Citations

Metabolic and bariatric surgery (MBS) is the most effective therapeutic intervention for patients with obesity, with sleeve gastrectomy (SG) being the most commonly performed primary MBS procedure. Long-term studies have demonstrated that 15–20% of patients require revisional bariatric surgery (RBS) due to weight-related issues or surgical complications. Despite the gold standard being laparoscopic revision, there are other available approaches such as open or robotic-assisted. An extensive literature review was performed for articles from their inception to February 2024. A descriptive review of MBS procedures (SG, Roux-en-Y gastric bypass (RYGB), single anastomosis duodeno-ileostomy (SADI) and biliopancreatic diversion-duodenal switch (BPD-DS)) was carried out to report and compare outcomes between primary and revisional bariatric surgery. A similar review was conducted to compare outcomes of revisional approaches (open, laparoscopic, robotic). RYGB remains the dominant RBS with a similar safety profile compared to revisional SADI and BPD-DS. In terms of the RBS surgical approach, all three options showed comparable short and long-term outcomes, with robotic RBS being associated with longer operative time and variable length of stay. Additional long-term studies are required to further validate our conclusions.

Abstract Glioblastoma (GBM) is a highly aggressive and infiltrative primary malignant brain tumor. Current standard-of-care for newly diagnosed GBM patients includes maximal safe surgical resection, followed by concurrent radiation with temozolomide (TMZ), and adjuvant TMZ chemotherapy. However, despite aggressive treatments, GBM patients have a poor prognosis, with a median survival of 14.6 months and a 5-year survival rate of 6.8%. The p53 protein is a critical tumor suppressor in the cell cycle. The expression level of p53 is tightly controlled by its negative regulator, murine double minute 2 (MDM2). Amplification of the MDM2 gene, found in 14 % of GBMs, can inactivate p53, leading to loss of tumor suppressor functions. Therefore, we are investigating a potent MDM2 antagonist – BI-907828 in GBM to restore the p53 tumor suppressor function by inhibiting the p53/MDM2 interactions. We aim to evaluate the PK/PD of BI-907828 and demonstrate a new translational paradigm to rethink the “Delivery – Potency – Efficacy” relationship in drug discovery and development for central nervous system (CNS) tumors. BI-907828 was evaluated for cytotoxicity and the inhibition effect to MDM2-p53 pathway. Systemic PK and transport mechanisms controlling CNS distribution were evaluated in wild-type and transgenic mice that lack of efflux transporters P-gp and BCRP. BI-907828 unbound fractions in cell media, mouse and human specimens were determined by using rapid equilibrium dialysis to evaluate “active” concentrations. Efficacy measures, including survival and free drug distribution in tumor were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nM. The CNS distribution of BI-907828 is limited by BBB efflux mediated by P-gp, resulting in a brain free partition coefficient Kp,uu of 0.002. Despite this seemingly “poor” BBB penetration, weekly administration of 10 mg/kg BI-907828 significantly extended median survival of orthotopic GBM108 xenografts to 218 days compared to 28 days with vehicle treatment (P < 0.0001). These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is severely limited by BBB efflux. In another words, in this case, this little drug distribution to brain is “enough” for extending survival of orthotopic GBM108 xenografts. Therefore, a comprehensive understanding of drug “Delivery – Potency – Efficacy” relationship is warranted in drug discovery development, especially for treatment of CNS tumors. Citation Format: Wenjuan Zhang, Rachael Vaubel, Juhee Oh, Ann Mlade, Surabhi Talele, Wenqiu Zhang, Katie Waller, Danielle Burgenske, Jann Sarkaria, William Elmquist. How much is enough? BI-907828: a MDM2-p53 antagonist with limited BBB penetration but potent efficacy in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B025.

Superior mesenteric artery syndrome (SMAS) is a rare and potentially life-threatening cause of small bowel obstruction in which the superior mesenteric artery impinges on the third portion of the duodenum. SMAS is typically encountered in patients with low body fat and a history of rapid weight loss and is often diagnosed as a chronic or subacute condition. Here, we describe a case of a healthy adolescent boy without typical SMAS prodromal symptoms presenting with a severe, hyperacute proximal small bowel obstruction due to SMAS. Complications arising from massive gastric and duodenal distension, including gastric, pancreatic and renal ischaemia, necessitated emergent surgical intervention consisting of the duodenojejunostomy bypass with partial gastric resection. The patient recovered without significant lasting consequences.

Abstract Aims Graft dysfunction (GD) after heart transplantation (HTx) can develop without evidence of cell- or antibody-mediated rejection. Cardiac magnetic resonance imaging (CMR) has an evolving role in detecting rejection; however, its role in biopsy-negative GD has not been described. This study examines CMR findings, evaluates outcomes based on CMR results, and seeks to identify the possibility of rejection missed through endomyocardial biopsy by using CMR in HTx recipients with biopsy-negative GD. Methods and results HTx recipients with GD [defined as a decrease in left ventricular ejection fraction (LVEF) by >5% and LVEF < 50%] in the absence of rejection by biopsy or allograft vasculopathy and who underwent CMR were included in the study. The primary outcome was a composite of all-cause mortality, re-transplantation, or persistent LVEF < 50%. Overall, 34 HTx recipients developed biopsy-negative GD and underwent CMR. Left ventricular late gadolinium enhancement (LGE) on CMR was observed in 16 patients with two distinct patterns: diffuse epicardial (n = 13) and patchy (n = 3) patterns. Patients with LGE developed GD later after HTx [4 (1.4–6.8) vs. 0.8 (0.3–1.2) years, P < 0.001], were more often symptomatic (88% vs. 56%, P = 0.06), and had greater haemodynamic derangement (pulmonary capillary wedge pressure: 19 ± 7 vs. 13 ± 3 mmHg, P = 0.002) as compared with those without LGE. No significant difference was observed in the primary composite outcome between patients with LGE and those without LGE (50% vs. 38% of patients with events, P = 0.515). During a median follow-up of 3.8 years, mean LVEF improved similarly in the LGE-negative (37–55%) and LGE-positive groups (32–55%) (P = 0.16). Conclusions Biopsy-negative GD occurs with and without LGE when assessed by CMR, indicative of possible rejection/inflammation occurring only in a subset of patients. Irrespective of LGE, LVEF improvement occurs in most GD patients, suggesting that other neurohormonal or immunomodulatory mechanisms may also contribute to GD development.

AbstractTixagevimab/cilgavimab (tix/cil) received emergency use authorization in December 2021 for pre‐exposure prophylaxis against COVID‐19 in moderately to severely immunocompromised patients. Our study aimed to describe the incidence of COVID‐19 infection and assess the immunologic risks associated with tix/cil in kidney, pancreas, liver, and heart transplant recipients. Retrospective chart review was completed to provide descriptive analysis. Outcomes data included COVID‐19 infection, severity of COVID‐19 infection, graft function, and rejection. Safety outcomes included cardiovascular (CV) and hypersensitivity events post tix/cil administration. A total of 410 transplant patients were included in the analysis: 20 heart, 92 liver, 243 kidney, 25 simultaneous pancreas/kidney, 23 simultaneous liver/kidney, and seven simultaneous heart/kidney. Twenty‐seven (6.5%) patients tested positive for COVID‐19 via PCR or antigen test post tix/cil. No apparent difference was observed in patients testing positive for COVID‐19 by type of organ transplant (p = .122). Twenty‐five of the 27 patients testing positive for COVID‐19 reported symptomatic infection, only nine of whom were hospitalized. No patients were mechanically ventilated and no deaths due to COVID‐19 occurred. No significant changes in graft function were observed. Clinically significant rejection was diagnosed and treated in four patients. COVID‐19 breakthrough infection rates remained low in immunocompromised solid organ transplant recipients who received tix/cil. No significant immunologic risks were observed.

AbstractAdolescents with chronic pain can at times present with disability out of proportion to diagnostic workup. This is also a defining feature of medical child abuse (MCA). The aim of this study was to identify themes from the clinical narratives of adolescents with chronic pain that may indicate concern for MCA. This qualitative, retrospective study at an academic children's hospital between 2011 and 2019 identified 37 adolescents aged 13–18 years old with chronic pain and varying levels of concern for MCA. Conventional, inductive content analysis was used to identify themes from the medical records of all patients, which were reviewed by an interdisciplinary panel of experts. Themes were organised into three tiers related to the level of concern for MCA: ‘Green zone’ themes including fatigue or sleep problems, psychosocial distress, and social withdrawal were common among all patients. ‘Yellow zone’ themes including fragmented care, caregiver catastrophising, caregiver misrepresentation, medical provider exasperation, and sick identity were more common among patients in whom medical providers raised concern for MCA. A single ‘red zone’ theme, reportable harm to the child, was only present in patients diagnosed by a child abuse paediatrician as having MCA. A visual display of the results is provided for further research and clinical application.

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.

Abstract Aims Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC. Methods and results Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects. Conclusion NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.

Abstract Background Abdominal pain (AP) is common in patients with active inflammatory bowel disease (IBD) and has been associated with poor quality of life (QOL). Despite greater therapeutic options, symptoms persist in a subset of patients. Data is lacking regarding AP in patients with objectively documented quiescent disease. Among endoscopic quiescent disease: (1) estimate prevalence of AP, (2) assess predictors of worse AP, (3) describe its impact on validated QOL measures. Methods This cross-sectional study used prospectively collected data from SPARC (Study of a Prospective Adult Research Cohort) IBD, a multicenter longitudinal study of well-phenotyped adult IBD patients initiated by the Crohn’s & Colitis Foundation in 2016. Quiescent IBD was defined as Mayo endoscopy score <2 for ulcerative colitis (UC) and SES-CD score <3 for Crohn’s disease (CD). Patient reported outcomes (PROs) within 30 days of endoscopy were analyzed. Patients with ostomy or IPAA were excluded. Self-reported AP was categorized as none, mild, or moderate/severe. Univariate statistics used Pearson’s Chi-square and Kruskal-Wallis tests. Results A total of 973 patients with quiescent IBD (606 CD; 367 UC) were included in the study (Table 1). AP was more commonly reported in quiescent CD (31.2% mild, 15.5% moderate/severe) as compared to quiescent UC (23.4% mild, 10.1% moderate/severe) (p<0.001). In the entire quiescent cohort, those with mild or moderate/severe AP were more likely to be female sex (63.1% mild; 67.4% moderate/severe; p<0.001), higher BMI (28.4 mild; 30.0 moderate/severe; p=0.008) and have more recent tobacco use (p=0.004). Ileocolonic involvement was more commonly seen in moderate/severe AP. Mild and moderate/severe AP was associated with subjective fecal urgency, stool frequency, and bloody stool (all p<0.001). Disease behavior in CD was not associated with abdominal pain. General well-being was poorer for those with more severe AP (p<0.001), though this did not appear to result in more frequent recent ED visits or hospitalizations. Figure 1 depicts the PROMIS responses. Overall, worse AP was associated with universal worse scores on all PROMIS measures and subscales (all p<0.001). Data suggested that more severe AP had the greatest impacts on the "Fatigue" subscale. Conclusion In this study of patients in SPARC IBD with endoscopic quiescent IBD the overall prevalence of AP was 41.7% overall and more commonly reported in CD as compared to UC. AP was associated with a greater prevalence of other symptoms, worse general well-being, and poorer quality of life across all measures. Further research is needed to elucidate the pathophysiology for presence of AP in quiescent IBD and develop personalized management approaches.

434 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR, potently inhibited FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and in phase I trials that included cholangiocarcinoma (CCA) patients (pts). Here we present the efficacy and safety of tinengotinib in a phase II clinical trial. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy therapy and ECOG PS 0 or 1 were treated with tinengotinib 10 mg QD. Four cohorts included: Cohort A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFRi), A2: FGFR2 fusion(s) with progression after prior response to FGFRi (acquired resistance); B: non-fusion FGFR alteration(s): C: FGFR wild-type ( FGFRwt). Primary endpoint was objective response rate (ORR) per RECIST v1.1. CTCAE V5.0 was used for safety assessments. Results: As of 7Aug2023, 48 pts with CCA were enrolled, 13 in Cohort A1, 10 in A2, 12 in B, 13 in C. Median age 61.5 [range 25-81] years old, 41.7% male, 58.3% had ≥ 3 lines of prior therapy. ECOG PS 0 in 47.9% pts. Among 35 pts with FGFR alterations, 80.0% had ≥ 1 prior FGFRi therapy, and 97.1% had prior chemotherapy. Forty (40) pts were efficacy evaluable. In A1, 1 out of 11 pts (9.1%) achieved PR with tumor reduction of 31.8%. In A2, 3 out of 8 pts (37.5%) achieved PR with tumor reduction of 40.7%, 47.0% and 54.6%. In B, 3 out of 9 pts (33.3%) achieved PR with tumor reduction of 36.5%, 48.6%, and 60.6%. No PR was observed in C. Overall DCR was 94.7% (18/19) in FGFR2 fusion/rearrangement pts (A1+A2), 88.9% (8/9) in other FGFR alterations pts (B), and 75% (9/12) in FGFRwt pts (C). Median progression-free survival (mPFS) was 5.26 months (95%CI, 2.86-9.10) in A1+A2, 5.98 months (95%CI, 1.87-NA) in B and 3.84 months (95% CI, 1.84-4.80) in C. Among 48 treated pts, treatment-related AEs (TRAEs) occurred in 45 (93.8%) pts, 14 (29.2%) in G1-2, 29 (60.4%) in G3 and 2 (4.2%) in G4. The most common G3 TRAEs were hypertension in 12 (25%), palmar-plantar erythrodysesthesia syndrome in 3 (6.3%), diarrhea in 3 (6.3%) and stomatitis in 3 (6.3%). One subject had G4 increased TSH and G4 increased lipase, and another subject had G4 posterior reversible encephalopathy syndrome. No G5 TRAE was observed. Conclusions: Tinengotinib has promising clinical benefit for FGFR2 fusion CCA after prior FGFRi and for non-fusion FGFR alterations. Tinengotinib-related toxicities were manageable. An ongoing randomized, controlled phase III study will evaluate the clinical efficacy, safety, and pharmacodynamic effect of Tinengotinib vs Physicians’ choice in subjects with FGFR2-altered refractory/relapsed CCA after prior chemotherapy and FGFRi therapy. Clinical trial information: NCT04919642 .