Is it resectable? A survey regarding tumor classification and vascular involvement.

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.

Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

The unfunded grant, now what? Advice, approach, and strategy.

BACKGROUND: Grant writing takes significant time and effort and often may be elusive, especially on a first attempt. After the rejection of a grant, many investigators face a dilemma regarding the best next steps. In this article, we discuss the options of revision versus resubmission and how to navigate these decisions. METHODS: The literature was surveyed, including review articles, personal perspectives, and editorial pieces regarding the grant writing and funding processes. The National Institute of Health database was reviewed, and data were extrapolated from the past 10 years of funding percentages and rates of both R01 initial applications and resubmissions. Recommendations were then generated based on pertinent literature and experience from the authors. RESULTS: The grant writing process involves many checkpoints between conception and funding. Only approximately 15% of R01 and R01-equivalent grants are accepted for funding on the initial submission. However, this statistic increases to >30% if the appropriate steps are taken to revise and resubmit the grant. These steps include consulting co-investigators, modifying hypotheses, drafting a succinct "Introduction" document, and many more. Knowing the options after the rejection of an original submission plays a huge role in the ultimate success of the grant. CONCLUSION: Although receiving funding for an original grant can be difficult, with appropriate guidance, it may seem more feasible than initially expected. Adequately responding to the critiques of the grant and revising the grant appropriately can make or break the outcome of the grant.

What would you do? A survey of HPB surgeons practice patterns.

BACKGROUND: The surgical decision making for pancreatic adenocarcinoma is complex. Although practice guidelines exist for many scenarios, these do not cover many common eventualities that may be encountered during these cases. We sought to identify the practice pattern variations amongst pancreatic surgeons in response to commonly experienced clinical scenarios. METHODS: A multiple-choice questionnaire was distributed to all full members of the IHPBA. Participant demographics, training history, and clinical practice information were obtained. The survey provided various operative scenarios and participants were asked how they would likely proceed. Responses were collected and stored anonymously in a secure database. Statistical analysis was performed using Stata 16.0. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. When asked about staging laparoscopy, the majority performed it selectively. For most respondents a pathological aorto-caval nodes was a reason to abort the procedure but most would have continued in the setting of a positive hepatic artery node. When encountering a single Segment 2 liver metastasis, participants who practiced in Europe were significantly more likely to resect and proceed compared to those in Asia and North America. Participants who had undergone only a Surgical Oncology fellowship were most likely to abort. With respect to direct colonic invasion, most participants would resect the specimen en bloc. Respondents who participated in fewer that 20 PDAC operations/year were most likely to abort. CONCLUSIONS: Surgical decision making in PDAC surgery is complex and there is significant disagreement on the correct management. While formal guidelines cannot exist for all situations, this survey highlights the need for consensus on commonly encountered operative scenarios.

Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

Understanding risk factors and microbial trends implicated in the development of Whipple-related surgical-site infections.

Objective: The purpose of this study is to understand the role of risk factors and postoperative complications seen in patients undergoing Whipple procedures in the development of surgical site infections. Our secondary goal was to evaluate whether microbial patterns differed between preoperative antibiotic classes, offering insight into the effectiveness of current practices while promoting antibiotic stewardship. Design: We performed a retrospective cohort study comparing patients with and without SSIs. Setting: This study was conducted at a tertiary-care center in the southeastern United States. Participants: Patients who underwent a Whipple procedure between 2012 and 2021 were acquired from the National Surgical Quality Improvement Program (NSQIP) database. Results: Patients with a bleeding disorder reported higher SSI rates (P = .04), whereas patients with a biliary stent reported lower surgical site infection (SSI) rates (P = .02) Those with postoperative complications had higher SSI rates, including delayed gastric emptying (P < .001) and pancreatic fistula (P < .001). Patients with longer operative times were 1.002 times more likely to develop SSIs (adjusted odds ratio [aOR], 1.002; 95% confidence interval [CI], 1.001-1.004; P = .006) whereas surgical indications for malignancy correlated with decreased SSIs risk (aOR, 0.578; 95% CI, 0.386-866) when adjusting for body mass index, surgical indication, and duration of surgical procedure. Conclusions: Optimizing preoperative management of modifiable risk factors for patients undergoing pancreatoduodenectomies and decreasing operative times may reduce SSI rates and patient and hospital burden. Further research is needed to understand whether stent placement reduces SSI risk in pancreatoduodenectomy.

Adjusting Drain Fluid Amylase for Drain Volume Does Not Improve Pancreatic Fistula Prediction.

INTRODUCTION: Drain fluid amylase (DFA) levels have been used to predict clinically relevant postoperative pancreatic fistula (CR-POPF) and guide postoperative drain management. Optimal DFA cutoff thresholds vary between studies, thereby prompting investigation of an alternative assessment technique. As DFA measurements could, in theory, be distorted by variations in ascites fluid production, we hypothesized that adjusting DFA for volume corrected drain fluid amylase (vDFA) would improve CR-POPF predictive models. METHODS: A single-institution retrospective cohort study of patients, who underwent pancreatoduodenectomies (PD) and distal pancreatectomies (DP) between 2013 and 2019, was performed. DFAs and vDFAs were measured on postoperative day (POD) 3. Clinicopathologic variables were compared between cohorts by univariable and multivariable analyses and Receiver operating characteristic (ROC) curves. RESULTS: Patients developing a CR-POPF were more likely to be male and have elevated DFA, vDFA, and body mass index (BMI). vDFA use did not contribute to a superior CR-POPF predictive model compared to DFA-a finding consistent on subanalysis of surgery type PD versus DP. In CR-POPF predictive models, DFA, vDFA, and male sex significantly improved CR-POPF predictive models when considering both surgery subtypes, while only DFA and vDFA significantly improved models when cohorts were segregated by surgery type. CONCLUSIONS: Postoperative DFA remains a preferred method of predicting CR-POPF as the proposed vDFA assessment technique only adds complexity without increased discriminability.

Are Lymph Node Metastases Associated With Survival in Black Patients With Pancreatic Cancer?

INTRODUCTION: Despite aggressive surgical care and systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Recent studies show that racial disparities in outcome also exist. We sought to investigate the association lymph node (LN) metastases had with survival between Black and White patients with PDAC after resection. METHODS: Retrospective analysis of 226 PDAC patients who underwent resection at a single institution from 2010 to 2018 was performed with attention to LN metastasis and patient race. The number of patients who received chemotherapy was also evaluated. RESULTS: One Hundred Seventy Five (77.4%) PDAC patients were White and 51 (22.6%) were Black. 130 (59.3%) patients had LN metastasis (LN+). LN+ and LN- groups were similar in race (P = 0.93), sex (P = 0.10) and age at the time of diagnosis (P = 0.45). Patients with LN + disease were more likely to present with larger tumors (3.4 versus 2.8 cm, P = 0.02) and higher T status (P = 0.001). White and Black patients had similar rates of LN metastasis (59% versus 58.8%, P = 1.0). The median survival for LN- Black and White patients were similar (43.2 versus 30.2 mo, P = 0.82). LN + Black patients trended towards receiving more systemic therapy than White LN + patients (55% versus 42%, P = 0.10). The median survival for LN + Black patients was significantly less than LN + White patients (17.5 versus 24.6 mo, P = 0.04). CONCLUSIONS: Black LN + PDAC patients have an inferior survival rate after resection when compared to their White counterparts. Our disparity in outcome cannot be solely explained by a difference in systemic treatment. Further investigation is warranted to determine racial differences in tumor biology or response to chemotherapy.

Hiding in Plain Sight: A Novel Microbial Driver for Colorectal Cancer?

SUMMARY: In this issue of Cancer Discovery, Drewes and colleagues demonstrate a surprising role for the common gut pathogen Clostridioides difficile in driving colorectal cancer in preclinical models through the bacterial toxin-dependent reprogramming of the epithelial and immune compartments. See related article by Drewes et al., p. 1873 (3).

Pearls and Pitfalls for Surgical Investigators in Basic and Translational Research.

Surgeon-scientists are uniquely positioned to contribute to our understanding of the fundamental biology of surgical disease and to bring a unique perspective that leads to innovation in the diagnosis and treatment of many conditions. However, it is broadly recognized that due to the changing landscape of surgery and science, the surgeon-scientists of today face multiple challenges in this pursuit. Today, surgeon-scientists face an increased pressure from their department and hospital to generate clinical revenue, decreased availability of grant funding, greater administrative burden, rising complexity of fundamental research, increased medical school debt, and a growing desire for work-life balance. Given that survival of surgeon-scientists is critical for the progress of not only surgery but medical innovation at large, many surgical societies, notably the Association for Academic Surgery (AAS) and the Society of University Surgeons (SUS) have focused on the issues faced by surgeon-scientists. In this regard, the Basic and Translational Research Committee of the AAS and the Research Committee of the SUS organized a hot topic session at the 2021 Academic Surgical Congress in which experts discussed and addressed many issues concerning the surgeon-scientist pathway. This manuscript provides an overview of the issues discussed at this session.

Prescription patterns of pancreatic enzyme replacement therapy for patients with pancreatic cancer in the United States.

BACKGROUND: Exocrine pancreatic insufficiency (EPI) is frequently seen in patients with pancreatic cancer (PDAC) and is thought to contribute to nutritional complications. While EPI can be pharmacologically temporized with pancreatic enzyme replacement therapy (PERT), there is lack of clear evidence informing its use in PDAC. Here we aim to survey pancreatic surgeons regarding their utilization of PERT in the management of EPI for PDAC. METHODS: An online survey was distributed to the members of The Americas Hepato-Pancreato-Biliary Association (AHPBA) and The Pancreas Club. RESULTS: 86.5% (180/208) of surgeons prescribe PERT for at least some resectable/borderline resectable PDAC cases. Only a minority of surgeons order investigations to confirm EPI before starting PERT (28.1%) or test for adequacy of therapy (28.3%). Few surgeons believe that PERT has an effect on overall survival (19.7%) or disease-free survival (6.25%) in PDAC. CONCLUSION: PERT is widely prescribed in patients with resectable/borderline resectable PDAC, but investigations establishing EPI and assessing PERT adequacy are underutilized. A substantial proportion of surgeons are unclear as to the effect of PERT on survival outcomes in PDAC. These data call for prospective studies to establish guidelines for optimal use of PERT and its effects on survival outcomes in PDAC.

Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation.

Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.

Minnelide synergizes with conventional chemotherapy by targeting both cancer and associated stroma components in pancreatic cancer.

Addition of nab-paclitaxel to gemcitabine offers a survival benefit of only 6 weeks over gemcitabine alone at a cost of increased toxicity in PDAC. The goal of the present study is to evaluate the efficacy of Minnelide, a water-soluble prodrug of triptolide, in combination with the standard of care regimen for chemotherapy with the added advantage of reducing the doses of these drugs to minimize toxicity. Pancreatic cancer cell lines were implanted subcutaneously or orthotopically in athymic nude or C57BL/6J mice. Subsequently, animals were randomized and received saline or minnelide or full dose chemotherapy or low dose chemotherapy or minnelide in combination with low dose chemotherapy. Our results show that a combination of low doses of Minnelide with Gemcitabine + nab-paclitaxel significantly inhibited tumor progression and increased the survival of tumor-bearing mice in comparison with conventional chemotherapy alone. Moreover, combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis and effectively targeted both cancer and the associated stroma. In vitro studies with a combination of low doses of triptolide and paclitaxel significantly decreased the cell viability, increased apoptosis and led to significantly increased M-phase cell cycle arrest in various pancreatic cancer cell lines as compared to either drug alone. Our results show that Minnelide synergizes with conventional chemotherapy leading to a significant reduction in the doses of these toxic drugs, all the while achieving better efficacy in the treatment of PDAC. This combination effectively targeted both the cancer and the associated stromal components of pancreatic cancer.

Does race affect the long-term survival benefit of systemic therapy in pancreatic adenocarcinoma?

BACKGROUND: Systemic therapy is a key management component of pancreatic ductal adenocarcinoma(PDAC). Racial disparities exist in PDAC, often linked to socioeconomic variables. We investigated the impact of race in PDAC patients who had undergone systemic therapy and surgical resection. METHODS: A retrospective analysis was performed for all patients who underwent surgical resection for PDAC from 2010 to 2018. RESULTS: 234 patients (78.2% White; 21.8% Black) were included. Black patients presented at a younger age with larger tumors. White patients benefited from systemic therapy with longer overall survival (35vs20 months, p = 0.002). This survival advantage was not present in Black patients (21vs15 months, p = 0.15). Black patients receiving systemic therapy had similar survival as White patients who did not (p = 0.81). CONCLUSION: Black PDAC patients present at younger ages and with larger initial tumors. In our population, White patients had a longer overall survival after both surgical and systemic therapy. These findings may indicate differences in tumor biology. Further prospective studies are needed.

Are We Undertreating Black Patients with Nonfunctional Pancreatic Neuroendocrine Tumors? Critical Analysis of Current Surveillance Guidelines by Race.

BACKGROUND: Pancreatic neuroendocrine tumor (PNET) survival outcomes differ by race. Current recommendations for surveillance of PNETs less than 2 cm in size are based on low malignant potential and low rates of lymph node metastases (LNM). We investigated whether these guidelines are universally applicable regardless of race. STUDY DESIGN: A multi-institutional analysis of patients with resected, nonfunctional, sporadic PNETs was performed initially using the US Neuroendocrine Study Group dataset with the National Cancer Database as a validation dataset. Patients with distant metastatic disease were excluded from analysis. RESULTS: A total of 453 (388 White and 65 Black) and 5,532 patients (4,772 White and 760 Black) were analyzed in the initial and validation datasets, respectively. White patients had a low incidence of LNM in tumors of less than 2 cm in both datasets (5% and 12%, respectively), which increased with tumor size. However, the incidence of LNM in Black patients was similar in the initial and validation datasets for tumors sized less than 2 cm (23% and 21%) and 2 to 3 cm (21% and 29%). Black patients had a significantly higher incidence of LNM in tumors less than 2 cm in size in the initial and validation datasets (p < 0.01) compared with White patients. CONCLUSIONS: The current recommendation for surveillance of PNETs of less than 2 cm in size is likely based on a low rate of LNM seen in a predominantly White population. The incidence of LNM in Black patients with tumors less than 2 cm in size is clinically relevant and concerning. Current guidelines may not be universally applicable, and a more aggressive approach to resection in Black patients with small PNETs may be warranted.

External validation of four Pancreatic Fistula Risk Score models in the Deep South US: Do racial disparities affect pancreatic fistula prediction?

BACKGROUND: Fistula Risk Score (FRS) models often lack adequate discrimination for clinically relevant postoperative pancreatic fistula (CR-POPF) on external validation. We tested four FRS models in the Deep South United States and sought to determine if CR-POPF discrimination was affected by racial disparities. METHODS: A single-institution retrospective cohort study of patients who underwent pancreatoduodenectomies between 2013 and 2019 was performed. FRS discrimination for CR-POPF was assessed using ROC curves for both the entire patient population, and for Black vs White patients. RESULTS: The Alternative FRS maintains adequate CR-POPF discrimination when considering the patient population as a whole, but inadequately predicts CR-POPF when applied to the Black patient population. The Sun-FRS provides adequate CR-POPF discrimination for Black patients when considering risk grade. Only soft pancreatic gland texture and small duct size were significantly associated with CR-POPF in this patient population. DISCUSSION: Institutions should assess their preferred FRS model to determine if it provides adequate CR-POPF discrimination among a racially diverse patient population. Further studies are needed to determine how racial disparities influence CR-POPF prediction to better guide postoperative management.

The Fate of Resectable Pancreatic Adenocarcinoma After Neoadjuvant Chemotherapy.

OBJECTIVES: Pancreatic cancer continues to be a major cause of cancer-related mortality. There has been a greater implementation of up-front chemotherapy for pancreatic adenocarcinoma patients. Although there are many theoretical benefits to neoadjuvant chemotherapy, its clinical impact is uncertain. We sought to understand the outcomes of patients with resectable and borderline-resectable pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy. METHODS: Patients were collected in a secure database from September 2018 to May 2020. Patients were excluded if they presented with locally advanced or metastatic disease, inability to complete chemotherapy, or if they were not a surgical candidate. RESULTS: Sixty-six patients with resectable disease underwent chemotherapy. Folinic acid/5-fluorouracil/irinotecan/oxaliplatin was used in 41 patients (62.1%) and gemcitabine-based regimens in 28 patients (42.4%, greater than 100% as some patients underwent both regimens). After restaging, 47 patients (71.2%) were thought to have resectable disease. Of these patients, 36 have been successfully resected to date. Metastatic disease was found in 12 patients (18.2%) and 6 patients (9.1%) had locally advanced disease. CONCLUSIONS: Most patients with resectable pancreatic cancer are resected after neoadjuvant chemotherapy, but a subset will develop local or distant progression. Further studies will be needed to determine which patients will progress locally and may benefit from an up-front surgical approach.

Staging exocrine pancreatic dysfunction.

Digestive capacity of the gastrointestinal tract, largely but not wholly, depends on exocrine pancreatic function to achieve near complete digestion and absorption of ingested food. Coefficient of fat absorption (CFA), the proportion of ingested fat absorbed (normal >93%), reflects digestive capacity. Exocrine pancreatic insufficiency (EPI) is the state of insufficient digestive capacity (CFA <93%) caused by severe loss of pancreatic exocrine function despite variable compensation by upregulation of extra-pancreatic lipolysis. Fecal elastase 1 (FE1) level is the most widely used, though imperfect, non-invasive test of pancreatic enzyme output. Decline in pancreas enzyme output, or pancreatic exocrine dysfunction (EPD), has a variable correlation with measurable decline in CFA. EPI results in steatorrhea, weight loss and nutrient deficiency, which are mitigated by pancreatic enzyme replacement therapy (PERT). We propose a staging system for EPD, based on measurement of fecal elastase (FE1) and, if necessary, CFA and serum fat-soluble vitamin levels. In Stage I (Mild) EPD, FE1 is 100-200 mcg/gm; if steatorrhea is present, non-pancreatic causes are likely. In Stage II (Moderate) EPD), FE1 is < 100 mcg/gm without clinical and/or laboratory evidence of steatorrhea. In Stage III, there are marked reductions in FE1 and CFA, but vitamin levels remain normal (Severe EPD or EPI without nutritional deficiency). In Stage IV all parameters are abnormal (Severe EPD or EPI with nutritional deficiency). EPD stages I and II are pancreas sufficient and PERT may not be the best or first approach in management of early-stage disease; it needs further study to determine clinical utility. The term EPI refers strictly to EPD Stages III and IV which should be treated with PERT, with Stage IV requiring micronutrient supplementation as well.