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Background Locally advanced unresectable pancreatic adenocarcinoma (LAC) is characterized by poor survival despite chemotherapy and conventional radiation therapy. We have recently reported on the safety of using irreversible electroporation (IRE) for the management of LAC. The purpose of this study was to evaluate the overall survival in patients with LAC treated with IRE. Methods A prospective, multi-institutional evaluation of 54 patients who underwent IRE for unresectable pancreatic cancer from December 2009 to October 2010 was evaluated for overall survival and propensity matched to 85 matched stage III patients treated with standard therapy defined as chemotherapy and radiation therapy alone. Results A total of 54 LAC patients have undergone IRE successfully, with 21 women, 23 men (median age, 61 (range, 45–80) years). Thirty-five patients had pancreatic head primary and 19 had body tumors; 19 patients underwent margin accentuation with IRE and 35 underwent in situ IRE. Forty-nine (90 %) patients had pre-IRE chemotherapy alone or chemoradiation therapy for a median duration 5 months. Forty (73%) patients underwent post-IRE chemotherapy or chemoradiation. The 90 day mortality in the IRE patients was 1 (2 %). In a comparison of IRE patients to standard therapy, we have seen an improvement in local progression-free survival (14 vs. 6 months, p  = 0.01), distant progression-free survival (15 vs. 9 months, p  = 0.02), and overall survival (20 vs. 13 months, p  = 0.03). Conclusions IRE ablation of locally advanced pancreatic tumors remains safe and in the appropriate patient who has undergone standard induction therapy for a minimum of 4 months can achieve greater local palliation and potential improved overall survival compared with standard chemoradiation–chemotherapy treatments. Validation of these early results will need to be validated in the current multi-institutional Phase 2 IDE study.

Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate β-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, β-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer. The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.

Background Several contemporary risk stratification tools are now being used since the development of the Charlson Comorbidity Index (CCI) in 1987. The purpose of this systematic review and meta-analysis was to compare the utility of commonly used co-morbidity indices in predicting surgical outcomes. Methods A comprehensive review was performed to identify studies reporting an association between a pre-operative co-morbidity measurement and an outcome (30-day/in-hospital morbidity/mortality, 90-day morbidity/mortality, and severe complications). Meta-analysis was performed on the pooled data. Results A total of 111 included studies were included with a total cohort size 25,011,834 patients. The studies reporting the 5-item Modified Frailty Index (mFI-5) demonstrated a statistical association with an increase in the odds of in-hospital/30-day mortality (OR:1.97,95%CI: 1.55–2.49, p  < 0.01). The pooled CCI results demonstrated an increase in the odds for in-hospital/30-day mortality (OR:1.44,95%CI: 1.27–1.64, p  < 0.01). Pooled results for co-morbidity indices utilizing a scale-based continuous predictor were significantly associated with an increase in the odds of in-hospital/30-day morbidity (OR:1.32, 95% CI: 1.20–1.46, p  < 0.01). On pooled analysis, the categorical results showed a higher odd for in-hospital/30-day morbidity (OR:1.74,95% CI: 1.50–2.02, p  < 0.01). The mFI-5 was significantly associated with severe complications (Clavien-Dindo ≥ III) (OR:3.31,95% CI:1.13–9.67, p  < 0.04). Pooled results for CCI showed a positive trend toward severe complications but were not significant. Conclusion The contemporary frailty-based index, mFI-5, outperformed the CCI in predicting short-term mortality and severe complications post-surgically. Risk stratification instruments that include a measure of frailty may be more predictive of surgical outcomes compared to traditional indices like the CCI.

Background This study was designed to evaluate the safety, efficiency, effectiveness, and overall long-term outcome in patients treated with microwave thermal ablation of hepatic tumors. Microwave ablation technology represents the next generation in ablative techniques for the treatment of hepatic malignancies. Currently there have been no large reports of its use in the United States with appropriate long-term follow-up. Methods An institutional review board-approved prospective phase II study of microwave ablation of hepatic malignancies from January 2004 to January 2009 was performed. All complications were recorded up to 90 days from operation and reported using an established five-point grading scale. Results One hundred patients underwent 270 ablations for hepatic malignancies. The most tumor types were as follows: metastatic colorectal cancer (50%), hepatocellular carcinoma (17%), metastatic carcinoid (11%), and other metastatic disease (22%). A majority of patents (53%) underwent combination hepatic resection and microwave ablation; 38% underwent ablation alone, 9% underwent ablation and additional organ resection, with 68% open procedures. Median tumor size was 3.0 (range, 0.6–6.0) cm, median number of tumors was 2 (range, 1–18), and median total ablation time was 13 (range, 5–45) min. Overall 90-day mortality was 0% and morbidity was 29%. One patient developed a hepatic abscess and no patients experienced bleeding complications. After a median follow-up of 36 months, 5 patients (5%) had incomplete ablation, 2 (2%) had local recurrence at the ablated site, and 37 (37%) developed intrahepatic recurrence at nonablated sites. Conclusions Microwave ablation of hepatic tumors is a safe and effective method for treating unresectable hepatic tumors, with a low rate of local recurrence.

Background/Objectives: There is increasing evidence that a subset of patients with stage IV pancreatic ductal adenocarcinoma (PDAC) and liver-only metastasis may benefit from surgical resection of both the primary tumor and metastatic lesions. Methods: A meta-analysis and systematic review were conducted in patients with stage IV PDAC and hepatic-only metastasis. A comprehensive literature search (January 2015–June 2023) was performed using PubMed with keywords including “pancreatic cancer”, “oligometastatic”, and “surgery”. Results: Sixteen articles were included in the final review and characterized based on patient selection factors and prognostic indicators. Seven studies reported hazard ratios (HRs) or Kaplan–Meier curves for survival in synchronous resected cohorts versus chemotherapy/palliation alone, which indicated a statistically significant survival benefit in the resection cohorts (pooled HR: 0.41, 95% CI: 0.31–0.53, p < 0.01). Prognostic indicators for synchronous and metachronous resection included lower pre-operative CA19-9, negative margin status of the primary tumor, moderate-to-well-differentiated tumors (grades I–II), and receiving pre-operative chemotherapy. Conclusions: Surgical/ablation selection factors are evolving, with priorities on (1) response to induction chemotherapy, (2) ability to achieve R0 resection, and (3) minimally invasive approaches remaining critical to optimal patient selection. Standardized radiologic and tumor marker evaluation and response to neoadjuvant therapy and optimizing performance status are critical to improved outcomes.

Purpose: To investigate if radiomics signatures generated from longitudinal CT scans could predict IRE treatment effectiveness and outcomes in patients with locally advanced pancreatic cancer (LAPC). Methods: A cohort of 50 (60% male, mean [SD] age 60.7 [8.7] years) LAPC patients treated with IRE were retrospectively selected. Preoperative and 12-week follow-up CT scans were reviewed by two radiologists for tumor segmentation. A total of 2078 features were extracted: shape (n = 16), texture (n = 68), filter (n = 1892), intensity (n = 18), and local texture (n = 84). Principal component analysis (PCA) was applied to develop composite radiomics features. Composite signatures and clinically relevant radiomics features were correlated with time to recurrence (TTR), time to local recurrence (TTLR), time to distant recurrence (TTDR), recurrence-free survival (RFS) and overall survival (OS). Risk stratification performance was evaluated using hazard ratios (HRs), and significance was evaluated using the log-rank test. Results: Statistically significant separation between high and low patient TTR risk groups was observed in the following: gray-level co-occurrence matrix (HR = 2.65, p < 0.01, median survival difference = 6.6 mo); composite radiomics features derived from the following feature groups: all radiomics features (HR = 2.27, p = 0.01, median survival difference = 6.4 mo), intensity features (HR = 3.13, p < 0.01, median survival difference = 14.0 mo), and filter features (HR = 2.27, p = 0.01, median survival difference = 6.4 mo). Conclusions: Pre-treatment radiomics signatures were significantly associated with LAPC patient outcomes. The observed correlations used pre-treatment CT scans, implying that the features predict the individual risk of disease recurrence.

BackgroundUnresectable intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, and currently there are moderately established chemotherapeutic [gemcitabine/cisplatin (Gem/Cis)] treatments to prolong survival. The purpose of this study was to assess the efficacy of irinotecan drug-eluting beads (DEBIRI) therapy by transarterial infusion in combination with systemic therapy in unresectable ICC.Patients and MethodsThis is a prospective, multicenter, open-label, randomized phase II study (Clin Trials: NCT01648023-DELTIC trial) of patients with ICC randomly assigned to Gem/Cis with DEBIRI or Gem/Cis alone. The primary endpoint was response rate.ResultsThe intention-to-treat population comprised 48 patients: 24 treated with Gem/Cis and DEBIRI and 22 with Gem/Cis alone (2 screen failures). The two groups were similar with respect to the extent of liver involvement (35% versus 38%) and presence of extrahepatic disease (29% versus 14%, p = 0.12). Median numbers of chemotherapy cycles were similar (6 versus 6), as were rates of grade 3/4 adverse events (34% for the Gem/Cis-DEBIRI group versus 36% for the Gem/Cis group). The overall response rate was significantly greater in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm at 2 (p < 0.04), 4 (p < 0.03), and 6 months (p < 0.05). There was significantly more downsizing to resection/ablation in the Gem/Cis-DEBIRI arm versus the Gem/Cis arm (25% versus 8%, p < 005), and there was improved median progression-free survival [31.9 (95% CI 8.5–75.3) months versus 10.1 (95% CI 5.3–13.5) months, p = 0.028] and improved overall survival [33.7 (95% CI 13.5–54.5) months versus 12.6 (95% CI 8.7–33.4) months, p = 0.048].ConclusionCombination Gem/Cis with DEBIRI is safe, and leads to significant improvement in downsizing to resection, improved progression-free survival, and overall survival.

Introduction Response rates to systemic chemotherapy for patients who have failed irinotecan-based chemotherapy for liver-dominant metastatic colorectal cancer range between 10 and 18 % with overall survival between 7 and 9 months. The aim of this study was to assess the efficacy and safety of hepatic arterial irinotecan therapy in patients with hepatic-dominant metastatic colorectal cancer who had failed systemic irinotecan. Methods This was a multi-institutional, multi-national, analysis of patients who received DEBIRI in the setting of unresectable liver-dominant metastatic colorectal cancer. Patients had received between 1 and 4 lines of prior chemotherapy, the majority of which included systemic irinotecan. Primary endpoints were toxicity profile and tumor response rate. Results 296 patients with unresectable liver metastases who had undergone 666 DEBIRI treatments were reviewed. 192 treatments were performed in patients who had received prior systemic irinotecan. 222 treatments were performed in irinotecan-naïve patients. The median number of DEBIRI treatments was 1 (range 1–8); median treatment dose was 100 mg (range 50–200 mg), with total hepatic treatment of approximately 100 mg (range 20/30–200/300 mg). All-grade adverse events occurred in 18 % of patients receiving prior systemic irinotecan compared with 15 % of patients receiving no prior systemic irinotecan (including chemo-naïve patients). Response rates in patients with prior systemic irinotecan were 44 % at 3 months, 43 % at 6 months, and 44 % at 12 months, compared with 45, 40, and 35 % during the same time point in patients without prior systemic irinotecan. All-grade adverse events occurred in 10, 20, 10, and 37 % of patients receiving 0, 1, 2, and 3+ lines of systemic chemotherapy, respectively. Overall survival was 90 %, 93 %, 90 %, 90 % at 6 months and 76 %, 71 %, 77 %, 87 % at 12 months in patients undergoing DEBIRI therapy after receiving 0, 1, 2, and 3+ lines of systemic chemotherapy, respectively. Conclusions The safety and efficacy of hepatic arterial drug-eluting irinotecan bead (DEBIRI) therapy are not affected by non-response to prior systemic irinotecan. While DEBIRI complete response rates are greatest and overall adverse events are least in chemotherapy-naïve individuals, it retains its respectable efficacy and low rate of serious adverse events even in the setting of previous administration of systemic chemotherapy.

Background This study was designed to develop a more robust predictive model, beyond T-stage alone, for incidental gallbladder cancer (IGBC) for discovering locoregional residual (LRD) and distant disease (DD) at reoperation, and estimating overall survival (OS). T-stage alone is currently used to guide treatment for incidental gallbladder cancer. Residual disease at re-resection is the most important factor in predicting outcomes. Methods All patients with IGBC who underwent reoperation at 10 institutions from 2000 to 2015 were included. Routine pathology data from initial cholecystectomy was utilized to create the gallbladder cancer predictive risk score (GBRS). Results Of 449 patients with gallbladder cancer, 262 (58 %) were incidentally discovered and underwent reoperation. Advanced T-stage, grade, and presence of lymphovascular (LVI) and perineural (PNI) invasion were all associated with increased rates of DD and LRD and decreased OS. Each pathologic characteristic was assigned a value (T1a: 0, T1b: 1, T2: 2, T3/4: 3; well-diff: 1, mod-diff: 2, poor-diff: 3; LVI-neg: 1, LVI-pos: 2; PNI-neg: 1, PNI-pos: 2), which added to a total GBRS score from 3 to 10. The scores were separated into three risk-groups (low: 3–4, intermediate: 5–7, high: 8–10). Each progressive GBRS group was associated with an increased incidence LRD and DD at the time of re-resection and reduced OS. Conclusions By accounting for subtle pathologic variations within each T-stage, this novel predictive risk-score better stratifies patients with incidentally discovered gallbladder cancer. Compared with T-stage alone, it more accurately identifies patients at risk for locoregional-residual and distant disease and predicts long-term survival as it redistributes T1b, T2, and T3 disease across separate risk-groups based on additional biologic features. This score may help to optimize treatment strategy for patients with incidentally discovered gallbladder cancer.

Background/Objectives: This study explores the optimization of exocrine pancreatic insufficiency (EPI) management in pancreatic adenocarcinoma patients, focusing on the scientific advancements and technological interventions available to improve patient outcomes, including oral pancreatic enzyme replacement therapy (PERT) and immobilized lipase cartridge (RELiZORB®). This was a prospective Institutional Review Board (IRB)-approved study from October 2019 through to August 2021 at the Louisville Medical Center in collaboration with Norton Healthcare and the University of Louisville Division of Surgical Oncology. Patients with a diagnosis of pancreatic adenocarcinoma (Stage 2 or 3) who underwent oncologic surgical resection were included in this study. Methods: Patients were contacted at pre-defined intervals (prior to surgery, before hospital discharge, and 2, 4, 6, and 12 weeks after surgery) to complete nutrition evaluation, EPI assessment, and quality of life questionnaires to identify the severity and frequency of gastrointestinal (GI) symptoms. Results: EPI symptoms were reported in 28 of the 35 total patients studied (80%). Jejunostomy tubes were placed during oncologic surgery in 25 of the 35 total patients studied (71%), and 12 of the 25 patients with a jejunostomy tube utilized enzyme cartridges to manage EPI symptoms while on supplemental tube feeding (48%). EPI symptoms were reported in 8 of the 10 patients without a feeding tube (80%), and their EPI symptoms were managed with PERT alone. EPI interventions, both oral PERT and immobilized cartridges, were associated with a decrease in EPI symptoms after surgery and improved quality of life (QOL). Conclusions: Overall, early optimization of EPI is crucial to enhance overall patient care, return to oncology therapy after surgery, and improve quality of life in pancreatic adenocarcinoma patients.