The United States experience with diagnosing and treating esophageal cancer during the SARS-CoV-2 pandemic: A retrospective cohort study.

The downstream effects on healthcare delivery during the initial wave of the COVID-19 pandemic remain unclear. The purpose of this study was to determine how the healthcare environment surrounding the pandemic affected the oncologic care of patients diagnosed with esophageal cancer. This was a retrospective cohort study evaluating patients in the National Cancer Database (2019-2020). Patients with esophageal cancer diagnoses were divided into pre-pandemic (2019) and pandemic (2020) groups. Patient demographics, cancer-related variables, and treatment modalities were compared. Among 26,231 esophageal cancer patients, 14,024 patients (53.5%) were in the pre-pandemic cohort and 12,207 (46.5%) were in the pandemic cohort. After controlling for demographics, patients diagnosed during the pandemic were more likely to have poorly differentiated tumors (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.08-1.42), pathologic T3 disease compared to T1 (OR 1.25, 95% CI 1.02-1.53), positive lymph nodes on pathology (OR 1.36, 95% CI 1.14-1.64), and to be pathologic stage IV (OR 1.51, 95% CI 1.29-1.76). After controlling for oncologic characteristics, patients diagnosed during the pandemic were more likely to require at least two courses of systemic therapy (OR 1.78, 95% CI 1.48-2.14) and to be offered palliative care (OR 1.13, 95% CI 1.04-1.22). While these patients were offered curative therapy at lower rates, this became non-significant after risk-adjustment (p = .15). The pandemic healthcare environment was associated with significantly increased risk-adjusted rates of patients presenting with advanced esophageal cancer. While this led to significant differences in treatment, most of these differences became non-significant after controlling for oncologic factors.

Group XIV C-type lectins: emerging targets in tumor angiogenesis.

C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each's role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.

Neoadjuvant Chemotherapy Versus Upfront Surgery for Resectable Pancreatic Adenocarcinoma: An Updated Nationwide Study.

OBJECTIVE: The objective of this study was to assess the association of survival with neoadjuvant chemotherapy (NAC) in resectable pancreatic adenocarcinoma (PDAC). BACKGROUND: The early control of potential micrometastases and patient selection using NAC has been advocated for patients with PDAC. However, the role of NAC for resectable PDAC remains unclear. METHODS: Patients with clinical T1 and T2 PDAC were identified in the National Cancer Database from 2010 to 2017. Kaplan-Meier estimates, and Cox regression models were used to compare survival. To address immortal time bias, landmark analysis was performed. Interactions between preoperative factors and NAC were investigated in subgroup analyses. A propensity score analysis was performed to compare survival between multiagent NAC and upfront surgery. RESULTS: In total, 4041 patients were treated with upfront surgery and 1,175 patients were treated with NAC (79.4% multiagent NAC, 20.6% single-agent NAC). Using a landmark time of 6 months after diagnosis, patients treated with multiagent NAC had longer median overall survival compared with upfront surgery and single-agent NAC. (35.8 vs 27.1 vs 27.4 mo). Multiagent NAC was associated with lower mortality rates compared with upfront surgery (adjusted hazard ratio, 0.77; 95% CI, 0.70-0.85), whereas single-agent NAC was not. The association of survival with multiagent NAC were consistent in analyses using the matched data sets. Interaction analysis revealed that the association between multiagent NAC and a lower mortality rate did not significantly differ across age, facility type, tumor location, CA 19-9 levels, and clinical T/N stages. CONCLUSIONS: The findings suggest that multiagent NAC followed by resection is associated with improved survival compared with upfront surgery.

Cholangiocarcinoma of the Middle Bile Duct: A Narrative Review.

Resectable cholangiocarcinoma (CCA) arising from the middle of the extrahepatic biliary tree has historically been classified as perihilar or distal CCA, depending on the operation contemplated or performed, namely the associated hepatectomy or pancreaticoduodenectomy, respectively. Segmental bile duct resection is a less invasive alternative for select patients harboring true middle extrahepatic CCA (MCC). A small, yet growing body of literature has emerged detailing institutional experiences with bile duct resection versus pancreaticoduodenectomy or concomitant hepatectomy for MCC. Herein, we provide a brief overview of the epidemiology, preoperative evaluation, and emerging systemic therapies for MCC, and narratively review the existing work comparing segmental resection with pancreaticoduodenectomy or less commonly, hepatectomy, for MCC, with emphasis on the surgical management and oncologic implications of the approach used.

Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

BACKGROUND: Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. METHODS: This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. RESULTS: Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. CONCLUSION: After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

Radiologic Occult Metastases in Pancreatic Cancer: Analysis of Risk Factors and Survival Outcomes in the Age of Contemporary Neoadjuvant Multi-agent Chemotherapy.

BACKGROUND: Radiologic occult metastatic disease (ROMD) in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo contemporary neoadjuvant chemotherapy (NAC) has not been well studied. This study sought to analyze the incidence, risk factors, and oncologic outcomes for patients who underwent the NAC approach for PDAC. METHODS: A retrospective review analyzed a prospectively maintained database of patients who had potentially resectable PDAC treated with NAC and were offered pancreatectomy at our institution from 2011 to 2022. Multivariable regression analysis was performed to assess risk factors associated with ROMD. Kaplan-Meier curves with log-rank analyses were generated to estimate time-to-event end points. RESULTS: The study enrolled 366 patients. Upfront and borderline resectable anatomic staging comprised 80% of the cohort, whereas 20% had locally advanced disease. The most common NAC regimen was FOLFIRINOX (n = 274, 75%). For 55 patients (15%) who harbored ROMD, the most common site was liver-only metastases (n = 33, 60%). The independent risk factors for ROMD were increasing CA19-9 levels during NAC (odds ratio [OR], 7.01; confidence interval [CI], 1.97-24.96; p = 0.008), indeterminate liver lesions (OR, 2.19; CI, 1.09-4.39; p = 0.028), and enlarged para-aortic lymph nodes (OR, 6.87; CI, 2.07-22.74; p = 0.002) on preoperative cross-sectional imaging. Receipt of palliative chemotherapy (p < 0.001) and eventual formal pancreatectomy (p = 0.04) were associated with survival benefit in the log-rank analysis. The median overall survival (OS) of the patients with ROMD was nearly 15 months from the initial diagnosis, with radiologic evidence of metastases occurring after a median of 2 months. CONCLUSIONS: Radiologic occult metastatic disease remains a clinical challenge associated with poor outcomes for patients who have PDAC treated with multi-agent NAC.

Exploration of Patient Retention in Seeking a Second Opinion: A Retrospective Cohort Study.

INTRODUCTION: It is common for cancer patients to seek a second opinion for a variety of reasons. Understanding what drives patients to choose to receive treatment with their second opinion provider may uncover opportunities to improve the second opinion process. Therefore, we sought to identify the patient, disease, and treatment characteristics that were associated with second opinion retention rates in patients seeking a second surgical opinion for breast, colon, and pancreatic cancer. METHODS: We conducted a retrospective cohort study to evaluate patients who sought a second opinion within a large academic health-care system for breast, colon, and pancreatic cancer. Electronic medical records were reviewed for second opinions. Patient demographics and characteristics were collected and compared between the retained group and the nonretained groups. RESULTS: A total of 237 patients obtained second opinions for breast, colorectal, and pancreatic cancer. Patients that were offered a different treatment plan at their second opinion were more likely to be retained for systemic therapy (P = 0.009) for pancreatic cancer and any treatment for colon cancer (P = 0.003). Seeing a radiation oncologist (P = 0.007) or a plastic surgeon (P = 0.02) during the multidisciplinary consultation increased retention rates for breast cancer. CONCLUSIONS: Surgeons can better identify patients that are more likely to be retained after a second opinion by the individual patient characteristics and treatment factors. Understanding the factors that lead to retention for these three cancer types may help physicians provide the best possible resources for most patients presenting for second opinion evaluations.

Prevalence and progression of intraductal papillary mucinous neoplasms of the pancreas in solid organ transplant recipients: A systematic review.

Solid organ transplantation (SOT) recipients are known to carry an increased risk of malignancy because of long-term immunosuppression. However, the progression of intraductal papillary mucinous neoplasm of the pancreas (IPMN) in this population remains unclear. We performed a systematic review by searching PubMed, Embase, Scopus, and Google Scholar. All studies containing IPMNs in solid organ transplantation recipients were screened. We included 11 studies in our final analysis, totaling 274 patients with IPMNs of the 8213 SOT recipients. The prevalence from 8 studies was 4.7% (95% CI 2.4%-7.7%) in a random-effects model with median study periods of 24 to 220 months. The median rate for all progressions from 10 studies was 20% (range, 0%-88%) within 13 to 41 months of the median follow-up time. By utilizing the results of 3 case-control studies, the relative risk from a random-effects model for progression (worrisome features and high-risk stigmata) of IPMNs was 0.39 (95% CI 0.12-1.31). No adenocarcinoma derived from IPMN was reported in the included studies. Overall, this study indicates that the progression of pretransplant IPMN does not increase drastically compared with the general nontransplant population. However, considering the limited literature, further studies are required for confirmation.

Intraoperative pancreatoscopy can improve the detection of skip lesions during surgery for intraductal papillary mucinous neoplasia: A pilot study.

OBJECTIVES: Intraoperative pancreatoscopy is a promising procedure that might guide surgical resection for suspected main duct (MD) and mixed type (MT) intraductal papillary mucinous neoplasms (IPMNs). The aim of the present study was to assess the diagnostic yield and clinical impact of intraoperative pancreatoscopy in patients operated on for MD and MT-IPMNs. METHODS: This is a retrospective cohort study. Patients undergoing surgery for suspected MD or MT-IPMN underwent intraoperative pancreatoscopy and frozen section analysis. In all patients who required extended resection due to pancreatoscopic findings, we compared the final histology with the results of the intraoperative frozen section analysis. RESULTS: In total, 46 patients, 48% females, mean age (range) 67 years (45-82 years) underwent intraoperative pancreatoscopy. No mortality or procedure related complications were observed. Pancreatoscopy changed the operative course in 30 patients (65%), leading to extended resections in 20 patients (43%) and to parenchyma sparing procedures in 10 patients (22%). Analyzing the group of patients who underwent extended resections, 7 (35%) displayed lesions that needed further surgical treatment (six high grade dysplasia and one with G1 pancreatic neuroendocrine tumor) and among those 7, just 1 (14%) would have been detected exclusively with histological frozen section analysis of the transection margin. The combination of both pancreatoscopy and frozen section analysis lead to 86% sensitivity and 92% specificity for the detection of pathological tissue in the remnant pancreas. CONCLUSION: Intraoperative pancreatoscopy is a safe and feasible procedure and might allow the detection of skip lesions during surgery for suspect MD-involving IPMNs.

"Conversion surgery" for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022.

Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called "conversion surgery", at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that "cancer biology is surpassing locoregional anatomical resectability" in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.

Endoscopic and Surgical Management of Non-Metastatic Ampullary Neuroendocrine Neoplasia: A Multi-Institutional Pancreas2000/EPC Study.

INTRODUCTION: Ampullary neuroendocrine neoplasia (NEN) is rare and evidence regarding their management is scarce. This study aimed to describe clinicopathological features, management, and prognosis of ampullary NEN according to their endoscopic or surgical management. METHODS: From a multi-institutional international database, patients treated with either endoscopic papillectomy (EP), transduodenal surgical ampullectomy (TSA), or pancreaticoduodenectomy (PD) for ampullary NEN were included. Clinical features, post-procedure complications, and recurrences were assessed. RESULTS: 65 patients were included, 20 (30.8%) treated with EP, 19 (29.2%) with TSA, and 26 (40%) with PD. Patients were mostly asymptomatic (n = 46; 70.8%). Median tumor size was 17 mm (12-22), tumors were mostly grade 1 (70.8%) and pT2 (55.4%). Two (10%) EP resulted in severe American Society for Gastrointestinal Enterology (ASGE) adverse post-procedure complications and 10 (50%) were R0. Clavien 3-5 complications did not occur after TSA and in 4, including 1 postoperative death (15.4%) of patients after PD, with 17 (89.5%) and 26 R0 resection (100%), respectively. The pN1/2 rate was 51.9% (n = 14) after PD. Tumor size larger than 1 cm (i.e., pT stage >1) was a predictor for R1 resection (p < 0.001). Three-year overall survival and disease-free survival after EP, TSA, and PD were 92%, 68%, 92% and 92%, 85%, 73%, respectively. CONCLUSION: Management of ampullary NEN is challenging. EP should not be performed in lesions larger than 1 cm or with a endoscopic ultrasonography T stage beyond T1. Local resection by TSA seems safe and feasible for lesions without nodal involvement. PD should be preferred for larger ampullary NEN at risk of nodal metastasis.

Cannabis use and post-operative complications in patients undergoing pancreatic resection.

BACKGROUND: Many states have legalized medical cannabis with various reported therapeutic benefits. However, there is little data assessing the effects of cannabis on surgical outcomes. We sought to compare post-operative pancreatic resection complications between cannabis users and non-users. METHODS: This is a single-center, retrospective review of patients who underwent Whipple or distal pancreatectomy from 1/2017-12/2020. The primary outcome was any in-hospital complication, using Clavien-Dindo. Multivariable regression analysis was performed. RESULTS: There were 486 patients who underwent Whipple (n=346, 71.2%) or distal pancreatectomy (n=140, 28.8%). Overall, 21.4% (n=104) reported cannabis use, of whom 80.8% were current users. Cannabis users were younger (60 vs. 66 years, p < 0.001), and more likely to have smoked tobacco (p=0.04), but otherwise had similar demographics as non-users. There were 288 (59.3%) patients who developed an in-hospital complication (grade 1-2, 75.3%; grade 3-5, 24.7%). A trend towards increased complications was observed with tobacco smoking (OR 1.33, 95% CI 0.91-1.94, p=0.14), but no association of cannabis use with complications was observed (OR 0.93, 95% CI 0.58-1.47, p=0.74). DISCUSSION: A significant proportion of patients undergoing pancreatic resection report cannabis use. These results suggest that there was no association between cannabis use and post-operative complications, future prospective evaluation is warranted.

Prognosis Based Definition of Resectability in Pancreatic Cancer: A Road Map to New Guidelines.

OBJECTIVE: To identify objective preoperative prognostic factors that are able to predict long-term survival of patients affected by PDAC. SUMMARY OF BACKGROUND DATA: In the modern era of improved systemic chemotherapy for PDAC, tumor biology, and response to chemotherapy are essential in defining prognosis and an improved approach is needed for classifying resectability beyond purely anatomic features. METHODS: We queried the National Cancer Database regarding patients diagnosed with PDAC from 2010 to 2016. Cox proportional hazard models were used to select preoperative baseline factors significantly associated with survival; final models for overall survival (OS) were internally validated and formed the basis of the nomogram. RESULTS: A total of 7849 patients with PDAC were included with a median follow-up of 19 months. On multivariable analysis, factors significantly associated with OS included carbohydrate antigen 19-9, neoadjuvant treatment, tumor size, age, facility type, Charlson/Deyo score, primary site, and sex; T4 stage was not independently associated with OS. The cumulative score was used to classify patients into 3 groups: good, intermediate, and poor prognosis, respectively. The strength of our model was validated by a highly significant randomization test, Log-rank test, and simple hazard ratio; the concordance index was 0.59. CONCLUSION: This new PDAC nomogram, based solely on preoperative variables, could be a useful tool to patients and counseling physicians in selecting therapy. This model suggests a new concept of resectability that is meant to reflect the biology of the tumor, thus partially overcoming existing definitions, that are mainly based on tumor anatomic features.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

Comparing neoadjuvant chemotherapy with or without radiation therapy for pancreatic ductal adenocarcinoma: National Cancer Database cohort analysis.

BACKGROUND: Neoadjuvant treatment is important for improving the rate of R0 surgical resection and overall survival outcome in treating patients with pancreatic ductal adenocarcinoma (PDAC). However, the true efficacy of radiotherapy (RT) for neoadjuvant treatment of PDAC is uncertain. This retrospective study evaluated the treatment outcome of neoadjuvant RT in the treatment of PDAC. METHODS: Collected from the National Cancer Database, information on patients with PDAC who underwent neoadjuvant chemotherapy (NAC) and pancreatectomy between 2010 to 2016 was used in this study. Short- and long-term outcomes were compared between patients who received neoadjuvant chemoradiotherapy (NACRT) and NAC. RESULTS: The study included 6936 patients, of whom 3185 received NACRT and 3751 NAC. The groups showed no difference in overall survival (NACRT 16.1 months versus NAC 17.4 months; P = 0.054). NACRT is associated with more frequent margin negative resection (86.1 versus 80.0 per cent; P < 0.001) but a more unfavourable 90-day mortality than NAC (6.4 versus 3.6 per cent; P < 0.001). The odds of 90-day mortality were higher in the radiotherapy group (odds ratio 1.81; P < 0.001), even after adjusting for significant covariates. Patients who received NACRT received single-agent chemotherapy more often than those who received NAC (31.5 versus 10.7 per cent; P < 0.001). CONCLUSION: This study failed to show a survival benefit for NACRT over NAC alone, despite its association with negative margin resection. The significantly higher mortality in NACRT warrants further investigation into its efficacy in the treatment of pancreatic cancer.

Hepatic thermal injury promotes colorectal cancer engraftment in C57/black 6 mice.

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide.

Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, neutrophils, regulatory T cells, and myofibroblasts. The precise mechanisms that regulate the composition of the TME and how they contribute to radiotherapy (RT) response remain poorly understood. In this study, we analyze changes in immune cell populations and circulating chemokines in patient samples and animal models of pancreatic cancer to characterize the immune response to radiotherapy. Further, we identify STAT3 as a key mediator of immunosuppression post-RT. We found granulocytic MDSCs (G-MDSCs) and neutrophils to be increased in response to RT in murine and human PDAC samples. We also found that RT-induced STAT3 phosphorylation correlated with increased MDSC infiltration and proliferation. Targeting STAT3 using an anti-sense oligonucleotide in combination with RT circumvented RT-induced MDSC infiltration, enhanced the proportion of effector T cells, and improved response to RT. In addition, STAT3 inhibition contributed to the remodeling of the PDAC extracellular matrix when combined with RT, resulting in decreased collagen deposition and fibrotic tissue formation. Collectively, our data provide evidence that targeting STAT3 in combination with RT can mitigate the pro-tumorigenic effects of RT and improve tumor response.

Pancreatic incidentalomas: Investigation and management.

The incidence of pancreatic incidentalomas (PIs) detected in otherwise asymptomatic patients is growing with the increasing quality and use of advanced imaging techniques. PI can present as isolated main pancreatic duct dilation or as a solid or cystic lesion. Although historically thought to be relatively rare, PIs are rather common, particularly cystic lesions of the pancreas, which can be detected in up to 49% of the general population. With the poor prognosis of pancreatic cancer, PIs are an opportunity for prevention and early diagnosis, but when managed poorly, they can also lead to overtreatment and unnecessary morbidity. The management of PI should begin with a dedicated pancreas protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) to accurately characterize duct size, lesion characteristics and establish an accurate baseline for subsequent follow up. Diagnosis and subsequent management depends on the extent of main duct dilation and solid versus cystic appearance. Solid lesions are highly concerning for malignancy. Cystic lesions can be further categorized as intraductal papillary mucinous neoplasms of the pancreas (IPMNs) or mucinous cystic neoplasms (MCNs), both of which harbour malignant potential, or as serous cystic neoplasms (SCNs) that are benign. In this paper, we summarize the major challenges related to PI and present pragmatic suggestions for management.

Landmark Series: Neoadjuvant Treatment in Borderline Resectable Pancreatic Cancer.

BACKGROUND: Borderline resectable pancreatic cancer (BRPC) is frequently encountered in high-volume centers. It has various definitions among different societies or institutions. PATIENTS AND METHODS: In this landmark series review, we summarize the critical randomized controlled studies that have defined the neoadjuvant and surgical management of BRPC. RESULTS: Surgical resection after neoadjuvant treatment is the mainstay of treatment and should involve margin-negative resection with regional lymphadenectomy. Several recently completed randomized controlled clinical trials have defined the role of neoadjuvant chemotherapy for patients with BRPC. The utilization of chemoradiation remains controversial. CONCLUSIONS: The definition of BRPC goes beyond the anatomic relationship between the tumor and vessels. We need to include biological and conditional dimensions. Neoadjuvant chemotherapy and surgery are associated with improved outcomes of BRPC. Understanding the molecular features of pancreatic cancer should lead to the discovery of novel biomarkers as well as a more personalized approach to guide individualized therapy.