The treatment armamentarium of chronic lymphocytic leukemia/small lymphocytic lymphoma continues to evolve. Despite the long term, durable responses with Bruton's tyrosine kinase inhibitor's, it is likely that finite treatment durations could become the standard of care as a result of continued, long-term responses.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon’s catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

Background National studies have reported racial and socioeconomic disparities in gastric cancer (GC) care. The current study evaluated adequate lymph node (LN) assessment (≥16 LNs) during resection for GC within a healthcare system servicing a socioeconomically disparate, mostly non-White population in the Southeast United States. Methods A retrospective cohort study of patients undergoing resection for GC between 2003-2019 was performed. Factors associated with adequate LN assessment including patient and tumor characteristics were analyzed. Results Among 202 patients, adequate LN assessment was performed in 97 (48%) patients. On univariable analysis, younger age, non-White race, lower Charlson Comorbidity Index (CCI), Medicaid or no insurance, D1+/D2 lymphadenectomy, clinical evidence of regional LN metastases, total gastrectomy, and receipt of neoadjuvant therapy were associated with adequate LN assessment. On multivariable analysis, non-White race (OR 2.79, 95% CI 1.38-5.65), CCI <4 (OR 2.14, 95% CI 1.15-3.96), and D1+/D2 lymphadenectomy (OR 3.63, 95% CI 1.96-6.74) were the only factors independently associated with adequate LN evaluation. Conclusions In the current study, non-White race, independent of socioeconomics, was significantly associated with adequate LN assessment. Future work is necessary to improve standardization and achieve higher rates of adequate LN assessment for all patients during resection for GC.

PURPOSE American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline” 2 was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline.” 2 RECOMMENDATIONS Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V 12Gy to brain tissue to ≤ 10 cm 3 is conditionally recommended. Additional information is available at www.asco.org/neurooncology-guidelines .

Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well‐studied. PURPOSE The purpose of this study was to investigate how obesity influences acute exercise responsiveness within skeletal muscle. METHODS Non‐obese (NO; n=19; 10F/9M; BMI=25.1 ± 2.8 kg/m 2 ) and Obese (O; n=21; 14F/7M; BMI=37.3 ± 4.6 kg/m 2 ) adults performed 30 minutes of single‐leg cycling at 70% of VO 2 peak. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3 and 6 hours post‐exercise to measure protein synthesis and gene expression. RESULTS The exercise‐induced fold change in mixed muscle protein synthesis trended (p=0.058) higher in NO (1.28 ± 0.54‐fold) compared to O (0.95 ± 0.42‐fold) and was inversely related to BMI (r=‐.374, p=0.027). RNA sequencing revealed 331 and 280 genes that were up or downregulated after exercise in NO and O, respectively. Gene set enrichment analysis showed O had blunted post‐exercise pathways related to MAPK signaling, chemokine‐mediated signaling, FC receptor mediated stimulation signaling, cell proliferation, apoptosis, and RNA polymerase II promotion. Quantitative polymerase chain reaction of select metabolic ( PGC1a, PGC1b, TFAM, PDK4, IRS, MAPK, and PRKAA1 ) and muscle growth ( SLC, TBC, MSTN, MyoD, TRIM32, FOX03, and FBXO3) genes were similar between groups 3 and 6 hours after exercise. Conclusion These data highlight several unique pathways in individuals with obesity that result in a blunted exercise response.

Introduction: Safety of vigorous exercise for individuals with appropriately-treated HCM remains debated. Physical activity practices in this population have not been described. The objective of this report is to describe physical activity pattern in HCM patients. Long term follow up which is ongoing will determine safety of vigorous exercise. Methods: The NIH-funded LIVE-HCM study prospectively enrolled individuals age 8-60 years with clinically overt HCM or patients with a positive genetic test for sarcomeric HCM. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1798 participants, 745 (41%) reported exercising vigorously, including 296 competitive athletes, with 59 at high-school or college varsity level, 770 (43%) were exercising at moderate, and 283 (16%) at low levels. Of those working, 6% described jobs more active than walking, including 16 in protective services, and 11 in sports/coaching. Clinical/demographic data including imaging characteristics and treatments, are shown in Table, and were mostly similar amongst the exercise-groups. Conclusions: Many patients with HCM are engaged in vigorous exercise including competitive athletics. Prospective follow-up of this cohort is ongoing. Comparison of arrhythmic outcomes outcomes in vigorous exercisers vs moderate/low level exercisers will help determine the safety of exercise in HCM patients.

AbstractIntroductionThe extravascular implantable cardioverter‐defibrillator (EV ICD) system with substernal lead placement is a novel nontransvenous alternative to current commercially available ICD systems. The EV ICD provides defibrillation and pacing therapies without the potential long‐term complications of endovascular lead placement but requires a new procedure for implantation with a safety profile under evaluation.MethodsThis paper summarizes the development of the EV ICD, including the preclinical and clinical evaluations that have contributed to the system and procedural refinements to date.ResultsExtensive preclinical research evaluations and four human clinical studies with >140 combined acute and chronic implants have enabled the development and refinement of the EV ICD system, currently in worldwide pivotal study.ConclusionThe EV ICD may represent a clinically valuable solution in protecting patients from sudden cardiac death while avoiding the long‐term consequences of transvenous hardware. The EV ICD offers advantages over transvenous and subcutaneous systems by avoiding placement in the heart and vasculature; relative to subcutaneous systems, EV ICD requires less energy for defibrillation, enabling a smaller device, and provides pacing features such as antitachycardia and asystole pacing in a single system.

AbstractObjectiveThe health benefits of exercise are well documented, but several exercise‐response parameters are attenuated in individuals with obesity. The goal of this pilot study was to identify molecular mechanisms that may influence exercise response with obesity.MethodsA multi‐omics comparison of the transcriptome, proteome, and phosphoproteome in muscle from a preliminary cohort of lean individuals (n = 4) and individuals with obesity (n = 4) was performed, before and after a single bout of 30 minutes of unilateral cycling at 70% maximal oxygen uptake (VO2 peak). Mass spectrometry and RNA sequencing were used to interrogate the proteome, phosphoproteome, and transcriptome from muscle biopsy tissue.ResultsThe main findings are that individuals with obesity exhibited transcriptional and proteomic signatures consistent with reduced mitochondrial function, protein synthesis, and glycogen synthesis. Furthermore, individuals with obesity demonstrated markedly different transcriptional, proteomic, and phosphoproteomic responses to exercise, particularly biosynthetic pathways of glycogen synthesis and protein synthesis. Casein kinase II subunit alpha and glycogen synthase kinase‐3β signaling was identified as exercise‐response pathways that were notably altered by obesity.ConclusionsOpportunities to enhance exercise responsiveness by targeting specific molecular pathways that are disrupted in skeletal muscle from individuals with obesity await a better understanding of the precise molecular mechanisms that may limit exercise‐response pathways in obesity.

PURPOSE Orteronel (TAK-700) is a nonsteroidal 17,20-lyase inhibitor suppressing androgen synthesis. We evaluated the clinical benefit of orteronel when added to androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer. METHODS In this open-label randomized phase III study, patients with metastatic hormone-sensitive prostate cancer were randomly assigned 1:1 to ADT with orteronel (300 mg oral twice daily; experimental arm) or ADT with bicalutamide (50 mg oral once daily; control arm). The primary objective was the comparison of overall survival (OS), targeting a 33% improvement in median survival. A stratified log-rank test with a one-sided P ≤ .022 would indicate statistical significance. Secondary end points were progression-free survival (PFS), prostate-specific antigen (PSA) level at 7 months (≤ 0.2 v 0.2 to ≤ 4 v > 4 ng/mL), and adverse event profile. RESULTS Among 1,279 patients included in the analysis, 638 were randomly assigned to the ADT plus orteronel arm and 641 to the control arm. The median age was 68 years; 49% had extensive disease. After a median follow-up of 4.9 years, there was a significant improvement in PFS (median 47.6 v 23.0 months, hazard ratio 0.58; 95% CI, 0.51 to 0.67; P < .0001) and PSA response at 7 months ( P < .0001), but not in OS (median 81.1 v 70.2 months, hazard ratio 0.86; 95% CI, 0.72 to 1.02; P = .040, one-sided). More grade 3/4 adverse events occurred in the experimental versus the control arms (43% v 14%). Postprotocol life-prolonging therapy was received by 77.4% of patients in the control arm and 61.3% of patients in the orteronel arm. CONCLUSION The study did not meet the primary end point of improved OS with orteronel. The lack of correlation of PFS and PSA response with OS raises concerns over assumption of their consistent surrogacy for OS in the context of extensive postprotocol therapy in this setting.