Citations

Abstract Context Data on diagnostic accuracy of dehydroepiandrosterone sulfate (DHEA-S) for mild autonomous cortisol secretion (MACS) and adrenal insufficiency (AI) are discrepant. Objective We conducted a systematic review and meta-analysis of published studies assessing the accuracy of DHEA-S in diagnosing MACS or AI. Methods From inception to January 8, 2024, we searched databases for original studies of at least 20 participants with MACS or AI. MACS was defined as postdexamethasone cortisol greater than 1.8 mcg/dL or postsurgical hypocortisolism. AI was defined by abnormal dynamic testing. QUADAS-2 was used to assess the risk of bias. Bivariate random effects meta-analysis was used to generate pooled diagnostic accuracy estimates. Results Seven studies on DHEA-S accuracy in diagnosing MACS (574 patients with MACS, 830 referent individuals), and 2 studies on DHEA-S accuracy in diagnosing AI (52 patients with AI, 59 referent individuals) were included. A meta-analysis of studies using DHEA-S cutoff between 60 and 70 mcg/dL to diagnose MACS demonstrated a sensitivity of 82% (95% CI, 64%-93%) and a specificity of 82% (95% CI, 74%-88%). In the 2 studies evaluating DHEA-S in diagnosing AI, the reference standard was a 1-mcg cosyntropin stimulation test. The sensitivity of DHEA-S for diagnosing AI ranged from 70.3% to 86.7%, and the specificity was 87.1%. Most studies were at a moderate risk of bias. Conclusion Based on limited heterogeneous evidence, measurement of DHEA-S provides additional value in diagnosing MACS, as well as AI.

BACKGROUND: This individual participant data meta-analysis aimed to determine whether time to treatment influences the effect of intraarterial thrombolysis (IAT), intravenous thrombolysis, and conservative standard therapy on visual outcomes in nonarteritic central retinal artery occlusion. METHODS: We searched MEDLINE, CENTRAL, and Embase up to June 2023 for studies reporting treatment modality and peri-treatment best-corrected visual acuity (BCVA) for ≥5 participants, excluding patients with nonsevere vision loss (BCVA <1.0 logarithm of the minimum angle of resolution [logMAR]) or treated after 24 hours of symptom onset. The primary outcome was recovery from severe vision loss (final BCVA <1.0 logMAR). We used mixed-effect models and local polynomial regression to investigate nonlinear relationships between time to treatment and recovery from severe vision loss. RESULTS: Of 4074 screened studies, individual participant data were sought from 52, with 35 contributing individual participant data for 1038 participants. In total, 783 patients met inclusion criteria (age, 64.8±13.3 years; 35.5% female; baseline BCVA, 2.3±0.5 logMAR). For every hour decrease in time to treatment, thrombolysis was associated with greater improvement in BCVA (intraarterial, 0.02 logMAR [95% CI, 0–0.04]; intravenous, 0.04 logMAR [95% CI, 0.00–0.07]) than conservative standard therapy (0.01 logMAR [95% CI, 0–0.02]). A nonlinear relationship was detected for intraarterial thrombolysis with a changepoint at 8 hours (95% CI, 6.7–9.4). Thrombolysis was associated with increased recovery from severe vision loss compared with conservative standard therapy (intraarterial within 6 hours: odds ratio, 2.72 [95% CI, 1.02–7.28], 27.2% versus 12.0%; intravenous within 4.5 hours: odds ratio, 3.32 [95% CI, 1.24–8.92], 28.8% versus 11.1%). Findings were consistent in subgroup analysis restricted to patients receiving recombinant tissue-type plasminogen activator. Monte-Carlo simulations showed that a randomized controlled trial would require 95 participants per group to achieve 80% power to detect an odds ratio of 3.0 for recovery from severe vision loss. CONCLUSIONS: Early intervention in nonarteritic central retinal artery occlusion is associated with improvement in visual recovery, with intraarterial thrombolysis and intravenous thrombolysis outperforming nonthrombolytic treatments. These findings warrant confirmation in sufficiently powered randomized controlled trials.

Abstract Introduction Biliary-tract cancers, including intra- and extra-hepatic cholangiocarcinoma and gallbladder carcinoma, are uncommon but highly lethal. They represent roughly 2–3 % of new cancer diagnoses yet contribute about 5 % of cancer-related deaths. Complete surgical resection remains the foundation of curative treatment, whereas the value of peri-operative chemotherapy continues to be debated. Materials and Methods The National Cancer Database (NCDB) was queried for patients diagnosed with non- metastatic biliary tract cancer at age 18 or older between 2004 and 2019. After excluding patients with unknown timing of surgery and chemotherapy, patients who died within 90 days of the most definitive primary site surgery, and patients lost to follow-up, we split the cohort into three groups according to the clinical stage (stage I-III). Then, we evaluated the overall survival (OS) between the different treatment modalities (surgery only, chemotherapy only, adjuvant chemotherapy following surgery, and neoadjuvant chemotherapy followed by surgery) in each group. We studied the OS using Kaplan-Meier estimates and multivariate Cox regression analyses to evaluate factors associated with OS. Results A total of 35,260 patients with non-metastatic biliary tract cancers were included in the analysis, of which 50.4% were females, 83% Caucasians, and 9.5% African Americans. The median age at diagnosis was 70 (range 18-90). 14,757 (41.9%) were stage I, 12,472 (35.4%) stage II, and 8,031 (22.8%) stage III. 7,286 (20.7%) had surgical resection only, 8,144 (23.1%) had chemotherapy only, 6,964 (19.7%) had surgical resection with perioperative chemotherapy, and 12,866 (36.5%) did not receive any treatment. We compared survival between different treatment modalities based on clinical stage. In stage I, patients treated with surgery alone exhibited superior median OS compared with those receiving adjuvant chemotherapy (65.7 vs 50.4 months, P < 0.001). Median OS after neoadjuvant chemotherapy was numerically higher than surgery alone (79.8 vs 65.7 months); however, this difference was not statistically significant (P = 0.63). Whereas in stage II, patients who were treated with adjuvant and neoadjuvant chemotherapy had better mOS compared to those treated with surgery only (33.9 and 40.3 vs 29.9 months with P<0.001 and P=0.005, respectively). The same trend was seen in stage III, patients who were treated with adjuvant and those treated with neoadjuvant chemotherapy had better mOS compared to surgery only (22.6 and 41.5 vs 19.5 months, respectively, with P<0.001 for all). In multivariate analysis, adjuvant and neoadjuvant chemotherapy did not affect the OS in all stages, except in stage III, where neoadjuvant chemotherapy was associated with better OS (HR 0.646, 95% CI 0.530-0.786; P<0.001). Conclusion Adjuvant and neoadjuvant chemotherapy do not seem to have a survival benefit in early-stage (stage I and II) biliary tract cancers, whereas neoadjuvant chemotherapy tends to improve OS in stage III.

ABSTRACT Background Urodynamic studies (UDS) are integral to the evaluation and management of lower urinary tract dysfunction. However, artifacts are frequently encountered, affecting both clinical interpretation and research reliability. Objective This expert narrative review examines the prevalence, classification, and clinical relevance of artifacts encountered during UDS, based on findings from the existing literature. Methods A focused literature review was conducted, analyzing studies that reported data on the sources and impact of UDS artifacts, particularly from the patient perspective. Emphasis was placed on identifying both technical and patient‐related contributors to artifact generation. Results Artifacts are common in UDS despite adherence to Good Urodynamic Practices recommended by the International Continence Society. Technical artifacts may stem from equipment‐related issues such as calibration errors, catheter displacement, and device variability. Patient‐related artifacts can arise from physical movement or test‐induced detrusor overactivity. These artifacts may lead to misinterpretation, misdiagnosis, and inappropriate interventions in clinical practice. Furthermore, they may affect the validity of research findings related to diagnostic tools for lower urinary tract symptoms. Conclusion Identifying and addressing UDS artifacts during the procedure or in post‐test interpretation is critical for accurate clinical decision‐making and reliable research outcomes. Efforts to minimize artifacts should be prioritized to improve the quality and utility of UDS.

Abstract Bioinformatics methods can be used to quantify mitochondrial DNA copy number from whole genome sequencing (WGS) data. We evaluated mitochondrial DNA copy number from human brain-derived WGS data using the fastMitoCalc tool. 341 Parkinson’s Disease cerebellum samples were compared with 74 age-matched controls from the North American Brain Expression Consortium. Parkinson’s Disease cerebellum had significantly higher mitochondrial DNA copy number compared with controls (P = 4.15e–7), and this effect was reproducible in four of five brain banks when analysis was restricted to each resource that contributed Parkinson’s Disease samples to this genetic dataset. Follow-on analyses of 128 Parkinson’s Disease cerebellum samples and 33 controls that had paired neuropathology data and clinical scores demonstrated a significant increase in mitochondrial DNA copy number with Unified Staging System for Lewy Body disorders stages and Unified Parkinson’s Disease Rating Scale (off meds) motor scores. Analysis of Lewy Body scores from ten brain regions showed cerebellum mitochondrial DNA copy number increased upon pathological infestation of α-synuclein aggregates in the brainstem and limbic system but did not increase after late-stage neocortical involvement. This genetics dataset supports previous observations of cerebellum activation in Parkinson’s Disease and suggests mitochondrial DNA copy number may increase to support this regional activation as a compensatory mechanism to pathology or motor symptoms.

PURPOSE Patients with cancer take different types of medications with varying schedules and settings. They are also sometimes instructed to stop medications due to toxicity. To measure self-reported nonadherence in this heterogeneous population, we modified and evaluated a measure originally developed to assess nonadherence to daily oral antihypertensives, the Domains of Subjective Extent of Nonadherence (DOSE-Nonadherence). METHODS The measure was refined in an iterative process incorporating feedback from patient investigators and participant interviews in English and Spanish. Branching logic was added for participant selection of medication administration setting: (1) only home, (2) only clinic, or (3) partly home/partly clinic. Participants reported their adherence to medications taken over a setting-specific reference period (1 week for home, 1 month for clinic medications). Participants who missed medications then reported on reasons for nonadherence. Adherence was dichotomized for analysis (complete adherence v any nonadherence). For participants who received clinic-administered medications, concordance between chart-abstracted and self-reported adherence was evaluated. RESULTS Seventy-three participants completed the measure (68% English; 32% Spanish; 86% female; 44% age ≥60 years). The majority had breast cancer; 64% had metastatic disease. Twenty-six percent (15/58) of participants who received medication in clinic and 24% (11/46) of those who took medication at home reported nonadherence. Participants felt able to respond accurately to both reference periods and perceived all reasons for nonadherence to be relevant. Among participants who completed the final version of the measure for clinic-administered medication, 96% (26/27) accurately reported their adherence compared with chart-abstracted data. CONCLUSION Our results support the validity of the DOSE-Nonadherence-Cancer for assessing cancer treatment nonadherence. This measure can be used to assess nonadherence in patients with cancer receiving a broad array of systemic therapies.

Abstract Purpose: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. Experimental Design: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. Results: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in &lt;10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with &gt;5-year overall survival. In addition, a 28-gene expression–based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. Conclusions: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.