Citations

Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.

Objective: To establish international benchmark values for relevant outcome parameters in robotic Whipple. Summary Background Data: For safe adoption of surgical innovation, robust quality control is essential. Benchmarking is a validated tool for assessing surgical performance. Recent international consensus identified establishing benchmark values for robotic Whipple as top priority. Methods: We analyzed consecutive patients undergoing robotic Whipple between 2020-2023 with a minimum one-year follow-up. Reference centers were required to perform ≥15 cases/year, be scientifically active in the field, and maintain a prospective database. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Benchmarks were established for 13 outcome parameters. Result: The benchmark cohort comprised 418 patients from 12 centers across four continents. Benchmark values were: conversion rate ≤4.3%, transfusion rate ≤2.1%, 6-month mortality ≤2.2%, major complications ≤23.2%, and CCI® ≤20.9. Clinically relevant pancreatic fistula (grade B/C) and hemorrhage (grade B/C) rates were ≤23.6% and ≤12.7%, respectively. For pancreatic ductal adenocarcinoma (n=123), the benchmark for lymph node yield was ≥20. Higher surgical difficulty was associated with increased overall postoperative morbidity (R 2 =0.38, P =0.019), higher center caseload with reduced pancreas-specific complications (R 2 =0.28, P =0.044). Independent POPF predictors included duct diameter ≤4 mm (OR 1.37, 95% CI: 1.03, 1.82), anticoagulation (OR 2.45, 95% CI: 1.47, 3.99), and indication other than PDAC (OR 2.33, 95% CI: 1.68, 3.27). Conclusions: This study establishes the first international benchmarks for robotic Whipple, demonstrating oncologic outcomes and morbidity comparable to open surgery with the benefits of minimally invasive surgery.

Abstract Background Small vessel vasculitides (SVV) comprise a heterogeneous group of cutaneous SVV (CSVV) that can be skin‐limited or systemic. Given their diverse forms and symptoms and the lack of a standardized diagnostic approach, it is crucial to establish clear and consensus‐driven recommendations for diagnosis. Objectives To standardize diagnosis for the detection of the type, extent, potential causes or underlying conditions of CSVV. Methods International experts comprised the panel. The Delphi panel data was collected through two rounds of questionnaires. Agreement was measured using an 11‐point Likert scale (0 = strongly disagree, 10 = strongly agree). A 7‐vote minimum was required for agreement on each statement. Delphi panel statements scoring 3–7 were discussed during the meeting. Results 20 experts participated in the first round of the Delphi panel, while 17 experts took part in the second. They agreed that the diagnosis of CSVV relies on a combination of clinical manifestations, laboratory findings and histopathology. Palpable purpura on the lower extremities is recognized as the most reliable hallmark for most SVV and a sign of immune complex vasculitis. When the latter is suspected, a skin biopsy for direct immunofluorescence (DIF) should be obtained from an early, partially blanchable macule because the type of perivascular immunoglobulin is important for further diagnosis. The proper selection of biopsy sites for routine HE biopsy depends on the morphology of lesions. A comprehensive medical history and selected laboratory testing should be conducted to investigate organ involvement, potential causes and associated conditions. The extent of diagnostic procedures should be based on the severity, duration, systemic symptoms and recurrence of SVV. Conclusions Experts reached a strong consensus on the management of CSVV patients, culminating in the first International Consensus Statement for adult CSVV. This statement proposes a practical management algorithm and underscores the importance of collaboration in rare diseases management.

Abstract Introduction There is wide variation in male fertility preservation practices. While physician preference accounts for some of this diversity, practice patterns often reflect multiple extrinsic factors including patient demographics, equipment availability, laboratory protocols, and state law. Objective We sought to characterize national trends in sperm retrieval and storage across reproductive urology practices in the United States. Methods An anonymous 34-item survey characterizing provider demographics, practice settings, fertility preservation procedures, andrology laboratory practices, and cryopreservation expenses was designed. Practicing reproductive urologists were identified using information available through professional societies. Our survey was constructed using the Qualtrics platform and distributed electronically between October 2024 and May 2025. Results 39 responses were received by urologists practicing across 21 states (response rate: 21%, n=189). A majority (74%, n=29) of survey responders practiced at academic medical centers, with others practicing at non-academic hospitals (8%, n=3) and private practices (13%, n=5). The most common indications for fertility preservation reported included oncologic care (42%), gamete storage for planned ART (31%), transgender care (18%), pre-vasectomy sperm banking (10%), and pre-deployment banking for military personnel (5%). Nearly all providers performed microsurgical sperm retrievals (97%, n=38, Figure) and oncologic testicular sperm extractions (85%, n=33) when indicated. More than half of providers offered conventional testicular sperm extractions (72%, n=28), microsurgical epididymal sperm aspirations (59%, n=23), testicular sperm aspirations (56%, n=22), penile vibratory stimulation (54%, n=21), or percutaneous epididymal sperm aspirations (52%, n=20). Fewer providers offered post-mortem sperm retrieval (49%, n=19), pre-pubertal testicular tissue cryopreservation (36%, n=14), or electroejaculation (31%, n=12). Most respondents (62%, n=24) had access to an on-site andrology laboratory. Semen analyses were evaluated using manual (53%, n=20), computer-assisted (11%, n=4), or combinatorial methods (26%, n=10). Though many (37%, n=14) providers were uncertain about institutional costs for semen specimen processing, a plurality of respondents (40%, n=15) reported fees ranging from $100-500 with the remainder (23%, n=9) reporting fees exceeding $500. Respondents most frequently reported semen storage fees ranging between $100-300 per year (39%, n=15), while approximately a third (31%, n=12) estimated these costs to range between $300-600 per year. However, 18% (n=7) of respondents reported higher costs for specimen storage and 13% (n=5) were uncertain about the expense of this service. Conclusions This multi-institutional, geographically diverse survey reveals significant variation in reproductive urology practice patterns and cost associated with semen analyses and storage. Future studies will explore differences in practice patterns to better understand the factors influencing this variation and their effect on male reproductive healthcare. In the absence of society guidelines, reproductive urologists must collaborate, share best practices, and maintain price transparency to ensure sperm retrieval remains accessible and affordable. Disclosure No

Abstract Introduction While microdeletions in the azoospermia factor (AZF) regions of the Y chromosome are a well-recognized cause of genetic male infertility, reproductive outcomes and broader health profiles among affected men remain poorly characterized. Objective We explore the distribution of AZF deletion subtypes and evaluate comorbidities and fertility management patterns in this unique population. Methods We performed a multi-institutional retrospective cohort study of men diagnosed with AZF deletions following evaluation by a reproductive urologist and genetic testing. The primary exposure variable was the AZF subtype (AZFa, AZFb, AZFc, or multilocus [e.g., AZFabc]).Clinical data were extracted to assess the presence of comorbidities, including hypertension, diabetes mellitus, hyperlipidemia, liver disease, and cardiac disease. Descriptive statistics were used to characterize the distribution of AZF subtypes, comorbidity profile, and outcomes of sperm retrieval procedures within our cohort. Results Among 40 men with confirmed AZF microdeletions across three academic centers, four patients with SRY translocations were excluded. Of the remaining 36, AZFc was the most common subtype (75%), followed by multilocus (16.6%), AZFa (5.5%), and AZFb (2.7%). The median age was 32.8 years (IQR: 29.2–33.6) and median BMI was 28.6 kg/m2 (IQR: 25.6–32.8). Comorbid conditions were identified in 8% of the cohort, with hyperlipidemia (13.9%), hypertension (11%), and diabetes (11%) most commonly reported. Sperm retrieval was attempted in 31% (n=11) of patients, exclusively among those with AZFc (n=10) andAZFb (n=1) deletions. Microscopic testicular sperm extraction (mTESE) was the predominant technique (91%). Sperm was successfully retrieved in 46% of these cases, all within the AZFc subgroup. Conclusions This study advances limited literature on AZF microdeletions by characterizing systemic health profiles and post-diagnosis infertility management. Our results support a broad phenotype associated with genetic causes of male infertility. In this cohort of men with YCMD, AZFc was the most prevalent subtype. Compared to national estimates for similarly aged men, our findings suggest that men with YCMD may have a distinct comorbidity profile compared to the general population, with an elevated prevalence of metabolic disease. Our findings reinforce male infertility as a heterogeneous condition that may serve as an early marker for broader metabolic disease. In addition, nearly all patients who underwent sperm retrieval were within the AZFc group. Fertility management trends favored mTESE, with moderate success rates in sperm retrieval, particularly among AZFc patients. Our results highlight provider preferences in surgical fertility management in patients withYCMD. Our findings underscore the need for a holistic approach to men with YCMD, addressing both surgical fertility management and systemic health risks. Clear patient counseling on sperm retrieval success rates and early identification of comorbidities may redefine outcomes for this unique population. Our results support a broad phenotype associated with genetic causes of male infertility. Disclosure No

Abstract Introduction Fertility preservation is an essential component to cancer survivorship. One third of male survivors experience infertility following gonadotoxic treatments, and expeditious preservation prior to therapy is recommended by oncology guidelines. However, this can be challenging given time constraints, lab expertise, and financial considerations. Objective We describe national practice patterns and identify barriers and facilitators regarding inpatient male fertility preservation. Methods An anonymous 34-item Qualtrics survey was sent to reproductive Urologists in the United States. Email addresses were obtained from public membership databases. Respondents were queried across several domains, including provider demographics, specific inpatient cryopreservation scenarios, and fertility preservation procedures. Results Thirty-nine (21%, n=39/189) responses were received. The majority of respondents were fellowship-trained reproductive urologists 89.7% (35). The majority (97.4%) of respondents offer microdissection testicular sperm extraction (mTESE) for fertility preservation, and many offer conventional TESE (71.8%), traditional ejaculated sperm cryopreservation (71.8%), or microsurgical epididymal sperm aspiration (59%). Only 30.8% of respondents offer electroejaculation. Respondents rate non-urology provider awareness of male cancer fertility preservation options at 5.05/10 on a Likert scale. Many (65%) respondents provide formal materials or education to nonurology providers to address this deficit. On average, respondents reported 2.6 inpatient oncofertility preservation consults per month (range 0-25, median=1). Most (60%) of respondents reported that <25% of these patients ultimately complete inpatient preservation. Financial burdens (97%), logistical hurdles (97%), limited awareness (97%), and concern for delay of oncologic care (92%) were identified as the most common barriers for patients precluding fertility preservation. In addition, 85% of respondents also listed difficulty coordinating with other specialists as a barrier. On free-text queries, respondents identified facilitators of fertility preservation as automatically triggered consults, use of an urgent cryopreservation pager, formal fertility preservation pathway within the order set, and utilization of an inpatient coordinator as facilitators that aid in achieving timely fertility preservation prior to gonadotoxic therapies. Conclusions Despite all reproductive urologists offering cryopreservation services and education regarding the urgency and priority of inpatient fertility preservation, less than a quarter of patients complete this process during hospitalization prior to initiation of treatment. This remains the consequence of numerous patient, provider, and facility level barriers, even in systems with robust referral processes. Inpatient fertility preservation remains an underutilized and often missed opportunity. Multidisciplinary interventions are needed to address ongoing barriers. Disclosure No

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 Introduction Male-factor infertility contributes to a substantial portion of infertility cases. Genetic factors are believed to play an important role, with Y chromosome microdeletions commonly identified among men with azoospermia. Due to the relatively high prevalence of these deletions, genetic testing for Y chromosome microdeletions has become a routine component of the diagnostic workup for infertile men. While deletions in the AZF (Azoospermia Factor) region are known to impair spermatogenesis, the hormonal profile in this population remains poorly characterized. Hormonal evaluation plays a key role in guiding treatment decisions, including the use of empirical medical therapy (EMT). However, there is limited data on hormonal profiles and EMT usage in men with AZF deletions. Objective We aimed to characterize preoperative hormonal profiles and evaluate the use and outcomes of EMT in men with AZF microdeletions undergoing surgical sperm retrieval. Methods We conducted a multi-institutional retrospective cohort study of men with genetically confirmed AZF micro-deletions, including AZFa, AZFb, AZFc, and combined deletions. Data were collected on preoperative serum gonadotropin levels (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), total testosterone (TT), and semen analysis parameters. Additionally, we evaluated patterns of empirical medical therapy (EMT) prescriptions and outcomes of surgical sperm retrieval. Results 40 men with confirmed Y-chromosomal micro-deletions across three academic centers was identified. Patients with SRY translocations (n=4) were excluded from the study. The final cohort included 27 patients with AZFc deletions (75%), 2 with AZFa (6%), 1 with AZFb (3%), and 6 with multilocus deletions (17%). FSH (reference: >7.6 mIU/mL) was elevated in 23 patients (64%), with a median of 19.6 IU/L (IQR: 14.4–25.8). LH (reference: >9 mIU/mL) was elevated in 8 patients (22%), with a median of 14.9 IU/L (IQR: 13.7–20.1). Overall median TT was 243.5 (7.7-379.7). TT was below the lower limit of normal (<300 ng/dL) in 13 patients (36%), with a median of 184 ng/dL (IQR: 133–233). Most patients were azoospermic on semen analysis (86%, n=31/36). Of the seven men treated with EMT, the majority (6/7, 86%) received clomiphene citrate. While there were differences in initial levels of TT, FSH, and LH for those treated with EMT compared to those without EMT, these were not statistically significant (Table 1). Among the 13 patients who underwent surgical sperm retrieval, 6 (46%) had successful outcomes; however, only one had received EMT. Conclusions Men with AZF deletions exhibit varying degrees of hormonal imbalance and rates of empirical medical therapy (EMT) use. Despite EMT, sperm retrieval outcomes were poor, with only 1 out of 7 EMT-treated patients achieving successful sperm retrieval. While hormonal differences were observed between those who received EMT and those who did not, these differences did not reach statistical significance. This is likely due to the limited sample size inherent to this rare patient population. Our findings underscore the variability in hormonal profiles and the unclear efficacy of EMT in promoting spermatogenesis in men with AZF deletions, highlighting the need for further research to inform standardized management strategies. Disclosure No

Abstract Introduction Oncologic testicular sperm extraction (oncoTESE) remains a poorly defined concept that is a heterogeneous and understudied fertility preservation option for cancer patients with male gonads. Given variation in practice patterns, reproductive insurance coverage, and provider availability, there is significant diversity among the accepted indications, desired evaluations, and surgical practices afforded to patients facing a cancer diagnosis. Objective This study aimed to characterize and help further define oncoTESE practice patterns across the United States. Methods A 34-item, anonymized survey assessed provider demographics and oncoTESE practice patterns, including indications, contraindications, workflows, and institutional barriers surrounding OncoTESE procedures. A survey was created and electronically distributed to reproductive urologists across the United States using email addresses obtained via society membership websites. Results Thirty-eight urologists (20%, 38/189) from 21 states responded to the survey. Most (95%, 36/38) were fellowship-trained reproductive urologists, and nearly all (87%, 33/38) reported offering oncoTESE to indicated patients. The most cited indications for oncoTESE were azoospermia (78%, 28/36), anejaculation (72%, 26/36), and severe oligozoospermia or cryptozoospermia on ejaculated specimen (53%, 19/36). Less commonly reported indications included prepubertal or peripubertal status (33%, 12/36) and elevated sperm DNA fragmentation (19%, 7/36). Relative contraindications included inability to consent (86%, 31/36), clinical instability (83%, 30/36), thrombocytopenia (61%, 22/36), and a history of remote chemotherapy (58%, 21/36). When asked how many semen analyses are obtained to confirm azoospermia before proceeding to oncoTESE in patients able to ejaculate, the majority reported two analyses (67%, 24/36), while 28% (10/36) reported one. There was stronger consensus that oncoTESE includes sperm retrieval during back-table orchiectomy (94%, 34/36) and ipsilateral microTESE during partial orchiectomy (86%, 31/36). Greater variability was noted regarding contralateral microTESE at the time of orchiectomy (64%, 23/36), procedures for non-genitourinary malignancies (61%, 22/36), and delayed procedures performed years after diagnosis (42%, 15/36). (Figure 1) Estimated patient costs for oncoTESE were most commonly reported as $2,000–$5,000 (39%, 14/36), followed by $500–$2,000 (22%, 8/36), $5,000–$10,000 (19%, 7/36), and over $10,000 (3%, 1/36); 14% (5/36) were unsure. On a 10-point Likert scale, the most significant barriers to performing oncoTESE were logistical challenges (mean 6.6, median 8), followed by patient cost (mean 5.4, median 5.5) and patient illness (mean 5.3, median 5.0). Conclusions This multi-institutional survey found strong agreement among reproductive urologists on core procedural elements, but substantial variation on oncoTESE definition, patient selection criteria, pre-procedural evaluation, and fertility preservation management. Similar institutional barriers across centers highlight opportunities to improve accessibility and standardize oncoTESE practices. Disclosure No

Abstract Background and Significance Somatic gain-of-function mutations in the PIK3CA gene can result in a range of vascular malformations (VMs). These rare disorders include lymphatic anomalies and PIK3CA-related overgrowth spectrum (PROS). VMs are noncancerous lesions that may be managed with treatments such as surgery, sclerotherapy, sirolimus, and non-mutant-selective PI3Kα inhibitors; however, use of systemic therapies in patients is frequently limited by drug-related adverse effects. In particular, inhibition of wild-type PI3Kα results in significant toxicity, including hyperglycemia, diarrhea and rash. RLY-2608 is a novel, allosteric, pan-mutant and isoform-selective oral PI3Kα inhibitor designed to have higher potency and improved tolerability. In a PIK3CAH1047R HUVEC xenograft mouse model, RLY-2608 demonstrated greater lesion regression and less insulin induction across clinically relevant dose levels than alpelisib (Llambi, VAC 2025). ReInspire (RLY-2608-201; NCT06789913) is an ongoing, global, multicenter study in patients with PIK3CA-driven VMs to assess the safety, pharmacokinetics, recommended adult and pediatric dosing, and efficacy of RLY-2608 based on target lesion volume and clinical outcome assessments. The design of this study, including dose selection, was informed by clinical data from the first-in-human study of RLY-2608 in adult patients with advanced solid tumors, including breast cancer (Varkaris et al, 2024). Study Design and Methods ReInspire is a 3-part study evaluating the safety and efficacy of RLY-2608 in approximately 277 patients two years of age and older with PIK3CA-driven VMs and PROS. RLY-2608 is administered orally in continuous cycles. The primary endpoints are safety, tolerability, recommended Phase 2 dose (RP2D), and efficacy of RLY-2608 per volumetric reduction on MRI (≥20% reduction from baseline to Week 24 in the sum of target lesion volumes) by blinded independent central review. Other endpoints include duration of response and change in age-appropriate clinical outcome assessments. Patients are enrolled in a staggered fashion by age, beginning with adult and adolescent participants 12 years and older (Group 1), and may be extended to pediatric participants 6 to <12 years (Group 2) and 2 to <6 years, based on review of cumulative clinical data. Part 1 is the open-label dose-finding portion, which initiates with randomization of Group 1 patients (n=45) to one of three dose levels with stratification according to prior alpelisib use, and will be followed by weight-based dose escalation using a Bayesian optimal interval (BOIN) design in Groups 2 and 3, if opened. Part 2 is a basket-style, open-label dose expansion that will evaluate the clinical activity of RLY-2608 at one or more RP2Ds in various populations in cohorts of 20 patients each based on Part 1 findings. Depending on the results of Parts 1 and 2, Part 3, a double-blinded, placebo-controlled, 2:1 randomized study (n=90), may be opened to patients 6 years of age and older. To enroll, patients are required to have a clinical diagnosis of PROS or a malformation within the ISSVA classifications, and the majority must have a documented activating PIK3CA mutation per local assessment of lesional tissue and/or cell-free DNA from the lesion or blood. Patients with other known pathogenic somatic or germline driver mutations (such as TIE2 (TEK) and AKT1) are not eligible. Patients must be a candidate for investigational systemic therapy; have severe, symptomatic, and/or progressive disease; and at least one target lesion amenable for volumetric assessment. Additionally, patients who have received disease-directed therapy must undergo a washout period for systemic treatment and local therapies including radiation, surgery and other procedures. Patients with Type 1 or 2 diabetes requiring antihyperglycemic medication or fasting plasma glucose ≥140 mg/dL, or glycosylated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) are not eligible. Statistical analyses will be primarily descriptive in nature in Parts 1 and 2, with statistical comparisons between RLY-2608 and placebo at Week 24. ReInspire is open to enrollment. Patients ≥12 years are now enrolling in Part 1. For more information, contact clinicaltrials@relaytx.com