Citations

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study established a role for maternal-fetal surgery for myelomeningocele (MMC) but was limited to patients with a maternal body mass index (BMI) less than 35 kg/m 2 . However, as the rate of obesity has increased globally, some centers have extended the Management of Myelomeningocele Study criteria to include patients with a BMI of 35 to 40 kg/m 2 . We used the Fetal MMC Consortium registry to analyze the complications associated with maternal-fetal surgery in patients with a maternal BMI < 35 kg/m 2 compared with 35 to 40 kg/m 2 . METHODS: The prospective observational Fetal MMC Consortium registry sponsored by the North American Fetal Therapy Network was used to extract deidentified “maternal complication” and “fetal/neonatal complication” data sets, corresponding to patients with complete entries related to maternal or fetal/neonatal complications, respectively. Demographics, clinical characteristics, and complications were recorded. Propensity score matching was conducted with a 2:1 algorithm, and outcomes were compared between patients with BMI < 35 kg/m 2 and those with BMI 35 to 40 kg/m 2 . RESULTS: Propensity score matching resulted in 156 patients with BMI < 35 kg/m 2 and 78 patients with BMI 35 to 40 kg/m 2 in the “maternal complication” data set, and 130 patients with BMI < 35 kg/m 2 and 65 patients with BMI 35 to 40 kg/m 2 in the “fetal/neonatal complication” data set. No significant differences in the median number of maternal (2.0 vs 2.0; P = .257) or median number of fetal/neonatal (1.0 vs 1.0; P = .409) complications were observed between the 2 cohorts. Furthermore, prematurity rates did not differ significantly between the BMI < 35 and BMI 35 to 40 cohorts. CONCLUSION: Maternal-fetal surgery for open neural tube defect closure is not associated with increased risks among patients with a maternal BMI of 35 to 40 kg/m 2 . Extending the initial inclusion criteria for prenatal MMC closure has the potential to expand access to patients with a higher risk for open neural tube defects.

Background. Living kidney donation (KD) evaluation particularly focuses on glomerular filtration rate (GFR). Assessing GFR in living kidney donors can be done by estimation (eGFR) or measurement (mGFR). This study aims to evaluate the impact of eGFR equations, focusing on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation for donor eligibility screening and the reclassification of donors excluded by eGFR criteria to mGFR assessments. Methods. Retrospective, single-center observational study of 2512 kidney donors evaluated between 2011 and 2023, at the Mayo Clinic. We performed analyses and comparisons of 4 eGFR formulae and 2 mGFR methods in terms of performance, eligibility criteria according to Kidney Disease: Improving Global Outcomes guidelines/age-adjusted criteria, eligibility reclassification, and subgroup analyses. Results. The CKD-EPI 2021 resulted in a higher percentage of patients being eligible for KD (81.4%) and achieved the highest P10 (32%–34%) and P30 (87%–88%) across all mGFR methods. When patients were deemed eligible for donation by any eGFR formula, 95% retained this status on reassessment with mGFR. Conversely, when an eGFR formula classified a patient as ineligible, this was revised to be eligible in about 90% of cases on reassessment with mGFR, with a higher reclassification rate observed when the IoCl was used instead of CrCl. Conclusions. The CKD-EPI 2021 performs best for screening potential KD. If a KD is deemed ineligible by CKD-EPI 2021, there is a high likelihood that they will be reclassified as eligible when assessed with mGFR. This study strongly supports using mGFR in donor evaluations, especially when the eGFR does not meet the criteria to ensure equity of access to being a living donor.

Abstract Objective The objective of this study was to summarize the available evidence regarding the clinical value and trend over time of lumbar cerebrospinal fluid (CSF) opening pressure utilization to diagnose spontaneous intracranial hypotension (SIH). Background CSF opening pressure obtained via lumbar puncture is one of the diagnostic criteria for SIH based on the International Criteria for Headache Disorders, 3rd Edition (ICHD‐3), but it has questionable utility as an initial investigation for diagnosing SIH. Methods The authors performed a systematic literature review and meta‐analysis. PubMed/MEDLINE, Scopus, and Cochrane Library were searched from inception to October 2022. Original studies and case series in English reporting three or more patients with suspected or known SIH and CSF pressure measurement were included. Meta‐analyses and meta‐regression were used to calculate pooled estimates and examine the impact of age, sex, and publication year on outcomes, including CSF pressure < 60 mm CSF, orthostatic headache, and positive findings on brain magnetic resonance imaging (MRI), spinal imaging, and radionuclide studies. Results For every 1‐year increase in the year of publication, the odds of reporting low CSF pressure decreased by 6.20% (adjusted odds ratio [aOR] = 0.94, aOR 95% confidence interval [CI] = [0.90, 0.97], p = 0.001), the odds of reporting a positive brain MRI increased by 4.67% (aOR = 1.05, aOR 95% CI = [1.01, 1.09], p = 0.026), and the odds of reporting orthostatic headache increased by 9.13% (aOR = 1.09, aOR 95% CI = [1.03, 1.15], p = 0.002). Each 1% increase in the percentage of patients with orthostatic headache was associated with a 3.13% increase in the odds of low CSF pressure (aOR = 1.03, aOR 95% CI = [1.01, 1.05], p = 0.003). Similarly, as the percentage of patients with low CSF pressure increased by 1%, there was a 2.53% increase in the odds of orthostatic headache (aOR = 1.03, aOR 95% CI = [1.01, 1.04], p = 0.005). It was estimated that 31.9% of patients with SIH had normal opening pressure (95% CI = [24.0%, 40.8%], prediction interval = [5.0%, 80.5%]). Every 1% increase in the percentage of patients with positive brain MRI was associated with a 5.25% increase in the odds of positive spinal imaging (aOR = 1.05, aOR 95% CI = [1.00, 1.11], p = 0.047). Age and positive radionuclide study did not significantly impact the outcomes measured. The corresponding I 2 for each outcome was reduced by controlling for study‐wide covariates believed to impact the prevalence of each outcome. Sensitivity analyses did not reveal discrepancies in results when studies requiring outcomes of interest were removed. Conclusion Our analysis found that recent studies indicate a reduced reliance on opening pressure for diagnosing SIH. Rather, results suggest an increasing reliance on contrast‐enhanced brain MRI, spine imaging, and clinical features for SIH diagnosis.

Abstract Aims Left ventricular assist devices (LVADs) are a critical intervention for advanced heart failure (HF), serving as destination therapy or bridge to transplantation. Obesity and diabetes impact outcomes in patients with LVADs. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) demonstrate cardiovascular benefits; however, their role in patients with LVADs remains underexplored. We evaluated the association of GLP1-RA therapy with cardiovascular outcomes in patients with LVADs. Methods This retrospective cohort study used the TriNetX database, a research network database from 98 healthcare organizations. We queried for all adult LVAD recipients (≥18 years) and were stratified into GLP1-RA users and non-users. Propensity score matching (PSM) (1:1) balanced demographics, comorbidities, medication use and laboratory data. Outcomes included heart transplantation rates, heart failure hospitalizations, all-cause mortality, all-cause hospitalizations and cardiovascular events. Logistic regression models were used to estimate adjusted odds ratios (aOR). Results After PSM, we included a total of 1036 adult LVAD recipients (518 GLP1-RA users, 518 matched non-users) with a mean follow-up time of 311.6 ± 98.4 days for the GLP1-RA cohort and 304.0 ± 111.5 days for the non-GLP1-RAs cohort. Mean age was 56.7 ± 12.2 years in the GLP1-RA cohort and 58.0 ± 12.5 years in the non-GLP1-RA cohort. Females comprised 28.0% of both cohorts while White patients represented 52.1% of the GLP1-RA group and 53.1% of the non-GLP1-RA group. GLP1-RA users had higher heart transplantation rates [n = 98 (18.9%) vs. n = 44 (8.5%); aOR 2.514 (95% CI: 1.720–3.673)]. Acute HF events and all-cause hospitalizations were lower among GLP1-RA users compared with non-users [n = 288 (55.6%) vs. n = 357 (68.9%); aOR 0.565 (95% CI: 0.438–728) and n = 324 (62.5%) vs. n = 390 (75.3%); aOR 0.548 (95% CI: 0.420–0.716)]. No differences were observed when comparing the GLP1-RA cohort with the non-GLP1-RA cohort in regard to all-cause mortality [n = 32 (6.2%) vs. n = 44 (8.5%); aOR 0.709 (95% CI: 0.442–1.138)], stroke [n = 42 (8.1%) vs. n = 58 (11.2%); aOR 0.700 (95% CI: 0.461–1.062)] or cardiac arrest [n = 18 (3.5%) vs. n = 17 (3.3%); aOR 1.061 (95% CI: 0.541–2.082)]. Conclusions GLP1-RA therapy in patients with advanced HF and LVADs is potentially associated with improved heart transplantation rates while decreasing hospitalization and acute HF event rates.

Background and Objectives: Peripheral nerve stimulation (PNS) is analgesic for some lower extremity neuropathic pain syndromes. PNS currently involves open surgical placement of electrode(s). Increasingly, ultrasound guidance is used for perioperative neural block. Minimally invasive placement of PNS electrodes for lower extremity targets using ultrasound guidance has not been reported. We hypothesized that ultrasound-guided placement of PNS electrodes was feasible. Methods: Four cadaver mid-thigh transected fresh frozen specimens were studied. Specimens were scanned utilizing a 14 to 7 MHz linear probe and electrodes were placed proximal to the tibial, peroneal, and sciatic nerves at various locations. Anatomical dissection was performed to check placement accuracy and evaluate for grossly visible neural injuries. Results: Acceptable locations for ultrasound-guided electrode placement were: (1) tibial nerve, approximately 8 to 14 cm superior to the medial malleolus above the tarsal tunnel, or at the upper popliteal fossa; (2) peroneal nerve, approximately 2 to 4 cm inferior to the lateral fibular head or at the upper popliteal fossa; (3) sciatic nerve immediately superior to the bifurcation (high popliteal area); and (4) lateral sural nerve at the lower popliteal fossa. No grossly visible neural injuries were seen. Electrode placements appeared to be in satisfactory locations for stimulation. Conclusions: Ultrasound imaging to facilitate peripheral nerve electrode placement is feasible. This new minimally invasive approach to lead placement requires further study to determine trial implantation criteria, optimal locations, anchoring techniques, and best clinical practice.

501 Background: Targeted treatment options have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), but oncology healthcare professionals (HCPs) who provide care for fewer numbers of patients with CLL are challenged to remain current with continuously changing treatment paradigms. To assess ongoing educational needs, we analyzed the treatment choices made by HCPs in an online survey for select cases of poor-prognosis CLL and compared these with the choices of experts in CLL treatment for the same clinical scenarios. Methods: As part of a CME program, HCPs could access an online algorithm to enter specific characteristics of a CLL case scenario and receive treatment recommendations from 5 US-based CLL experts. Experts made recommendations in July 2024 for 146 possible case patients built into the algorithm. After entering their case characteristics, HCPs were asked to enter their planned treatment prior to viewing the expert recommendations. We compared expert and HCP treatment choices across various case scenarios that were entered into the algorithm, with a focus on previously untreated CLL with del(17p)/mutated TP53 or R/R CLL. Results: Between August 2024 and February 2025, 346 cases were entered into the algorithm by 174 HCPs. Among responding HCPs, 38% were based in the UK/EU, 24% in the US, and 10% in Asia; 62% treated ≤10 patients with CLL per month and 49% sought recommendations for a specific patient in their practice. Among 231 cases of previously untreated CLL entered, 91 (39%) sought recommendations for del(17p)/mutated TP53 disease. For cases with no major comorbidities and previously untreated CLL with del(17p)/mutated TP53 , all experts recommended acalabrutinib or zanubrutinib; in 19 cases submitted by HCPs practicing in locations where second-generation BTK inhibitors (BTKi) are approved for CLL (including the US, EU, and Japan), 58% planned 1 of these treatments for this case scenario, 17% planned ibrutinib-based therapy, and 11% planned venetoclax-based therapy. Among case scenarios requiring third-line therapy after progressing with 2 regimens including a covalent BTKi and venetoclax plus an anti-CD20 Ab (with progression <2 years after completing treatment), all experts would recommend a noncovalent BTKi (eg, pirtobrutinib), with 1 expert indicating they would also consider CAR T-cell therapy. For the same case scenario among 6 US-based HCPs, 1 planned pirtobrutinib and 3 planned CAR T-cell therapy. Overall, after reviewing expert recommendations, 61% of HCP respondents whose planned treatment differed from the experts indicated that they would change their approach, and 20% indicated barriers to implementing the recommendations. Conclusions: Our findings provide insight into potential educational needs among HCPs who manage patients with CLL, suggesting that targeted expert-led education could benefit these HCPs.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.

Abstract BACKGROUND Adamantinomatous craniopharyngiomas (ACPs) are rare, partially cystic central nervous system tumors driven by the WNT/β-catenin pathway. As they grow, ACPs compress the surrounding pituitary gland, optic chiasm, and third ventricle. ACPs are highly morbid tumors with enormous quality of life impact on patients, often early in life. Thus, better treatments are needed. Current ACP treatment consists of maximally safe surgical resection with radiation for residual disease. Complete surgical resection is challenging, and recurrence is common. Targeted systemic chemotherapy is not routinely used for ACP treatment. Interleukin-6 (IL-6) levels are elevated within ACPs compared to normal brain tissue, making IL-6 an intriguing therapeutic target. Treatment response of ACP to tocilizumab alone or in combination with bevacizumab has been reported in children. MATERIAL AND METHODS We retrospectively reviewed the medical records of three adults with recurrent ACP who received combination treatment with bevacizumab and tocilizumab on a compassionate basis between June 2022 and April 2025 at Mayo Clinic in Rochester, MN. We collected demographic, clinical, treatment, radiologic, and outcome data. RESULTS All three patients were male and median age at initial ACP diagnosis was 38 years (range: 32-42 years). All patients underwent subtotal resection followed by radiation therapy. One patient had repeat surgical resection and two patients required interventions for hydrocephalus. At the time of ACP recurrence, all patients had visual impairment, endocrine dysfunction, and headaches. All patients received bevacizumab (7.5 mg/kg q3 weeks) and tocilizumab (8 mg/kg q3 weeks [n=2] or 4 mg/kg q4 weeks [n=1]). While receiving combination therapy, ACP tumor volume decreased on magnetic resonance imaging for all three patients (64%, 68%, and 29% reduction). None exhibited tumor growth since starting combination therapy. One patient had a small intraparenchymal hemorrhage, suspected secondary to radiation-induced cavernous malformation, so bevacizumab was discontinued, and he remains on tocilizumab alone. The other two patients continue combination therapy (for 344 and 351 days). Two patients experienced improvement in vision, and one had improvement in cognition. Possible adverse effects of treatment included sinus infections, fatigue, neutropenia, and hypertension. CONCLUSION Treatment with combination bevacizumab and tocilizumab was associated with shrinkage of ACP tumors and clinical improvements and obviated the need for further surgery or radiation in all three patients. This combination of medications may reprogram the tumor microenvironment, leading to ACP involution. This well-tolerated regimen provides a noninvasive option for treatment of recurrent ACP, and potentially initial ACP treatment, and may improve quality of life for patients.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2 years) with NF1 who have symptomatic PN not amenable to complete resection. We report updated results from the LTFU phase of the pivotal, phase 2b ReNeu trial (NCT03962543) evaluating the efficacy and safety of mirdametinib. MATERIALS AND METHODS In ReNeu, mirdametinib capsules or tablets for oral suspension (2 mg/m2 BID, max 4 mg BID) are administered in 3-weeks-on/1-week-off 28-day cycles. Following the 24-cycle (~2 years) treatment phase, patients could continue mirdametinib in an optional LTFU phase. These analyses are inclusive of the treatment and LTFU phases (data cutoff: June 12, 2024; an additional 9 months of cumulative data following the primary analysis). Exploratory analyses reported here included confirmed objective response rate (ORR; proportion of patients with ≥20% reduction of target PN volume from baseline on consecutive MRI scans within 2 to 6 months, assessed by blinded independent central review), duration of response (DoR), change from baseline in target PN volume, and safety. RESULTS Fifty-eight adults and 56 children were dosed with mirdametinib. Median (range) duration of mirdametinib treatment was 21.8 (0.4, 54.4) months in adults and 25.4 (1.6, 48.5) months in children. Among LTFU-eligible patients, 26/31 (84%) adults and 32/37 (86%) children entered the LTFU. Confirmed ORR was 47% (27/58; 95% CI, 33%, 60%) in adults and 55% (31/56; 95% CI, 42%, 69%) in children. Of patients with a confirmed objective response, 18 adults and 19 children achieved a deep response (best target PN volume reduction from baseline of &gt;50%). Median (range) best percentage change from baseline in target PN volume was -41% (-90%, 13%) in adults and -43% (-98%, 48%) in children. Median DoR was not reached. Treatment-related adverse events (TRAEs) in ≥25% of patients were dermatitis acneiform, diarrhoea, nausea, and vomiting in adults, and diarrhoea, dermatitis acneiform, and paronychia in children. Grade ≥3 TRAEs occurred in 17% of adults and 25% of children. Dose interruptions, dose reductions, and discontinuations due to TRAEs occurred in 9%, 17%, and 22%, respectively, of adults, and in 14%, 14%, and 9%, respectively, of children. CONCLUSIONS An increase in confirmed ORR was observed with longer duration of mirdametinib treatment, with additional deep responses achieved in both adults and children with NF1-PN. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals identified in the LTFU phase. SUPPORTED BY SpringWorks Therapeutics, Inc.