Background The objective of this study was to identify trends in the diagnosis and treatment of cystic neoplasms of the pancreas using a retrospective review of patients from a surgical database at ...an academic referral center during a 33-year period. Methods Patient characteristics, including demographics, pathology, and survival, were analyzed over 5 time periods between 1978 and 2011. Results A total of 851 consecutive patients underwent resection for a cystic neoplasm of the pancreas during a 33-year period. Sixty-five percent of patients were female, and mean age was 60 years. The most common pathologic diagnoses were intraductal papillary mucinous neoplasm (38%), mucinous cystic neoplasm (23%), serous cystadenoma (16%), and cystic neuroendocrine neoplasm (7%). There was a stepwise increase in the number of resections across time periods (67 between 1978 and 1989; 376 between 2005 and 2011), with a parallel increase in the proportion of incidentally discovered lesions (22% to 50%). Diagnosis of intraductal papillary mucinous neoplasm was very uncommon in the first 2 time periods (before the first recognition of intraductal papillary mucinous neoplasm as a distinct entity) but predominated in the last 2 (41% and 49%), and cystic neuroendocrine neoplasms, which constituted 3% of the cystic neoplasms in the first time-period, now comprise more than 8% of pancreatic cystic neoplasms. The proportion of malignant neoplasms decreased over time (41% between 1978 and 1989; 12% between 2005 and 2011), reflecting probably the earlier diagnosis and treatment of premalignant neoplasms. Although operative mortality was minimal (4/849, 0.5%), the postoperative complication rate was 38%. Overall 5-year survival for all mucinous lesions was 87%. Conclusion Cystic neoplasms of the pancreas are being diagnosed and treated with increasing frequency. At present, most are incidentally discovered intraductal papillary mucinous neoplasms.
In the past decade, the use of neoadjuvant therapy (NAT) has increased for patients with borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Data on pancreatic fistula and ...related overall survival (OS) in this setting are limited.
To compare postoperative complications in patients undergoing either upfront resection or pancreatectomy following NAT, focusing on clinically relevant postoperative pancreatic fistula (CR-POPF) and potential associations with OS.
This retrospective cohort study was conducted on data from patients who underwent pancreatic resection for PDAC at the Massachusetts General Hospital from January 1, 2007, to December 31, 2017.
Pancreatic cancer surgery with or without NAT.
Overall morbidity and CR-POPF rates were compared between NAT and upfront resection. Factors associated with CR-POPF were assessed with univariate and multivariate analysis. Survival data were analyzed by Kaplan-Meier curves and a Cox proportional hazards regression model.
Of 753 patients, 364 were men (48.3%); median (interquartile range) age was 68 (61-75) years. A total of 346 patients (45.9%) received NAT and 407 patients (54.1%) underwent upfront resection. At pathologic examination, NAT was associated with smaller tumor size (mean SD, 26.0 15.3 mm vs 32.7 14.4 mm; P < .001), reduced nodal involvement (102 25.1% vs 191 55.2%; P < .001), and higher R0 rates (257 74.3% vs 239 58.7%; P < .001). There were no significant differences in severe complication rate or 90-day mortality. The rate of CR-POPF was 3.6-fold lower in patients receiving NAT vs upfront resection (13 3.8% vs 56 13.8%; P < .001). In addition, factors associated with CR-POPF changed after NAT, and only soft pancreatic texture was associated with a higher risk of CR-POPF (38.5% vs 6.3%; P < .001). Survival analysis showed no differences between patients with or without CR-POPF after upfront resection (26 vs 25 months; P = .66), but after NAT, a worse overall survival rate was observed in patients with CR-POPF (17 vs 34 months; P = .002). This association was independent of other established predictors of overall survival by multivariate analysis (hazard ratio, 2.80; 95% CI, 1.44-5.45; P < .002).
Neoadjuvant therapy may be associated with a significant reduction in the rate of CR-POPF. In addition, standard factors associated with CR-POPF appear to be no longer applicable following NAT. However, once CR-POPF occurs, it is associated with a significant reduction in long-term survival. Patients with CR-POPF may require closer follow-up and could benefit from additional therapy.
Distal pancreatectomy (resection of the pancreatic body and tail) can be performed with or without preservation of the spleen. Splenic preservation has the advantages of fewer postoperative ...complications such as abscesses in the resection bed, shorter length of hospitalization, and avoidance of the long-term risk of post-splenectomy sepsis related to encapsulated bacteria. Two techniques can be used to save the spleen: either by dissecting out the splenic artery and vein with division of the arterial and venous branches between the pancreas and the splenic artery and vein; or by resecting the splenic artery and vein along with the pancreas but with careful preservation of the vascular collaterals in the splenic hilum, which allows the spleen to survive on the short gastric vessels (Warshaw technique). The latter method has been shown to be associated with a shorter operation, less blood loss, and a shorter hospitalization. In general the Warshaw technique is easier, especially for laparoscopic pancreatectomy. The subsequent appearance of enlarged gastric veins (varices) is to be expected as a consequence of loss of the splenic vein but has not led to bleeding from these natural collaterals during long-term follow up.
pNENs are relative indolent tumors with heterogeneous clinical presentation at diagnosis. It is important to establish aggressive subgroups of pNENs and identify potential therapeutic targets. ...Patients with pNEN (322 cases) were included to examine the association between glycosylation biomarkers and clinical/pathological traits. The molecular and metabolic features stratified by glycosylation status were assessed by RNA‐seq/whole exome sequencing and immunohistochemistry. A considerable proportion of patients had elevated glycosylation biomarkers (carbohydrate antigen CA 19‐9, 11.9%; CA125, 7.5%; carcinoembryonic antigen CEA, 12.8%). CA19‐9 (hazard ratio HR = 2.26, P = .019), CA125 (HR = 3.79, P = .004) and CEA (HR = 3.16, P = .002) were each independent prognostic variables for overall survival. High glycosylation group, defined as pNENs with elevated level of circulating CA19‐9, CA125 or CEA, accounted for 23.4% of all pNENs. High glycosylation (HR = 3.14, P = .001) was an independent prognostic variable for overall survival and correlated with G3 grade (P < .001), poor differentiation (P = .001), perineural invasion (P = .004) and distant metastasis (P < .001). Epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA‐seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival (P = .020). A clinical trial focusing on EGFR expressed pNENs was initiated (NCT05316480). Thus, pNEN with aberrant glycosylation correlates with a dismal outcome and suggests potential therapeutic target of EGFR.
What's new?
Pancreatic neuroendocrine neoplasms (pNEN) have heterogenous pathological and clinical features and diverse clinical outcomes. Markers capable of identifying aggressive subgroups of pNENs in particular, which could facilitate clinical management, are lacking. In the present study, the authors examined relationships between glycosylation markers and different features of pNENs. Nearly one‐quarter of pNENs were found to have high levels of glycosylation markers, including carbohydrate antigen (CA) 19‐9, CA125 and carcinoembryonic antigen. High glycosylation predicted poor prognosis and correlated with G3 grade and features of more aggressive disease. High glycosylation pNENs further exhibited overexpression of epidermal growth factor receptor, a therapeutic target.
Background Since Allen O. Whipple published his seminal paper in 1935, the procedure that bears his name has been performed widely throughout the world and is now a common operation in major medical ...centers. The goal of this study was to investigate the evolution of pancreatoduodenectomy at the Massachusetts General Hospital (MGH). Methods We sought to identify all pancreatoduodenectomies performed at the MGH since 1935. Cases were obtained from a computerized database, hospital medical records, and the MGH historical archive. Demographics, diagnosis, intraoperative variables and short-term surgical outcomes were recorded. Results The first pancreatoduodenectomy at the MGH was carried out in 1941; since then, 2,050 Whipple procedures have been performed. Pancreatic ductal adenocarcinoma was the most frequent indication (36%). Pylorus preservation has been the most important variation in technique, accounting for 45% of Whipple procedures in the 1980s; observation of frequent delayed gastric emptying after this procedure led to decline in its use. Pancreatic fistula was the most frequent complication (13%). Operative blood replacement and reoperation rates have decreased markedly over time; the most frequent indication for reoperation was intra-abdominal bleeding. Mortality has decreased from 45% to 0.8%, with sepsis and hypovolemic shock being the most frequent causes of death. Mean duration of hospital stay has decreased from >30 to 9.5 days, along with an increasing readmission rate (currently 19%). Conclusion The Whipple procedure in the 21st century is a well-established operation. Improvements in operative technique and perioperative care have contributed in making it a safe operation that continues evolving.
On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to ...evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy.
Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon.
Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX.
After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.
Patient-derived xenograft (PDX) tumors are powerful tools to study cancer biology. However, the ability of PDX tumors to model the biological and histological diversity of pancreatic ductal ...adenocarcinoma (PDAC) is not well known. In this study, we subcutaneously implanted 133 primary and metastatic PDAC tumors into immunodeficient mice. Fifty-seven tumors were successfully engrafted and even after extensive passaging, the histology of poorly-, moderately-, and well-differentiated tumors was maintained in the PDX models. Moreover, the fibroblast and collagen contents in the stroma of patient tumors were recapitulated in the corresponding PDX models. Analysis of the clinicopathological features of patients revealed xenograft tumor engraftment was associated with lymphovascular invasion (P = 0.001) and worse recurrence-free (median, 7 vs. 16 months, log-rank P = 0.047) and overall survival (median, 13 vs. 21 months, log-rank P = 0.038). Among successful engraftments, median time of growth required for reimplantation into new mice was 151 days. Reflective of the inherent biological diversity between PDX tumors with rapid (<151 days) and slow growth, differences in their growth were maintained during extensive passaging. Rapid growth was additionally associated with lymph node metastasis (P = 0.022). The association of lymphovascular invasion and lymph node metastasis with PDX formation and rapid growth may reflect an underlying biological mechanism that allows these tumors to adapt and grow in a new environment. While the ability of PDX tumors to mimic the cellular and non-cellular features of the parental tumor stroma provides a valuable model to study the interaction of PDAC cells with the tumor microenvironment, the association of successful engraftment with adverse clinicopathological features suggests PDX models over represent more aggressive forms of this disease.
This study evaluated the potential role of immune cells and molecules in the pathogenesis and clinical course of pancreatic neuroendocrine tumors (PanNET).
Surgically resected PanNETs (
= 104) were ...immunohistochemically analyzed for Ki67 index, mitotic rate, macrophage, CD4
cells, and CD8
T-cell infiltration, as well as HLA class I, PD-L1, and B7-H3 expression. Results were correlated with clinicopathologic characteristics as well as with disease-free (DFS) and disease-specific (DSS) survival.
The median age of the 57 WHO grade 1 and 47 WHO grade 2 patients was 55 years. High intratumoral CD8
T-cell infiltration correlated with prolonged DFS (
= 0.05), especially when the number of tumor-associated macrophages (TAM) was low. In contrast, high peritumoral CD4
cell and TAM infiltration was associated with a worse DFS and DSS. PD-L1 and B7-H3 were expressed in 53% and 78% PanNETs, respectively. HLA class I expression was defective in about 70% PanNETs. HLA-A expression correlated with favorable DSS in PD-L1-negative tumors (
= 0.02). TAM infiltration (
= 0.02), WHO grade (
= 0.04), T stage (
= 0.01), and lymph node positivity (
= 0.04) were independent predictors of DFS. TAM infiltration (
= 0.026) and T stage (
= 0.012) continued to be predictors of DFS in WHO grade 1 PanNET patients. TAM infiltration was the sole independent predictor of DSS for WHO grade 1 and 2 patients (
= 0.02). Therefore, this biomarker may contribute to identifying WHO grade 1 patients with poor prognosis.
TAM infiltration appears to be the most informative prognostic biomarker in PanNET. It may represent a useful immunotherapeutic target in patients with PanNET.
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