Citations

Abstract Purpose: Germ cell tumors (GCTs) pose significant diagnostic challenges due to the limited sensitivity and specificity of current tumor markers. Hereby we utilize phage immunoprecipitation sequencing (PhIP-Seq) technique to develop a unique immunosignature panel (iSIGN) with high sensitivity and specificity to improve the diagnosis and differentiation of GCTs. Patients and Methods: Serum samples from patients with confirmed gonadal or extragonadal GCTs and controls were collected from Mayo Clinic repositories. Controls included benign testicular lesions, autoimmune diseases, neurodegenerative disorders, and other cancers. Samples were randomized into development and validation cohorts. PhIP-Seq identified antigen-autoantibody interactions, and enrichment scores were calculated to develop a biomarker panel distinguishing GCT from non-GCT cases. A second biomarker panel was developed to predict seminoma from nonseminoma cases. Results: A total of 427 serum samples were analyzed, including 150 from GCT patients and 277 controls. For our primary model to distinguish GCT cases (GCT-iSIGN), 24 peptides from 16 antigens were identified based on significant differential autoantibody binding enrichment in GCT patients (p < 0.05), ≥2 peptides per antigen, and enrichment scores ≥ 2.5-fold. GCT-iSIGN was highly sensitive (93%) and specific (99%) for identifying GCT cases from controls with an area under curve (AUC) of 0.93 and 9% Unknown Case Rate (UCR). The secondary panel (Sem-iSIGN) included 17 peptides corresponding to 5 unique proteins with high specificity (93%), moderate sensitivity (65%) and AUC of 0.77 to distinguish seminoma from nonseminoma GCT cases. Conclusion: This study demonstrates the potential use of PhIP-Seq to identify unique immunosignature panels that can serve as reliable biomarkers for GCT. These panels address the limitations of traditional markers and other proteomic techniques. This immunosignature model represents a cost-effective, stable, and scalable approach to enhancing GCT diagnosis and management. Citation Format: M Bakri Hammami, Andrew Knight, Haidara Kherbek, Brian Costello, Silvana De Lorenzo, Bradley C. Leibovich, John C. Cheville, Yong Guo, Jessica Sagen, Janet E. Olson, Alicia Algeciras-Schimnich, Sean J. Pittock, John R. Mills, Surendra Dasari, Divyanshu Dubey. iSIGN panel identifies germ cell tumors via whole-proteome phage immunoprecipitation sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B027.

Objectives To develop an internationally validated, structured robot‐assisted radical nephroureterectomy (RARNU) training programme through expert consensus. Materials and Methods A RARNU‐specific questionnaire was developed/adapted from previously published, validated questionnaires for robot‐assisted urological procedures. This included five key domains and 11 surgical steps. In all, 30 upper tract urothelial carcinoma experts were invited to participate. A two‐stage modified Delphi approach was employed. Consensus was defined as ≥80% agreement. Modifications and additional statements were proposed during the second round following qualitative/quantitative feedback from the initial round. Results Response rates for the first and second Delphi rounds were 80% (24/30) and 92% (22/24), respectively. All agreed that adoption of a standardised training curriculum can improve clinical outcomes during the RARNU learning curve. There was ≥92% agreement on all proposed RARNU steps. Five RARNU clinical modules of increasing complexity were defined using individual step difficulty and number of prior RARNU cases required, with ≥96% agreement among respondents. Respondents unanimously agreed that the final assessment should be based on a procedure‐specific scale focusing on the hilar dissection, ureteric dissection, and bladder cuff excision steps. No consensus was reached for the annual minimum RARNU volume required for eligibility as a RARNU curriculum host centre. Conclusion This is the first structured training curriculum for RARNU using international expert consensus. This will help guide surgical educators and trainees toward independent completion of a full RARNU.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox—blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management. Clinical inertia represents a major barrier on the clinician side, as well as workload and limited education. Common barriers on the patient side include limited English proficiency, low health literacy, and nonadherence with misaligned incentives, limited resources, lack of structured clinical pathways, and reimbursement issues. New innovations in the field of RNA-targeted therapies and device-based interventions could prevent and potentially even cure diseases previously designated as chronic health conditions, such as hypertension. Such novel therapies could potentially overcome several major barriers to effective treatment, including nonadherence. Drug development of novel, long-acting treatments requires consideration of specific clinical trial design aspects, including safety collection, benefit: risk assessment, the development and assessment of novel, qualitative surrogate end points, such as time-in-therapeutic range, the use of representative trial settings as well as the definition of standard of care in placebo-controlled trials, which should be of reasonably high-quality allowing for credible evaluation of effectiveness. Here, we provide an overview on barriers to effective treatment and a framework for trials assessing novel treatments for cardiovascular disease risk factors, including early and broad implementation programs.

Increasing evidence strongly links neuroinflammation to Alzheimer’s disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in IL1B and CCL3 expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes’ role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.

Background: Acute disseminated encephalomyelitis (ADEM) is a demyelinating syndrome observed in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) but there are limited data on application of this definition to its cerebral attacks or in adults with this disease. Methods: We analyzed patients from the Mayo Clinic MOGAD cohort ( n = 263) with cerebral attacks. We assessed whether children (<18 years-old) and adults (⩾18 years-old) fulfilled the 2013 ADEM definition. Results: We identified 89 patients (children, 34; adults, 55) and 55/89 (62%) were of female sex. Acute magnetic resonance imaging (MRI) abnormalities included: poorly demarcated T2 lesions (white matter, 85 (96%); deep gray matter, 41 (46%); T1-hypointense lesions (42 (47%)). Forty-two patients did not fulfill the ADEM definition due to: monofocal syndrome, 9; or no encephalopathy, 33. The remaining 47 patients (53%: children, 27/34 (79%); adults, 20/55 (36%)) fulfilled the ADEM definition, and 14 had preceding attacks, and 34 had subsequent attacks relative to ADEM episode. The features in children and adults with ADEM were broadly comparable. Conclusion: Applying the ADEM definition to MOGAD cerebral attacks highlighted that an update of the 2013 ADEM definition would be beneficial and could explicitly state its application to both adults and children and allow it to be applied to attacks at any time during the disease course.

Abstract Clinical question What are the benefits and harms of medications for adults with type 2 diabetes at varied risks of cardiovascular and kidney related complications? Context Emerging clinical trials of novel medications have demonstrated benefits on cardiovascular, kidney, and weight related outcomes in people with type 2 diabetes. Dynamically updated practice guidelines adhering to standards of trustworthiness are necessary in response to a rapidly evolving evidence base and the availability of multiple medication alternatives. This living practice guideline incorporates the latest available medications and evidence and provides recommendations stratified by risks of cardiovascular and kidney complications to inform diabetes management. Recommendations The panel issued risk-stratified recommendations regarding four prioritised medications for adults with type 2 diabetes (SGLT-2 inhibitors, GLP-1 receptor agonists, finerenone and tirzepatide): • Lower risk (three or fewer cardiovascular risk factors without established cardiovascular disease (CVD) or chronic kidney disease (CKD)): weak recommendation against SGLT-2 inhibitors or GLP-1 receptor agonists. • Moderate risk (more than three cardiovascular risk factors without established CVD or CKD; or established CVD and/or CKD at lower risk of complications): weak recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation against finerenone in adults with CKD. • Higher risk (established CVD and/or CKD at higher risk of complications, or established heart failure): strong recommendation in favour of SGLT-2 inhibitors or GLP-1 receptor agonists; and a weak recommendation in favour of finerenone in adults with CKD. • Across risk strata: weak recommendation in favour of tirzepatide in adults with obesity. About this guideline and how it was created An international panel including two patient partners, clinicians, and methodologists produced these recommendations. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits, harms and burdens of treatment from an individual patient perspective. Recommendations were informed by a linked living systematic review and network meta-analysis evaluating relative benefits and harms updated to 31 July 2024; and by linked systematic reviews addressing risk prediction models and values and preferences of adults with type 2 diabetes. Candidate therapeutics are prioritised based on availability of sufficient randomised trial data, relevance to a global audience and likelihood of changing practice. This is the first version of the living guideline. The guideline is part of the BMJ Rapid Recommendations series. MAGICapp displays the most recent version of the guideline and full content including evidence summaries and decision aids; major updates will be published in The BMJ . We encourage re-use, adaptation and translation of these living guidelines, and recognise that the lack of availability or high costs of some medications may be prohibitive and will impact on how these recommendations are implemented across different health care systems.

The Dublin ISUP Consensus Conference covered the proceedings on the best practice recommendations on nonurachal glandular lesions of the urinary bladder, bladder diverticular cancers, and molecular features of bladder and urachal glandular lesions. The conference proceedings on urachal neoplasms (except for their molecular features) are published elsewhere. The rationale for convening this conference was the lack of structured and consented pathologic recommendations in these rare lesions. Consensus by participants was reached on the following statements: (1) intestinal metaplasia with dysplasia is considered to be a precursor to primary bladder adenocarcinoma; (2) dysplasia arising from cystitis glandularis should be reported in terms of focality (focal or nonfocal) and grade (low or high); (3) the term “adenocarcinoma” should only be used for carcinomas showing pure (nonurothelial) morphology and should not be used interchangeably in urothelial carcinoma with “glandular differentiation” because of the pathobiological differences and management implications; (4) the different histologic subtypes of bladder adenocarcinoma should be specified in the report; (5) immunohistochemistry has an ancillary role in the work up of bladder adenocarcinoma versus gastrointestinal or Müllerian-type adenocarcinomas; (6) lymphovascular invasion should be included as a parameter when reporting bladder adenocarcinoma; (7) representative or targeted sampling will be sufficient for bladder diverticulum resection specimens; and (8) molecular analysis in genomic profiling should be performed only in advanced or metastatic bladder and urachal adenocarcinomas for targetable therapy. This report on glandular (nonurachal) lesions of the bladder from the Dublin ISUP consensus conference will serve as a best practice recommendation and as a guide for future research on these relatively rare lesions.

Abstract Aging increases the vulnerability of kidneys to injury and impairs their regenerative capacity. SIRT3 expression declines with aging and is associated with multiple age‐related pathologies. The expression profile and functional role of SIRT3 in renal aging remain unclear. Here, SIRT3 expression in aging kidneys is assessed and analyzed for its promoter methylation patterns using methylation‐specific PCR (MSP). It is found that aging exacerbates UUO‐induced renal fibrosis, associated with downregulated SIRT3 expression. Mechanistically, age‐related SIRT3 downregulation is mediated by hypermethylation of its promoter region. SIRT3 knockout exacerbated renal fibrosis in young mice subjected to UUO, whereas SIRT3 overexpression attenuated fibrosis in aged UUO mice. Integration of RNA‐seq and immunoprecipitation‐mass spectrometry (IP‐MS) analyses revealed that SIRT3 deficiency leads to hyperacetylation of GSK3β at lysine 15 (K15). This K15 hyperacetylation inhibited GSK3β activity, consequently stabilizing its substrate β‐catenin. Furthermore, self‐assembled PEG‐PCL‐PEG micelles are designed and synthesized to encapsulate hydrophobic honokiol (HKL). These micelles significantly enhanced the aqueous solubility and oral bioavailability of free HKL, maintained stable blood concentrations, and ultimately improved its anti‐fibrotic efficacy. These findings propose novel therapeutic strategies for managing renal fibrosis in the aging population and provide a foundation for developing new drugs and combination therapies.

Abstract: Papillary eccrine adenoma/tubular apocrine adenoma (PEA/TAA) is a rare sweat gland neoplasm. Because PEA/TAA shares morphologic features with other sweat gland tumors, including digital papillary adenocarcinoma, histologic diagnosis may be challenging. We report a case of PEA/TAA presenting as a nodule on the left foot of a 43-year-old man. Histopathologic examination revealed a well-circumscribed dermal proliferation of variably sized glands composed of ductal cells with an outer layer of myoepithelial cells. By immunohistochemistry, the ductal tumor cells showed strong, diffuse expression of BRAF V600E, and the myoepithelial cells were positive for p63. This case illustrates the utility of immunohistochemistry in the diagnosis of this rare neoplasm. Particularly when PEA/TAA is located on an acral site, distinction from digital papillary adenocarcinoma is critical, because these tumors show significant differences in clinical behavior.