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To assess the incidence and relationship of cognitive/intellectual impairments to pain problems, seventy-three adults with musculoskeletal pain seen in a PM&R outpatient clinic were screened using the Neurobehavioral Cognitive Status Examination (NCSE). Subjective pain complaints were assessed using portions of the McGill Pain Questionnaire. Patients with prior diagnoses of neurocognitive problems or those who had taken narcotic analgesics in the last 24 hours were excluded. Results showed that 32 percent of subjects had impaired performance in at least one cognitive domain. Individuals with poorer performance on the NCSE had higher levels of reported pain or disability and psychological distress. Possible factors contributing to poor performance on cognitive tasks include psychological disorders or distress, undiagnosed organic brain dysfunction, social/psychological factors such as education, or a combination of these. Results suggest the need for further research to understand the relationship of poor performance on cognitive tasks to the etiology, maintenance and rehabilitation of pain problems.

ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.

LBA4 Background: Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains invariably fatal. Prostate-specific membrane antigen (PSMA) is highly expressed in mCRPC lesions. 177Lu-PSMA-617 is a targeted radioligand therapy that delivers ß-particle radiation to PSMA-expressing cells and surrounding microenvironment. Method: VISION was an international, randomized, open-label phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive mCRPC previously treated with next-generation androgen receptor signaling inhibition and 1–2 taxane regimens. PSMA positivity (threshold greater than liver) was determined by central review of 68Ga-PSMA-11 scans. Patients were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care (SOC) versus SOC alone. SOC was investigator determined but excluded cytotoxic chemotherapy and radium-223. The alternate primary endpoints were radiographic progression-free survival (rPFS) using PCWG3 criteria by independent central review (ICR) and overall survival (OS). Under the null hypothesis, median rPFS was assumed to be 4 months and OS 10 months for 177Lu-PSMA-617 + SOC for a hazard ratio (HR) of 1.00. Under the alternative hypothesis, median rPFS was assumed to be 6 months for a HR of 0.67 and median OS was assumed to be 13.7 months for a HR of 0.7306. Key secondary endpoints were objective response rate (ORR; RECIST v1.1), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). Results: Between 4 June 2018 and 23 October 2019, 831 of 1179 screened patients were randomized 2:1 to receive 177Lu-PSMA-617 + SOC (n = 551) or SOC only (n = 280). Median study follow-up was 20.9 months at the data cut-off (27 January 2021). Treatment groups were balanced in terms of demographics and baseline characteristics. 177Lu-PSMA-617 + SOC significantly improved rPFS versus SOC alone (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001, one-sided). The alternate primary endpoint of OS was also significantly improved versus SOC alone (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001, one-sided). All key secondary endpoints were statistically significant between the treatment arms in favor of 177Lu-PSMA-617 + SOC, including ICR-determined ORR (29.8% vs 1.7%), ICR-determined DCR (89.0% vs 66.7%) and time to first SSE (median time, 11.5 vs 6.8 months; HR, 0.50). While a higher rate of high-grade treatment-emergent adverse events was observed with 177Lu-PSMA-617 (52.7% vs 38.0%), therapy was well tolerated. Conclusions: 177Lu-PSMA-617 plus SOC treatment is a well-tolerated regimen that improves rPFS and prolongs OS compared with SOC alone in men with advanced-stage PSMA-positive mCRPC, supporting its adoption as a standard of care. Clinical trial information: NCT03511664.

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