Oncogenic pathway signatures predict the risk of progression and recurrence in well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS). METHODS: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed. RESULTS: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFß oncogenic pathway were independently associated with the risk of recurrence. CONCLUSIONS: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence.

Center-level variation in hospitalization costs of pancreaticoduodenectomy for pancreatic cancer.

BACKGROUND: Pancreaticoduodenectomy is a highly morbid operation with significant resource utilization. Using a national cohort, we examined the interhospital variation in pancreaticoduodenectomy hospitalization cost in the United States. METHODS: Adults undergoing elective pancreaticoduodenectomy in the setting of pancreatic cancer were tabulated from the 2016-2020 Nationwide Readmissions Database. A 2-level mixed-effects model was developed to evaluate the interhospital variation in pancreaticoduodenectomy hospitalization costs. Institutions within the top decile of risk-adjusted expenditures were defined as high-cost hospitals. Multivariable regression models were fitted to examine the association between high-cost hospital status and outcomes of interest. To account for the effects of complications on expenditures, a subgroup analysis comprising of patients with no adverse events was conducted. RESULTS: The study included an estimated 24,779 patients with a median hospitalization cost of $38,800. After mixed-effects modeling, 40.9% of the cost variation was attributable to hospital, rather than patient, factors. Multivariable regression models revealed an association between high-cost hospital status and greater odds of complications and longer length of stay. Among patients without an adverse event, interhospital cost variation remained significant at 61.0%, and treatment at high-cost hospitals was similarly linked to longer length of stay. CONCLUSION: Our study identified significant interhospital variation in pancreaticoduodenectomy hospitalization costs in the United States. Although high-cost hospital status was associated with increased odds of complications, variation remained significant even among patients without an adverse event. These results suggest the important role of hospital practices as contributors to expenditures. Further efforts to identify drivers of costs and standardize pancreatic surgical care are warranted.

Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

PURPOSE: DOTATATE PET/CT (DOTATATE) is superior to conventional imaging in detecting metastasis for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, limited availability, high-cost, and additive radiation exposure necessitate guidelines for its use. This study seeks to investigate the relationship between clinical characteristics and metastasis on DOTATATE. METHODS: This was a retrospective analysis of 815 patients who underwent DOTATATE at UCLA from 2014 to 2022. After applying inclusion and exclusion criteria, the study cohort consisted of 163 patients with pathologically diagnosed GEP-NETs, who either underwent primary tumor resection within 1-year prior, or had not undergone resection at the time of DOTATATE imaging. The presence of metastasis was determined using DOTATATE. Fisher's exact test, chi-squared test, and Mann-Whitney test were conducted to compare intergroup difference. Multivariate analysis was performed to identify clinical characteristics associated with metastasis on DOTATATE. RESULTS: Of patients with GEP-NETs, 40.5% (n = 66) were diagnosed with metastases by using DOTATATE. Those with metastatic disease were more likely to exhibit a larger primary tumor size (median 3.4 vs. 1.2, cm, P < 0.001), elevated serum chromogranin A level (CgA, median 208 vs. 97, mg/ml, P = 0.005), and higher tumor grade (P < 0.001). Primary tumor size ≥2 cm and serum CgA level ≥150 ng/mL for metastatic disease had a sensitivity and specificity of 64% and 89%, and 72% and 59%, respectively. Multivariate analysis demonstrated that primary tumor size (≥2/<2, cm, odds ratio [OR] 47.90, P < 0.001), tumor functionality (functional/nonfunctional, adjusted OR 10.17 P = 0.008), serum CgA level (≥150/<150, ng/ml, OR 6.25, P = 0.005), and tumor grade G2 (G2/G1, OR 9.6, P < 0.001) were independently associated with metastases on DOTATATE. CONCLUSIONS: Among patients with GEP-NETs, primary tumor size ≥2 cm, serum CgA level ≥150 ng/mL, and tumor grade G2 are associated with an increased risk of metastases on DOTATATE, and these predictors may be helpful to identify patients where DOTATATE is indicated for complete staging.

The impact of the California state lockdown during the COVID-19 pandemic on management of patients with pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVES: The SARS-COVID-19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation. METHODS: We retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into "pre-lockdown" and "post-lockdown" groups based on timing of pathologic diagnosis. RESULTS: In the 12 months pre-lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post-lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post- versus pre-lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post-lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post-lockdown era (median 23 vs. 26 days, p < 0.001). CONCLUSIONS: The COVID-19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post-lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody-Drug Conjugate for Treatment of CLDN18.2-Positive Cancers.

Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.

Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell-intrinsic Amplification of Type I IFN Signaling.

PURPOSE: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity. EXPERIMENTAL DESIGN: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo. RESULTS: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation. CONCLUSIONS: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Construction of a radiogenomic association map of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC. METHODS: In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses. RESULTS: Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P < 0.05). CONCLUSIONS: A CT-transcriptomic RG map for PDAC composed of semantic and quantitative traits with associated biology processes predictive of overall survival, was constructed, that serves as a reference for further mechanistic studies for non-invasive phenotyping of pancreatic tumors.

Race, Insurance, and Sex-Based Disparities in Access to High-Volume Centers for Pancreatectomy.

BACKGROUND: With a large body of literature demonstrating positive volume-outcome relationships for most major operations, minimum volume requirements have been suggested for concentration of cases to high-volume centers (HVCs). However, data are limited regarding disparities in access to these hospitals for pancreatectomy patients. METHODS: The 2005-2018 National Inpatient Sample (NIS) was queried for all elective adult hospitalizations for pancreatectomy. Hospitals performing more than 20 annual cases were classified as HVCs. Mixed-multivariable regression models were developed to characterize the impact of demographic factors and case volume on outcomes of interest. RESULTS: Of an estimated 127,527 hospitalizations, 79.8% occurred at HVCs. Patients at these centers were more frequently white (79.0 vs 70.8%; p < 0.001), privately insured (39.4 vs 34.2%; p < 0.001), and within the highest income quartile (30.5 vs 25.0%; p < 0.001). Adjusted analysis showed that operations performed at HVCs were associated with reduced odds of in-hospital mortality (adjusted odds ratio [AOR], 0.43; 95% confidence interval [CI], 0.34-0.55), increased odds of discharge to home (AOR, 1.17; 95% CI, 1.04-1.30), shorter hospital stay (ß, -0.81 days; 95% CI, -1.2 to -0.40 days), but similar costs. Patients who were female (AOR, 0.88; 95% CI, 0.79-0.98), non-white (black: AOR, 0.66; 95% CI, 0.59-0.75; Hispanic: AOR, 0.56; 95% CI, 0.47-0.66; reference, white), insured by Medicaid (AOR, 0.63; 95% CI, 0.56-0.72; reference, private), and within the lowest income quartile (AOR, 0.73; 95% CI, 0.59-0.90; reference, highest) had decreased odds of treatment at an HVC. CONCLUSIONS: For those undergoing pancreatectomies, HVCs realize superior clinical outcomes but treat lower proportions of female, non-white, and Medicaid populations. These findings may have implications for improving access to high-quality centers.

Robotic versus open pancreaticoduodenectomy in elderly patients: a propensity score-matched analysis.

BACKGROUND: Pancreaticoduodenectomy (PD) is complex procedure with high morbidity in the elderly. This retrospective study aimed to compare post-operative outcomes in patients ≥75 years of age who underwent robot-assisted (RA)PD and open PD. METHODS: We analyzed 2502 patients ≥75 years of age who underwent PD from 2015 to 2018 in the National Surgical Quality Improvement Program (NSQIP) database. RAPD and open PD patients were propensity score matched 1:5 to assess the 30-day outcomes of interest: postoperative complications, length of stay, discharge destination, and readmissions. RESULTS: Of 725 matched patients, 110 underwent RAPD, 615 OPD, and 12 were converted to an open operation. Post-operative outcomes were largely similar between cohorts. RAPD was associated a shorter length of stay (median 8 days, interquartile range [IQR] 6 to 11) than OPD (median 8 days, IQR 7 to 13) (p = 0.003). However, RAPD was associated with more readmissions (28.1% vs. 17.7%; p = 0.02). CONCLUSIONS: RAPD in patients ≥75 years of age appears to be safe and has a similar complication profile to open PD. Randomized or well-designed prospective matched studies are needed to confirm these findings.

Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer.

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. SIGNIFICANCE: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.

18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models.

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.

Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand-Addicted Pancreatic Cancer.

WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) show growth dependency on autocrine WNT ligand signaling and are susceptible to agents that block WNT ligand acylation by Porcupine O-acyltransferase, which is required for proper WNT ligand processing and secretion. For this study, global transcriptomic, proteomic, and metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the Porcupine inhibitor (PORCNi) LGK974. LGK974 disrupted cellular bioenergetics and mitochondrial function through actions that included rapid mitochondrial depolarization, reduced mitochondrial content, and inhibition of oxidative phosphorylation and tricarboxylic acid cycle. LGK974 also broadly altered transcriptional activity, downregulating genes involved in cell cycle, nucleotide metabolism, and ribosomal biogenesis and upregulating genes involved in epithelial-mesenchymal transition, hypoxia, endocytosis, and lysosomes. Autophagy and lysosomal activity were augmented in response to LGK974, which synergistically inhibited tumor cell viability in combination with chloroquine. Autocrine WNT ligand signaling dictates metabolic dependencies in RNF43-mutant PDAC through a combination of transcription dependent and independent effects linked to mitochondrial health and function. Metabolic adaptations to mitochondrial damage and bioenergetic stress represent potential targetable liabilities in combination with PORCNi for the treatment of WNT ligand-addicted PDAC.

Emotional Regulation in Surgery: Fostering Well-Being, Performance, and Leadership.

Emotional regulation is increasingly gaining acceptance as a means to improve well-being, performance, and leadership across high-stakes professions, representing innovation in thinking within the field of surgical education. As one part of a broader cognitive skill set that can be trained and honed, emotional regulation has a strong evidence base in high-stress, high-performance fields. Nevertheless, even as Program Directors and surgical educators have become increasingly aware of this data, with emerging evidence in the surgical education literature supporting efficacy, hurdles to sustainable implementation exist. In this white paper, we present evidence supporting the value of emotional regulation training in surgery and share case studies in order to illustrate practical steps for the development, adaptation, and implementation of emotional regulation curricula in three key developmental contexts: basic cognitive skills training, technical skills acquisition and performance, and preparation for independence. We focus on the practical aspects of each case to elucidate the challenges and opportunities of introducing and adopting a curricular innovation into surgical education. We propose an integrated curriculum consisting of all three applied contexts for emotional regulation skills and advocate for the dissemination of such a longitudinal curriculum on a national level.