Minimally Invasive Techniques for Gastrectomy.

Gastric adenocarcinoma is an aggressive disease and a leading cause of cancer-related deaths worldwide. Surgery entails either a total or a subtotal gastrectomy. These complex operations carry elevated morbidity and mortality with an extended recovery time. As such, research has focused on minimizing these risks and enhancing postoperative care. Robotic surgery is a newer platform that helps overcome some of the limitations of laparoscopy through three-dimensional vision, better mobility, and improved surgeon dexterity. As such, many surgeons have embraced robotics and advocated for their implementation in cancer surgery. This review will discuss the technical considerations of performing a robotic gastrectomy.

CD200 is overexpressed in the pancreatic tumor microenvironment and predictive of overall survival.

Pancreatic cancer is an aggressive disease with a 5 year survival rate of 13%. This poor survival is attributed, in part, to limited and ineffective treatments for patients with metastatic disease, highlighting a need to identify molecular drivers of pancreatic cancer to target for more effective treatment. CD200 is a glycoprotein that interacts with the receptor CD200R and elicits an immunosuppressive response. Overexpression of CD200 has been associated with differential outcomes, depending on the tumor type. In the context of pancreatic cancer, we have previously reported that CD200 is expressed in the pancreatic tumor microenvironment (TME), and that targeting CD200 in murine tumor models reduces tumor burden. We hypothesized that CD200 is overexpressed on tumor and stromal populations in the pancreatic TME and that circulating levels of soluble CD200 (sCD200) have prognostic value for overall survival. We discovered that CD200 was overexpressed on immune, stromal, and tumor populations in the pancreatic TME. Particularly, single-cell RNA-sequencing indicated that CD200 was upregulated on inflammatory cancer-associated fibroblasts. Cytometry by time of flight analysis of PBMCs indicated that CD200 was overexpressed on innate immune populations, including monocytes, dendritic cells, and monocytic myeloid-derived suppressor cells. High sCD200 levels in plasma correlated with significantly worse overall and progression-free survival. Additionally, sCD200 correlated with the ratio of circulating matrix metalloproteinase (MMP) 3: tissue inhibitor of metalloproteinase (TIMP) 3 and MMP11/TIMP3. This study highlights the importance of CD200 expression in pancreatic cancer and provides the rationale for designing novel therapeutic strategies that target this protein.

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer.

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.

The Influence of Intraoperative Blood Loss on Fistula Development Following Pancreatoduodenectomy.

OBJECTIVE: To investigate the role of intraoperative estimated blood loss (EBL) on development of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). BACKGROUND: Minimizing EBL has been shown to decrease transfusions and provide better perioperative outcomes in PD. EBL is also felt to be influential on CR-POPF development. METHODS: This study consists of 5534 PDs from a 17-institution collaborative (2003-2018). EBL was progressively categorized (≤150mL; 151-400mL; 401-1,000 mL; > 1,000 mL). Impact of additive EBL was assessed using 20 3- factor fistula risk score (FRS) scenarios reflective of endogenous CR-POPF risk. RESULTS: CR-POPF developed in 13.6% of patients (N = 753) and median EBL was 400 mL (interquartile range 250-600 mL). CR-POPF and Grade C POPF were associated with elevated EBL (median 350 vs 400 mL, P = 0.002; 372 vs 500 mL, P < 0.001, respectively). Progressive EBL cohorts displayed incremental CR-POPF rates (8.5%, 13.4%, 15.2%, 16.9%; P < 0.001). EBL >400mL was associated with increased CR-POPF occurrence in 13/20 endogenous risk scenarios. Moreover, 8 of 10 scenarios predicated on a soft gland demonstrated increased CR-POPF incidence. Hypothetical projections demonstrate significant reductions in CR-POPF can be obtained with 1-, 2-, and 3-point decreases in FRS points attributed to EBL risk (12.2%, 17.4%, and 20.0%; P < 0.001). This is especially pronounced in high-risk (FRS7-10) patients, who demonstrate up to a 31% reduction (P < 0.001). Surgeons in the lowest-quartile of median EBL demonstrated CR-POPF rates less than half those in the upper-quartile (7.9% vs 18.8%; P < 0.001). CONCLUSION: EBL independently contributes significant biological risk to CR-POPF. Substantial reductions in CR-POPF occurrence are projected and obtainable by minimizing EBL. Decreased individual surgeon EBL is associated with improvements in CR-POPF.

Identification of circulating plasma ceramides as a potential sexually dimorphic biomarker of pancreatic cancer-induced cachexia.

Background: Cancer patients who exhibit cachexia lose weight and have low treatment tolerance and poor outcomes compared to cancer patients without weight loss. Despite the clear increased risk for patients, diagnosing cachexia still often relies on self-reported weight loss. A reliable biomarker to identify patients with cancer cachexia would be a valuable tool to improve clinical decision making and identification of patients at risk of adverse outcomes. Methods: Targeted metabolomics, that included panels of amino acids, tricarboxylic acids, fatty acids, acylcarnitines, and sphingolipids, were conducted on plasma samples from patients with confirmed pancreatic ductal adenocarcinoma (PDAC) with and without cachexia and control patients without cancer (n=10/group, equally divided by sex). Additional patient samples were analyzed (total n=95) and Receiver Operating Characteristic (ROC) analyses were performed to establish if any metabolite could effectively serve as a biomarker of cachexia. Results: Targeted profiling revealed that cachectic patients had decreased circulating levels of three sphingolipids compared to either non-cachectic PDAC patients or patients without cancer. The ratio of C18-ceramide to C24-ceramide (C18:C24) outperformed a number of other previously proposed biomarkers of cachexia (area under ROC = 0.810). It was notable that some biomarkers, including C18:C24, were only altered in cachectic males. Conclusions: Our findings identify C18:C24 as a potentially new biomarker of PDAC-induced cachexia that also highlight a previously unappreciated sexual dimorphism in cancer cachexia.

The Fistula Risk Score Catalog: Toward Precision Medicine for Pancreatic Fistula After Pancreatoduodenectomy.

OBJECTIVE: This study aims to present a full spectrum of individual patient presentations of pancreatic fistula risk, and to define the utility of mitigation strategies amongst some of the most prevalent, and vulnerable scenarios surgeons encounter. BACKGROUND: The FRS has been utilized to identify technical strategies associated with reduced CR-POPF incidence across various risk strata. However, risk-stratification using the FRS has never been investigated with greater granularity. By deriving all possible combinations of FRS elements, individualized risk assessment could be utilized for precision medicine purposes. METHODS: FRS profiles and outcomes of 5533 PDs were accrued from 17 international institutions (2003-2019). The FRS was used to derive 80 unique combinations of patient "scenarios." Risk-matched analyses were conducted using a Bonferroni adjustment to identify scenarios with increased vulnerability for CR-POPF occurrence. Subsequently, these scenarios were analyzed using multivariable regression to explore optimal mitigation approaches. RESULTS: The overall CR-POPF rate was 13.6%. All 80 possible scenarios were encountered, with the most frequent being scenario #1 (8.1%) - the only negligible-risk scenario (CR-POPF rate = 0.7%). The moderate-risk zone had the most scenarios (50), patients (N = 3246), CR-POPFs (65.2%), and greatest non-zero discrepancy in CR-POPF rates between scenarios (18-fold). In the risk-matched analysis, 2 scenarios (#59 and 60) displayed increased vulnerability for CR-POPF relative to the moderate-risk zone (both P < 0.001). Multivariable analysis revealed factors associated with CR-POPF in these scenarios: pancreaticogastrostomy reconstruction [odds ratio (OR) 4.67], omission of drain placement (OR 5.51), and prophylactic octreotide (OR 3.09). When comparing the utilization of best practice strategies to patients who did not have these conjointly utilized, there was a significant decrease in CR-POPF (10.7% vs 35.5%, P < 0.001; OR 0.20, 95% confidence interval 0.12-0.33). CONCLUSION: Through this data, a comprehensive fistula risk catalog has been created and the most clinically-impactful scenarios have been discerned. Focusing on individual scenarios provides a practical way to approach precision medicine, allowing for more directed and efficient management of CR-POPF.

A risk-adjusted analysis of drain use in pancreaticoduodenectomy: Some is good, but more may not be better.

BACKGROUND: Intraperitoneal drain placement decreases morbidity and mortality in patients who develop a clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD). It is unknown whether multiple drains mitigate CR-POPF better than a single drain. We hypothesized that multiple drains decrease the complication burden more than a single drain in cases at greater risk for CR-POPF. METHODS: The Fistula Risk Score (FRS), mitigation strategies (including number of drains placed), and clinical outcomes were obtained from a multi-institutional database of PDs performed from 2003 to 2020. Outcomes were compared between cases utilizing 0, 1, or 2 intraperitoneal drains. Multivariable regression analysis was used to evaluate the optimal drainage approach. RESULTS: A total of 4,292 PDs used 0 (7.3%), 1 (45.2%), or 2 (47.5%) drains with an observed CR-POPF rate of 9.6%, which was higher in intermediate/high FRS zone cases compared with negligible/low FRS zone cases (13% vs 2.4%, P < .001). The number of drains placed also correlated with FRS zone (median of 2 in intermediate/high vs 1 in negligible/low risk cases). In intermediate/high risk cases, the use of 2 drains instead of 1 was not associated with a reduced rate of CR-POPF, average complication burden attributed to a CR-POPF, reoperations, or mortality. Obviation of drains was associated with significant increases in complication burden and mortality - regardless of the FRS zone. CONCLUSION: In intermediate/high risk zone cases, placement of a single drain or multiple drains appears to mitigate the complication burden while use of no drains is associated with inferior outcomes.

The effect of high intraoperative blood loss on pancreatic fistula development after pancreatoduodenectomy: An international, multi-institutional propensity score matched analysis.

BACKGROUND: The association between intraoperative estimated blood loss and outcomes after pancreatoduodenectomy has, thus far, been rarely explored. METHODS: In total, 7,706 pancreatoduodenectomies performed at 18 international institutions composing the Pancreas Fistula Study Group were examined (2003-2020). High estimated blood loss (>700 mL) was defined as twice the median. Propensity score matching (1:1 exact-match) was employed to adjust for variables associated with high estimated blood loss and clinically relevant pancreatic fistula occurrence. The study was powered to detect a 33% clinically relevant pancreatic fistula increase in the high estimated blood loss group, with α = 0.05 and ß = 0.2. RESULTS: The propensity score model included 966 patients with high estimated blood loss and 966 patients with lower estimated blood loss; all covariate imbalantces were solved. Patients with high estimated blood loss patients experienced higher clinically relevant pancreatic fistula rates (19.4 vs 12.6%, odds ratio 1.66; P < .001), as well as higher severe complication rates (27.8 vs 15.6%), transfusions (50.1 vs 14.3%), reoperations (9.2 vs 4.0%), intensive care unit transfers (9.9 vs 4.8%) and 90-day mortality (4.7 vs 2.0%, all P < .001). High estimated blood loss was an independent predictor for clinically relevant pancreatic fistula (odds ratio 1.78, 95% confidence interval 1.37-2.32), as were prophylactic Octreotide administration (odds ratio 1.95, 95% confidence interval 1.46-2.61) and soft pancreatic texture (odds ratio 5.32, 95% confidence interval 3.74-5.57; all P < .001). Moreover, a second model including 1,126 pancreatoduodenectomies was derived including vascular resections as additional confounder (14.0% vascular resections performed in each group). On multivariable regression, high estimated blood loss was confirmed an independent predictor for clinically relevant pancreatic fistula reduction (odds ratio 1.80, 95% confidence interval 1.32-2.44; P < .001), whereas vascular resection was not (odds ratio 0.64, 95% confidence interval 0.34-1.88; P = .156). CONCLUSION: This study better establishes the relationship between estimated blood loss and outcomes after pancreatoduodenectomy. Despite inherent contributions to blood loss, its minimization is an actionable opportunity for clinically relevant pancreatic fistula reduction and performance optimization in pancreatoduodenectomy. Accordingly, practical insights are offered to achieve this goal.

Using Endoscopic Optical Coherence Tomography to Detect and Treat Early-Stage Pancreatic Cancers.

We developed a novel technology capable of detecting early-stage pancreatic cancers using high-resolution three-dimensional endoscopic optical coherence tomography (Endo-OCT), and treating them using high dose rate brachytherapy (HDR) under the Endo-OCT image guidance. This technology integrates our custom-built ultra-high resolution endoscopic three-dimensional OCT diagnostic imaging device with a commercial high dose rate brachytherapy system (HDR), resulting in a compact, portable, easy-to-operate, and low-cost Endo-OCT image-guided high dose rate brachytherapy (OCT-IGHDR) system. The system has the dual functions of diagnosis and treatment that can precisely detect and measure the location and size of the early-stage pancreatic cancer or premalignant lesions and then treat them from the inside of the pancreatic duct with an accurate and focused dose while greatly reducing the radiation toxicity to the neighboring tissues and organs. This minimally-invasive treatment technology could avoid the potential complications from surgery and reduces the high operation cost. This technology could also be applied to treat diseases of the esophagus, rectum, bronchus, and other aerodigestive organs that are suitable for use with an endoscopic device. In this article, we describe the concept of this technology and the preliminary experiments that could demonstrate the concept by using this homemade Endo-OCT machine to image the pancreatic duct for diagnosis of early-stage pancreatic cancer or premalignant lesions and to perform Endo-OCT image-guided brachytherapy.

Surgeon experience contributes to improved outcomes in pancreatoduodenectomies at high risk for fistula development.

BACKGROUND: Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood. METHODS: The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models. RESULTS: Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22-0.74). CONCLUSION: Surgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss.

Association of pre-existing mental illness with all-cause and cancer-specific mortality among Medicare beneficiaries with pancreatic cancer.

BACKGROUND: Among patients with pancreatic cancer, the association of pre-existing mental illness with long-term outcomes remains unknown. METHODS: Individuals diagnosed with pancreatic adenocarcinoma were identified in the SEER-Medicare database. Patients were classified as having mental illness if an ICD9/10CM code for anxiety, depression, bipolar disorder, schizophrenia or other psychotic disorder was recorded. RESULTS: Among the 54,234 Medicare beneficiaries with pancreatic cancer, roughly 1 in 12 (n = 4793, 8.83%) individuals had a diagnosis of a mental illness. The majority (n = 4029, 84.1%) had anxiety or depression, while 16% (n = 764) had bipolar/schizophrenic disorders. On multivariable analysis, among patients with early stage cancer, individuals with pre-existing anxiety/depression and bipolar/schizophrenic disorders had 22% (OR 0.78, 95% CI 0.69-0.86) and 46% (OR 0.54, 95% CI 0.42-0.70) reduced odds, respectively, to undergo cancer-directed surgery. Furthermore, patients with a pre-existing history of bipolar/schizophrenic disorders had a 20% (HR 1.20, 95% CI 1.21-1.40) higher risk of all-cause mortality and 27% (HR 1.27, 95% CI 1.17-1.37) higher risk of pancreatic cancer-specific mortality compared to individuals without a history of mental illness. CONCLUSION: One in twelve patients with pancreatic cancer had a pre-existing mental illness. Individuals with mental illness were more likely to have worse overall and cancer-specific long-term outcomes.

Wide variation in inpatient opioid utilization following hepatopancreatic surgery.

BACKGROUND: Inpatient opioid utilization following major surgery remains relatively unknown. We sought to characterize inpatient opioid consumption following hepatopancreatic surgery and determine factors associated with the variability in opioid utilization. METHODS: Adult patients who underwent hepatopancreatic surgery at a single institution were identified. Multimodal pain management strategies assessed included opioids (oral morphine equivalents, OME), acetaminophen, ibuprofen and ketorolac. RESULTS: Among 2,054 patients, the median total OME utilized was 465 (129-815) during a patient's hospitalization following hepatopancreatic surgery. The interquartile range for total OMEs administered following hepatopancreatic surgery was as high as 940 OMEs (125 oxycodone-5mg pills) following a pancreaticoduodenectomy versus 520 OMEs (69 oxycodone-5mg pills) following a hemi-hepatectomy. Despite relatively high use of acetaminophen post-operatively (n = 1,588, 77.0%), multimodal pain control with acetaminophen and ibuprofen was infrequent (n = 175, 8.5%). Furthermore, individuals with high opioid utilization used on average 147 OMEs (20 oxycodone-5mg pills) the day before discharge versus 44 OME (6 oxycodone-5mg pills) among patients with expected opioid utilization. CONCLUSIONS: Marked variability in inpatient opioid consumption following hepatopancreatic surgery was noted. Future work is necessary to decrease the variability in inpatient opioid prescribing practices to promote the safe and effective management of pain.

Women in hepatopancreaticobiliary surgery: is there a pipeline problem?

BACKGROUND: Women are underrepresented in hepatopancreatobiliary (HPB) surgery. We investigated whether this is a pipeline problem by looking at the percentage of women trainees presenting at Americas Hepato-Pancreato-Biliary Association (AHPBA) and then determining their ultimate career path. METHODS: We extracted gender, level of training, and career path of first authors of abstracts presented at the 2007 and 2012 AHPBA conferences. Chi-square analysis and Fisher's exact test were used to examine gender trends. RESULTS: 85 authors in 2007 and 109 in 2012 met inclusion criteria. 16.5% of presenters were female in 2007 compared to 22.9% in 2012. Just over 50% of authors went into academic medicine in 2007 (55%) and 2012 (59%) which did not differ by gender (p = 0.868 in 2007, p = 0.174 in 2012). 41.2% of first authors from 2007 to 2012 went into an HPB related field which did not differ significantly by gender (p = 0.450 for 2007, p = 0.626 for 2012). CONCLUSION: Similar percentages of men and women who present at AHPBA ultimately obtain an HPB related job, however, more men than women trainees present at AHPBA. More efforts to encourage women to go into HPB surgery early may help eliminate this gender gap.

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

INTRODUCTION: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

Radiographic characteristics of neuroendocrine liver metastases do not predict clinical outcomes following liver resection.

BACKGROUND: Previous research has demonstrated that specific radiographic criteria, including the presence of calcifications and the enhancement pattern on computed tomography (CT) imaging, correlates with clinicopathologic features and outcomes of patients with gastroenteropancreatic neuroendocrine tumors (NET). We sought to investigate whether these radiographic characteristics were prognostic among patients with neuroendocrine liver metastases (NELM) undergoing surgical resection. METHODS: The preoperative contrast-enhanced CT scans of all patients who underwent resection of NELM at a single institution between 2000-2015 were retrospectively reviewed. The presence of calcifications was determined on non-contrast phase imaging. Enhancement on the arterial phase scan was categorized as hyperenhancing, hypoenhancing, or mixed. Relevant clinicopathologic characteristics as well as recurrence-free survival (RFS) and overall survival (OS) were compared between groups. RESULTS: Among 82 patients who underwent resection of NELM, 57 had available data on calcifications while 51 had data available on arterial enhancement patterns. Among all patients, median age was 58 (IQR: 47-63) and the majority were female (N=48, 59.5%). The most common primary tumor locations were pancreas (N=25, 30.5%) and small bowel (N=27, 32.9%). The most commonly performed operations were right hepatectomy (N=29, 35.4%), bisegmentectomy (N=15, 18.3%), and segmentectomy (N=14, 17.1%). Median tumor number was 4 (IQR: 2-9), median Ki-67 was 5% (IQR: 2-10%), and median size of the largest liver metastasis was 4.5 (IQR: 2.8-7.7) cm. Twelve (21%) patients had tumor calcifications. Among patients with and without calcifications there were no differences in demographics, clinicopathologic characteristics, RFS (P=0.772) or OS (P=0.095). Arterial enhancement was hypoenhancing in 23 (45.1%), hyperenhancing in 10 (19.6%), and mixed in 18 (35.3%). Similarly, there were no differences between arterial enhancement groups in demographics, clinicopathologic characteristics, RFS (P=0.618) or OS (P=0.268). CONCLUSIONS: Radiographic characteristics on contrast-enhanced CT are not associated with the outcomes of patients undergoing resection of NELM. Future investigations should evaluate the prognostic impact of functional neuroendocrine imaging.

Neoadjuvant Capecitabine/Temozolomide for Locally Advanced or Metastatic Pancreatic Neuroendocrine Tumors.

OBJECTIVES: The combination chemotherapy regimen capecitabine/temozolomide (CAPTEM) is efficacious for metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs), but its role in the neoadjuvant setting has not been established. METHODS: The outcomes of all patients with locally advanced or resectable metastatic PNETs who were treated with neoadjuvant CAPTEM between 2009 and 2017 at 2 high-volume institutions were retrospectively reviewed. RESULTS: Thirty patients with locally advanced PNET (n = 10) or pancreatic neuroendocrine hepatic metastases (n = 20) received neoadjuvant CAPTEM. Thirteen patients (43%) exhibited partial radiographic response (PR), 16 (54%) had stable disease, and 1 (3%) developed progressive disease. Twenty-six (87%) patients underwent resection (pancreatectomy [n = 12], combined pancreatectomy and liver resection [n = 8], or major hepatectomy alone [n = 6]); 3 (18%) declined surgery despite radiographic PR, and 1 (3%) underwent aborted pancreatoduodenectomy. Median primary tumor size was 5.5 cm, and median Ki-67 index was 3.5%. Rates of PR were similar across tumor grades (P = 0.24). At median follow-up of 49 months, median progression-free survival was 28.2 months and 5-year overall survival was 63%. CONCLUSIONS: Neoadjuvant CAPTEM is associated with favorable radiographic objective response rates for locally advanced or metastatic PNET and may facilitate selection of patients appropriate for surgical resection.

Molecular Diagnosis of Cystic Neoplasms of the Pancreas: a Review.

BACKGROUND: The prevalence of incidental pancreatic cystic neoplasms (PCNs) has increased dramatically with advancements in cross-sectional imaging. Diagnostic imaging is limited in differentiating between benign and malignant PCNs. The aim of this review is to provide an overview of biomarkers that can be used to distinguish PCNs. METHODS: A review of the literature on molecular diagnosis of cystic neoplasms of the pancreas was performed. RESULTS: Pancreatic cysts can be categorized into inflammatory and non-inflammatory lesions. Inflammatory cysts include pancreatic pseudocysts. Noninflammatory lesions include both mucinous and non-mucinous lesions. Mucinous lesions include intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm. Non-mucinous lesions include serous cystadenoma and solid-pseudopapillary tumor of the pancreas. Imaging, cyst aspiration, and histologic findings, as well as carcinoembryonic antigen and amylase are commonly used to distinguish between cyst types. However, molecular techniques to detect differences in genetic mutations, protein expression, glycoproteomics, and metabolomic profiling are important developments in distinguishing between cyst types. DISCUSSION: Nomograms incorporating common clinical, laboratory, and imaging findings have been developed in a better effort to predict malignant IPMN. The incorporation of top molecular biomarker candidates to nomograms may improve the predictive ability of current models to more accurately diagnose malignant PCNs.

Travel to a high volume hospital to undergo resection of gallbladder cancer: does it impact quality of care and long-term outcomes?

BACKGROUND: The relationship of volume and travel distance to patient outcomes after resection of gallbladder cancer (GBC) remains poorly defined. METHODS: The 2004-2015 National Cancer Database was used to identify GBC resection patients and examine the impact of travel distance, hospital volume and both on overall survival (OS) and quality of care indicators. RESULTS: Among 10,174 patients undergoing surgery for GBC, the majority of patients were Caucasian (N = 8,175, 80%) and had a Charlson-Deyo comorbidity score of 0 (N = 6,785, 67%). On unadjusted survival analysis increasing travel distance and hospital volume were associated with improved OS (both p < 0.001). After controlling for competing risk factors, the 4th quartile of hospital volume was associated with a decreased hazard of death (HR 0.831, 95% CI 0.751-0.920, p < 0.001). When both hospital volume and travel distance were included, the association with improved OS persisted only for hospital volume (4th quartile HR 0.835, 95% CI 0.753-0.925, p < 0.001), whereas there was no independent association of increasing travel distance with OS. CONCLUSIONS: Both increasing travel distance and hospital volume were associated with improved OS; however, adjusted models demonstrated that the impact of travel distance was mediated through hospital volume.

Endoscopic Ultrasound-Guided Confocal Laser Endomicroscopy Increases Accuracy of Differentiation of Pancreatic Cystic Lesions.

BACKGROUND & AIMS: Imaging patterns from endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) have been associated with specific pancreatic cystic lesions (PCLs). We compared the accuracy of EUS with nCLE in differentiating mucinous from nonmucinous PCLs with that of measurement of carcinoembryonic antigen (CEA) and cytology analysis. METHODS: We performed a prospective study of 144 consecutive patients with a suspected PCL (≥20 mm) who underwent EUS with fine-needle aspiration of pancreatic cysts from June 2015 through December 2018 at a single center; 65 patients underwent surgical resection. Surgical samples were analyzed by histology (reference standard). During EUS, the needle with the miniprobe was placed in the cyst, which was analyzed by nCLE. Fluid was aspirated and analyzed for level of CEA and by cytology. We compared the accuracy of nCLE in differentiating mucinous from nonmucinous lesions with that of measurement of CEA and cytology analysis. RESULTS: The mean size of dominant cysts was 36.4 ± 15.7 mm and the mean duration of nCLE imaging was 7.3 ± 2.8 min. Among the 65 subjects with surgically resected cysts analyzed histologically, 86.1% had at least 1 worrisome feature based on the 2012 Fukuoka criteria. Measurement of CEA and cytology analysis identified mucinous PCLs with 74% sensitivity, 61% specificity, and 71% accuracy. EUS with nCLE identified mucinous PCLs with 98% sensitivity, 94% specificity, and 97% accuracy. nCLE was more accurate in classifying mucinous vs nonmucinous cysts than the standard method (P < .001). The overall incidence of postprocedure acute pancreatitis was 3.5% (5 of 144); all episodes were mild, based on the revised Atlanta criteria. CONCLUSIONS: In a prospective study, we found that analysis of cysts by nCLE identified mucinous cysts with greater accuracy than measurement of CEA and cytology analysis. EUS with nCLE can be used to differentiate mucinous from nonmucinous PCLs. ClincialTrials.gov no: NCT02516488.

Analysis of Authorship in Hepatopancreaticobiliary Surgery: Women Remain Underrepresented.

INTRODUCTION: Given the need to increase female representation in hepatopancreatobiliary (HPB) surgery, as well as the need to increase the academic pipeline of women in this subspecialty, we sought to characterize the prevalence of female authorship in the HPB literature. In particular, the objective of the current study was to determine the proportion of women who published HPB research articles as first, second, or last author over the last decade. METHODS: All articles pertaining to hepatopancreaticobiliary (HPB) surgery appearing in seven surgical journals (Annals of Surgery, British Journal of Surgery, JAMA Surgery, Annals of Surgical Oncology, HPB (Oxford), Surgery, and Journal of Gastrointestinal Surgery) were reviewed for the years 2008 and 2018. Information on sex of author, country of author's institution, and article type was collected and entered into a computerized database. RESULTS: Among the 1473 index articles included in the final analytic cohort, 414 (28%) publications had a woman as the first or last author, while the vast majority (n = 1,059, 72%) had a man as the first or last author. The number of female first authors increased from 15.6% (n = 92/591) in 2008 to 25.7% (n = 227/882) in 2018 (p < 0.001). There were no differences in the proportion of second (n = 123/536, 23.0% vs n = 214/869, 24.6%, p = 0.47) or last (n = 44/564, 7.8% vs n = 88/875, 10.1%, p = 0.15) authors. Women were more likely to publish papers appearing in medium-impact journals (OR 1.40, 95% CI 1.04-1.88) and articles with a female author were more likely to be from a North American institution (referent: North America, Asia OR 0.43, 95% CI 0.31-0.59 vs Europe OR 0.67, 95% CI 0.51-0.87). CONCLUSION: Women first/last authors in HPB research articles have increased over the past 10 years from 22 to 32%. Women as last authors remain low, however, as only 1 in 10 papers had a senior woman author. These data should prompt HPB leaders to find solutions to the gap in female authorship including mentorship of young female researchers and surgeons.