Publications

PURPOSE: The Promoting Resilience in Stress Management (PRISM) intervention is a brief, positive psychological skills-based intervention delivered by lay-coaches with demonstrated efficacy at decreasing distress in young adults with cancer. We recently completed a pilot trial of "PRISM for women with breast cancer" (PRISM-BC) and demonstrated feasibility. Here, we conducted qualitative analyses to better understand the experiences of women who participated in PRISM-BC.

METHODS: For this single-armed, pilot study of PRISM-BC, we recruited women who were receiving chemotherapy for any stage of breast cancer. All received the PRISM intervention, including six individual, virtual sessions and access to a companion mobile app for skill practice. Following PRISM completion, participants completed a 30-60-minute semi-structured, qualitative interview. We employed coding reliability thematic analysis to identify themes, with two team members applying codes to ensure satisfactory inter-rater reliability.

RESULTS: Women (N=33) were on average 54.1 years old (SD=9.5); most had early stage disease (76%), identified as Black/African American (58%), and downloaded the companion app (70%). We identified four themes: 1) PRISM was helpful due to both new skill acquisition and experiential relevance; 2) The app was helpful to many, but barriers prevented use among some; 3) Both facilitators and barriers to PRISM engagement were present; 4) Opportunities exist to tailor PRISM further to the specific needs of breast cancer survivors CONCLUSION: PRISM was well-received among women with breast cancer. Future work should examine the efficacy of PRISM in larger, controlled trials in breast oncology incorporating suggested modifications (e.g., content around medication adherence).

BACKGROUND: Sulfonylureas (SU) are widely used for diabetes management in older adults but can cause hypoglycemia, which may be worsened by drug interactions. We applied high-throughput data mining to identify medications that could increase hypoglycemia risk when taken with SU.

METHODS: Using Medicare, MarketScan, and Optum Clinformatics (2003-2022), we identified patients aged ≥ 65 years who experienced a severe hypoglycemic event after at least 90 days on SU. We evaluated all medications dispensed in the 90 days before the event using a case-crossover (CCO) design. We adjusted for time-varying confounding and direct effect of the evaluated medications (precipitant) using a case-case time-control (CCTC) approach and metformin as control. We computed odds ratios (ORs) for its association with hypoglycemia. The false discovery rate (FDR) was controlled at 0.05 to adjust for multiple testing. To reduce confounding from other diabetes medications, we analyzed non-diabetes and diabetes medications separately.

RESULTS: Among 1607 candidate drugs received before experiencing hypoglycemia, 86 non-diabetes medications showed a CCO OR ≥ 1.00. With metformin as control, sulfamethoxazole/trimethoprim (CCTC OR 1.76, p < 0.01, FDR q < 0.01) and metronidazole (CCTC OR 2.17, p < 0.01, FDR q = 0.04) were associated with severe hypoglycemia. Among 10 diabetes medications, insulin showed increased association (CCO OR 1.22, p < 0.01); however, once adjusted for the drug's direct effects, CCTC OR was 1.03 (p = 0.47, FDR q = 0.47).

CONCLUSIONS: Using a high-throughput data mining approach, we identified two antibiotics (sulfamethoxazole/trimethoprim and metronidazole) that may increase hypoglycemia risk in older adults on sulfonylureas. Given the exploratory nature of this study, these findings warrant further investigation.

BACKGROUND: The US Food and Drug Administration (FDA)-mandates Risk Evaluation and Mitigation Strategy (REMS) programs for certain drugs with serious side effects help ensure that the benefits of use outweigh the risks. REMS materials-including enrollment forms, fact sheets, and medication guides-inform patients and caregivers about drug risks and program requirements.

OBJECTIVE: To explore how effectively REMS materials communicate drug risk information and program requirements to patients and caregivers and to identify patients' and caregivers' preferences for risk communication.

METHODS: Interviews with patients and caregivers of patients prescribed REMS-covered drugs focused on REMS materials. Transcripts were coded manually, with answers to closed-ended questions tabulated in Excel.

RESULTS: The study included 43 patients and six caregivers across eight REMS-covered drugs: alemtuzumab, ambrisentan, clozapine, isotretinoin, lenalidomide, pegvaliase, pomalidomide, and sodium oxybate. Most participants were female (N = 42, 86%), white/non-Hispanic (N = 40, 82%), and college educated (N = 37, 76%). The average age was 40 years, with 27 (55%) having annual family incomes over $100,000. Most participants learned about REMS-covered drugs via printed information (N = 36, 73%), mostly REMS materials; conversations with providers about drug risks and benefits (N = 29, 59%); and websites found on their own (N = 42, 86%). Nearly all participants (N = 47, 96%) felt well-informed about drug risks and benefits, and most participants taking self-administered drugs (N = 28, 67%) reported understanding safe use "very well." However, knowledge gaps emerged around REMS-related risks and reasons for safe use measures; some participants misunderstood REMS enrollment forms as legal protections, not safety measures. Patients also widely varied in their valuations of REMS materials, with some feeling informed and empowered and others confused or intimidated. Preferences for risk communication varied; most participants (N = 36, 73%) wanted to receive information verbally from providers, with several wanting visual aids, summaries, and other resources.

DISCUSSION: Gaps in patients' and caregivers' understanding of REMS programs and drug risks highlight the merits of reviewing communication materials and strategies. Clear, concise, and comprehensive educational documents could promote understanding and adherence to REMS requirements.

BACKGROUND AND AIMS: Diabetes is associated with increased risk of cardiovascular and renal disease. This study investigated the role of peptidylarginine deiminase 4 (PAD4), neutrophil extracellular traps (NETs), and inflammasome activation in diabetic cardiomyopathy (DCM) and kidney disease (DKD).

METHODS: Endomyocardial biopsies (EMB) from heart failure (HF) patients (n = 20) with or without diabetes were stained for NETs. Wild-type (WT) and PAD4⁻/⁻ mice were subjected to streptozotocin (STZ)-induced diabetes and cardiac function, blood glucose, body weight, and exercise tolerance were assessed longitudinally. NETosis and ASC specks were evaluated in mouse and human neutrophils. Cardiac and renal fibrosis was assessed by Sirius Red/Fast Green staining. Confocal microscopy, ELISA, and flow cytometry were used to quantify NETs, IL-1β, von Willebrand factor (VWF), cytokine transforming growth factor beta-1 (TGF-β1), and neutrophil infiltration.

RESULTS: Myocardial NET burden was increased in HF patients with diabetes. High glucose triggered inflammasome activation in human neutrophils. After STZ, PAD4⁻/⁻ and WT mice developed hyperglycaemia and weight loss, yet only WT neutrophils showed increased NETosis and ASC speck formation. Only diabetic WT mice exhibited elevated IL-1β and VWF levels, impaired cardiac function, reduced exercise tolerance, and pulmonary oedema; PAD4⁻/⁻ mice were protected. Wild-type diabetic hearts and kidneys showed greater fibrosis, neutrophil infiltration, NETs, and TGF-β1 levels. Kidney injury in WT mice was reflected by albuminuria and renal fibrosis, whereas PAD4⁻/⁻ mice preserved renal function.

CONCLUSIONS: Diabetes promotes neutrophil inflammasome activation and NETosis, driving cardiac and renal inflammation and fibrosis. Peptidylarginine deiminase 4 deficiency prevents heart failure and preserves kidney function in experimental diabetes.

BACKGROUND: Fimepinostat, an oral dual inhibitor of histone deacetylase (HDAC) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), has shown activity in preclinical models of Myc-driven pediatric malignancies. This Phase 1 trial aimed to determine the recommended pediatric Phase 2 dose (RPP2D), describe the toxicity profile, and evaluate the pharmacokinetics of fimepinostat in children with relapsed and refractory solid and central nervous system (CNS) tumors.

METHODS: This multicenter, Phase 1 study enrolled patients ages 1-21 years with relapsed or refractory solid tumors, CNS tumors, or lymphoma. The dose-escalation phase followed a 3 + 3 design, starting at 27.5 mg/m2 and escalating to 45 mg/m2. Following dose escalation, three expansion cohorts were opened including cohorts for patients with Myc(n)-driven neuroblastoma, Myc-driven extracranial solid tumors, and diffuse large B-cell lymphoma or Burkitt lymphoma. The pharmacokinetics of fimepinostat and its metabolites were studied after the first dose.

RESULTS: Twenty-six patients were enrolled, with 25 receiving treatment. The median age was 13.6 years (range: 4.1-20.9). In the dose-escalation phase, 12 patients were evaluable for DLT assessment. The RPP2D was initially determined to be 45 mg/m2 but was revised to 35 mg/m2 after observing DLTs in the dose-expansion phase. Treatment-related adverse events were primarily hematologic and gastrointestinal. No objective responses were observed in 23 evaluable patients. Three patients had stable disease for over four cycles, including a patient with MYCN amplified neuroblastoma with stable disease for 24 cycles. Pharmacokinetic analysis showed significant interpatient variability and rapid conversion of fimepinostat to its metabolites.

CONCLUSION: Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02909777.

BackgroundBasilar artery occlusion (BAO) is a rare stroke type, with subtypes like vertebrobasilar tandem occlusion (VBTO), complicating treatment. Mechanical thrombectomy (MT) is increasingly used, but evidence on its safety and effectiveness in VBTO compared to isolated BAO (iBAO) remains limited.MethodsPubMed, Cochrane Central, Embase, Web of Science, and ScienceDirect were searched till May 2025. The risk ratios (RR) were pooled along with 95% Confidence intervals (CI) under the random effects model using Review Manager. The Newcastle Ottawa Scale and GRADE assessment were used to assess the quality of studies and certainty of evidence. Successful recanalization was defined as a Thrombolysis in Cerebral Infarction (TICI) score of ≥2b. The modified Rankin Scale (mRS) is a scale used to assess the severity of stroke, with functional independence defined as an mRS score of 0-2. Publication bias was assessed using funnel plots and Egger's regression test.ResultsNine studies, pooling a total of 737 patients, were included in this analysis. MT showed no significant difference in functional independence in the VBTO group compared to the iBAO group (RR = 1.25; 95% CI: 0.73, 2.12; p = .42). The successful recanalization was also comparable between the VBTO and iBAO arms when MT was performed (RR = 0.96; 95%CI 0.81, 1.13; p = .60). The risk of symptomatic intracerebral hemorrhage (sICH) was significantly increased when MT was performed in the VBTO arm compared to the iBAO group (RR = 2.20; 95%CI : 1.09, 4.46]; p = .03). The mortality rates were also comparable between the two groups (RR = 1.28; 95% CI 0.78, 2.10; p = .33). Also, in the VBTO patients, the successful recanalization rate showed no significant difference between the clean and dirty road techniques (RR = 1.04; 95% CI 0.90, 1.20; p = .63).ConclusionWhen MT was performed on VBTO and iBAO patients, the efficacy endpoints-such as functional independence and successful recanalization-and the safety endpoint of mortality were comparable. However, the risk of sICH was higher in the VBTO group.

BACKGROUND AND AIMS: Financial toxicity, the combined objective burden and subjective distress that affects patients' medical care, is not well described in patients with IBD. We aimed to characterize financial toxicity in patients with IBD.

METHODS: We designed and administered a de-identified survey to patients with IBD. The primary outcome, financial toxicity, was defined as a score <22 on the COST-FACIT scale, a validated measure. We constructed multivariable logistic regression models to evaluate associations adjusting for age, sex, race, type of IBD, IBD medications, household income and education level.

RESULTS: Respondents (n=669) had a median age of 49 years, were 62% female and 92% White. 52% were currently treated with advanced IBD-therapy and 58% reported IBD in remission/minimal activity. 53% were employed full-time. 61% had an annual household income ≥$100,000. 69% had private insurance and 31% had Medicare.21% reported trouble paying medical bills in the past year; 34% of working adults missed work in the past 7 days because of IBD. 39% experienced financial toxicity. Adjusting for confounders, adults <65 years were more likely to experience toxicity than older adults (aOR: 6.78, 95%CI: 2.60-17.65). Those with education less than a Bachelor's Degree (aOR: 2.73, 95%CI: 1.70-4.37), annual household income <$60,000 (aOR: 3.71, 95%CI: 2.14-6.42) and women were more likely to experience financial toxicity (aOR: 1.90; 95%CI: 1.28-2.81).

CONCLUSIONS: Financial toxicity was prevalent among patients with IBD, particularly among younger adults, those with lower income and education and women. Enquiring about financial toxicity should be incorporated into IBD clinical practice.

The mTOR protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2-Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved amongst at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.

BACKGROUND: Brain-infiltrating tumour cells from high-grade glioma remain shielded from drug treatments by the blood-brain barrier, leading to inevitable recurrence. Microbubble-enhanced transcranial focused ultrasound (MB-FUS) enables controlled blood-brain barrier opening (BBBO), permitting localised drug delivery. We aimed to assess safety and feasibility of MB-FUS plus standard-of-care chemotherapy for individuals with high-grade glioma.

METHODS: BT008NA was an open-label, single-arm, phase 1/2 trial conducted at five sites in the USA and Canada (part of the ReFOCUSED Consortium). Key eligibility criteria were participants with newly diagnosed high-grade glioma (glioblastoma as per WHO 2016 classification), aged 18-80 years, with normal organ function, a baseline Karnofsky Performance Status score of 70 or higher, who had received maximal safe resection and 6-week chemoradiotherapy and were to start standard-of-care monthly adjuvant temozolomide chemotherapy (150 mg/m2 of body surface area). MRI-guided, 220 kHz transcranial MB-FUS treatments were delivered in periresectional (tumour-infiltrative) regions, on any of the first 3 days of a 28-day temozolomide cycle, for up to six cycles. Primary outcomes were safety (adverse events) and feasibility (BBBO: new contrast enhancement on post-procedure T1-weighted MRI). Protocol-prespecified secondary outcomes were overall survival and progression-free survival. Analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03551249 (USA) and NCT03616860 (Canada), and is closed to enrolment.

FINDINGS: Between Oct 16, 2018, and March 9, 2022, we enrolled 34 participants, all evaluable for prespecified primary and secondary endpoints, with a mean age of 51·5 years (SD 13·0) and median follow-up 44·5 months (95% CI 34·9-57·3). By self-reporting, 18 (53%) participants were female and 16 (47%) male, 28 (82%) were White, and 34 (100%) were non-Hispanic. 176 adverse events were captured: 54 (31%) chemotherapy-related, 10 (6%) disease-related, 87 (49%) related to undergoing MB-FUS (40 [46%] grade 1, 46 [53%] grade 2, and one [1%] grade 3), and 25 (14%) unrelated. Two (1%) of the adverse events were grade 5 (disease-related deaths), three (2%) grade 4 (temozolomide-related haematological abnormalities), and eight (5%) grade 3 (three [2%] temozolomide-related, one [1%] MB-FUS-related, three [2%] disease-related, and one [1%] unrelated); these occurred across seven (21%) of 34 participants. No treatment-related deaths occurred during the trial. BBBO was visualised in all treatments. Median overall survival was 31·3 months (95% CI 21·1-not reached) and median progression-free survival was 13·5 months (9·9-26·9) with patient-specific disease courses found concordant with trajectories of MB-FUS-enriched plasma cell-free DNA.

INTERPRETATION: MB-FUS plus temozolomide is a safe combinatorial therapeutic approach for individuals with high-grade glioma, with the potential to improve survival and enable non-invasive plasma biomarker-based disease surveillance (sono-liquid biopsy), warranting randomised controlled trials.

FUNDING: National Institutes of Health and Insightec.

BACKGROUND: The surrogacy value of distant disease-free survival for overall survival has not been validated in neoadjuvant randomised controlled trials (RCTs) for early breast cancer. Here, we assess the trial-level surrogacy value of distant disease-free survival for overall survival.

METHODS: In this pooled analysis, we included individual patient data from RCTs of neoadjuvant therapy for early breast cancer conducted by the German Breast Group (GBG) and the German Gynecological Oncology Breast Study Group (AGO-B) with available data on distant disease-free survival and overall survival. We used the trial-level measure of surrogacy R2trial from two-stage meta-analytical copula methods to quantify the association between treatment effects on overall survival and distant disease-free survival, overall and in prespecified clinical and pathological subgroups. According to ReSEEM guidelines, R2trial values of 0·7 or higher represent strong correlations, values between 0·69 and 0·5 represent moderate correlations, and values of less than 0·5 represent weak correlations.

FINDINGS: 11 RCTs, with a total of 15 neoadjuvant treatment comparisons and 12 247 patients, were included in the analysis. Overall, there was a strong association between copula model-based hazard ratios (HRs) for overall survival and copula model-based HRs for distant disease-free survival (R2trial=0·91 [95% CI 0·82-1·00]). No significant heterogeneity of results was observed across the majority of subgroups analysed (pheterogeneity>0·05 in all subgroups), with the exception of subgroups defined by tumour molecular features, such as tumour progesterone receptor status, HER2 status, and molecular subtypes. For molecular subtypes, the R2trial for the association between distant disease-free survival and overall survival was higher than 0·7, indicating strong surrogacy in hormone receptor-negative and HER2-negative tumours (R2trial=0·89 [95% CI 0·75-1·00]) and hormone receptor-negative and HER2-positive tumours (0·73 [0·36-1·00]), and below the 0·5 threshold for weak surrogacy in hormone receptor-positive and HER2-negative tumours (0·33 [0·00-0·83]) and hormone receptor-positive and HER2-positive tumours (0·11 [0·00-0·55]; pheterogeneity=0·021).

INTERPRETATION: With adequate follow-up, distant disease-free survival is a robust surrogate endpoint for predicting final overall survival outcomes in neoadjuvant RCTs for early breast cancer in most contexts. However, the distant disease-free survival surrogacy appears to be weak for the hormone receptor-positive and HER2-negative and for the hormone receptor-positive and HER2-positive molecular subtypes. These latter findings warrant further investigation in more recent RCTs enrolling higher-risk patient populations.

FUNDING: None.