Citations

Abstract Background: Combination immune checkpoint inhibitor (ICI) therapy represents a standard-of-care for patients with metastatic melanoma. However, >40% of patients do not respond to treatment and severe immune-related toxicity affects up to 60% of patients. Accordingly, we need more precise ways to select patients for combination ICIs. To address this, we developed LiquidTME, a liquid biopsy method based on Spatial EcoTyper (Cancer Res (2025) 85 (8_Supplement_1): 153) that leverages a deep learning approach to noninvasively assess the tumor microenvironment from cell-free DNA (cfDNA) methylation data. LiquidTME was previously trained to predict ICI response using 78 patients with advanced melanoma treated at Yale University. Here we performed a blinded validation of LiquidTME in coordination with clinicians at Washington University (WashU). Methods: The WashU cohort consisted of pre-ICI plasma from 34 patients with advanced melanoma, each treated with ipilimumab and nivolumab (n=27) or relatlimab and nivolumab (n=7). ICI response was classified as durable clinical benefit (DCB) or no durable benefit (NDB) by a board-certified oncologist. Tumor mutational burden (TMB) was determined for 27 patients using commercial CLIA assays and analyzed as nonsynonymous mutations (mt) per megabase (Mb), using the FDA-approved 10 mt/Mb cutpoint for TMB-high and -low groups. The WashU cohort was sent to a scientific team that was blinded to all clinical and TMB data. Cell-free DNA was extracted from 2 mL plasma per patient and subjected to enzymatic methyl-seq (EM-seq) at a median depth of 15x. LiquidTME was performed on the resulting profiles, yielding a binary response prediction and a continuous response score for each sample. Test results were locked down and returned. Both assays were compared by AUC and two-sided Wilcoxon rank-sum tests for response classification, and Kaplan-Meier analysis for progression-free survival (PFS). Results: Median follow-up time of the cohort was 21.6 months. LiquidTME performed on cycle 1 day 1 pre-ICI plasma significantly stratified PFS with a hazard ratio (HR) of 0.27 (P = 0.005), with LiquidTME(+) patients achieving a median PFS of 1.7 years longer than LiquidTME(-) patients. LiquidTME distinguished DCB from NDB with an AUC of 0.77 (P = 0.007). Similar performance was seen across distinct combination ICI regimens. In patients with TMB data, LiquidTME maintained whole-cohort performance with a PFS HR of 0.30 (P < 0.03; AUC = 0.77). In contrast, TMB high vs. low subsets failed to stratify PFS (HR = 0.49; P = 0.17) or response (AUC = 0.53; P = 0.8). Conclusion: LiquidTME identified durable responders to combination ICI from pretreatment plasma in this blinded validation cohort of melanoma patients. Given its favorable performance, LiquidTME shows promise as a clinical tool to guide personalized immunotherapy decision-making. Citation Format: Aadel A. Chaudhuri, David Y. Chen, Tucker Hansen, Mirna Jarosz, Vincent A. Miller, Aaron M. Newman. Blinded clinical validation of LiquidTME, a cell-free DNA assay for predicting response to immunotherapy by noninvasively profiling the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1040.

Abstract Background: Multidisciplinary research networks often face challenges in harmonizing metrics and measures across participating sites, limiting the ability to aggregate data and generate generalizable insights. To address this barrier within the Connecting Patient Populations to Clinical Trials (CP2CT) Network, the Data, Evaluation, and Coordinating Center (DECC) coordinated the establishment of a unified framework that supports comparable evaluation and enhances the scientific impact of network-wide activities. Methods: Consensus was developed through a structured, iterative, and collaborative process: (1) drafting initial constructs, metrics, measures, and benchmarks informed by Network site materials and relevant literature; (2) soliciting qualitative and quantitative feedback from Network sites via Basecamp, an innovative online collaborative workspace for construct development; (3) conducting open dialogue sessions followed by systematic review and integration of site feedback; and (4) refining all elements through repeated feedback cycles until no further modifications were requested. Each iteration strengthened the clarity, coherence, and scientific precision of the final constructs. Results: A total of seven constructs were incorporated into the consensus-development process: clinical trials referral, clinical trials accrual, participants’ awareness of clinical trials, participants’ knowledge of clinical trials, providers’ awareness of NCI-supported clinical trials, providers’ engagement with NCI-supported clinical trials, and providers’ referral to NCI-supported clinical trials. For each construct, the Network established a conceptual definition (broad description of the construct), an operational definition (specification of how the construct is measured or observed), benchmarks (standards for assessing performance), metrics (quantitative indicators of performance), and measures (tools used to quantify inputs, processes, or outcomes). Common measures were developed for two constructs—clinical trials accrual and participants’ knowledge of clinical trials. Although full consensus was not achieved across all four Network sites for every construct, at least three sites reached consensus for the remaining five constructs. Conclusion: This consensus-building initiative resulted in the development of a unified, scientifically grounded framework. By harmonizing key elements related to clinical trial referral, accrual, awareness, knowledge, and provider engagement, the Network has established foundational tools that enable cross-site data comparability and facilitate more rigorous assessment of efforts to connect diverse patient populations to clinical trials. This framework positions the Network to inform strategies that improve equitable clinical trial participation. Citation Format: Folakemi T. Odedina, Jennifer Le-Rademacher, Robert Freimuth, Cristina Orozco, Laura Lectora, Timethia Bonner, Holly Thorson, Connecting Patient Populations to Clinical Trials(CP2CT) Program Evaluation Work Group, Connecting Patient Populations to Clinical Trials(CP2CT) Steering Committee. Development of and consensus building towards shared metrics, measures and benchmarks for the connecting patient populations to clinical trials (CP2CT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 860.

Abstract Introduction Detecting and estimating blood volume loss are important for the diagnosis and management of life-threatening hemorrhage. There is a direct relationship between percent blood volume loss (BVL%) and falling in stroke volume (SV); furthermore, there is a direct relationship between diminishing SV and the corrected flow time of the carotid artery (ccFT). Therefore, we hypothesized that change in ccFT (ccFTΔ) would directly relate with BVL% in a phlebotomy paradigm. Materials and Methods A prospective, convenience sample of healthy volunteers was studied. Volunteers underwent blood donation protocol in a physiology lab. A wireless, wearable Doppler ultrasound system monitored ccFT during blood donation. Traditional vital signs were also measured throughout. The relationship between traditional vital signs as well as ccFTΔ were compared to BVL% using 2 mixed linear regression models. Results Data from 20 subjects and blood donations comprising 46,123 cardiac cycles are included. On average 413.5 ± 39 mL of blood were drawn representing 8.6 ± 1.6% BVL%. There was a significant and strong linear relationship between BVL% and ccFTΔ during blood draw with the regression slope demonstrating that for every 1 ms reduction in ccFT there was a 0.4% reduction in blood volume. Conclusions In healthy subjects and when blood loss is the sole mechanism for falling SV, we estimate that for every 1 ms reduction in ccFT, there is an approximate 0.4 BVL%. Validation of these results in patients with traumatic hemorrhage is underway.

ABSTRACT Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by antibody‐mediated platelet destruction, often driven by long‐lived plasma cells (LLPCs) resistant to conventional therapies. While most patients respond to corticosteroids and intravenous immunoglobulin (IVIG), a subset develops life‐threatening refractory disease. In this case series, we describe three patients aged 39, 85, and 58 with life‐threatening, multi‐agent refractory ITP and platelet nadirs < 2 × 10 9 /L who failed corticosteroids, IVIG, and thrombopoietin receptor agonists (TPO‐RAs). Following salvage therapy with daratumumab, a monoclonal antibody targeting CD38, all three patients achieved rapid hematologic recovery, with platelet count normalization within 1 week. This accelerated response allowed for urgent clinical stabilization, including safe anticoagulation and surgical intervention. The efficacy of daratumumab likely stems from a dual mechanism: the depletion of CD38+ LLPCs and the immediate modulation of Fc‐receptor‐mediated platelet clearance. These observations suggest that CD38‐targeted therapy can bypass traditional treatment resistance to achieve near‐immediate remission in high‐complexity, high‐risk clinical settings. While these results are compelling, prospective clinical trials are warranted to define the long‐term safety, durability, and optimal dosing of anti‐CD38 therapies in refractory ITP populations.

Importance The management of infectious and inflammatory lesions of the breast remains controversial. The expert panel focused on management recommendations for 3 of the most common infectious breast conditions, as very few evidence-based guidelines for the management of these conditions exist. Observations Clinicians should distinguish between infectious and noninfectious lactational mastitis (LM) because the former often requires interventions whereas the latter requires supportive care only. Patients with infectious LM often have thick fluid collections that are not amenable to aspiration and usually require a stab incision with drain placement (but no packing) to resolve the infection. Operative drainage is only required if the patient cannot tolerate an office procedure. If a phlegmon is present, antibiotics should be prescribed for at least 10 days. The diagnosis of granulomatous mastitis (GM) requires pathology confirmation with characteristic findings on core biopsy. Cystic neutrophilic granulomatous mastitis (CNGM) is a specific form of GM associated with a granulomatous reaction to Corynebacterium infection and should be empirically treated with doxycycline. For patients without findings characteristic of CNGM and no other associated bacterium identified, there is no role for empiric antibiotic use. Granulomatous mastitis cases often recur and can take up to 18 months to resolve. Patients who have GM cases with worsening symptoms should be treated with repeated intralesional steroid injections; surgical excision or repeated aspirations should be avoided. Cases refractory to intralesional steroid injection may require oral steroids or even advanced biologic agents such as methotrexate or azathioprine. Periductal mastitis with squamous metaplasia of lactiferous ducts (PDM-SMOLD) is a distinct entity from other periductal mastitis cases that can present with recurrent abscesses and should be treated with antibiotics and aspiration for fluid collections. Operative excision for PDM-SMOLD is required for those patients who present with a fistula or recurrent episodes typically using a radial incision to remove the diseased ducts within and below the nipple. Conclusions and Relevance Evidence-informed, consensus-, and expert opinion–based guidelines for the management of infectious and inflammatory conditions of the breast were developed. Clinicians can use these guidelines to appropriately manage these conditions for which clinical care often varied in the past.

Background: Statins have been associated with a reduced risk of primary liver cancer (PLC), primarily hepatocellular carcinoma (HCC). However, the optimal use for effective protection and whether benefits vary by patient characteristics remain unclear. We evaluated the association between statin use and PLC risk in metabolic-dysfunction-associated steatotic liver disease (MASLD), considering cumulative exposure and potential effect modifiers. Methods: We conducted a retrospective cohort study using the Veteran Affairs electronic health records. Patients with chronically elevated liver enzymes and metabolic dysfunction, without other chronic liver diseases, were identified between 2007 and 2009 and followed through 2019 for incident PLC. Statin exposure was assessed at baseline and during the follow-up, with dose standardization by LDL-lowering potency (simvastatin-equivalent units). Time to PLC was analyzed using Cox models adjusted for covariates, considering potential interactions. Results: Among 329,577 patients (92% male; median age 62 years), 0.82% developed PLC (median follow-up of 9.7 years). Baseline statin use showed a significantly lower PLC risk (adjusted hazard ratio 0.64; 95% CI, 0.57–0.71; p < 0.0001). No significant interaction was observed with age, sex, metabolic syndrome, or cirrhosis. Higher cumulative statin exposure demonstrated a dose-dependent risk reduction, remaining significant at simvastatin-equivalent doses > 15,561 mg annually after accounting for incident cirrhosis. Atorvastatin/rosuvastatin use provided comparable protection, despite different lipophilicity, and demonstrated stronger effects than others. Conclusions: In MASLD, statin therapy was associated with a dose-dependent PLC risk reduction. High-intensity therapy (simvastatin-equivalent > 40 mg daily) conferred substantial protection regardless of age, sex, insulin resistance, or cirrhosis, supporting a potential statin-based PLC chemoprevention in MASLD.

ABSTRACT Background Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors improve glycemic and cardiovascular outcomes in type 2 diabetes mellitus (T2DM). However, their impact on quality of life (QoL) and patient‐reported outcomes (PROs) has not been systematically evaluated. We conducted a systematic review and meta‐analysis to assess the effect of SGLT2 inhibitors on QoL in patients with T2DM. Methods MEDLINE, Embase, Scopus, Cochrane and ClinicalTrials.gov were searched until 18 August 2025 for randomised controlled trials and post hoc analyses of SGLT2 inhibitors reporting validated QoL or PRO outcomes in adults with T2DM. A random‐effects model was used to estimate mean differences (MD) or odds ratios (OR) with 95% CIs. Subgroup analyses compared SGLT2 inhibitors with placebo and active comparators. Risk of bias was assessed using the Cochrane RoB‐2 tool. Results Ten studies including 5294 patients (SGLT2i: 2807; control: 2487) were included. SGLT2 inhibitors significantly improved: EQ‐5D Index score versus placebo (MD: 0.04, p = 0.008), DTR‐QoL against active comparators (MD: 6.99; p = 0.0006), DTSQ compared to active comparators (MD: 0.54; p = 0.006) and IWQoL (MD: 1.44; p = 0.005) versus placebo. Improvements were also observed in SHIELD WQ‐9 overall QoL (OR: 2.11; p = 0.005), emotional health (OR: 2.16; p = 0.006), self‐esteem (OR: 2.26; p = 0.006) and work performance (OR: 1.99; p = 0.04) compared with placebo. Conclusion Randomised evidence suggests SGLT2 inhibitors enhance EQ‐5D Index score, diabetes‐specific QoL and several PROs in T2DM, particularly in physical, emotional and treatment satisfaction domains, supporting their earlier use in this population.

Background Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSDs) are heritable connective tissue disorders characterized by widespread fragile soft connective tissue affecting the skin, ligaments, joints, vasculature, and internal organs. Although hEDS and HSD are autosomal-dominant conditions and would be expected to display a 1:1 sex ratio, studies report higher prevalence in women. Objectives The purpose of this exploratory study was to determine whether self-reported sexual problems differed between females and males diagnosed with hEDS or HSD compared with controls with chronic pain but no hypermobility. Methods In this exploratory retrospective study, we examined 1,407 patients diagnosed with hEDS or HSD according to the 2017 diagnostic criteria for eight indicators of sexual problems based on a validated screening tool. Results Patients in each diagnosis primarily self-reported as White, non-Hispanic females (90%). Of the 1,407 patients who attended the EDS Clinic, 976 (69%) were diagnosed with HSD, 240 (17%) with hEDS, and 191 (14%) were chronic pain controls with neither diagnosis. For HSD, 937 (96%) were females vs. 39 (4%) males (24:1 females to males), while for hEDS, 210 (88%) were females vs. 30 (13%) males (7:1 females to males), and controls were 165 (86%) females vs. 26 (14%) males (6:1 females to males). Females with hEDS reported significantly higher rates of sexual issues than chronic pain controls, including sexual problems (69%, p = 0.018), problems with sexual interest (41%, p = 0.023), sexual pain (45%, p = 0.006), and orgasm difficulty (34%, p = 0.022) compared with males with hEDS or males or females with HSD. In contrast, males diagnosed with hEDS did not report any sexual problems over controls, and males and females diagnosed with HSD reported only one issue—more problems with sexual interest—compared with controls (females p = 0.019, males p = 0.018). However, the small number of males in this study limits conclusions that can be drawn for them. Conclusions This study is unique because we examine sex differences in sexual problems in patients with hEDS and HSD. Our findings indicate a higher percentage of sexual problems in females with hEDS than chronic pain controls without hypermobility, but this was not observed for females with HSD.

Background Current literature has shown benefit of radial pressure wave (RPW) and focused shockwave (FSW) for management of proximal hamstring tendinopathy (PHT), although there remains a lack of consensus on treatment parameters and optimal patient positioning. Purpose The purpose of this narrative review and clinical commentary is to report what has been described for patient positioning during treatment of PHT with RPW or FSW and propose an alternative side lying approach. Methods A search was conducted of MEDLINE/PubMed and EMBASE electronic databases for studies published from January 2005 to January 2026. Key search terms included proximal hamstring tendinopathy, shockwave therapy, extracorporeal shockwave treatment, radial pressure wave, hamstring tendinosis, hamstring tendinitis, and hamstring pain. Studies were included if they evaluated RPW or FSW for the treatment of PHT. Results Six manuscripts were identified for inclusion, two randomized controlled trials (RCT), two retrospective reviews, and two case reports; a total of 217 patients (145 female, 72 male) with PHT were treated with RPW and/or FSW. One RCT provided an in-depth description of patient positioning during shockwave treatment with the patient supine, with the hip and knee flexed, compared to other manuscripts detailing clinical focusing techniques only. One case report involving a para swimmer included a figure of treatment with the patient in a prone position. Improvement in patient reported outcomes with RPW and/or FSW was noted, with one RCT showing no differences between physiotherapy compared to RPW and FSW treatment. Conclusion RPW and FSW have some evidence regarding their benefits for treatment of PHT but controlled studies are limited and no consensus on treatment protocols or patient positioning during treatment have been determined. The authors’ preferred approach in treating PHT involves having the patient side lying with the hip and knee flexed to allow patient and clinician comfort while also creating compression of the proximal hamstring about the ischial tuberosity. It remains unclear how variance in patient positioning affects patient-reported outcomes. Future studies using RPW and FSW should include documentation of patient positioning when evaluating RPW and FSW efficacy. Level of Evidence 5

Abstract Malignant histiocytic neoplasms (MHNs) are rare tumors derived from the mononuclear phagocyte system (MPS), encompassing histiocytic sarcoma, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, and other high-grade MPS lineage tumors. Despite advances in understanding histiocytic neoplasms, MHNs remain diagnostically challenging and lack standardized treatment algorithms. Current classification systems differ in lineage framing and fail to address mixed or ambiguous phenotypes, contributing to diagnostic uncertainty and inconsistent care. To address these gaps, the Histiocyte Society convened an international working group of pathologists and oncologists, including World Health Organization and International Consensus Classification contributors, to harmonize nomenclature, define minimum diagnostic criteria, and develop pragmatic treatment recommendations. Using a modified Delphi process and case-based review, the group formulated &gt;40 consensus statements spanning classification, pathology, molecular testing, clinical evaluation, and therapeutic strategies. Key recommendations include the adoption of a unified MHN designation, use of a minimum immunophenotypic panel, integration of broad molecular profiling, and the documentation of previous hematopoietic malignancy. Treatment algorithms emphasize surgical resection for unifocal disease and targeted therapy or immune checkpoint inhibition for multifocal disease when actionable mutations or programmed death ligand 1 expression are present. These consensus recommendations aim to reduce diagnostic ambiguity, standardize reporting, and improve outcomes for both pediatric and adult patients. Future priorities include international registries to refine risk stratification and biomarker-driven trials exploring targeted therapy, immunotherapy, and combination approaches.