Single-nucleus expression characterization of non-enhancing region of recurrent high-grade glioma.

Background: Non-enhancing (NE) infiltrating tumor cells beyond the contrast-enhancing (CE) bulk of tumor are potential propagators of recurrence after gross total resection of high-grade glioma. Methods: We leveraged single-nucleus RNA sequencing on 15 specimens from recurrent high-grade gliomas (n = 5) to compare prospectively identified biopsy specimens acquired from CE and NE regions. Additionally, 24 CE and 22 NE biopsies had immunohistochemical staining to validate RNA findings. Results: Tumor cells in NE regions are enriched in neural progenitor cell-like cellular states, while CE regions are enriched in mesenchymal-like states. NE glioma cells have similar proportions of proliferative and putative glioma stem cells relative to CE regions, without significant differences in % Ki-67 staining. Tumor cells in NE regions exhibit upregulation of genes previously associated with lower grade gliomas. Our findings in recurrent GBM paralleled some of the findings in a re-analysis of a dataset from primary GBM. Cell-, gene-, and pathway-level analyses of the tumor microenvironment in the NE region reveal relative downregulation of tumor-mediated neovascularization and cell-mediated immune response, but increased glioma-to-nonpathological cell interactions. Conclusions: This comprehensive analysis illustrates differing tumor and nontumor landscapes of CE and NE regions in high-grade gliomas, highlighting the NE region as an area harboring likely initiators of recurrence in a pro-tumor microenvironment and identifying possible targets for future design of NE-specific adjuvant therapy. These findings also support the aggressive approach to resection of tumor-bearing NE regions.

Comparative Effectiveness of Psychotherapy vs Antidepressants for Depression in Heart Failure: A Randomized Clinical Trial.

Importance: Heart failure (HF) affects more than 6 million adults in the US and more than 64 million adults worldwide, with 50% prevalence of depression. Patients and clinicians lack information on which interventions are more effective for depression in HF. Objective: To compare the effectiveness of behavioral activation psychotherapy (BA) vs antidepressant medication management (MEDS) on patient-centered outcomes inpatients with HF and depression. Design, Setting, and Participants: This pragmatic randomized comparative effectiveness trial was conducted from 2018 to 2022, including 1-year follow-up, at a not-for-profit academic health system serving more than 2 million people from diverse demographic, socioeconomic, cultural, and geographic backgrounds. Participant included inpatients and outpatients diagnosed with HF and depression, and data were analyzed as intention-to-treat. Data were analyzed from 2022 to 2023. Interventions: BA is an evidence-based manualized treatment for depression, promoting engagement in personalized pleasurable activities selected by patients. MEDS involves the use of an evidence-based collaborative care model with care managers providing coordination with patients, psychiatrists, and primary care physicians to only administer medications. Main Outcomes and Measures: The primary outcome was depressive symptom severity at 6 months, measured using the Patient Health Questionnaire 9-Item (PHQ-9). Secondary outcomes included physical and mental health-related quality of life (HRQOL), measured using the Short-Form 12-Item version 2 (SF-12); heart failure-specific HRQOL, measured using the Kansas City Cardiomyopathy Questionnaire; caregiver burden, measured with the Caregiver Burden Questionnaire for Heart Failure; emergency department visits; readmissions; days hospitalized; and mortality at 3, 6, and 12 months. Results: A total of 416 patients (mean [SD] age, 60.71 [15.61] years; 243 [58.41%] male) were enrolled, with 208 patients randomized to BA and 208 patients randomized to MEDS. At baseline, mean (SD) PHQ-9 scores were 14.54 (3.45) in the BA group and 14.31 (3.60) in the MEDS group; both BA and MEDS recipients experienced nearly 50% reduction in depressive symptoms at 3, 6, and 12 months (eg, mean [SD] score at 12 months: BA, 7.62 (5.73); P < .001; MEDS, 7.98 (6.06); P < .001; between-group P = .55). There was no statistically significant difference between BA and MEDS in the primary outcome of PHQ-9 at 6 months (mean [SD] score, 7.53 [5.74] vs 8.09 [6.06]; P = .88). BA recipients, compared with MEDS recipients, experienced small improvement in physical HRQOL at 6 months (mean [SD] SF-12 physical score: 38.82 [11.09] vs 37.12 [10.99]; P = .04), had fewer ED visits (3 months: 38% [95% CI, 14%-55%] reduction; P = .005; 6 months: 30% [95% CI, 14%-40%] reduction; P = .008; 12 months: 27% [95% CI, 15%-38%] reduction; P = .001), and spent fewer days hospitalized (3 months: 17% [95% CI, 8%-25%] reduction; P = .002; 6 months: 19% [95% CI, 13%-25%] reduction; P = .005; 12 months: 36% [95% CI, 32%-40%] reduction; P = .001). Conclusions and Relevance: In this comparative effectiveness trial of BA and MEDS in patients with HF experiencing depression, both treatments significantly reduced depressive symptoms by nearly 50% with no statistically significant differences between treatments. BA recipients experienced better physical HRQOL, fewer ED visits, and fewer days hospitalized. The study findings suggested that patients with HF could be given the choice between BA or MEDS to ameliorate depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03688100.