Citations

Abstract Background Cadaveric dissection remains a preferred and irreplaceable learning modality among neurosurgery residents. We aimed to develop and describe a tiered, quantifiable, and practical curriculum for cranial neurosurgical anatomy education. We report the structure and evaluation of our 2-year pilot study to serve as a suggested guide for other neurosurgery programs. Methods Our Complex Cranial Dissection Program is tailored to the needs of junior-level neurosurgery residents based on their postgraduation years 1 to 4. Dissections are performed in a sequential manner, each of which emphasize a particular set of manual skills and neuroanatomical knowledge. Dissections are scored on a scale of 10 points. The grading was based on specific landmarks and anatomical structures, which need to be exposed, explored, and preserved. Results Out of 16 residents, 14 individuals (87.5%) attended the dissections in the first iteration of the program and 16 individuals (100%) attended the dissections in the second iteration. A total of 17 dissections were performed across all years. In survey feedback about the program, 100% (Year 1) and 94% (Year 2) of residents considered the assigned dissections to be appropriate for their respective training levels. Further, 100% (Year 1) and 94% (Year 2) of residents endorsed that the dissections were important and helpful for their practice prior to similar operating room experiences. Conclusion The development and implementation of structured dissection programs within residency training, along with dedicated staff, and objective feedback serve a crucial role in neurosurgical education to further develop and enhance surgical skills in the operative setting.

e16342 Background: Pancreatic cancer poses a major challenge due to its high mortality rates and is known as one of the deadliest cancers. The increasing mortality in addition to the aggressive nature of the tumor may be due to major cardiovascular and cerebrovascular events (MACCE). The key to mitigating the risk of pancreatic cancer as well as MACCE, is primary prevention of common risk factors including tobacco use, obesity, dietary factors, alcohol use, and physical activity. Understanding that many of these factors are directly and indirectly influenced by income status, this study aims to explore the relationship between household income on MACCE in pancreatic cancer patients. Methods: Using ICD-10 codes, patients with pancreatic cancer were identified from National Inpatient Sample 2019 database. We included all-cause in-hospital mortality (ACIHM), acute myocardial infarction (AMI), arrythmia, cerebrovascular accident (CVA), and sudden cardiac death (SCD) as MACCE for the outcomes. Baseline characteristics including demographics, comorbidities; and MACCE outcomes were studied using chi-square for categorical or ANOVA for continuous data (statistical significance determined as p-value < 0.05) and results were stratified based on median household income quartiles. Results: Of the 114,235 patients identified with pancreatic cancer who were admitted to the hospital, 25% (28,570) belonged to the first income quartile ($1-47,999), 23.8% (27,235) belonged to the second income quartile ($48,000-60,999), 26.38% (30,135) belonged to the third income quartile ($61,000-81,999), and 24.76% (28,295) belonged to the fourth income quartile ($82,000+). When compared to the patients in the fourth quartile, the adjusted odds ratio (aOR) was found to be higher for all MACCE outcomes for patients in first quartile. The aOR for ACIHM in the first quartile was found to be 1.24 (95% CI 1.06-1.46, p = 0.006) as compared to patients in the fourth quartile. Additionally, the aOR for AMI, was found to be statistically significant in patients belonging to the first quartile at 1.30 (95% CI 1.01-1.70, p = 0.047). Similarly, the aORs for both arrhythmia and SCD were also higher in the population from the first quartile at 3.67 (95% CI 1.10-12.28, p = 0.03) and 1.45 (95% CI 1.01-2.09, p = 0.049). https://docs.google.com/document/d/1v84LyPoGL406_7SDxO1N-wKxwujSgFpf/edit?usp = sharing&ouid = 110330426831507953030&rtpof = true&sd = true. Conclusions: As compared to patients in fourth income quartile, the aOR was found to be higher for all MACCE outcomes for patients in the first income quartile, indicating a vast variation based on income strata. This hints towards a complex interplay of healthcare disparities including but not limited to difficult access to quality healthcare including subspecialities. Further research may be pertinent to explore the causes of this clear disparity to ensure equitable healthcare for all patient population.

TPS2098 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating tumor (ct) and cell-free (cf) DNA levels in blood due to the blood-brain barrier (BBB). This limits the identification of blood-based tumor biomarkers along with the development and use of biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with intravenously administered microbubble oscillators, leads to non-invasive disruption of the BBB. This trial aims to evaluate the utility of LIFU for boosting blood ctDNA and cfDNA for enhanced liquid biopsy in GBM patients. Methods: LIBERATE is an ongoing, prospective, multi-center, self-controlled, pivotal trial evaluating safety and technical efficacy of LIFU-based BBB disruption for increasing blood ctDNA and cfDNA levels in adults (aged 18-80 years) with GBM. Patients with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being enrolled. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV microbubbles for enhanced sonication effects, after which MR-guided BBB disruption using a 220 kHz LIFU device is performed with real-time acoustic feedback control for effective microbubble activation. Before and after procedure, phlebotomy and MRI brain are performed to evaluate outcomes. Primary study endpoint is defined, per subject, as ratio between their cfDNA level in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. Primary study hypothesis is that BBB disruption with LIFU leads to a ≥2-fold rise in blood cfDNA. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in blood cfDNA sample obtained 1-hour post-LIFU and the biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N = 50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known specific somatic mutations in ctDNA from blood samples collected before and after LIFU, (2) estimation of ctDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine the time of greatest yield, (3) correlation of MRI parameters related to grading of BBB disruption and ctDNA-based biomarkers from post-LIFU blood samples. Patient enrollment commenced in 2022 and 22 patients have been recruited by January 2024. Clinical trial information: NCT05383872 .

TPS2101 Background: Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective therapy and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination treatment that utilizes a drug, aminolevulinic acid HCL (SONALA-001), and a device, the Exablate 4000 Type 2.0, to deliver non-ablative MR-guided focused ultrasound (MRgFUS) to tumor. Preclinical studies have shown that SDT-induced sonoluminescence activates protoporphyrin IX (PpIX), which in turn generates reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that SONALA-001 SDT was well-tolerated and not associated with off-target cellular or radiographic effects, and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). Methods: SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of 10 mg/kg iv SONALA-001 in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Treatments take place every 4 weeks. In phase 1, sonication energy escalation utilizes an accelerated titration design with a single subject for dose level 1, followed by cohorts 2 and 3 with 3+3 design for additional dose escalation. SONALA-001 is administered 6 to 12 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of SONALA-001 SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Clinical trial information: NCT05370508 .

601 Background: EOP is an I-SPY2 neoadjuvant sub-study designed to test the tolerability and impact of novel endocrine-based strategies in stage 2/3 BC pts predicted to have lower benefit from chemotherapy. Amcenestrant (A) is an oral selective estrogen receptor degrader (SERD) with activity in hormone receptor positive (HR+) HER2- metastatic BC. Methods: EOP eligibility included pts screened for the main I-SPY2 trial with HR+ HER2-, MammaPrint (MP) low risk Stage 2/3 BC. Pts with MP High risk tumor signatures were eligible if clinically node-negative (cN-). Pts were stratified by SET index and menopausal status. Pts were randomized to 3 arms: A 200 mg qd (A), A + abemaciclib 150 mg bid (AA), A + letrozole 2.5 mg qd (AL). Premenopausal pts received concurrent ovarian function suppression. Treatment was for 6 mos followed by surgery. Baseline (BL) and 3-wk biopsies were performed. Breast MRIs were conducted at BL (T0), 3 wks (T1), 12 wks (T2), 6 mos (T3). The primary endpoint was feasibility, defined as >75% of pts completing >75% study therapy. Results: Between May 2021 and Aug 2022, 74 pts were randomized: 31 A, 21 AA, 22 AL. Median age 50 years, 54% premenopausal, 38% clinically node-positive (cN+). 41% pts had ductal, 38% lobular, 11% mixed ductal/lobular histology. Mean BL tumor Ki67 (central testing) was 16.9%, 88% MP low, 76% SET index Hi. Pt and tumor characteristics were balanced across the 3 arms. Treatment in all 3 arms was feasible with 95% of pts completing >75% study therapy. Most common AEs include grade 1-2 hot flashes (69%) and fatigue (66%). Grade 3 AEs include neutropenia (2 pts) and diarrhea (1 pt) in AA. Table summarizes key response endpoints, which were similar between pre- and postmenopausal pts. Of 28 cN+ pts, 2 (7%) were pathologically node-negative (pN-). Mean MRI Functional Tumor Volume (cc) change between T0->T1, T1->T2, T2->T3, T0->T3 was -6.06 (-34.2%), -3.55 (-29.2%), -0.829 (-20.1%), -11.3 (-68.4%), respectively, similar across arms (p=0.396).ctDNA was detected in 10/59 (17%) pts at T0. ctDNA became undetectable in 6 pts, decreased in 4 pts, and went from ctDNA undetectable at baseline to detectable at T3 in 2 pts. Conclusions: Six months of neoadjuvant endocrine therapy (NET) with the oral SERD amcenestrant is feasible, well-tolerated, and demonstrates anti-proliferative and anti-tumor activity in pre- and postmenopausal pts. NET provides a rich platform for biomarker discovery and investigating response to endocrine therapy. Clinical trial information: NCT01042379 . [Table: see text]

Abstract A phase 2, international, open-label, nonrandomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary end point was objective response rate (ORR); secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n = 38 angioimmunoblastic T-cell lymphoma (AITL), n = 25 PTCL not otherwise specified, and n = 2 other T-cell lymphomas. The ORR was 39.7% (95% confidence interval [CI], 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in patients with AITL (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the nonresponder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pretreated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. This trial was registered at www.ClinicalTrials.gov as #NCT02464228.

2658 Background: Immune checkpoint inhibitors provide limited benefit in patients with immunologically cold tumors, characterized by a lack of T cells. This creates a niche for T cell-inducing agents such as TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFa-IRES-hIL2). While the 5/3 chimeric oncolytic adenovirus platform prompts potent immunogenic capacity per se, this virus has been armed with TNFa and IL-2 selected based on their ability to activate and attract T cells into tumors. TILT-123 capsid modification, and double selectivity devices for virus replication in cancer cells only, allow intravenous use of TILT-123. This is an important advantage over conventional oncolytic viruses whose widespread use has been hindered by the need for intratumoral injection. Methods: Here we report tumor transduction, pharmacokinetic and immune effects of a single intravenous administration of TILT-123 from three Phase 1 dose escalation clinical trials (TUNIMO-NCT04695327, TUNINTIL-NCT04217473, and PROTA-NCT05271318), with a total of 52 patients. Overall, the most common tumor types were melanoma (20), ovarian cancer (18) and sarcoma (7). In each of these trials, the first TILT-123 injection was performed intravenously, and a tumor biopsy collected 7 days later. Peripheral blood was collected before and after systemic TILT-123 treatment. No other therapy was administered concurrently. Presence of virus in blood was detected with qPCR, while presence of virus in tumor biopsies was measured with immunohistochemistry (IHC) for adenovirus proteins. Immune changes in tumors were evaluated by IHC. Results: TILT-123 was detected in the peripheral blood of all treated patients. Virus concentration was highest at 1 hour after administration, with lower levels seen 16 hours post-injection. Concurrently, IFN-γ levels increased in the patients´ serum. The lowest TILT-123 blood concentrations were observed with the lowest dose, with progressive increases in subsequent cohorts. At higher doses, TILT-123 was detected circulating in blood one week post-administration. Treatment was safe and no dose-limiting toxicity was encountered. Overall, signs of TILT-123 transduction in tumors were observed in 75% of patients evaluated in all three trials, 80% in TUNIMO patients, and 63.64% in TUNINTIL patients. Early results from PROTA suggest a positive effect of TILT-123 in tumors from all cohorts´ dosages studied. Conclusions: In summary, intravenous injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration. These data suggest that TILT-123 could be developed as an intravenous therapy. However, further increases in tumor transduction could be achieved by using multiple intravenous injections of TILT-123. Clinical trial information: NCT04695327 ; NCT04217473 ; NCT05271318 .