Citations

Background Genetics may influence symptoms experienced by breast cancer survivors (BCS) by moderating the effects of stress-reducing interventions, including the Mindfulness-Based Stress Reduction (MBSR(BC)) program, to reduce symptom severity. As part of a larger clinical trial, the aim of this study was to evaluate genetic variants as moderators of MBSR(BC) on improvements among BCS in cognitive functioning and symptoms. Methods BCS ( n = 128) were randomized to MBSR(BC) or the Breast Cancer Education Support Program. Objective neuropsychological and subjective measures of cognitive performance, and psychological and physical symptoms were collected at baseline, 6, 12, and 26 weeks. Linear mixed models were implemented to identify MBSR(BC)’s effects over time. A total of 22 single nucleotide polymorphisms (SNPs) from 20 genes known to be related to these symptoms were investigated using genomic DNA. These SNPs were tested as moderators of MBSR(BC) program effects. Results Results showed MBSR(BC) participants experienced significantly greater benefits in cognitive functioning, however, the level of benefit varied based on one’s genetic profile. Effects sizes, consistency across similar measures were investigated. Among 22 candidate SNPs, rs4680 in COMT, rs1800497 in ANKK1, and rs6277 in DRD2 demonstrated the strongest, most consistent positive effects in moderating MBSR(BC)’s impact on cognitive outcomes. Conclusions Although the effects were small, this translational research may potentially identify BCS with genotypes that would be most influenced by the MBSR(BC) program. These results may be used to develop personalized intervention programs tailored to the genetic profile of each breast cancer survivor who received chemotherapy or chemotherapy and radiation. Trial Registration ClinicalTrials.gov, https://www.ClinicalTrials.gov Registration Number: NCT02786797.

Background In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers. Methods Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts. Results A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes. Conclusions This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma. Trial registration number NCT02500797.

Abstract Objective The presence of comorbidities can substantially affect patients’ quality of life, but data regarding their impact on idiopathic inflammatory myopathies (IIMs) are limited. Methods We examined the prevalence of comorbidities in IIM patients, other autoimmune rheumatic diseases (oAIRDs) and healthy controls (HCs), using data from the self-reported COVAD-2 survey. We defined basic multimorbidity (BM) as the presence of ≥2 non-rheumatic chronic conditions and complex multimorbidity (CM) as the presence of ≥3 non-rheumatic chronic conditions affecting ≥3 organ systems. Hierarchical clustering on principal components was performed for grouping. Results Among the COVAD respondents, 1558 IIMs, 4591 oAIRDs and 3652 HCs were analysed. IIMs exhibited a high burden of comorbidities (odds ratio [OR]: 1.62 vs oAIRDs and 2.95 vs HCs, P < 0.01), BM (OR: 1.66 vs oAIRDs and 3.52 vs HCs, P < 0.01), CM (OR: 1.69 vs AIRDs and 6.23 vs HCs, P < 0.01) and mental health disorders (MHDs) (OR: 1.33 vs oAIRDs and 2.63 vs HCs, P < 0.01). Among the IIM patients, those with comorbidities or MHDs had lower PROMIS Global Physical (PGP), PROMIS Global Mental (PGM), and PROMIS Physical Function (SF10) scores, and higher fatigue (F4a) scores (all P < 0.001). PGP, PGM, SF10a and F4a were influenced by age, active disease, BM and MHDs. Four distinct clusters were identified among the IIMs according to comorbidities and PROMIS scores. Conclusion Patients with IIMs have a higher burden of comorbidities that influence physical and mental health, identifiable as clinical clusters for optimized and holistic management approaches.

Importance Office-based phototherapy is cost-effective for psoriasis but difficult to access. Home-based phototherapy is patient preferred but has limited clinical data, particularly in patients with darker skin. Objective To compare the effectiveness of home- vs office-based narrowband UV-B phototherapy for psoriasis. Design, Setting, and Participants The Light Treatment Effectiveness study was an investigator-initiated, pragmatic, open-label, parallel-group, multicenter, noninferiority randomized clinical trial embedded in routine care at 42 academic and private clinical dermatology practices in the US. Enrollment occurred from March 1, 2019, to December 4, 2023, with follow-up through June 2024. Participants were 12 years and older with plaque or guttate psoriasis who were candidates for home- and office-based phototherapy. Interventions Participants were randomized to receive a home narrowband UV-B machine with guided mode dosimetry or routine care with office-based narrowband UV-B for 12 weeks, followed by an additional 12-week observation period. Main Outcomes and Measures The coprimary effectiveness outcomes were Physician Global Assessment (PGA) dichotomized as clear/almost clear skin (score of ≤1) at the end of the intervention period and Dermatology Life Quality Index (DLQI) score of 5 or lower (no to small effect on quality of life) at week 12. Results Of 783 patients enrolled (mean [SD] age, 48.0 [15.5] years; 376 [48.0%] male), 393 received home-based phototherapy and 390 received office-based phototherapy, with 350 (44.7%) having skin phototype (SPT) I/II, 350 (44.7%) having SPT III/IV, and 83 (10.6%) having SPT V/VI. A total of 93 patients (11.9%) were receiving systemic treatment. At baseline, mean (SD) PGA was 2.7 (0.8) and DLQI was 12.2 (7.2). At week 12, 129 patients (32.8%) receiving home-based phototherapy and 100 patients (25.6%) receiving office-based phototherapy achieved clear/almost clear skin, and 206 (52.4%) and 131 (33.6%) achieved DLQI of 5 or lower, respectively. Home-based phototherapy was noninferior to office-based phototherapy for PGA and DLQI in the overall population and across all SPTs. Home-based phototherapy, compared to office-based phototherapy, was associated with better treatment adherence (202 patients [51.4%] vs 62 patients [15.9%]; P < .001), lower burden of indirect costs to patients, and more episodes of persistent erythema (466 of 7957 treatments [5.9%] vs 46 of 3934 treatments [1.2%]; P < .001). Both treatments were well tolerated with no discontinuations due to adverse events. Conclusions and Relevance In this randomized clinical trial, home-based phototherapy was as effective as office-based phototherapy for plaque or guttate psoriasis in everyday clinical practice and had less burden to patients. Trial Registration ClinicalTrials.gov Identifier: NCT03726489

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. Nutritional metabolic interventions may fundamentally change the tumor microenvironment and improve outcomes. A ketogenic diet (KD) (lower carbohydrate, moderate protein, higher fat) can significantly reduce glucose and insulin and stimulate ketogenesis. Triplet chemotherapy with gemcitabine/cisplatin/nab-paclitaxel has been associated with a median OS 16.4 months, PFS 10.1 months in patients with metastatic PDAC in the first-line setting. Recently, KD plus triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and prolong animal survival over chemotherapy alone (Yang et al, Med, 2022). Tumor growth inhibition was associated with glucose depletion, altered TCA substrate use and NADH elevation. Methods: In this Phase II trial, patients with treatment-naive metastatic PDAC were randomized to triplet chemotherapy with a medically supervised ketogenic diet (MSKD) or continuing their usual diet (non-MSKD). The MSKD is supported by Virta Health, who offers tracking of daily ketone (beta-hydroxybutyrate, BHB) and glucose levels, a web-based application, education, and communication with a remote care team to ensure sustained nutritional ketosis (BHB 0.5–3.0mM). Patients with BMI < 18, type 1 DM or history of DKA were excluded. Primary endpoint was PFS. Secondary endpoints: DCR (PR+CR+SD ≥ 9 weeks), change in CA 19-9 (CA125, CEA if not CA 19-9 expressers), average fasting insulin levels, HbA1c, body weight, gut microbiome, serum metabolites, QOL (QLQ- C30). Results: A total of 36 patients with untreated metastatic PDAC were enrolled. Among 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to each arm. Both groups had similar baseline weight, HgbA1c, insulin and BHB levels (all p>0.05). Nine patients had type 2 DM; 6 required insulin. In the MSKD group, 15/16 achieved nutritional ketosis at any point during the study, with mean BHB of 0.57 mM (95% CI 0.40–0.73) and median proportion of days in ketosis of 39.4% (range 0-95.8%) by daily ketone tracking. Lab data showed significantly higher mean ± SD maximum change in BHB in the MSKD (0.5 ± 0.9 mmol/L) versus non-MSKD (–0.2 ± 0.3 mol/L) group (p = 0.018). There were no significant differences between groups in maximum change in weight, HbA1C, or insulin (all p > 0.05). The most common MSKD-related adverse events were Gr 1-2 fatigue (n=4), constipation (n=3), weight loss (n=3), and none stopped MSKD due to adverse events.Conclusion: A medically supervised ketogenic diet is feasible in patients with metastatic PDAC receiving triplet chemotherapy, with median proportion of days in ketosis of 39.4% and an acceptable safety profile. The MSKD is associated with comparable changes in insulin and HgbA1c levels compared to the non-MSKD diet, and sustained ketosis does not result in significantly greater weight loss. MSKD warrants further prospective exploration and analyses of the primary endpoint and correlative studies are ongoing. Citation Format: Gayle S Jameson, Erkut Borazanci, Diana L Hanna, Caroline GP Roberts, Meredith S Pelster, Richard C Frank, Angela T Alistar, Julia E Wiedmeier-Nutor, Sandra D Algaze, Brandon Fell, Sarah J Hallberg, Denise J Roe, Betsy C Wertheim, Derek Cridebring, Joshua D Rabinowitz, Stephen Gately, Daniel D Von Hoff, Drew W Rasco. Randomized phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer: initial results of safety and feasibility of the medically supervised ketogenic diet [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B012.

The objective of this project was to develop a standardized list of renally eliminated and potentially nephrotoxic drugs that will help inform initiatives to improve medication safety. Several available lists of medications from the published literature including original research articles and reviews, and from regulatory agencies, tertiary references, and clinical decision support systems were compiled, consolidated, and compared. Only systemically administered medications were included. Medication combinations were included if at least 1 active ingredient was considered renally dosed or potentially nephrotoxic. The medication list was reviewed for completeness and clinical appropriateness by a multidisciplinary team of individuals with expertise in critical care, nephrology, and pharmacy. An initial list of renally dosed and nephrotoxic drugs was created. After reconciliation and consensus from clinical experts, a standardized list of 681 drugs is proposed. The proposed evidence-based standardized list of renally dosed and potentially nephrotoxic drugs will be useful to harmonize epidemiologic and medication quality improvement studies. In addition, the list can be used for clinical purposes with surveillance in nephrotoxin stewardship programs. We suggest an iterative re-evaluation of the list with emerging literature and new medications on an approximately annual basis.

Abstract Background The CDC reported a 35% increase in hospital-onset (HO) carbapenem-resistant Enterobacterales (CRE) infections during the COVID-19 pandemic. We evaluated patient outcomes following HO and community-onset (CO) CRE bloodstream infections (BSI). Methods Patients prospectively enrolled in CRACKLE-2 from 56 hospitals in 10 countries between 30 April 2016 and 30 November 2019 with a CRE BSI were eligible. Infections were defined as CO or HO by CDC guidelines, and clinical characteristics and outcomes were compared. The primary outcome was desirability of outcome ranking (DOOR) 30 days after index culture. Difference in 30-day mortality was calculated with 95% CI. Results Among 891 patients with CRE BSI, 65% were HO (582/891). Compared to those with CO CRE, patients with HO CRE were younger [median 60 (Q1 42, Q3 70) years versus 65 (52, 74); P < 0.001], had fewer comorbidities [median Charlson comorbidity index 2 (1, 4) versus 3 (1, 5); P = 0.002] and were more acutely ill (Pitt bacteraemia score ≥4: 47% versus 32%; P < 0.001). The probability of a better DOOR outcome in a randomly selected patient with CO BSI compared to a patient with HO BSI was 60.6% (95% CI: 56.8%–64.3%). Mortality at 30-days was 12% higher in HO BSI (192/582; 33%) than CO BSI [66/309 (21%); P < 0.001]. Conclusion We found a disproportionately greater impact on patient outcomes with HO compared to CO CRE BSIs; thus, the recently reported increases in HO CRE infections by CDC requires rigorous surveillance and infection prevention methods to prevent added mortality.