Citations

50 Background: A+B is commonly used as first line systemic therapy in HCC patients with CP-B liver function, although in the IMbrave150 clinical trial, its efficacy was only assessed in patients with CP-A liver function. We evaluated outcomes in patients with CP-B liver function and compared to those with CP-A. Methods: We completed a multi-institution, retrospective review of patients with HCC from Mayo Clinic and University Hospitals Seidman Cancer Center, who had received A+B in the first line setting between March 2018 and November 2023. CP score was calculated at time of treatment, response was assessed, and progression free (PFS) and overall (OS) survival were determined using the Kaplan Meier method. Results: Among 322 patients with HCC, median age was 66.5 years, 78.6% were male, and 82.6% were white. Eighty-six patients (27%) had CP-B liver function, while 226 (70%) had CP-A and 10 (3%) had CP-C. Etiology of liver disease in patients with CP-B included hepatitis B in 7.0%, hepatitis C in 38.4%, alcohol use in 30.2%, and metabolic associated steatohepatitis in 20.9%. Median OS in patients with CP-B liver function was 6.4 months, while mOS was 21.6 months for those with CP-A ( p<0.0001). Further stratifying, mOS in those with CP-B7 was 9.1 months, CP-B8 was 5.5 months, and CP-B9 was 4.0 months. 12-month OS in patients with CP-B was 32.4%, compared to 69.3% in CP-A. Median PFS was 4.8 months in those with CP-B and 8.9 months in those with CP-A. Median PFS in those with CP-B7, -B8, and -B9 was 6.4 months, 2.7 months, and 2.7 months, respectively. Among those with CP-B, 1 patient had a complete response, 17 (19.8%) had a partial response, 29 (33.7%) had stable disease, and 37 (43.0%) had progressive disease. Adverse events in CP-B patients included hypertension in 14.0% (grade 3 in 1 patient), bleeding in 16.3% (grade 3 or greater in 11.6%), fatigue in 38.4%, and an immune-related adverse event in 17.4% (grade 3 in 5.8%). Conclusions: Patients with advanced HCC and CP-B7 liver function may still benefit from A+B. Importantly, no additional safety risks were identified in this subgroup. Those with CP-B8 and CP-B9 have significantly worse survival than those with CP-B7 and the likelihood of benefit from systemic therapy is minimal. It is important for providers to address the impact of baseline liver function on expected outcomes in patient with HCC.

Background Obesity is intricately associated with type-2 diabetes (T2D) and other cardiovascular conditions, increasing morbidity, mortality, and health care costs. Metabolic and bariatric surgeries (MBS) have shown promising results in significant weight loss and T2D remission, but existing predictive scores for post-MBS diabetes remission do not consider insulin dosage, potentially overlooking a critical factor. Methods A retrospective analysis of patients with T2D who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). The study focused on insulin dosage impact, divided into quartiles, on remission rates post-MBS. The effectiveness of RYGB vs SG was compared within insulin dose quartiles with up to 5 years of follow up. Results A total of 508 patients (64% female, 94.9% White, mean age 53.5 ± 10.5 years, BMI (46.0 ± 8.3 kg/m 2 ) were included in the analysis. This study demonstrates a profound association between insulin dosage quartiles and T2D remission after MBS. Patients with lower insulin requirements showed superior remission rates; those in the lowest quartile had remission rates of 73%, 70%, and 62% at 1, 3, and 5 years, respectively, compared to 34%, 37%, and 36% in the highest quartile ( P < 0.001 across all intervals). RYGB surgery showed a significantly better remission in the second and third insulin quartiles, suggesting its effectiveness over SG for patients with mid-range insulin requirements. Conclusion This study underscores the importance of considering insulin dosage when predicting T2D remission post-MBS. The findings advocate for a more nuanced selection of MBS procedures based on individual insulin profiles, potentially enhancing diabetes remission outcomes.

AbstractBackground and ObjectivesCriminal‐legal (CL) referrals to addiction treatment have historically had low utilization of medications for opioid use disorder (MOUD). While state differences have been reported, an in‐depth longitudinal analysis of state‐by‐state differences is lacking.MethodsThe Substance Abuse and Mental Health Services Administration Treatment Episode Dataset‐Admissions 2000–2020 provided data for individuals entering their initial treatment with an opioid as their primary substance. Outcome was planned use of MOUD, assessing odds ratio (OR) of CL referrals relative to non‐CL referrals cumulatively over the 21‐year period and as incremental change (change in relative disparity) using effect sizes, stratified by each state.Results2,187,447 cases met the criteria. Planned MOUD occurred in 37.7% of non‐CL clients versus 6.5% of CL clients (OR = 0.11, 95% confidence interval = 0.11–0.12). For all clients, planned MOUD increased from 2000 (33.9%) to 2020 (44.8%). This increase was blunted within CL clients, increasing from 2000 (6.4%) to 2020 (13.3%). Rhode Island saw the greatest improvements in equity.Discussion and ConclusionsWhile rates of planned MOUD increased over the 21 years, a significant disparity persisted among CL clients in most states. As opioid use disorders and opioid‐related overdoses are more prevalent among those involved with the CL system, improving this has high impact.Scientific SignificanceProvides the most comprehensive analysis of state‐by‐state inequities in MOUD access for CL relative to non‐CL referrals over a 21‐year period through use of a national data set. Positive outliers are used as case examples for others to follow in pursuit of more equitable care.

Background Minimally invasive (MIS) treatment of hallux valgus (HV) deformity is increasing in popularity. A 2-mm diameter burr is used to create a distal first metatarsal osteotomy prior to capital fragment translation and fixation. The metatarsal will shorten by the burr’s diameter (2 mm). Plantar or dorsal capital fragment displacement may also cause load transference and possibly transfer metatarsalgia. The purpose of this study is to examine the effect of MIS HV on forefoot loading mechanics with respect to metatarsal shortening and sagittal plane displacement. Methods Four lower-limb cadaveric specimens were studied. A pedobarography pressure-sensing mat was used to record forefoot plantar pressure in a controlled weight-bearing stance position. Control and postosteotomy measurements were obtained with the capital fragment fixated in 3 possible positions: 0 mm, 5 mm dorsal, and 5 mm plantar displacement. Pedobarography data yielded pressure data within measurable graphical depictions. Raw mean contact pressure measurements were taken under the first and fourth metatarsal heads to establish medial and lateral forefoot loading pressure ratios. An a priori power analysis was performed based on previous peer-reviewed pedobarographic data, and our study was adequately powered. Results Around 40 measurements were recorded, and ratios of medial-to-lateral forefoot loading were constructed. Medial forefoot pressure control versus 0 mm displacement, and control versus dorsal displacement were not found to be statistically significant ( p = 0.525, p = 0.55, respectively). Medial pressure significantly increased when comparing control versus plantar displacement ( P = .006). Lateral pressure significantly increased with dorsal displacement of the osteotomy ( P = .013). Conclusion Our study found that MIS HV correction did not cause an increase in lateral forefoot pressure loading when sagittal plane displacements were controlled. Plantar displacement increased medial loading, and dorsal displacement increased lateral loading. It may be valuable for surgeons to consider metatarsal head position postosteotomy, as a decrease in medial loading and subsequent increase in lateral loading may lead to lateral forefoot pain and transfer metatarsalgia. Levels of Evidence: IV.

Objective Peripheral nerve stimulation (PNS) is an emerging neuromodulation modality, yet there remains limited data highlighting its long-term effectiveness. The objective of this study was to report real-world data on pain intensity and opioid consumption after temporary and permanent PNS for chronic pain up to 24 months postimplantation. Methods A retrospective study was conducted on all patients who received PNS implants at a multi-centered enterprise between January 1, 2014 and February 24, 2022. The two co-primary outcomes were: (1) change in pain intensity (11-point Numerical Rating Scale) from baseline to 12 months postimplant; and (2) comparison of the change in pain intensity between temporary and permanent PNS cohorts 12 months postimplant. Results 126 patients were included in this analysis. Pain intensity significantly decreased 12 months postimplant in the overall cohort (mean difference (MD) −3.0 (95% CI −3.5 to −2.4), p<0.0001). No significant difference in this reduction was identified between temporary and permanent PNS cohorts (MD 0.0 (95% CI −1.1 to 1.0), p=1.00) 12 months postimplantation. Pain intensity significantly decreased in the overall, temporary, and permanent cohorts at all secondary time points (3, 6, and 24 months). No change in daily opioid consumption was observed at 6 and 12 months postimplant in the overall cohort. Conclusion This study found that both temporary and permanent PNS may be effective for reducing pain intensity in patients with chronic pain up to 24 months postimplantation, although no changes in opioid consumption were observed. The decrease in pain intensity was comparable between patients receiving temporary versus permanent implants, highlighting that temporary PNS may achieve long-lasting clinical benefits. However, given the substantial loss to follow-up, further large-scale studies are needed to solidify conclusions about the efficacy of PNS.

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity – e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC ) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.

Abstract Background Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. Methods This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. Results Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P &lt; .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. Conclusions CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of postprocedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in 4 databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8,086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% (95% confidence intervals, −0.8% to 3.5%; I 2 = 0.00), which was predominantly of mild severity (67%) and uniformly nonfatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber, or passes, although we noted trends toward higher risk in studies published after 2015, those using higher gauge needles (19 G vs 22 G/25 G), and those performing EUS-guided through-the-needle biopsy. DISCUSSION: We note with high certainty that pancreatitis after EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-guided through-the-needle biopsy may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

4601 Background: Cretostimogene grenadenorepvec is a type-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the retinoblastoma pathway. Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mode of action. Cretostimogene monotherapy recently received Food and Drug Administration (FDA) Fast Track and Breakthrough Therapy Designations (BTD) in the BCG-Unresponsive, High-Risk, non-Muscle Invasive Bladder Cancer with Carcinoma in Situ (BCG-UR HR NMIBC with CIS) indication with a Complete Response (CR) at any time rate of 76%. This phase-2 study assessed the potential synergy between intravesical cretostimogene and pembrolizumab in patients with BCG-UR, HR NMIBC, with CIS, with or without Ta/T1 tumors. This combination has also received BTD from the FDA. Methods: 35 pts were treated with cretostimogene (1x1012 viral particles) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. Cretostimogene induction was given as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Pts with persistent CIS or high-grade Ta tumors at the 3mo assessment were eligible for re-induction. Pembrolizumab was administered for up to 24mo. Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12mo. The primary endpoint was CR at 12mo. Secondary endpoints included CR at any time, duration of response (DOR), CR at 24mo, cystectomy-free survival, and safety. Exploratory endpoints included analyses of baseline viral receptor expression, free E2F levels, PD-L1 status, urinary cytokine panels and measures of viral replication. Results: 30/35 pts are evaluable per protocol for the primary endpoint. Five pts discontinued prior to the 12mo time point. The CR rate in the Intention to Treat (ITT) population at 12mo and any time, was 57% (20/35) (95% CI 40-73%) and 83% (29/35) (95% CI 66-93%), respectively. Median DOR has not been reached but exceeds 21mo. The current CR rate in the ITT population at 24mo is 46% (16/35) (95% CI 29-63%). Three pts have yet to reach the 24mo time point. Cystectomy-free survival at 21mo is 80%. Complete data on the ITT and evaluable patient cohorts will be presented. Analyses of treatment-related adverse events (AE) are consistent with the individual agents and demonstrate no synergistic toxicity. Conclusions: The efficacy and safety of cretostimogene plus pembrolizumab for treatment of BCG-UR, HR NMIBC with CIS demonstrates best-in-class CR and DOR compared to current FDA-approved therapies, with an acceptable AE profile. Further investigation of this promising combination therapy is warranted and may serve to address a considerable unmet need. Clinical trial information: NCT04387461 .