Neoadjuvant chemotherapy is associated with improved disease-free survival in pancreatic cancer patients undergoing pancreaticoduodenectomy with vascular resection.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAC) is becoming favored for all pancreatic adenocarcinoma (PDAC). Patients with seemingly resectable disease infrequently still display vascular involvement intraoperatively. Outcomes following NAC versus upfront surgery in patients undergoing pancreaticoduodenectomy (PD) with vascular resection are unknown. METHODS: We performed a retrospective cohort study of PDAC patients who underwent PD with vascular resection between January 1, 2013, to December 31, 2020, within a single academic center. Clinicopathologic characteristics and disease-free survival (DFS) were compared between NAC versus upfront surgery cohorts using the Kaplan-Meier estimate and Cox proportional-hazards regression model. RESULTS: Eighty-one patients who underwent PD with vascular resection for PDAC were included. Forty-six patients (56%) received NAC. The NAC cohort more often had pathologic N0 status (47.8% vs. 8.6%, p < 0.001), had decreased vascular invasion (11% vs. 40%, p = 0.002), and completed chemotherapy (80% vs. 40%, p < 0.01). The NAC cohort demonstrated improved DFS (40.5 vs. 14.3 months, p = 0.007). In multivariable analysis, NAC remained independently associated with increased DFS (HR = 0.48, p = 0.02). CONCLUSIONS: NAC was associated with improved clinicopathologic outcomes and DFS in PD with vascular resection. These findings demonstrate the advantage of NAC in PDAC patients undergoing PD with vascular resection.

Sarcoma in patients with Lynch syndrome and response to immunotherapy.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant genetic predisposition to multiple malignancies and is characterized by deficient DNA mismatch repair. Increased incidence of sarcomas is not formally ascribed to LS; however, increasing evidence suggests a preponderance of these malignancies in affected families. Sarcomas typically possess a low tumor mutational burden and incite a poor immune infiltrate, thereby rendering them poorly responsive to immunotherapy. METHODS: We searched the University of California, Los Angeles (UCLA) sarcoma program database for patients with a diagnosis of sarcoma and LS from 2016 to 2023. Three such patients were identified and all three were treated with PD1 blockade. RESULTS: We present three cases of LS-associated sarcomas (two soft tissue sarcoma and one osteosarcoma) with increased tumor mutational burdens. These patients were each treated with an anti-PD1 antibody and experienced a response far superior to that reported for non-LS-associated sarcomas. CONCLUSIONS: Increased mutational burden and immune infiltrate are observed for sarcomas associated with LS. Although unselected patients with sarcoma have demonstrated poor response rates to immunotherapy, our findings suggest that patients with Lynch-associated sarcomas are more likely to respond to treatment with anti-PD1. These patients should be given consideration for immunotherapy.

Laparoscopic compared to open approach for distal gastrectomy may reduce pneumonia risk for patients with gastric cancer.

Background: Whether laparoscopic approach to gastrectomy for gastric cancer (GC) reduces the risk of pneumonia remains unknown. In this study, we compared pneumonia outcomes for patients with GC who underwent either laparoscopic gastrectomy (LG) or open gastrectomy (OG). Methods: The ACS NSQIP database was queried to identify patients with GC who underwent LG or OG between Jan 2012 - Dec 2018. Outcomes were compared using regression models. A post-hoc analysis was performed for elderly patients. Results: The study cohort included 2661 patients, 23.4 % undergoing LG. Laparoscopic approach lowered pneumonia risk (OR 0.47, p = .028) and reduced hospital length of stay, (5.3 vs 7.1 days, p < .001). Elderly patients undergoing LG demonstrated similar benefits. Risk factors for pneumonia included advanced age, dyspnea and weight-loss, whereas laparoscopic approach reduced this risk. Conclusions: LG in patients with GC has both statistically and clinically significant advantages over OG with respect to pneumonia. Further studies are needed to validate the relationship between postoperative pneumonia and surgical approach for gastrectomy.

Surgical and Endoscopic Resection of Duodenal Neuroendocrine Tumors Have Similar Disease-Specific Survival Outcome.

BACKGROUND: Duodenal neuroendocrine tumors (dNETs) are rare, and their management is not well-defined. National Comprehensive Cancer Network (NCCN) guidelines recommend surgical resection of large dNETs (> 2 cm) and endoscopic resection of small tumors (< 2 cm). We compared the survival outcomes between surgical and endoscopic resection in various dNET sizes. METHODS: A retrospective cohort study was conducted using patient data from Surveillance, Epidemiology, and End Results Program (SEER) database. Variables analyzed included age, tumor size, grade, stage, and lymph node status. Disease-specific survival (DSS) was compared for endoscopic and surgical groups in dNET size strata: 0-0.5, 0.5-1, 1-2, 2-3, and > 3 cm. Kaplan-Meier and multivariable Cox proportional hazards models were used for survival analysis. RESULTS: The study included 465 patients, with 124 (26.7%) undergoing surgical resection. The average age was 61.9 years, and tumor sizes ranged from 0.1 to 10.5 cm. Endoscopic resection had 40.5% of tumors between 0 and 0.5 cm, while surgery had only 21% (p < 0.001). In the surgical cohort, 79.8% had grade 1 tumors compared to 88.3% in the endoscopy group (P = 0.024). Among surgically resected cases, 48.4% (60 patients) had lymph node involvement. Age, tumor size, grade, and stage did not significantly predict survival after surgical resection. Stratified by tumor size, no difference in DSS was observed between surgery and endoscopy groups. CONCLUSIONS: Endoscopic resection demonstrated similar survival outcomes to surgical resection across dNET sizes in this national analysis. Given the risks and the lack of survival benefits for surgery, endoscopic resection may be beneficial for both small and large tumors. Further studies are warranted to validate the current NCCN guidelines.

Learning Curves in Establishing a New Minimally Invasive Pancreas Program.

INTRODUCTION: Robotic pancreaticoduodenectomy (rPD) is a complex operation with a reported learning curve of 80 cases. Two recent graduates of a formal robotic complex general surgical oncology training program have been performing rPD at our institution since 2016, which had no previous institutional experience with rPD. OBJECTIVE: To evaluate the learning curve associated with developing a new robotic pancreaticoduodenectomy (rPD) program by fellowship trained surgeons with institutional support. METHODS: Sixty patients undergoing rPD from 2016 to 2022 were reviewed for and compared with proficiency benchmarks set by the University of Pittsburg experience. RESULTS: By 30 cases, operative time met the proficiency benchmark of 391 minutes. Additionally, the entire cohort had comparable rates of clinically relevant postoperative pancreatic fistula (6.7% vs 3%, P = .6), 30-day mortality (0% vs 3%, P = .18), major complications (Clavien >2; 23% vs 17%, P = .14), and length of stay (6 vs 7 days, P = .49) when compared to the benchmark. CONCLUSION: Perioperative outcomes were comparable to proficiency benchmarks from initiation of the new rPD program, and operative time reached proficiency benchmark by 30 cases. This data suggests that graduates of formal rPD training programs can safely establish new minimally invasive pancreas programs at sites with no previous institutional rPD experience.

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.

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.

Disparities in Utilization and Outcomes of Minimally Invasive Techniques for Gastric Cancer Surgery in the United States.

BACKGROUND: This study investigated national implementation patterns and perioperative outcomes of minimally invasive gastrectomy (MIG) in gastric cancer surgery in the United States. METHODS: The National Inpatient Sample (NIS) was queried for patients who underwent elective gastrectomy for gastric cancer from 2008-2018. The MIG versus open gastrectomy approach was correlated with hospital factors, patient characteristics, and complications. RESULTS: There was more than a fivefold increase in MIG from 5.8% in 2008 to 32.9% in 2018 (nptrend < 0.001). Patients undergoing MIG had a lower Elixhauser Comorbidity Index (p = 0.001). On risk adjusted analysis, black patients (AOR = 0.77, p = 0.024) and patients with income below 25th percentile (AOR = 0.80, p = 0.018) were less likely to undergo MIG. When these analyses were limited to minimally invasive capable centers only, these differences were not observed. Hospitals in the upper tertile of gastrectomy case volume, Northeast, and urban teaching centers were more likely to perform MIG. Overall, MIG was associated with a 0.7-day decrease in length of stay, reduced risk adjusted mortality rates (AOR = 0.58, p = 0.05), and a $4,700 increase in total cost. CONCLUSIONS: In this national retrospective study, we observe socioeconomic differences in patients undergoing MIG, which is explained by hospital level factors in MIG utilization. We demonstrate that MIG is associated with a lower mortality compared with open gastrectomy. Establishing MIG as a safe approach to gastric cancers and understanding regional differences in implementation patterns can inform delivery of equitable high-quality health care.

Pathological treatment response has different prognostic implications for pancreatic cancer patients treated with neoadjuvant chemotherapy or chemoradiotherapy.

BACKGROUND: Pathological treatment effect of resected pancreatic adenocarcinoma after neoadjuvant therapy has prognostic implications. The impact for patients who received chemotherapy alone or chemoradiotherapy is not well defined. METHODS: Patients with localized pancreatic adenocarcinoma who had pancreatectomy after neoadjuvant therapy at 3 centers from 2011 to 2017 were retrospectively analyzed. The chemotherapy and chemoradiotherapy groups were evaluated separately. RESULTS: Of 525 patients, 148 received neoadjuvant chemotherapy and 377 received chemoradiotherapy. The chemoradiotherapy group had a better treatment effect (score 0: 10%, score 1: 30%, score 2: 42%, and score 3: 18%) than the chemotherapy group (score 0: 2%, score 1: 8%, score 2: 35%, and score 3: 55%) (P < .001). Median overall survival was similar between the 2 groups (25.8 vs 26.4 months). Median overall survival for score 0/1, 2, or 3 was 72.2, 38.5, and 20.0 months in the chemotherapy group and 37.9, 24.5, and 19.0 months in the chemoradiotherapy group. Score 2 in the chemotherapy group was associated with better overall survival compared to score 3 (adjusted hazard ratio: 0.49, P = .005), whereas only combined score 0/1 reached significance over score 2 for the chemoradiotherapy group (hazard ratio: 0.63, P = .006). CONCLUSION: The prognostic significance of pathological treatment effect for localized pancreatic adenocarcinoma differs for patients receiving neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy.

Poorly differentiated histologic grade correlates with worse survival in SMAD4 negative pancreatic adenocarcinoma patients.

BACKGROUND AND OBJECTIVES: This study investigated the influence of the transcription factor SMAD4 on overall patient survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: The SMAD4 status of 125 surgically resected PDAC specimens at a large academic center from 2014 to 2017 was routinely determined prospectively and correlated with clinicopathologic characteristics and overall survival. RESULTS: SMAD4 loss was identified in 62% of patients and was not associated with overall survival (OS). On multivariate Cox proportional hazards survival analysis, histologic grade was the best predictor of survival in the SMAD4(-) population (adjusted hazard ratio = 4.8, p < .0001). In the SMAD4(+) population, histologic grade was not associated with survival on multivariate analysis. In the SMAD4(-) population, median OS for well/moderately differentiated patients and poorly differentiated patients was 39.6 and 8.6 months, respectively. CONCLUSION: In this large cohort of resected PDAC, routine SMAD4 assessment identified a subpopulation of patients with SMAD4(-) and histologically poorly differentiated tumors that had significantly poor prognosis with median OS of 8.6 months. Characterization of the role of SMAD4 within the context of poorly differentiated tumors may help settle the controversy regarding SMAD4 in PDAC and lead to identification of personalized therapeutic strategies for subgroups of PDAC.

DNA Checkpoint and Repair Factors Are Nuclear Sensors for Intracellular Organelle Stresses-Inflammations and Cancers Can Have High Genomic Risks.

Under inflammatory conditions, inflammatory cells release reactive oxygen species (ROS) and reactive nitrogen species (RNS) which cause DNA damage. If not appropriately repaired, DNA damage leads to gene mutations and genomic instability. DNA damage checkpoint factors (DDCF) and DNA damage repair factors (DDRF) play a vital role in maintaining genomic integrity. However, how DDCFs and DDRFs are modulated under physiological and pathological conditions are not fully known. We took an experimental database analysis to determine the expression of 26 DNA DDCFs and 42 DNA DDRFs in 21 human and 20 mouse tissues in physiological/pathological conditions. We made the following significant findings: (1) Few DDCFs and DDRFs are ubiquitously expressed in tissues while many are differentially regulated.; (2) the expression of DDCFs and DDRFs are modulated not only in cancers but also in sterile inflammatory disorders and metabolic diseases; (3) tissue methylation status, pro-inflammatory cytokines, hypoxia regulating factors and tissue angiogenic potential can determine the expression of DDCFs and DDRFs; (4) intracellular organelles can transmit the stress signals to the nucleus, which may modulate the cell death by regulating the DDCF and DDRF expression. Our results shows that sterile inflammatory disorders and cancers increase genomic instability, therefore can be classified as pathologies with a high genomic risk. We also propose a new concept that as parts of cellular sensor cross-talking network, DNA checkpoint and repair factors serve as nuclear sensors for intracellular organelle stresses. Further, this work would lead to identification of novel therapeutic targets and new biomarkers for diagnosis and prognosis of metabolic diseases, inflammation, tissue damage and cancers.

Acute and Chronic Increases of Circulating FSTL1 Normalize Energy Substrate Metabolism in Pacing-Induced Heart Failure.

BACKGROUND: FSTL1 (follistatin-like protein 1) is an emerging cardiokine/myokine that is upregulated in heart failure (HF) and is found to be cardioprotective in animal models of cardiac injury. We tested the hypothesis that circulating FSTL1 can affect cardiac function and metabolism under baseline physiological conditions and in HF. METHODS AND RESULTS: FSTL1 was acutely (10 minutes) or chronically (2 weeks) infused to attain clinically relevant blood levels in conscious dogs with cardiac tachypacing-induced HF. Dogs with no cardiac pacing and FSTL1 infusion served as control. 3H-oleate and 14C-glucose were infused to track the metabolic fate of free fatty acids and glucose. Cardiac uptake of lactate and ketone bodies and systemic respiratory quotient were also measured. HF caused a shift from prevalent cardiac and systemic fat to carbohydrate oxidation. Although acute FSTL1 administration caused minimal hemodynamic changes at baseline, in HF dogs it enhanced cardiac oxygen consumption and transiently reversed the changes in free fatty acid and glucose oxidation and systemic respiratory quotient. In HF, chronic FSTL1 infusion stably normalized cardiac free fatty acid, glucose, ketone body consumption, and systemic respiratory quotient, while moderately improving diastolic and contractile function. Consistently, FSTL1 prevented the downregulation of medium-chain acyl-CoA dehydrogenase-a representative enzyme of the free fatty acid oxidation pathway. Complementary in vitro experiments in primary cardiac and skeletal muscle myocytes showed that FSTL1 stimulated oxygen consumption through AMPK (AMP-activated kinase) activation. CONCLUSIONS: These findings support a novel function for FSTL1 and provide the first direct evidence that a circulating cardiokine/myokine can alter myocardial and systemic energy substrate metabolism, in vivo.

A pivotal role for p53: balancing aerobic respiration and glycolysis.

The genetic basis of increased glycolytic activity observed in cancer cells is likely to be the result of complex interactions of multiple regulatory pathways. Here we review the recent evidence of a simple genetic mechanism by which tumor suppressor p53 regulates mitochondrial respiration with secondary changes in glycolysis that are reminiscent of the Warburg effect. The biological significance of this regulation of the two major pathways of energy generation by p53 remains to be seen.