Citations

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.

Abstract Introduction Chronic scrotal content pain (CSCP), defined as three or more months of scrotal pain interfering with daily life, affects approximately 100,000 men annually in the United States. Historically, the absence of standardized guidelines led to wide variability in diagnosis and treatment. At the time of our study design and data collection, no formal guidance existed for CSCP. In April 2025, after the study’s completion, the American Urological Association (AUA) published its first clinical guidelines for CSCP. Our findings now offer important context regarding real-world practice patterns before guideline publication. Objective To characterize diagnostic and treatment strategies for CSCP among U.S. reproductive urologists. Methods An anonymous 25-question Qualtrics survey was distributed to U.S.-based reproductive urologists. The survey assessed physician demographics, diagnostic evaluations, conservative and surgical treatment strategies, and perceived patient outcomes. Descriptive statistics were calculated, and comparisons were performed using Mann-Whitney U, chi-square, or Fisher’s exact tests, as appropriate. Results Of 183 invited physicians, 41 (22.4%) completed the survey in full. All respondents were fellowship-trained, practicing urologists, with most board-certified (82.9%). Respondents were nearly evenly split between ≤5 years (48.8%) and >5 years (51.2%) in practice. Among ten conservative treatment options, reassurance (41.5%) and NSAIDs (31.7%) were the most frequently selected first-line treatments, with median ranks of 2.5 and 2, respectively (Figure 1). Opioid medications were the least favored (median rank: 10), with 56.1% ranking them last. Pelvic floor physical therapy (PFPT) had a favorable median rank of 3 and was ranked higher by those with ≤5 years in practice compared to those in practice >5 years (median: 3 vs. 4, p = 0.019). GABA analogues and tricyclic antidepressants were assigned median ranks of 6 and 7.5, respectively. The most commonly performed surgical procedure for CSCP was microsurgical denervation of the spermatic cord (MDSC, 95.1%), followed by varicocelectomy (92.7%), vasectomy reversal (78.0%), epididymectomy (73.2%), and orchiectomy (51.2%). For post-vasectomy pain syndrome, MDSC was preferred by 63.4%, followed by vasectomy reversal (22.0%) and epididymectomy (9.8%). Among those performing vasectomy reversals, 80% of patients paid out-of-pocket (IQR: 50.0–93.5%). Respondents perceived surgical management as more effective than conservative treatment, with median complete symptom resolution rates of 70% (IQR: 50–80%) versus 25% (IQR: 10–40%) (p < 0.001). Only 7.3% reported using validated tools like the Chronic Orchialgia Symptom Index (COSI) to evaluate patient outcomes. Conclusions Our study offers a contemporary snapshot of CSCP management among reproductive urologists, revealing substantial variability in practice. Surgery was consistently perceived as more effective than conservative approaches. These findings underscore areas of alignment and divergence with the newly released AUA guidelines and support the need for future comparative trials and implementation studies to guide standardized, evidence-based care. Disclosure No

Abstract The diagnosis of T‐cell neoplasms remains one of the most challenging areas in hematopathology due to the immunophenotypic heterogeneity and subtle aberrancies often present in these entities. This “Best Practice” manuscript provides a practical framework for laboratories to design, validate, and interpret immunophenotyping studies of immature and mature T‐cell neoplasms. We outline the utility of key antigens in the screening and classification of T‐cell lymphomas/leukemia including TRBC1 and TRBC2. Analytical strategies using the “difference from normal” method and template‐based gating are discussed, along with validation considerations aligned with CLSI H62 guidelines. By integrating these principles into laboratory workflows, this manuscript aims to standardize and improve the assessment of T‐cell neoplasms across diverse clinical settings.

AbstractMetabolic syndrome (MetS) is a prevalent comorbidity in patients with chronic pain conditions. Emerging evidence suggests that the relationship between MetS and chronic pain is bidirectional. This interplay involves complex mechanisms, including proinflammatory mediators in nociceptive modulation and pain‐induced lifestyle changes affecting metabolic function. This scoping review examines the association between MetS and chronic pain. We conducted a scoping review, including 28 studies. This review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses Extension for Scoping Reviews guidelines. We included observational studies (cross‐sectional, case–control, and cohort studies) from the following databases: Ovid MEDLINE, EMBASE, Cochrane Central, Cochrane Database of Systematic Reviews, and Scopus. We identified studies on migraine (n = 9), spinal pain (n = 8), general chronic pain (n = 4), fibromyalgia syndrome (n = 3), carpal tunnel syndrome (n = 1), osteoarthritis (n = 1), shoulder pain (n = 1), and neuropathic pain (n = 1). Most studies used a cross‐sectional design and standard criteria to define MetS, with some exceptions. Individuals with MetS and spinal pain, fibromyalgia, or general chronic pain showed higher pain scores and increased functional limitations. MetS was common in patients with migraine, but its effect on pain severity was inconclusive. The relationship between MetS and other pain conditions requires further investigation to clarify the association and potential mechanisms. MetS is prevalent in patients with chronic pain and is associated with worse pain and functional outcomes. Health care providers should acknowledge the wide spectrum of MetS beyond obesity. This understanding may help identify those at risk for more severe chronic pain.

Context.— Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information. Objective.— To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening. Design.— Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to 44 elements, including 23 elements required by the College of American Pathologists and/or the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If present, the element’s location on the report was recorded. Results.— A total of 69 genomics reports from 31 laboratories were reviewed. Overall, the reports were compliant with regulatory requirements but showed variability in both format and content. Six of 7 required reporting elements (per CLIA, 42 CFR [Code of Federal Regulations] 493.1291) were included in 90% of the reports. However, these elements were often located in different report sections. Only patient demographics were always found in a specific report section (header). Conclusions.— These results show that reports are overall compliant with regulatory requirements, despite some reporting elements being less consistently reported. The lack of consistent presentation of the data elements presents an opportunity to improve the communication of molecular testing results to clinicians and patients.

Objectives To identify Reddit users’ viewpoints and inquiries about spinal cord stimulation (SCS) for chronic back pain using Reddit databases. Methods We performed a qualitative analysis of public, anonymous threads and comments from targeted subreddits within the Reddit community. We used the Python Reddit API Wrapper to extract relevant data. A qualitative descriptive approach was employed, using natural language processing to identify and categorize common questions, concerns, and opinions shared by patients regarding SCS. Results Our analysis included 112 posts and 448 comments. The tone of comments was neutral (n=231), followed by negative (n=121) and positive (n=96). 13 users actively encouraged other users to try the procedure, while 25 advised against it. The main topics of discussions revolved around pain relief expectations and adverse events. Almost half of users commenting about pain relief expectations reported experiencing considerably lower improvement than anticipated. Pocket pain, lead fracture/migration, infection risk, and scars were common topics of discussion among users. Furthermore, users shared strategies to mitigate postoperative discomfort and offered insights into device selection based on MRI conditionality, reprogramming need, and charging prerequisites. Conclusion Our Reddit analysis identified potential targets for enhanced dialog between physicians and patients around anticipated pain relief, complications, and postoperative care. Reddit and other social media platforms may offer valuable opportunities for healthcare professionals to improve engagement with patients.

Background: Aspirin is the most frequently used antiplatelet monotherapy for secondary prevention in patients with established ASCVD. Trials comparing monotherapy with a P2Y12i versus aspirin have shown variable results. Methods: Medline, Embase, & Cochrane Central databases were searched to identify RCTs comparing monotherapy with a P2Y12i versus aspirin for secondary prevention in patients with established ASCVD (ischemic stroke, coronary, or peripheral artery disease). The primary outcome of interest was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, & major bleeding. The DerSimonian and Laird random-effects model was used to calculate risk ratios (RR) & the corresponding 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins I 2 value. Results: 9 eligible RCTs (5 with clopidogrel & 4 with ticagrelor) with 62,336 patients were included in our analyses. Monotherapy with P2Y12i significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84 - 0.95, I 2 =0), & MI by 19% (0.81, 95% CI 0.71 - 0.92, I 2 =0) as compared with aspirin monotherapy (Figure). There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), & all-cause mortality (1.01, 95% CI 0.92 - 1.11) between the 2 treatment groups. There was no significant difference in the risk of major bleeding with P2Y12i monotherapy as compared with aspirin (0.97, 95% CI 0.66 - 1.43, I 2 =0). Results were consistent irrespective of the P2Y12i. Conclusion: P2Y12i monotherapy is associated with a significant reduction in atherothrombotic events as compared with aspirin alone without an increased risk of major bleeding.

Context.— Machine learning applications in the pathology clinical domain are emerging rapidly. As decision support systems continue to mature, laboratories will increasingly need guidance to evaluate their performance in clinical practice. Currently there are no formal guidelines to assist pathology laboratories in verification and/or validation of such systems. These recommendations are being proposed for the evaluation of machine learning systems in the clinical practice of pathology. Objective.— To propose recommendations for performance evaluation of in vitro diagnostic tests on patient samples that incorporate machine learning as part of the preanalytical, analytical, or postanalytical phases of the laboratory workflow. Topics described include considerations for machine learning model evaluation including risk assessment, predeployment requirements, data sourcing and curation, verification and validation, change control management, human-computer interaction, practitioner training, and competency evaluation. Data Sources.— An expert panel performed a review of the literature, Clinical and Laboratory Standards Institute guidance, and laboratory and government regulatory frameworks. Conclusions.— Review of the literature and existing documents enabled the development of proposed recommendations. This white paper pertains to performance evaluation of machine learning systems intended to be implemented for clinical patient testing. Further studies with real-world clinical data are encouraged to support these proposed recommendations. Performance evaluation of machine learning models is critical to verification and/or validation of in vitro diagnostic tests using machine learning intended for clinical practice.

Introduction Epidural steroid injections and epidural blood patches commonly involve the injection of a small amount of radiocontrast media under fluoroscopy to properly identify the target tissue or anatomic space and prevent off-target or intravascular delivery of therapeutic or diagnostic drugs. Iodinated low osmolar non-ionic contrast media is the standard preparation used as it is considered safe and cost-effective, but gadolinium-based preparations have been used as an alternative for patients with an ‘iodine’-related or radiocontrast media allergy label to prevent hypersensitivity reactions. The risk of neurotoxic events when gadolinium is inadvertently injected into the intrathecal space has been reported in recent years, raising concerns when gadolinium-based contrast media is used in lieu of iodinated low osmolar non-ionic contrast media. Methods A retrospective review was conducted of patients who received gadolinium-based contrast media for procedures with risk of inadvertent intrathecal access from January 1, 2019 to May 1, 2022. Information on patient demographics, allergy label information, and procedure description was documented for all patients who received gadolinium-based contrast media for axial spine procedures (including epidural steroid injections, epidural blood patch procedures, and selective nerve root blocks), and all side effects reported within 1 month of the procedure were recorded. Saved fluoroscopy images of all procedures for which there was concern for possible gadolinium-based contrast media-related side effect were reviewed for evidence of inadvertent intrathecal gadolinium-based contrast media administration. Descriptive statistical analysis was performed using REDCap and IBM SPSS Statistics V.28. Results We identified 508 patients who received gadolinium-based contrast media during a fluoroscopically guided axial spine procedure. These patients underwent 697 epidural procedures and 23 patients were identified as experiencing an adverse event that could be consistent with possible, probable, or clear signs of exposure to intrathecal gadolinium. Our calculated adverse event rate was 3.3%. Ten patients required additional medical evaluation or treatment. Discussion Almost all patients in our cohort had an allergy label on their chart that guided the provider to switch to gadolinium-based contrast media, but most were incomplete, ill-defined, or related to allergy to iodine but not iodinated contrast media. Such practice is not recommended based on current guidelines. The current study raises concern regarding the use of gadolinium-based contrast media in axial spine procedures, with the risk of potential severe adverse events, without evidence-based need for avoiding iodinated contrast media.

Significance Statement The lack of rapidly progressive murine models reflecting the more severe end of the spectrum of autosomal recessive polycystic kidney disease (ARPKD) inhibits progress to understanding ARPKD pathogenesis. Defects in primary cilia have been implicated in polycystic kidney disease, but their potential role is poorly understood. The authors generated and characterized new mouse and rat models of ARPKD and autosomal dominant polycystic kidney disease (ADPKD) and investigated the interaction between causative genes for these two conditions. Their digenic models demonstrated a synergistic interaction that better reflects the early-onset disease characteristic of ARPKD. Analysis of mRNA expression in the models highlighted different disrupted pathways, but with a commonality of dysregulated mechanisms associated with primary cilia. These models may improve understanding of ARPKD and preclinical testing for this disease. Background Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes PKD1 or PKD2 (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by PKHD1 (encoding fibrocystin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD’s mild phenotype in murine models versus in humans has hampered investigating its pathogenesis. Methods To study the interaction between Pkhd1 and Pkd1 , including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes. Results The genetic interaction was synergistic in both species, with digenic animals exhibiting phenotypes of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction between Pkhd1 and Pkd1 depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. Pkhd1 loss did not alter expression, maturation, or localization of the ADPKD polycystin proteins, with no interaction detected between the ARPKD FPC protein and polycystins. RNA-seq analysis in the digenic and monogenic mouse models highlighted the ciliary compartment as a common dysregulated target, with enhanced ciliary expression and length changes in the digenic models. Conclusions These data indicate that FPC and the polycystins work independently, with separate disease-causing thresholds; however, a combined protein threshold triggers the synergistic, cystogenic response because of enhanced dysregulation of primary cilia. These insights into pathogenesis highlight possible common therapeutic targets.