Enhancing Neoadjuvant Virotherapy's Effectiveness by Targeting Stroma to Improve Resectability in Pancreatic Cancer.

About one-fourth of patients with pancreatic ductal adenocarcinoma (PDAC) are categorized as borderline resectable (BR) or locally advanced (LA). Chemotherapy and radiation therapy have not yielded the anticipated outcomes in curing patients with BR/LA PDAC. The surgical resection of these tumors presents challenges owing to the unpredictability of the resection margin, involvement of vasculature with the tumor, the likelihood of occult metastasis, a higher ratio of positive lymph nodes, and the relatively larger size of tumor nodules. Oncolytic virotherapy has shown promising activity in preclinical PDAC models. Unfortunately, the desmoplastic stroma within the PDAC tumor microenvironment establishes a barrier, hindering the infiltration of oncolytic viruses and various therapeutic drugs-such as antibodies, adoptive cell therapy agents, and chemotherapeutic agents-in reaching the tumor site. Recently, a growing emphasis has been placed on targeting major acellular components of tumor stroma, such as hyaluronic acid and collagen, to enhance drug penetration. Oncolytic viruses can be engineered to express proteolytic enzymes that cleave hyaluronic acid and collagen into smaller polypeptides, thereby softening the desmoplastic stroma, ultimately leading to increased viral distribution along with increased oncolysis and subsequent tumor size regression. This approach may offer new possibilities to improve the resectability of patients diagnosed with BR and LA PDAC.

Mortality and failure-to-rescue after esophagectomy in the procedure-targeted National Surgical Quality Improvement Program registry.

BACKGROUND: The association between procedural volume and esophagectomy outcomes has been established, but the relationship between higher levels of care and esophagectomy outcomes has not been explored. This study aims to investigate whether hospital participation in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) esophagectomy-targeted registry is associated with superior outcomes. METHODS: The 2016-2020 ACS NSQIP standard and esophagectomy-targeted registries were queried. Esophagectomy outcomes were analyzed overall and stratified by esophagectomy type (Ivor Lewis vs. transhiatal vs. 3-field McKeown). RESULTS: A total of 2181 and 5449 esophagectomy cases were identified in the standard and targeted databases (68% Ivor Lewis esophagectomy). The median age was 65 years and 80% were male. Preoperative characteristics were largely comparable. On univariate analysis, targeted hospitals were associated with lower mortality (2% vs. 4%, p < 0.01) and failure-to-rescue rates (11% vs. 17%, p < 0.01), higher likelihood of an optimal outcome (62% vs. 58%, p = 0.01), and shorter hospital stay (median 9 vs. 10 days, p < 0.01). On multivariable analysis, Ivor Lewis esophagectomy at targeted centers was associated with reduced odds of mortality [odds ratio (OR) 0.57 and 95% confidence intervals 0.35-0.90] and failure-to-rescue [OR 0.54 (0.33-0.90)] with no difference in serious morbidity or optimal outcome. There was no statistically significant difference in odds of mortality or failure to rescue in targeted versus standard centers when performing transhiatal or McKeown esophagectomy. CONCLUSIONS: Esophagectomy performed at hospitals participating in the targeted ACS NSQIP is associated with roughly half the risk of mortality compared to the standard registry. The factors underlying this relationship may be valuable in quality improvement.

Complications and failure-to-rescue after pancreatectomy and hospital participation in the targeted American College of Surgeons National Surgical Quality Improvement Program registry.

BACKGROUND: More than 700 hospitals participate in the American College of Surgeons National Surgical Quality Improvement Program, but most pancreatectomies are performed in 165 centers participating in the pancreas procedure-targeted registry. We hypothesized that these hospitals ("targeted hospitals") might provide more specialized care than those not participating ("standard hospitals"). METHODS: The 2014 to 2019 pancreas-targeted and standard American College of Surgeons National Surgical Quality Improvement Program registry were reviewed regarding patient demographics, comorbidities, and perioperative outcomes using standard univariate and multivariable logistic regression analyses. Primary outcomes included 30-day mortality and serious morbidity. RESULTS: The registry included 30,357 pancreatoduodenectomies (80% in targeted hospitals) and 14,800 distal pancreatectomies (76% in targeted hospitals). Preoperative and intraoperative characteristics of patients treated at targeted versus standard hospitals were comparable. On multivariable analysis, pancreatoduodenectomies performed at targeted hospitals were associated with a 39% decrease in 30-day mortality (odds ratio, 0.61; 95% confidence interval, 0.50-0.75), 17% decrease in serious morbidity (odds ratio, 0.83; 95% confidence interval, 0.77-0.89), and 41% decrease in failure-to-rescue (odds ratio, 0.59; 95% confidence interval, 0.47-0.74). These differences did not apply to distal pancreatectomies. Participation in the targeted registry was associated with higher rates of optimal surgery for both pancreatoduodenectomy (odds ratio, 1.33; 95% confidence interval, 1.25-1.41) and distal pancreatectomy (odds ratio, 1.17; 95% confidence interval, 1.06-1.30). CONCLUSION: Mortality and failure-to-rescue rates after pancreatoduodenectomy in targeted hospitals were nearly half of rates in standard American College of Surgeons National Surgical Quality Improvement Program hospitals. Further research should delineate factors underlying this effect and highlight opportunities for improvement.

Adherence to Extended Venous Thromboembolism Prophylaxis and Outcomes After Complex Gastrointestinal Oncologic Surgery.

BACKGROUND: Clinical guidelines recommend extended venous thromboembolism (VTE) prophylaxis for cancer patients after major gastrointestinal (GI) operations. However, adherence to the guidelines has been low, and the clinical outcomes not well defined. METHODS: This study retrospectively analyzed a random 10 % sample of the 2009-2022 IQVIA LifeLink PharMetrics Plus database, an administrative claims database representative of the commercially insured population of the United States. The study selected cancer patients undergoing major pancreas, liver, gastric, or esophageal surgery. The primary outcomes were 90-day post-discharge VTE and bleeding. RESULTS: The study identified 2296 unique eligible operations. During the index hospitalization, 52 patients (2.2 %) experienced VTE, 74 patients (3.2 %) had postoperative bleeding, and 140 patients (6.1 %) had a hospital stay of at least 28 days. The remaining 2069 operations comprised 833 pancreatectomies, 664 hepatectomies, 295 gastrectomies, and 277 esophagectomies. The median age of the patients was 49 years, and 44 % were female. Extended VTE prophylaxis prescriptions were filled for 176 patients (10.4 % for pancreas, 8.1 % for liver, 5.8 % for gastric cancer, and 6.5 % for esophageal cancer), and the most used agent was enoxaparin (96 % of the patients). After discharge, VTE occurred for 5.2 % and bleeding for 5.2 % of the patients. The findings showed no association of extended VTE prophylaxis with post-discharge VTE (odds ratio [OR], 1.54; 95 % confidence interval [CI], 0.81-2.96) or bleeding (OR, 0.72, 95 % CI, 0.32-1.61). CONCLUSIONS: The majority of the cancer patients undergoing complex GI surgery did not receive extended VTE prophylaxis according to the current guidelines, and their VTE rate was not higher than for the patients who received it.

Morbidity of colectomy during pancreatoduodenectomy: An analysis of the pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program Registry.

BACKGROUND: Pancreatoduodenectomy is a complex operation with considerable morbidity and mortality. Locally advanced tumors may require concurrent colectomy. We hypothesized that a concurrent colectomy increases the risk associated with pancreatoduodenectomy. METHODS: This retrospective review of the 2014-2019 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program registry classified operations as pancreatoduodenectomy (PD) versus pancreatoduodenectomy/colectomy (PD+C). The two groups were compared with respect to demographics, comorbidities, disease characteristics, intraoperative variables, and postoperative outcomes. Main effect models were developed to examine the effect of concurrent colectomy on outcomes after adjusting for potential confounders. RESULTS: Of 24 421 pancreatoduodenectomies, 430 (1.8%) involved concurrent colectomy. PD + C patients had less comorbidities (obesity 19% vs. 27%, hypertension 43% vs. 53%, diabetes 20% vs. 26%) and were associated with malignant diagnosis (94% vs. 83%), vascular resection (28% vs. 18%), and longer operative time (median 6.9 vs. 6 h). On multivariable analysis, concurrent colectomy was independently associated with serious morbidity (adjusted odds ratio [OR] 2.62, 95% confidence interval [CI]: 1.94-3.54) but not mortality (OR 1.44 [0.63-3.31]). CONCLUSIONS: Concurrent colectomy at the time of pancreatoduodenectomy significantly increased the odds of serious morbidity but did not affect mortality. This should be considered in operative planning, preoperative counseling, and sequencing of cancer-directed treatments.

Predictors of Sentinel Lymph Node Metastasis in Patients with Thin Melanoma: An International Multi-institutional Collaboration.

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for patients with T1b melanomas and T1a melanomas with high-risk features; however, the proportion of patients with actionable results is low. We aimed to identify factors predicting SLNB positivity in T1 melanomas by examining a multi-institutional international population. METHODS: Data were extracted on patients with T1 cutaneous melanoma who underwent SLNB between 2005 and 2018 at five tertiary centers in Europe and Canada. Univariable and multivariable logistic regression analyses were performed to identify predictors of SLNB positivity. RESULTS: Overall, 676 patients were analyzed. Most patients had one or more high-risk features: Breslow thickness 0.8-1 mm in 78.1% of patients, ulceration in 8.3%, mitotic rate > 1/mm2 in 42.5%, Clark's level ≥ 4 in 34.3%, lymphovascular invasion in 1.4%, nodular histology in 2.9%, and absence of tumor-infiltrating lymphocytes in 14.4%. Fifty-three patients (7.8%) had a positive SLNB. Breslow thickness and mitotic rate independently predicted SLNB positivity. The odds of positive SLNB increased by 50% for each 0.1 mm increase in thickness past 0.7 mm (95% confidence interval [CI] 1.05-2.13) and by 22% for each mitosis per mm2 (95% CI 1.06-1.41). Patients who had one excised node (vs. two or more) were three times less likely to have a positive SLNB (3.6% vs. 9.6%; odds ratio 2.9 [1.3-7.7]). CONCLUSIONS: Our international multi-institutional data confirm that Breslow thickness and mitotic rate independently predict SLNB positivity in patients with T1 melanoma. Even within this highly selected population, the number needed to diagnose is 13:1 (7.8%), indicating that more work is required to identify additional predictors of sentinel node positivity.

Artificial Intelligence in Liver Transplantation.

BACKGROUND: Advancements based on artificial intelligence have emerged in all areas of medicine. Many decisions in organ transplantation can now potentially be addressed in a more precise manner with the aid of artificial intelligence. METHOD/RESULTS: All elements of liver transplantation consist of a set of input variables and a set of output variables. Artificial intelligence identifies relationships between the input variables; that is, how they select the data groups to train patterns and how they can predict the potential outcomes of the output variables. The most widely used classifiers to address the different aspects of liver transplantation are artificial neural networks, decision tree classifiers, random forest, and naïve Bayes classification models. Artificial intelligence applications are being evaluated in liver transplantation, especially in organ allocation, donor-recipient matching, survival prediction analysis, and transplant oncology. CONCLUSION: In the years to come, deep learning-based models will be used by liver transplant experts to support their decisions, especially in areas where securing equitability in the transplant process needs to be optimized.

Adjuvant Transarterial Chemoembolization Following Curative-Intent Hepatectomy Versus Hepatectomy Alone for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The role of adjuvant transarterial chemoembolization (TACE) for patients with resectable hepatocellular carcinoma (HCC) undergoing hepatectomy is currently unclear. We performed a systematic review of the literature using the MEDLINE, Embase, and Cochrane Library databases. Random-effects meta-analysis was carried out to compare the overall survival (OS) and recurrence-free survival (RFS) of patients with resectable HCC undergoing hepatectomy followed by adjuvant TACE vs. hepatectomy alone in randomized controlled trials (RCTs). The risk of bias was assessed using the Risk of Bias 2.0 tool. Meta-regression analyses were performed to explore the effect of hepatitis B viral status, microvascular invasion, type of resection (anatomic vs. parenchymal-sparing), and tumor size on the outcomes. Ten eligible RCTs, reporting on 1216 patients in total, were identified. The combination of hepatectomy and adjuvant TACE was associated with superior OS (hazard ratio (HR): 0.66, 95% confidence interval (CI): 0.52 to 0.85; p < 0.001) and RFS (HR: 0.70, 95% CI: 0.56 to 0.88; p < 0.001) compared to hepatectomy alone. There were significant concerns regarding the risk of bias in most of the included studies. Overall, adjuvant TACE may be associated with an oncologic benefit in select HCC patients. However, the applicability of these findings may be limited to Eastern Asian populations, due to the geographically restricted sample. High-quality multinational RCTs, as well as predictive tools to optimize patient selection, are necessary before adjuvant TACE can be routinely implemented into standard practice. PROSPERO Registration ID: CRD42021245758.

Clinical Trials of Systemic Chemotherapy for Resectable Pancreatic Cancer: A Review.

Importance: Adjuvant chemotherapy is the standard of care for resected pancreatic ductal adenocarcinoma (PDAC) based on level 1 evidence, but some studies suggest that a neoadjuvant approach (which is standard for borderline resectable PDAC) may be preferable for upfront resectable PDAC. An in-depth review was conducted of all randomized clinical trials that investigated neoadjuvant and adjuvant treatment of patients with resectable or resected PDAC, focusing on trial design, characteristics of enrolled population, and long-term outcomes. Observations: The existing resectable PDAC trials have good internal validity but variable applicability because of their restrictive eligibility criteria. In these trials, overall survival is the criterion standard end point, but disease-free survival is more feasible, proximate, and specific to the assigned intervention (at the cost of subjective outcome assessment) and thus an acceptable end point in certain contexts. The prolonged survival in the PRODIGE 24 trial highlights both the success of mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the importance of patient selection. Neoadjuvant and perioperative trials have shown promising preliminary results; however, the number of patients who are not subsequently eligible for surgery reflects the limitations of this approach. Head-to-head comparisons of neoadjuvant and adjuvant treatments are limited to date in Western countries. Precision oncology with genomic and somatic testing for actionable mutations has promising preliminary results and may refine the management of PDAC, although the implications for early-stage disease and neoadjuvant therapy are unknown. Conclusions and Relevance: This review found that adjuvant chemotherapy with mFOLFIRINOX is currently the standard of care in fit patients with resected PDAC; however, the role of neoadjuvant treatment is expanding. Precision oncology may help individualize the treatment regimen and sequence and improve outcomes. Enrollment of patients with resectable PDAC in clinical trials is strongly encouraged.

Risk of venous thromboembolism in patients with elevated INR undergoing hepatectomy: an analysis of the American college of surgeons national surgical quality improvement program registry.

BACKGROUND: Patients undergoing hepatectomy can have elevated INR and may have venous thromboembolism (VTE) prophylaxis withheld as a result. We sought to examine the association between preoperative INR elevation and VTE following hepatectomy. METHODS: Hepatectomies captured in the American College of Surgeons National Surgical Quality Improvement Program registry between 2007 and 2016 were analyzed. Univariable and multivariable models examined the effect of incremental increases in preoperative INR on 30-day VTE, perioperative transfusion, serious morbidity, and mortality, adjusting for potential confounders. RESULTS: We included 25,220 elective hepatectomies (62.4% partial lobectomies, 10.1% left hepatectomies, 18.6% right hepatectomies, 9.2% trisegmentectomies). The median age of the patients was 60 years and 49% were male. INR was elevated in 3089 patients (12.2%): 1.1-1.2 in 8.1%, 1.2-1.4 in 3.3%, and 1.4-2.0 in 0.9%. Incremental elevations in INR were independently associated with increasing risk for postoperative VTE [odds ratio (OR) 1.15, 95% confidence intervals 1.01-1.31], perioperative transfusion [OR 1.35 (1.28-1.43)], serious morbidity [OR 1.35 (1.28-1.43)], and mortality [OR 1.76 (1.56-1.98)]. CONCLUSION: Elevation in preoperative INR was counter-intuitively associated with increased risk of both VTE and perioperative transfusion following hepatectomy. The role of perioperative thromboprophylaxis warrants further investigation to determine optimal care in patients with elevated preoperative INR.

Symptom Burden of Nonresected Pancreatic Adenocarcinoma: An Analysis of 10,753 Patient-Reported Outcome Assessments.

OBJECTIVES: Pancreatic adenocarcinoma (PAC) is a debilitating disease. We sought to analyze symptom burden and trajectories after diagnosis of PAC and identify predictors of severe symptoms for nonresected patients. METHODS: This was a retrospective review of linked administrative health care databases examining patients with PAC not undergoing resection. Primary outcome was severe patient-reported symptoms (Edmonton Symptom Assessment System ≥7). Multivariable modified Poisson regression models were used to identify factors associated with reporting severe symptoms. RESULTS: A total of 10,753 symptom assessments from 2168 patients were analyzed. The median age was 67 years, and 47% were female; median survival was 7 months. Most common severe symptoms were tiredness (54.7%), anorexia (53.6%), overall impaired well-being (45.3%), and drowsiness (37.1%). Severity of symptoms decreased 1 month after diagnosis and plateaued 4 months after diagnosis. Female sex, comorbidities, and older age were associated with reporting severe symptoms; recent radiation treatment and residence in a rural community were associated with reporting less severe symptoms. CONCLUSIONS: The prevalence of severe symptoms in patients with nonresected PAC was high, but potentially modifiable. We identified vulnerable groups of patients that may benefit from focused interventions. This information is important for patient counseling and design of supportive care strategies.

Population-Level Symptom Assessment Following Pancreaticoduodenectomy for Adenocarcinoma.

Importance: Postoperative morbidity associated with pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) remains as high as 70%. However, to our knowledge, few studies have examined quality of life in this patient population. Objective: To identify symptom burden and trajectories and factors associated with high symptom burden following PD for PA. Design, Setting, and Participants: This population-based cohort study of patients undergoing PD for PA diagnosed between 2009 and 2015 linked population-level administrative health care data to routinely prospectively collected Edmonton Symptom Assessment System (ESAS) scores from 2009 to 2015, with a data analysis undertaken in 2018. Exposures: Baseline characteristics, including age, sex, income quintile, rurality, immigration status, and comorbidity burden, as well as treatment characteristics, including year of surgery and receipt of chemotherapy. Main Outcome and Measures: The outcome of interest was moderate to severe symptoms (defined as ESAS ≥4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being. The monthly prevalence of moderate to severe symptoms was presented graphically for each symptom. Multivariable regression models identified factors associated with the reporting of moderate to severe symptoms. Results: We analyzed 6058 individual symptom assessments among 615 patients with PA who underwent resection (285 women [46.3%]) with ESAS data. Tiredness (443 [72%]), impaired well-being (418 [68%]), and lack of appetite (400 [65%]) were most commonly reported as moderate to severe. The proportion of patients with moderate to severe symptoms was highest immediately after surgery (range, 14%-66% per symptom) and decreased over time, stabilizing around 3 months (range, 8%-42% per symptom). Female sex, higher comorbidity, and lower income were associated with a higher risk of reporting moderate to severe symptoms. Receipt of adjuvant chemotherapy was not associated with the risk of moderate to severe symptoms. Conclusions and Relevance: There is a high prevalence of symptoms following PD for PA, with improvement over the first 3 months following surgery. In what to our knowledge is the largest cohort reporting on symptom burden for this population, we have identified factors associated with symptom severity. These findings will aid in managing patients' perioperative expectations and designing strategies to improve targeted symptom management.

Low rates of specialized cancer consultation and cancer-directed therapy for noncurable pancreatic adenocarcinoma: a population-based analysis.

BACKGROUND: Although advancements in systemic therapy have improved the outlook for pancreatic adenocarcinoma, it is not known if patients get access to these therapies. We aimed to examine the patterns and factors associated with access to specialized cancer consultations and subsequent receipt of cancer-directed therapy for patients with non-curative pancreatic adenocarcinoma. METHODS: We conducted a population-based analysis of noncurative pancreatic adenocarcinoma diagnosed over 2005-2016 in Ontario by linking administrative health care data sets. Our primary outcomes were specialized cancer consultation and receipt of cancer-directed therapy (chemotherapy or a combination of chemo- and radiation therapy [chemoradiation therapy]). We examined specialized cancer consultation with hepato-pancreatico-biliary surgery, medical and radiation oncology. We used multivariable logistic regression to identify factors associated with medical oncology consultation and cancer-directed therapy. RESULTS: Of 10 881 patients, 64.9% had a consultation with specialists in medical oncology, 35.1% with hepatopancreatico-biliary surgery and 24.7% with radiation oncology. Sociodemographic characteristics were not associated with the likelihood of medical oncology consultation. Of these patients, 4144 received cancer-directed therapy, representing 38.1% of all patients and 58.6% of those who consulted with medical oncology. Of 6737 patients not receiving cancer-directed therapy, 2988 (44.4%) had a consultation with medical oncology. Older age and lowest income quintile were independently associated with lower likelihood of cancer-directed therapy. If the first specialized cancer consultation was with medical or radiation oncology, the likelihood of cancer-directed therapy was significantly higher compared with surgery. INTERPRETATION: A considerable proportion of patients with noncurable pancreatic adenocarcinoma in Ontario did not have a specialized cancer consultation and most did not receive cancer-directed therapy. We identified disparities in specialized cancer consultation and receipt of systemic cancer-directed therapy that indicate potential gaps in assessment.

Fluoroquinolone-based versus ß-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials.

Complicated intra-abdominal infections (cIAIs) are common and confer significant morbidity, mortality and costs. In this era of evolving antimicrobial resistance, selection of appropriate empirical antimicrobials is paramount. This systematic review and meta-analysis of randomised controlled trials compared the effectiveness and safety of fluoroquinolone (FQ)-based versus ß-lactam (BL)-based regimens for the treatment of patients with cIAIs. Primary outcomes were treatment success in the clinically evaluable (CE) population and all-cause mortality in the intention-to-treat (ITT) population. Subgroup analyses were performed based on specific antimicrobials, infection source and isolated pathogens. Seven trials (4125 patients) were included. FQ-based regimens included moxifloxacin (four studies) or ciprofloxacin/metronidazole (three studies); BL-based regimens were ceftriaxone/metronidazole (three studies), carbapenems (two studies) or piperacillin/tazobactam (two studies). There was no difference in effectiveness in the CE (2883 patients; RR = 1.00, 95% CI 0.95-1.04) or ITT populations (3055 patients; RR = 0.97, 95% CI 0.94-1.01). Mortality (3614 patients; RR = 1.04, 95% CI 0.75-1.43) and treatment-related adverse events (2801 patients; RR = 0.97, 95% CI 0.70-1.33) were also similar. On subset analysis, moxifloxacin was slightly less effective than BLs in the CE (1934 patients; RR = 0.96, 95% CI 0.93-0.99) and ITT populations (1743 patients; RR = 0.94, 95% CI 0.91-0.98). Although FQ- and BL-based regimens appear equally effective and safe for the treatment of cIAIs, limited data suggest slightly inferior results with moxifloxacin. Selection of empirical coverage should be based on local bacterial epidemiology and patterns of resistance as well as antimicrobial stewardship protocols.