Citations

Objective: To describe long-term quality of life (QOL) and gastrointestinal (GI) symptoms in patients who underwent pancreatoduodenectomy for pancreatic cancer in the modern era. Background: As advances in pancreatic cancer management improve outcomes, it is essential to assess long-term patient-reported outcomes after surgery. Methods: Patients who underwent curative intent pancreatoduodenectomy for pancreatic cancer between January 2011 and June 2019 from a single center were identified. Patients alive ≥3 years after surgery were considered long-term survivors (LTS). LTS who were alive in June 2022 received a 55-question survey to assess their QOL (EORTC-QLQ-C30) and GI symptoms (EORTC-PAN26 and Problem Areas in Diabetes Questionnaire). Responses were compared against population norms. Clinicodemographic characteristics in LTS versus non-LTS and survey completion were compared. Results: Six hundred seventy-two patients underwent pancreatoduodenectomy for pancreatic cancer; 340 were LTS. One hundred thirty-seven patients of the 238 eligible to complete the survey responded (response rate: 58%). Compared to the US general population, LTS reported significantly higher QOL (75 vs 64; P<0.001), less nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and constipation, but more diarrhea (all P<0.001). Most patients (n=136/137, 99%) reported experiencing postoperative GI symptoms related to pancreatic insufficiency (n=71/135, 53%), reflux (n=61/135, 45%), and delayed gastric emptying (n=31/136, 23%). Most patients (n=113/136, 83%) reported that digestive symptoms overall had little to no impact on QOL, and 91% (n=124/136) would undergo surgery again. Conclusions: Despite known long-term complications following pancreatoduodenectomy, cancer survivors appear to have excellent QOL. Specific long-term gastrointestinal symptoms data should be utilized for preoperative education and follow-up planning.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms ‘diffuse’ and ‘idiopathic.’ We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Abstract Background: DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants across the genome. Methods: We applied a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer data from the Colon Cancer Family Registry (CCFR; 5,735 cases and 3,688 controls), and Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 8,865 cases and 10,285 controls) studies. A DEPTH score &gt; 1 was used to identify candidate susceptibility regions common to both analyses. We compared DEPTH results against those from conventional genome-wide association study (GWAS) analyses of these two studies as well as against 132 published susceptibility regions. Results: Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous colorectal cancer GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the human leukocyte antigen locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data. Conclusions: DEPTH can identify candidate susceptibility regions for colorectal cancer not identified using conventional analyses of larger datasets. Impact: DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Introduction: Although the prevalence of atrial fibrillation (AF) is higher in men than in women, the onset of AF appears to diminish the survival advantage in women. The pathophysiologic factors underlying survival outcome in AF are not well understood. Methods: A cohort of 3480 Olmsted County, Minnesota residents (mean age 72.8±14 years, 51.8% female) with incident AF who underwent transthoracic echocardiography within 30 days of AF diagnosis [median (IQR) 1, 1-6 days] were retrospectively studied. We examined the association of clinical parameters and survival according to gender. Kaplan-Meier and Cox proportional hazards models were used to compare overall survival in males and females. Results: Females were older and slimmer than males and more frequently had hypertension, prior stroke, and had higher CHA 2 DS 2 vasc score, pulse pressure and effective arterial elastance. Women also had smaller LV end diastolic dimension with higher LV ejection fraction, LA volume index, E/e prime ratio, and PASP (43.6±13.8 vs 39.1±13.3; <.001). During a mean follow-up of 7.4±6.2 years (median 6.6 years), 2569 patients died. Women had a lower 5-year survival compared to men. The probability of 1- and 5-year survival rates for women vs men were 80.2% vs 84.1% at 1 year and 54.4% vs 63.7% at 5 years (log-rank P <.001). In multivariable Cox regression analysis, after accounting for potential confounders, the independent predictors of mortality were age (HR 1.07 [95% CI 1.06-1.08]), PASP (per 5 unit increment) (HR 1.11 [95% CI 1.09-1.12]), effective arterial elastance (HR 1.06 [95% CI 1.01-1.12]), previous heart failure (HR 1.34 [95% CI 1.20-1.49]), diabetes (HR 1.33 [95% CI 1.20-1.48]), prior stroke (HR 1.26 [95% CI 1.13-1.41]), smoking (HR 1.13 [95% CI 1.06-1.20]), chronic lung disease (HR 1.32 [95% CI 1.20-1.45]), peripheral arterial disease (HR, 1.32 [95% CI 1.18-1.48]), and chronic kidney disease (HR, 1.52 [95% CI 1.38-1.69]). Conclusions: In a community-based cohort of patients with incident AF, markers of arterial stiffness and diastolic dysfunction were more prevalent in women compared to men and were strongly predictive of mortality. Our findings suggest that vascular stiffness may underlie the increased risk of mortality observed in women after a new diagnosis of AF.

Introduction: Doxorubicin (DOX) is widely used for chemotherapy, but cardiotoxicity and cardiomyopathy are major adverse effects. The canonical transient receptor potential 6 gene ( TRPC6) is a putative risk gene for cardiomyopathy. Recently, a TRPC6 N338S mutation was found in a patient with DOX-induced heart failure. However, the TRPC6 N338S mutant has not been characterized, and how it affects cardiac function is unknown. Hypothesis: We hypothesized that TRPC6 N338S is a gain-of-function mutation producing intracellular Ca 2+ overload in cardiomyocytes. Methods: Using patch clamp recording, molecular biological and molecular docking analyses, we assessed the function of TRPC6 N338S heterologously expressed in HL-1 cardiac cells. Results: TRPC6 N338S significantly increased the current densities of TRPC6 (defined as 1 μM BI-749327 sensitive components, a highly selective TRPC6 inhibitor) in HL-1 cells at baseline and after exposure to 50 μM 1-oleoyl 2-acetyl-sn-glycerol (OAG, an activator of TRPC6), compared to cells expressing TRPC6 WT. Moreover, a 24-h pretreatment with 0.5 μM DOX further potentiated the OAG effects on TRPC6 WT currents with a significantly greater response in the N338S currents. Ca 2+ imaging also showed enhanced intracellular Ca 2+ levels in cells expressing the N338S mutant with OAG and DOX treatment. Biological studies found that the cytoplasmic and surface expression of TRPC6 WT and N338S mutant were identical in HL-1 cells, but those of TRPC6 N338S were markedly upregulated after treatment with 0.5 μM DOX, compared to TRPC6 WT. Molecular docking and dynamics simulation analysis unraveled that OAG binds to a pocket constituted by the pore-helix, S5 and S6 domains of TRPC6 through polar interactions. OAG binds to the same site in TRPC6 N338S with shortened interfacial distances due to additional polar and hydrogen bonding between OAG and the N338S mutant. Conclusions: TRPC6 N338S mutation strengthens the interaction with OAG, stabilizes the OAG-TRPC6 N338S complex, and enhances the OAG effects. Treatment with DOX significantly increases the expression and function of TRPC6 N338S in HL-1 cells. Hence, the TRPC6 N338S is a gain-of-function mutation and may contribute to cardiotoxicity in patients with anthracycline treatment.

TPS7587 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of MCL, but these agents are not curative. cBTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage especially in rapidly proliferating tumors with high BTK protein turnover such as MCL, which can manifest as acquired resistance to BTKi. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates and was well tolerated in patients (pts) with MCL regardless of prior therapy (including cBTKi), number of prior lines of therapy, or reason for prior cBTKi discontinuation. Pirtobrutinib was approved by the FDA in January 2023 for R/R MCL after 2 prior lines of therapy including a BTKi. The objective of this study is to establish whether pirtobrutinib is superior to investigator’s choice of cBTKi in pts with previously treated, BTKi naïve MCL. Methods: BRUIN MCL-321 (NCT04662255) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator’s choice of cBTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in pts with previously treated, BTKi naïve MCL. Approximately 500 pts will be randomized 1:1 and stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Enrollment for this study is ongoing. Adults with a diagnosis of MCL who have received ≥ 1 prior line of systemic therapy for MCL and are BTKi naïve are eligible. Pts must have measurable disease by imaging per Lugano criteria and have progressed on or relapsed following the most recent line of therapy. A history of current or prior CNS involvement, significant cardiovascular disease, stroke or intracranial hemorrhage within 6 months of randomization, and autologous stem cell transplant (SCT), allogeneic SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization are key exclusion criteria. Progression-free survival (PFS) per Lugano criteria assessed by an independent review committee is the primary endpoint. Overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and pt reported outcomes are secondary endpoints. Clinical trial information: NCT04662255 .

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Background: There is limited data on Vedolizumab utilization in elderly patients. Our study aims to assess the effectiveness and safety of Vedolizumab in this subset population. Materials and Methods: Databases including Cochrane Central, Embase, Medline (via Ovid), Scopus, and Web of Science were searched in August 2022 to identify studies that assessed Vedolizumab therapy in elderly patients. Pooled proportion and risk ratios (RR) were calculated. Results: Total 11 studies with 3546 IBD patients (1314 elderly and 2232 young) were included in the final analysis. Pooled rate of overall and serious infections in the elderly cohort was 8.45% (95% CI=6.27-11.29; I223%) and 2.59% (95% CI=0.78-8.29; I276%), respectively. However, there was no difference in overall infection rates between elderly and young patients. Pooled rate of endoscopic, clinical, and steroid-free remission for elderly IBD patients was 38.45% (95% CI=20.74-59.56; I293%), 37.95% (95% CI=33.08-43.06; I213%), and 38.8% (95% CI=31.6-46.4; I277%), respectively. Elderly patients had lower steroid-free remission rates [RR 0.85, 95% CI=0.74-0.99; I20%, P=0.03]; however, there was no difference in rates of clinical (RR 0.86, 95% CI=0.72-1.03; I20%, P=0.10) or endoscopic remission (RR 1.06, 95% CI=0.83-1.35; I20%, P=0.63) compared with younger patients. Pooled rate of IBD-related surgery and IBD-related hospitalizations was 9.76% (95% CI=5.81-15.92; I278%) and 10.54% (95% CI=8.37-13.2; I20%), respectively for the elderly cohort. There was no statistical difference in IBD-related surgeries between elderly and young IBD patients, RR 1.20 (95% CI=0.79-1.84; I216%), P=0.4. Conclusions: Vedolizumab is equally safe and effective for clinical and endoscopic remission in elderly and younger populations.