Citations

Abstract Introduction: Erythromelalgia is a descriptive term for burning pain and erythema in distal extremities, often worsened by heat and improved by cold. Inherited erythromelalgia has been primarily linked to gain-of-function variants in SCN9A , encoding voltage-gated sodium channel NaV1.7. However, approximately 65% to 85% of patients with erythromelalgia do not have pathogenic SCN9A variants. Objectives: The objective of this study was to uncover and assess gene variants potentially associated with pediatric-onset erythromelalgia. Methods: With IRB approval and informed consent, probands and families with erythromelalgia underwent next-generation sequencing. A list of genes of interest was produced based on Mendelian inheritance models. Selected gene candidates were assessed using the Sequence Kernel Association Test-Optimal (SKAT-O). Results: Sixty-two probands with erythromelalgia and their relatives were included in Mendelian analysis, which identified variants in PR domain zinc finger protein 12 ( PRDM12 ) and dihydropyrimidinase-like protein 2 ( DPYSL2 ). In a targeted 12-gene rare-variant set analysis using SKAT-O, zinc finger homeobox protein 2 ( ZFHX2 ) showed evidence of association ( P = 6.9 × 10 −4 ), surpassing Bonferroni correction for 12 tests (α = 4.17 × 10 −3 ), whereas KIF1B showed only a nominal association signal ( P = 0.03) that did not survive multiple-testing correction. Conclusion: Genes associated with both increased and decreased pain sensitivity are of considerable interest for elucidating pain mechanisms and analgesic development. As rare variants in PRDM12 and DPYSL2 were identified in a pediatric erythromelalgia cohort and a gene-based rare-variant association signal for ZFHX2 was identified, replication and functional validation are needed.

Health care–related out‐of‐pocket and indirect costs may create financial barriers to initial and/or continued receipt of care among patients with cancer, and subsequent financial toxicity is associated with worse oncologic and quality of life outcomes. Recognition and mitigation of risk factors for financial toxicity are essential to the provision of equitable, high‐quality care.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

Background: Total kidney volume (TKV), a prognostic biomarker in ADPKD, is used to stratify high risk individuals. eGFR measures may carry significant error in ADPKD compared to measured GFR(mGFR). This retrospective study investigates the association between height adjusted TKV (htTKV) and eGFR derived from race-free CKD-EPI equations utilizing creatinine and cystatin C. Methods: eGFR was calculated using 3 race-free CKD-EPI formulas: creatinine-based (CKD-EPI creatinine), cystatin C (CKD-EPI cys), and creatinine-cystatin C (CKD-EPI creatinine-cystatin C) equations on 697 Mayo Clinic ADPKD patients. Correlations between eGFR and TKV measures were estimated and stratified by MIC class risk groups and CKD. Linear regression models were computed to predict ln(htTKV) from the 3 eGFR data sets. The eGFR measures were compared to iothalamate-based mGFR in a subset of patients (n=50). Results: A correlation between eGFR measures and htTKV (Pearson correlation r of -0.53 to -0.54), varied by MIC stratification. Pearson correlation was -0.47 to -0.48 for MIC 1A and 1B, -0.67 to -0.71 for MIC 1C, and -0.67 to -0.68 for MIC 1D and 1E. All equations were significantly associated with htTKV levels, with similar adjusted beta values (95% CI) of -0.15 (-0.17 to -0.13), -0.14 (-0.16 to -0.12), -0.15 (-0.16 to -0.13), for CKD-EPI creatinine, CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C, respectively. Compared to mGFR, the CKD-EPI creatinine-cystatin C equation was the least biased (mean -0.86 (95% CI: -3.09 to 1.37)) versus CKD-EPI creatinine (2.31 (-0.73 to 5.34)) or CKD-EPI cystatin C (-3.54 (-5.86 to -1.21)), and most precise, with 1-P30 of 16% (95% CI 7.2% to 29.1%), compared to 18% (8.6% to 31.4%) for CKD-EPI creatinine, or 20% (10.0% to 33.7%) for CKD-EPI cystatin C. Conclusion: A moderate correlation between eGFR and htTKV associated with MIC stratification. Associations between htTKV and all 3 CKD-EPI equations were similar. CKDEPIcrcys tended to be the least biased and most precise equation when compared to mGFR and may be a reasonable alternative.

Treatment of participants with intermediate-risk prostate cancer with focal irreversible electroporation and radiation therapy was technically feasible and showed acceptable patient-reported outcomes and no severe adverse events over 1 year.

PURPOSE Systematic integration of tobacco cessation treatment within cancer centers is needed to improve smoking cessation outcomes among cancer patients and survivors. The current study characterizes baseline rates of tobacco use, use of cessation support, and changes in tobacco use over time among 756 participants diagnosed with cancer and enrolled in 9 ECOG-ACRIN Cancer Research Group trials. MATERIALS AND METHODS Participants completed surveys at trial enrollment and at 3- and 6-month follow-ups. Descriptive statistics were used to characterize patient characteristics and selected items from the Cancer Patient Tobacco Use Questionnaire (C-TUQ). Generalized estimating equations were used to examine the time point effect on tobacco product use. RESULTS At baseline, 11% of participants (n = 740) currently smoked cigarettes. Among participants with data available at all time points (n = 443), prevalence of current smoking was stable over time, with 7.2% of participants (n = 32) reporting current smoking at baseline, 7.0% (n = 31) at the 3-month follow-up assessment, and 6.8% (n = 30) at the 6-month follow-up assessment. Most participants (n = 77/104) who smoked cigarettes within the year prior to their cancer diagnosis continued smoking after their diagnosis, and during (n = 44/72) and following completion (n = 30/46) of their treatment. Sixty-two percent of participants (n = 81) who were currently smoking at baseline reported using smoking cessation medication and 32.1% reported use of nonpharmacologic smoking cessation support since their cancer diagnosis. In longitudinal analyses, the odds of using cigarettes since their cancer diagnosis, 3-month follow-up, and 6-month follow-up was higher than the odds of using cigarettes for the past 30 days at baseline (odds ratio [OR] = 1.97, OR = 1.62, and OR = 1.50, respectively; all p s < .01). CONCLUSION Smoking persists over time among patients with cancer enrolled in therapeutic cancer trials. Findings highlight the importance of increasing access to integrated and longitudinal smoking cessation support.

Abstract Background Ultrasound (US)‐guided hydrodissection is a minimally invasive treatment for cubital tunnel syndrome (CuTS) with promising early results. However, data on patient‐perceived outcomes, durability of relief, and impact on surgical need remain limited. Objective To assess the effectiveness of US‐guided cubital tunnel hydrodissection in improving CuTS symptoms via patient‐centered outcomes. Design Retrospective chart review with cross‐sectional telephone follow‐up. Setting Quaternary medical center multidisciplinary outpatient hand clinic. Participants Seventeen patients (19 arms) with clinical CuTS who received US‐guided hydrodissection from one physician. Interventions Patients were contacted by telephone for cross‐sectional outcome assessment. Main Outcome Measures Patient‐reported improvements in weakness, paresthesias, and/or pain, percent pain relief, symptom improvement duration, adverse events, and Patient Global Impression of Change (PGIC) scores. Results At mean 7 ± 5 month follow‐up, improvement in weakness, paresthesia, and pain was reported in 12 (63%) extremities (95% confidence interval [CI] 41%–85%; p < .001) . Pain relief ≥50% occurred in 12 (63%) and ≥75% in 8 (42%) extremities, with mean duration 4 months. PGIC scores showed 14 (74%; 95% CI 54%–94%; p < .001) at least “minimally improved” and 8 (42%) (95% CI 20%–64%; p < .001) “much improved.” No adverse events occurred. Two patients without improvement underwent surgical decompression with anterior transposition at 1 and 3 months after hydrodissection, achieving 90%–100% pain relief and “much or very much improved” PGIC scores. Of 19 extremities, 7 (37%) were McGowan Grade I and 12 (63%) Grade II; none were Grade III. Grade II extremities showed significantly greater overall symptom relief ( p = .004) and pain relief ≥50% ( p = .004). PGIC scores did not differ significantly between grades (both p > .062). Conclusion US‐guided cubital tunnel hydrodissection was associated with meaningful symptom improvement and no adverse events. Limitations include small sample size, no control group, single operator, and potentially time‐limited relief. The procedure appears safe and a potential nonoperative treatment option.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Background: Alzheimer’s disease (AD) and cerebrovascular pathology are the two most common causes of dementia, frequently co-occurring in older people. Community-based neuropathology studies indicate that vascular disease accounts for approximately one-third of the population-attributable risk of dementia, controlling for other pathologies (including AD). The proportion with vascular disease as co-pathology is likely to be higher (50–70%). The most common vascular substrate is cerebral small vessel disease, which includes small artery fibrosis (arteriolosclerosis), vascular amyloid deposits (cerebral amyloid angiopathy), and monogenic forms of small vessel disease, the commonest being Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Post-stroke cognitive impairment following both ischemic stroke and intracerebral hemorrhage also contributes. Aims and Methods: In this World Stroke Organization (WSO) scientific statement, we assembled a multi-disciplinary international group of experts to review the vascular contribution to dementia, encompassing both vascular and neurodegenerative dementia. This statement has been reviewed and approved by the WSO executive. Results: We summarize the epidemiology, neuropathology, cognitive profile, clinical impact and management of vascular disease in dementia and discuss the recent VasCog-2-WSO diagnostic criteria. We consider the substantial overlap with clinical stroke and with AD dementia. We catalog transcriptomic and proteomic studies that have revealed novel candidate molecules ( COL4A1/4A2, HTRA1, TRIM47, FOXF2 ) as possible treatment targets. We appraise imaging-based biomarkers relevant to vascular disease and potential biochemical markers (vascular endothelial growth factor-A, placental growth factor, interleukin-6, matrix metalloproteinase-9, cathepsin-B). We highlight the potential for vascular interventions to treat not only vascular dementia but also the vascular component of neurodegenerative dementia. We review recent clinical trials targeting multiple pathways, including nitric oxide signaling, high blood pressure, the GABAergic system, angiogenic activity, microglial inhibition, PDE3 and PDE5 inhibition, as well as dietary supplementation with omega-3 fatty acids, s-equol and vitamin E. Finally, we consider upcoming opportunities and challenges relevant to vascular disease in dementia. Conclusion: The vascular contribution to dementia is i) substantial, ii) increasingly understood at molecular and mechanistic levels, iii) a source of potential treatment opportunities. Data Access Statement: no original data are presented in this document.