Sarcopenia in Patients With Rectal Adenocarcinoma: An Opportunity for Preoperative Rehabilitation.

BACKGROUND: Sarcopenia, defined as low skeletal muscle mass, affects up to 60% of rectal adenocarcinoma patients receiving neoadjuvant chemoradiation (NACRT), with negative impact on patient outcomes. Identifying modifiable risk factors may decrease morbidity and mortality. METHODS: A retrospective review of rectal cancer patients from a single academic center from 2006 to 2020 was performed. Sixty-nine patients with pre- and post-NACRT CT imaging were included. Skeletal muscle index (SMI) was calculated as total L3 skeletal muscle divided by height squared. Sarcopenia thresholds were 52.4 cm2/m2 for men and 38.5 cm2/m2 for women. Student T-test, chi-square test, multivariable regression, and multivariable Cox hazard analysis were performed. RESULTS: 62.3% of patients lost SMI from pre- to post-NACRT imaging, with a mean change of -7.8% (±19.9%). Eleven (15.9%) patients were sarcopenic at presentation, increasing to 20 (29.0%) following NACRT. Mean SMI decreased from 49.0 cm2/m2 (95% CI: 42.0 cm2/m2-56.0 cm2/m2) to 38.2 cm2/m2 (95% CI: 33.6 cm2/m2-42.9 cm2/m2) (P = .003). Pre-NACRT sarcopenia correlated with post-NACRT sarcopenia (OR 20.6, P = .002). Percent decrease in SMI was associated with a 5% increased mortality risk. CONCLUSION: The presence of sarcopenia at diagnosis and its association with post-NACRT sarcopenia suggests an opportunity for a high-impact intervention.

Consequences of anti-vascular endothelial growth factor treatment lapse in patients with retinal vein occlusion.

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) treatments are the first-line treatment for Retinal Vein Occlusion (RVO). Although effectiveness and safety of these treatments is well documented, knowledge regarding the effect of lapses in anti-VEGF treatment among RVO patients is lacking. The purpose of this study is to analyse the anatomic and visual outcomes from a lapse in anti-VEGF treatment in patients with RVO. METHODS: This retrospective case-control study evaluated 136 patients diagnosed with RVO and treated with anti-VEGF between January 2012 and June 2020 at Cole Eye Institute, Cleveland Clinic. Patients were divided into two cohorts: RVO patients with no lapse in anti-VEGF treatment (control group) and RVO patients with a lapse ≥3 months (lapse group). Central subfield thickness (CST) and best corrected visual acuity (BCVA) were collected pre-lapse, the first appointment post-lapse, and at 3-, 6-, and 12-month follow-up appointments. RESULTS: Lapse patients (n = 68) and control patients (n = 68) had similar pre-lapse CST (p = 0.466) and BCVA (p = 0.303). Lapse patients experienced a significant increase in CST after discontinuing anti-VEGF therapy (lapse: 400.6 ± 192.1 µm, control: 333.0 ± 111.1 µm, p = 0.024). This persisted 12 months post-lapse after re-initiation of anti-VEGF agents (lapse: 381.6 ± 161.1 µm, control: 307.5 ± 95.4 µm, p = 0.030). Lapse patients also experienced a decrease in BCVA after lapse (lapse: 54.3 ± 25.1 ETDRS, control: 64.4 ± 17.8 ETDRS, p < 0.001) that recovered after 6 months of anti-VEGF treatment. CONCLUSIONS: RVO patients with any lapse of anti-VEGF treatment are at risk for poorer anatomic and visual outcomes. Though BCVA normalizes upon treatment resumption, patients experience a statistically significant increase in CST that does not recover.

A Virtual Curriculum to Increase Exposure to Oncologic Subspecialties for Undergraduate Medical Students.

Medical student exposure to oncology is imperative given the prevalence of cancer, growing need for survivorship care, and ever-evolving therapies. Our institution offers a Cancer Care Elective for undergraduate medical students focused on clinical shadowing, but the COVID-19 pandemic necessitated completely redesigning a virtual alternative. In this study, we utilize a post-elective survey to 1) assess whether the novel virtual elective effectively promoted student learning and 2) identify which components were most impactful. We created an entirely virtual, semester-long course with structured mentorship, subspecialty panels, physician-led didactics, and patient exposure. Students attended multidisciplinary tumor boards and presented on oncologic topics. A post-elective survey assessed the course's impact on students' knowledge and the perceived value of each elective component. Of the 29 enrolled students, 12 responded to our survey (41%). Most students reported that the elective highly enhanced their understanding of medical (67%), surgical (75%), and pediatric (66%) oncology. The highest rated didactic involved patients discussing their cancer journeys, with 80% of students reporting that this session enhanced their understanding of patient-physician collaboration. Students reported that physician mentorship helped them better understand oncology (90%) and promoted interest in pursuing an oncologic career (100%). This study demonstrates that our virtual Cancer Care Elective was effective at increasing student understanding of oncology in practice. The results also suggest that patient exposure and physician mentorship are particularly educational and encouraging.

USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors.

BRCA1-deficient tumor cells have defects in homologous-recombination repair and replication fork stability, resulting in PARP inhibitor sensitivity. Here, we demonstrate that a deubiquitinase, USP1, is upregulated in tumors with mutations in BRCA1. Knockdown or inhibition of USP1 resulted in replication fork destabilization and decreased viability of BRCA1-deficient cells, revealing a synthetic lethal relationship. USP1 binds to and is stimulated by fork DNA. A truncated form of USP1, lacking its DNA-binding region, was not stimulated by DNA and failed to localize and protect replication forks. Persistence of monoubiquitinated PCNA at the replication fork was the mechanism of cell death in the absence of USP1. Taken together, USP1 exhibits DNA-mediated activation at the replication fork, protects the fork, and promotes survival in BRCA1-deficient cells. Inhibition of USP1 may be a useful treatment for a subset of PARP-inhibitor-resistant BRCA1-deficient tumors with acquired replication fork stabilization.

Human CHD1 is required for early DNA-damage signaling and is uniquely regulated by its N terminus.

CHD1 is a conserved chromatin remodeling enzyme required for development and linked to prostate cancer in adults, yet its role in human cells is poorly understood. Here, we show that targeted disruption of the CHD1 gene in human cells leads to a defect in early double-strand break (DSB) repair via homologous recombination (HR), resulting in hypersensitivity to ionizing radiation as well as PARP and PTEN inhibition. CHD1 knockout cells show reduced H2AX phosphorylation (γH2AX) and foci formation as well as impairments in CtIP recruitment to the damaged sites. Chromatin immunoprecipitation following a single DSB shows that the reduced levels of γH2AX accumulation at DSBs in CHD1-KO cells are due to both a global reduction in H2AX incorporation and poor retention of H2AX at the DSBs. We also identified a unique N-terminal region of CHD1 that inhibits the DNA binding, ATPase, and chromatin assembly and remodeling activities of CHD1. CHD1 lacking the N terminus was more active in rescuing the defects in γH2AX formation and CtIP recruitment in CHD1-KO cells than full-length CHD1, suggesting the N terminus is a negative regulator in cells. Our data point to a role for CHD1 in the DSB repair process and identify a novel regulatory region of the protein.

Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair.

Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability of EOCs and for their cellular hyper-dependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. Previous studies have implicated the DNA polymerase θ (Polθ also known as POLQ, encoded by POLQ) in a pathway required for the repair of DNA double-strand breaks, referred to as the error-prone microhomology-mediated end-joining (MMEJ) pathway. Whether Polθ interacts with canonical DNA repair pathways to prevent genomic instability remains unknown. Here we report an inverse correlation between HR activity and Polθ expression in EOCs. Knockdown of Polθ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, while knockdown of Polθ in HR-deficient EOCs enhances cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, Polθ contains RAD51 binding motifs and it blocks RAD51-mediated recombination. Our results reveal a synthetic lethal relationship between the HR pathway and Polθ-mediated repair in EOCs, and identify Polθ as a novel druggable target for cancer therapy.

Human CHD2 is a chromatin assembly ATPase regulated by its chromo- and DNA-binding domains.

Chromodomain helicase DNA-binding protein 2 (CHD2) is an ATPase and a member of the SNF2-like family of helicase-related enzymes. Although deletions of CHD2 have been linked to developmental defects in mice and epileptic disorders in humans, little is known about its biochemical and cellular activities. In this study, we investigate the ATP-dependent activity of CHD2 and show that CHD2 catalyzes the assembly of chromatin into periodic arrays. We also show that the N-terminal region of CHD2, which contains tandem chromodomains, serves an auto-inhibitory role in both the DNA-binding and ATPase activities of CHD2. While loss of the N-terminal region leads to enhanced chromatin-stimulated ATPase activity, the N-terminal region is required for ATP-dependent chromatin remodeling by CHD2. In contrast, the C-terminal region, which contains a putative DNA-binding domain, selectively senses double-stranded DNA of at least 40 base pairs in length and enhances the ATPase and chromatin remodeling activities of CHD2. Our study shows that the accessory domains of CHD2 play central roles in both regulating the ATPase domain and conferring selectivity to chromatin substrates.