Who Do We Fail to Rescue after Pancreatoduodenectomy? Outcomes Among >4000 Procedures Expose Windows of Opportunity.

OBJECTIVE: Our investigation on in-hospital mortality after 4474 pancreatoduodenectomies aimed to identify time-dependent risks as well as windows of opportunity to rescue patients from complications. BACKGROUND: Pancreatoduodenectomy is generally considered a safe procedure with a 1-10% perioperative mortality based on complexity and surgical volume. Yet, patients are susceptible for life-threatening complications particularly with extended resections. Recognition of distinct vulnerabilities over time while patients recover is required to permit focused monitoring, sophisticated resource allocation, and greatest surgical safety. METHODS: Patients who deceased in-hospital after pancreatoduodenectomy between 2003-2021 were retrieved from the institutional pancreatectomy registry and analyzed in detail with respect to their postoperative course. RESULTS: Among 4474 pancreatoduodenectomies, 156 patients deceased in-hospital (3.5%). When assessing root causes of mortality, we observed 3 different clusters of complications which were postpancreatectomy-specific (47.4%), visceral vasculature-associated (25.6%), or cardiopulmonary in origin (23.7%). The median times of root cause onset in the 3 categories were postoperative day (POD) 9, POD 4.5 ( P =0.008) and POD 3 ( P <0.001), and medians of in-hospital mortality were POD 31, POD 18 ( P =0.009) and POD 8 ( P <0.001), respectively. Intervals between root cause onset and mortality varied with medians of 23 days, 11 days ( P =0.017), and 1 days ( P <0.001). The 3 categories were similarly distributed between different types of surgical complexity. CONCLUSION: Postpancreatectomy-specific complications prompt almost half of in-hospital mortalities after pancreatoduodenectomy, with rather long intervals for interventions to prevent failure to rescue. In contrast, visceral vasculature-related events and cardiopulmonary complications dominate early in-hospital mortalities with short intervals until mortality, demanding rigorous management of such events or preoperative conditioning. These data externally validate a previous high-volume initiative and highlight distinct windows of opportunity to optimize perioperative safety.

Preoperative Surgical or Endoscopic Bile Duct Drainage in Pancreatic Cancer.

BACKGROUND: Patients with pancreatic cancer and obstructive jaundice routinely undergo endoscopic stent placement (ES). It is well known that ES causes bacterial contamination and infectious complications after pancreatic resection. OBJECTIVE: To compare short-term outcomes and survival in patients undergoing pancreatic head resection after preoperative ES vs preoperative surgical drainage (SD) via T-tube insertion. METHODS: Patients with obstructive jaundice who underwent SD or ES from 2016 to 2022 were identified from a prospective database. Outcome analyses included microbiological bile contamination, overall morbidity and assessment of the overall complication burden using the Comprehensive Complication Index (CCI). Overall survival was investigated by Kaplan‒Meier analysis. RESULTS: A total of 55 patients with SD were identified and matched with 110 ES patients. After the primary intervention, ES patients experienced more complications (ES: 17.3% vs. SD: 3.6%; P=0.013). The overall complication burden after pancreatic resection was higher in ES patients than in SD patients (CCI: 27.2 vs. 19.9; P=0.022). Additionally, bacterial contamination of the bile was more frequent in ES patients compared to SD individuals (94.3% vs. 7.1%; P<0.001) with similar bacteria in 83.3% of postoperative abdominal infections in ES patients. While overall survival did not differ between the two groups, patients with postinterventional complications after ES had an impaired survival compared to those without complications (11.3 mo vs. 20.4 mo; P=0.03). CONCLUSION: SD for obstructive jaundice in resectable pancreatic cancer is associated with a lower overall complication burden. Additionally, patients with complications after ES experience worse overall survival. These findings indicate to rethink our standards of treatment of obstructive jaundice in patients with pancreatic cancer.

Portal vein resection in pancreatic neuroendocrine neoplasms.

BACKGROUND: Surgery offers the only cure for borderline resectable or locally advanced pancreatic neuroendocrine neoplasms. Data on incidence, perioperative and long-term outcomes of portal vein resection for pancreatic neuroendocrine neoplasms are scarce. This study aimed to analyze the outcome and prognostic factors of portal vein resection in surgery for pancreatic neuroendocrine neoplasms. METHODS: Consecutive patients were analyzed. Portal vein resection was classified according to the International Study Group of Pancreatic Surgery. Clinicopathologic features and overall and disease-free survival were assessed and compared with standard resection in a matched-pair analysis. RESULTS: A total of 54 of 666 (8%) resected pancreatic neuroendocrine neoplasms patients underwent portal vein resection, including 7 (13%) tangential resections with venorrhaphy (type 1), 2 (4%) patch reconstructions (type 2), 35 (65%) end-to-end anastomoses (type 3), and 10 (19%) graft interpositions (type 4); 52% of those underwent pancreatoduodenectomy, 22% distal pancreatectomy, and 26% total pancreatectomy. Postoperative portal vein thrombosis occurred in 19%. Postoperative pancreatic fistula grades B and C (9% vs 16%; P = .357), complications Clavien-Dindo grade ≥IIIb (28% vs 13%; P = .071), and 90-day mortality rate (2% each) were not significantly different compared with 108 matched patients. The 5-year overall survival was 45% (standard resection: 68%; P = .432), and the 5-year disease-free survival was 25% (standard resection: 34%; P = .716). Radical resection was associated with 5-year overall survival of 51% and 5-year disease-specific survival of 75%. CONCLUSION: This is the largest single-center analysis evaluating perioperative and long-term outcomes of portal vein resection for pancreatic neuroendocrine neoplasms. The postoperative complication rate after portal vein resection is comparable with standard resection. The 90-day mortality is low. Radical resection leads to excellent 5-year oncological survival.

Distal Pancreatectomy: Extent of Resection Determines Surgical Risk Categories.

BACKGROUND: Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality. OBJECTIVE: To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system. METHODS: All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data, and postoperative outcomes were analyzed and compared among the 4 groups. RESULTS: A total of 2135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P <0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality. CONCLUSIONS: Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.

Patient reported outcomes of duodenum-preserving pancreatic head resection in chronic pancreatitis: high effectivity is impaired by prolonged non-surgical management.

BACKGROUND: Chronic pancreatitis (CP) causes suffering and socioeconomic burden. This study evaluated perioperative results and patient-reported outcomes (PRO) in CP patients treated with duodenum-preserving pancreatic head resection (DPPHR). METHODS: Data were analyzed of CP patients undergoing DPPHR between 01/2001-10/2014. PROs were measured using a specifically designed questionnaire and the EORTC QLQ-C30/PAN26. Associations between treatment variables and PROs were examined. RESULTS: Of 332 patients who received DPPHR, most (n = 251, 75.6%) underwent the Berne modification. Surgical morbidity was 21.5% (n = 71) and 90-day mortality 1.5% (n = 5). Median follow-up was 79.9 months, 5-year survival 90.5%, and 1.8% of patients developed pancreatic cancer. Of 283 patients alive, 178 (62.9%) returned questionnaires. Referral for surgery was self-initiated (38.0% of cases), by gastroenterologists (27.5%) and by general practitioners (21.1%). QoL improved in 78.7% of patients, remained stable in 12.1%, and worsened in 9.1%. Median Izbicki scores decreased from 90 to 5 points after surgery (p < 0.0001). Time from diagnosis to DPPHR was an independent, proportional predictor of a higher postoperative Izbicki score (p = 0.04). CONCLUSION: DPPHR is an effective, safe treatment for CP. A delay in surgery decreases surgical effectivity, hence CP patients should be referred to surgery early to ensure satisfactory outcomes.

Long-term quality of life after resection of retroperitoneal soft tissue sarcoma.

INTRODUCTION: Retroperitoneal soft tissue sarcoma (RPS) is characterized by high recurrence rates. Since complete tumor resection, often necessitating multivisceral resection, enables long-term survival in both primary and recurrent disease, health related quality of life (QoL) after RPS resection has attracted increasing interest. However, data regarding this topic is limited. Here, we multidimensionally assessed long-term QoL after RPS resection. METHODS: Five previously validated (1. EORTC QLQ-C30, 2. WEMWBS, 3. FoP-Q-SF, 4. PC-PTSD, 5. Pro-CTCAE) were sent to patients having undergone resection of primary, recurrent and metastasized RPS at Heidelberg University Hospital between 10/2001 and 12/2020. Multivariable linear regression models were used to test associations between clinical/demographic variables and patient reported outcomes (PROs). RESULTS: Questionnaires were answered by 127 patients (71% response rate). The median interval between RPS diagnosis and assessment of PROs was 80 months. The overall Global Health score was 64.1 and comparable to the general German population. RPS patients reported deficits regarding emotional and social functioning, whereas physical limitations were less pronounced. Besides diarrhea, abdominal symptoms were comparable to the overall population. Tumor recurrences, the number of surgeries, multivisceral resections or postoperative complications did not significantly affect long-term QoL ratings. CONCLUSION: RPS patients rate their QoL relatively high, even after multiple and multivisceral resections. Psychosocial well-being should be monitored in follow-up sessions to offer tailored support if necessary, thus improving postoperative care.

Farnesoid X receptor activation inhibits pancreatic carcinogenesis.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that controls bile acid (BA) homeostasis, has also been proposed as a tumor suppressor for breast and liver cancer. However, its role in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains controversial. We recently found that FXR attenuates acinar cell autophagy in chronic pancreatitis resulting in reduced autophagy and promotion of pancreatic carcinogenesis. Feeding Kras-p48-Cre (KC) mice with the BA chenodeoxycholic acid (CDCA), an FXR agonist, attenuated pancreatic intraepithelial neoplasia (PanIN) progression, reduced cell proliferation, neoplastic cells and autophagic activity, and increased acinar cells, elevated pro-inflammatory cytokines and chemokines, with a compensatory increase in the anti-inflammatory response. Surprisingly, FXR-deficient KC mice did not show any response to CDCA, suggesting that CDCA attenuates PanIN progression and decelerate tumorigenesis in KC mice through activating pancreatic FXR. FXR is activated in pancreatic cancer cell lines in response to CDCA in vitro. FXR levels were highly increased in adjuvant and neoadjuvant PDAC tissue compared to healthy pancreatic tissue, indicating that FXR is expressed and potentially activated in human PDAC. These results suggest that BA exposure activates inflammation and suppresses autophagy in KC mice, resulting in reduced PanIN lesion progression. These data suggest that activation of pancreatic FXR has a protective role by reducing the growth of pre-cancerous PDAC lesions in response to CDCA and possibly other FXR agonists.

Surgery for intraductal papillary mucinous neoplasms in young patients: High-risk population.

BACKGROUND: Intraductal papillary mucinous neoplasms of the pancreas are uncommon in young individuals. Management of these patients is challenging because the risk of malignancy and recurrence after surgery remains unclear. The aim of the present study was to assess the long-term risk for intraductal papillary mucinous neoplasm recurrence after surgery for intraductal papillary mucinous neoplasms in patients ≤50 years of age. METHODS: Perioperative and long-term follow-up data of patients who had undergone surgery for intraductal papillary mucinous neoplasms between 2004 and 2020 were extracted from a prospective unicentric database and retrospectively analyzed. RESULTS: Seventy-eight patients underwent surgical treatment for benign intraductal papillary mucinous neoplasms (low-grade n = 22 and intermediate-grade n = 21) and malignant intraductal papillary mucinous neoplasms (high-grade n = 16 and intraductal papillary mucinous neoplasm-associated carcinoma n = 19). Severe postoperative morbidity (Clavien-Dindo ≥III) was found in 14 patients (18%). The median length of hospital stay was 10 days. No perioperative mortality was observed. The median length of follow-up was 72 months. Recurrence of intraductal papillary mucinous neoplasm-associated carcinoma was found in 6 patients (19%) with malignant intraductal papillary mucinous neoplasm and 1 patient (3%) with benign intraductal papillary mucinous neoplasm. CONCLUSION: Surgery for intraductal papillary mucinous neoplasm is safe and can be performed with low morbidity and potentially no mortality in young patients. Given the high rate of malignancy (45%), these patients with intraductal papillary mucinous neoplasms represent a high-risk population, and prophylactic surgical treatment should be considered in these patients with long life expectancies. Regular clinical and radiologic follow-up examinations are important to rule out disease recurrence, which is high, especially in patients with intraductal papillary mucinous neoplasm-associated carcinoma.

Distal Pancreatectomy With En Bloc Celiac Axis Resection (DP-CAR) for Locally Advanced Pancreatic Cancer: A Safe and Effective Procedure.

OBJECTIVE: To determine perioperative and oncologic outcomes after distal pancreatectomy with en bloc resection of the celiac axis (DP-CAR). BACKGROUND: DP-CAR can be used in a selective group of patients to resect locally advanced pancreatic cancer involving the celiac axis or common hepatic artery without arterial reconstruction by preserving retrograde blood flow via the gastroduodenal artery to the liver and stomach. METHODS: We analyzed all consecutive patients who had undergone DP-CAR between May 2003 and April 2022 at a tertiary hospital specialized in pancreatic surgery and present one of the largest single-center studies. RESULTS: A total of 71 patients underwent DP-CAR. Additional venous resection (VR) of the mesenterico-portal axis was performed in 31 patients (44%) and multivisceral resection (MVR) in 42 patients (59%). Margin-free (R0) resection was achieved in 40 patients (56%). The overall 90-day mortality rate was 8.4% for the entire patient cohort. After a cumulated experience of 16 cases, the 90-day mortality dropped to 3.6% in the following 55 patients. Extended procedures with (+) additional MVR with or without (+/-) VR resulted in higher major morbidity (Clavien-Dindo ≥IIIB; standard DP-CAR: 19%; DP-CAR + MVR +/- VR: 36%) and higher 90-day mortality (standard DP-CAR: 0%; DP-CAR + MVR +/- VR: 11%). Median overall survival after DP-CAR was 28 months. CONCLUSIONS: DP-CAR is a safe and effective procedure but requires experience. Frequently, surgical resection has to be extended with MVR and VR to accomplish tumor resection, which results in promising oncologic outcomes. However, extended resections were associated with increased morbidity and mortality.

Plasma extracellular vesicle messenger RNA profiling identifies prognostic EV signature for non-invasive risk stratification for survival prediction of patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal of all cancers and the median survival of PDAC patients is only 6-8 months after diagnosis. While decades of research effort have been focused on early diagnosis and understanding of molecular mechanisms, few clinically useful markers have been universally applied. To improve the treatment and management of PDAC, it is equally relevant to identify prognostic factors for optimal therapeutic decision-making and patient survival. Compelling evidence have suggested the potential use of extracellular vesicles (EVs) as non-invasive biomarkers for PDAC. The aim of this study was thus to identify non-invasive plasma-based EV biomarkers for the prediction of PDAC patient survival after surgery. METHODS: Plasma EVs were isolated from a total of 258 PDAC patients divided into three independent cohorts (discovery, training and validation). RNA sequencing was first employed to identify differentially-expressed EV mRNA candidates from the discovery cohort (n = 65) by DESeq2 tool. The candidates were tested in a training cohort (n = 91) by digital droplet polymerase chain reaction (ddPCR). Cox regression models and Kaplan-Meier analyses were used to build an EV signature which was subsequently validated on a multicenter cohort (n = 83) by ddPCR. RESULTS: Transcriptomic profiling of plasma EVs revealed differentially-expressed mRNAs between long-term and short-term PDAC survivors, which led to 10 of the top-ranked candidate EV mRNAs being tested on an independent training cohort with ddPCR. The results of ddPCR enabled an establishment of a novel prognostic EV mRNA signature consisting of PPP1R12A, SCN7A and SGCD for risk stratification of PDAC patients. Based on the EV mRNA signature, PDAC patients with high risk displayed reduced overall survival (OS) rates compared to those with low risk in the training cohort (p = 0.014), which was successfully validated on another independent cohort (p = 0.024). Interestingly, the combination of our signature and tumour stage yielded a superior prognostic performance (p = 0.008) over the signature (p = 0.022) or tumour stage (p = 0.016) alone. It is noteworthy that the EV mRNA signature was demonstrated to be an independent unfavourable predictor for PDAC prognosis. CONCLUSION: This study provides a novel and non-invasive prognostic EV mRNA signature for risk stratification and survival prediction of PDAC patients.

Distal Bile Duct Cancer: Radical (R0 > 1 mm) Resection Achieves Favorable Survival.

OBJECTIVE: Evaluation of the outcome after resection for distal bile duct cancer (DBC) with focus on the impact of microscopic histopathological resection status R0 (>1 mm) versus R1 (≤1 mm) vs R1 (direct). SUMMARY BACKGROUND DATA: DBC is a rare disease for which oncologic resection offers the only chance of cure. METHODS: Prospectively collected data of consecutive patients undergoing pancreaticoduodenectomy for DBC were analyzed. Histopathological resection status was classified according to the Leeds protocol for pancreatic ductal adeno carcinoma (PDAC) (PDAC; R0 >1 mm margin clearance vs R1 ≤1 mm vs R1 direct margin involvement). RESULTS: A total of 196 patients underwent pancreaticoduodenectomy for DBC. Microscopic complete tumor clearance (R0>1 mm) was achieved in 113 patients (58%). Median overall survival (OS) of the entire cohort was 37 months (5- and 10-year OS rate: 40% and 31%, respectively). After R0 resection, median OS increased to 78 months with a 5-year OS rate of 52%. Negative prognostic factors were age >70 years ( P < 0.0001, hazard ratio (HR) 2.48), intraoperative blood loss >1000 mL ( P = 0.0009, HR 1.99), pN1 and pN2 status ( P = 0.0052 and P = 0.0006, HR 2.14 and 2.62, respectively) and American Society of Anesthesiologists score >II ( P = 0.0259, HR 1.61). CONCLUSIONS: This is the largest European single-center study of surgical treatment for DBC and the first to investigate the prognostic impact of the revised PDAC resection status definition in DBC. The results show that this definition is valid in DBC and that "true" R0 resection (>1 mm) is a key factor for excellent survival. In contrast to PDAC, there was no survival difference between R1 (≤1 mm) and R1 (direct).

Completion Pancreatectomy After Pancreatoduodenectomy: Who Needs It?

OBJECTIVE: The objective of this study was to identify the indications for and report the outcomes of completion pancreatectomy (CPLP) in the postoperative course after pancreatoduodenectomy (PD). BACKGROUND: CPLP may be considered or even inevitable for damage control after PD. METHODS: A prospectively maintained database of all patients undergoing PD between 2001 and 2019 was searched for patients who underwent CPLP in the postoperative course after PD. Baseline characteristics, perioperative details, and outcomes of CPLP patients were analyzed and specific indications for CPLP were identified. RESULTS: A total of 3953 consecutive patients underwent PD during the observation period. CPLP was performed in 120 patients (3%) after a median of 10 days following PD. The main indications for CPLP included postpancreatectomy acute necrotizing pancreatitis [n=47 (39%)] and postoperative pancreatic fistula complicated by hemorrhage [n=41 (34%)] or associated with uncontrollable leakage of the pancreatoenteric anastomosis [n=23 (19%)]. The overall 90-day mortality rate of all 3953 patients was 3.5% and 37% for patients undergoing CPLP. CONCLUSIONS: Our finding that only very few patients (3%) need CPLP suggests that conservative, interventional, and organ-preserving surgical measures are the mainstay of complication management after PD. Postpancreatectomy acute necrotizing pancreatitis, uncontrollable postoperative pancreatic fistula, and fistula-associated hemorrhage are highly dangerous and represent the main indications for CPLP after PD.

Portal Vein Resection in Pancreatic Cancer Surgery: Risk of Thrombosis and Radicality Determine Survival.

OBJECTIVE: To evaluate the outcomes of pancreatic cancer [pancreatic ductal adenocarcinoma (PDAC)] surgery with concomitant portal vein resection (PVR), focusing on the PVR type according to the International Study Group of Pancreatic Surgery (ISGPS). BACKGROUND: Surgery offers the only chance for cure in PDAC. PVR is often performed for borderline or locally advanced tumors. METHODS: Consecutive patients with PDAC operated between January 2006 and January 2018 were included. Clinicopathologic characteristics and outcomes were analyzed and tested for survival prediction. RESULTS: Of 2265 PDAC resections, 1571 (69.4%) were standard resections and 694 (30.6%) were resections with PVR, including 149 (21.5%) tangential resections with venorrhaphy (ISGPS type 1), 21 (3.0%) resections with patch reconstruction (type 2), 491 (70.7%) end-to-end anastomoses (type 3), and 33 (4.8%) resections with graft interposition (type 4). The 90-day mortality rate was 2.6% after standard resection and 6.3% after resection with PVR ( P <0.0001). Postoperative portal vein thrombosis and pancreas-specific surgical complications most frequently occurred after PVR with graft interposition (21.2% and 48.5%, respectively). In multivariable analysis, age 70 years and above, ASA stages 3/4, increased preoperative serum carbohydrate antigen 19-9, neoadjuvant treatment, total pancreatectomy, PVR, higher UICC stage, and R+ resections were significant negative prognostic factors for overall survival. Radical R0 (>1 mm) resection resulted in 23.3 months of median survival. CONCLUSIONS: This is the largest single-center, comparative cohort study of PVR in PDAC surgery, showing that postoperative morbidity correlates with the reconstruction type. When radical resection is achieved, thrombosis risk is outweighed by beneficial overall survival times of nearly 2 years.

Oncological Outcome of Conversion Surgery After Preoperative Chemotherapy for Metastatic Pancreatic Cancer.

OBJECTIVE: To investigate the outcome of conversion surgery in patients with metastatic pancreatic cancer (mPDAC) and to identify patients who may benefit from this approach. BACKGROUND: The role of conversion surgery in patients with mPDAC and exceptional response to chemotherapy remains unclear. METHODS: Patients who underwent surgical exploration for mPDAC following chemotherapy between 2006 and 2019 were included. Data on demographics, oncologic treatment, pathology, and postoperative outcomes were analyzed. Univariate and multivariate survival analyses were performed. RESULTS: Some 173 patients received preoperative chemotherapy and underwent surgical exploration. Ninety-three patients underwent resection of the primary tumor and metastatic sites, 80 patients underwent exploration only. In the resection subgroup, 45 patients had complete pathological response of metastases (ypM0) and 48 patients had residual metastases (ypM1). ypM0 status was associated with lower carcinoembryonic antigen levels and lower ypN stage. Overall survival after resection was 25.5 months in ypM0, 10.7 months in ypM1, and 8.1 months in patients without resection ( P <0.001). Additional adjuvant chemotherapy was significantly associated with prolonged survival in resected patients (29.0 vs 14.8 mo, P =0.024) as well as in ypM0 (29.1 vs 19.2 mo, P =0.047). Multivariable analysis identified conversion surgery, carbohydrate antigen 19-9 (CA19-9) and time of resection as independent prognostic markers for the entire cohort. CA19-9, ypM0 and adjuvant treatment were independent predictors of survival in the resection subgroup. CONCLUSION: In patients with mPDAC and ypM0 status after chemotherapy, surgical resection is associated with encouraging survival. mPDAC patients with exceptional response to chemotherapy may be candidates for exploration and for resection in ypM0. Adjuvant chemotherapy may provide an additional survival advantage.

Blood-Based Diagnosis and Risk Stratification of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasm (IPMN).

PURPOSE: Intraductal papillary mucinous neoplasm (IPMN) is a precursor of pancreatic ductal adenocarcinoma. Low-grade dysplasia has a relatively good prognosis, whereas high-grade dysplasia and IPMN invasive carcinoma require surgical intervention. However, diagnostic distinction is difficult. We aimed to identify biomarkers in peripheral blood for accurate discrimination. EXPERIMENTAL DESIGN: Sera were obtained from 302 patients with IPMNs and 88 healthy donors. For protein biomarkers, serum samples were analyzed on microarrays made of 2,977 antibodies. A support vector machine (SVM) algorithm was applied to define classifiers, which were validated on a separate sample set. For microRNA biomarkers, a PCR-based screen was performed for discovery. Biomarker candidates confirmed by quantitative PCR were used to train SVM classifiers, followed by validation in a different sample set. Finally, a combined SVM classifier was established entirely independent of the earlier analyses, again using different samples for training and validation. RESULTS: Panels of 26 proteins or seven microRNAs could distinguish high- and low-risk IPMN with an AUC value of 95% and 94%, respectively. Upon combination, a panel of five proteins and three miRNAs yielded an AUC of 97%. These values were much better than those obtained in the same patient cohort by using the guideline criteria for discrimination. In addition, accurate discrimination was achieved between other patient subgroups. CONCLUSIONS: Protein and microRNA biomarkers in blood allow precise diagnosis and risk stratification of IPMN cases, which should improve patient management and thus the prognosis of IPMN patients. See related commentary by Löhr and Pantel, p. 1387.

Central pancreatectomy prevents postoperative diabetes.

BACKGROUND: Central pancreatectomy (CP) can be performed as an alternative surgical approach to distal pancreatectomy (DP) in the treatment of benign or low-grade malignant lesions located in the neck and body of the pancreas, aiming to reduce loss of parenchyma and therefore organ failure. The objective of this study was to evaluate the short- and long-term outcome of CP in comparison to DP. METHODS: Patients who received CP in a large tertiary care pancreatic surgery center between 2001 and 2020 were identified from a prospectively maintained database and compared via propensity score matching with patients receiving DP during the same time period. Perioperative rate of complications and long-term outcome of pancreatic endocrine and exocrine function were evaluated. RESULTS: One hundred and seven patients undergoing open CP were compared to 107 patients with open DP. No significant difference in rates or severity of most surgical complications could be found including postoperative pancreatic fistula, intraabdominal fluid collection, delayed gastric emptying and wound infection. However, patients receiving CP had a significantly higher risk of grade C postpancreatectomy hemorrhage (PPH) (CP: 10 patients, 9.3% versus DP: 1 patient, 0.9%; p = .0019). Perioperative mortality was comparable. Long-term follow-up of 60 matched pairs revealed significantly less patients with new-onset diabetes after CP (eight patients, 13.3%) compared to DP (22 patients, 36.7%, p = .0056). CONCLUSION: CP offers an improved endocrine long-term outcome at the expense of a higher risk of PPH without increased perioperative mortality. As evidence on this parenchyma sparing surgical technique is sparse, more prospective data are needed.

Presence of low-grade IPMN at the pancreatic transection margin does not have prognostic significance after resection of IPMN-associated pancreatic adenocarcinoma.

INTRODUCTION: Resection margin status is a well-established prognosticator in pancreatic cancer. The prognostic impact of IPMN dysplasia at the pancreatic transection margin in IPMN-associated carcinoma (IPMN-Ca) remains unclear, hence institutional practices on additional resections vary. METHODS: Patients undergoing partial pancreatectomy or attempted partial pancreatectomy converted to total pancreatectomy for IPMN-Ca between 04/2002 and 12/2018 were identified. Final pathology of the definitive pancreatic transection margin was identified. The association between the presence of IPMN dysplasia at the margin and overall survival (OS) was assessed. RESULTS: Of 302 patients with IPMN-Ca, 181 (59.9%) patients received partial pancreatoduodenectomy, 61 (20.2%) distal pancreatectomy, and 60 (19.9%) were converted to total pancreatectomy. Median OS was 98.6 months in R0 (≥1 mm), 39.3 months in R1 (<1 mm), and 22.0 months in R1(direct) resected patients, respectively (p < 0.0001). No IPMN dysplasia at the definitive margin was present in 103 (34.1%), low-grade in 131 (43.4%), and high-grade/R1 in 8 (2.6%) patients. Low-grade dysplasia or total pancreatectomy were not associated with shorter OS compared to dysplasia-free margin across the entire cohort. Sensitivity analyses confirmed a lack of prognostic relevance of low-grade IPMN dysplasia at the pancreatic margin in R0 resected IPMN-Ca and in R0 resected UICC stage IA/IB IPMN-Ca. CONCLUSIONS: Low-grade IPMN at the transection margin is not associated with shorter overall survival after partial pancreatectomy for IPMN-Ca. Additional resections for low-grade dysplasia, up to total pancreatectomy do not result in a survival benefit and should be omitted. Due to limited sample size, high-grade dysplasia could not be analyzed.

Glucocorticoid-induced microRNA-378 signaling mediates the progression of pancreatic cancer by enhancing autophagy.

Glucocorticoids (GCs) are widely used in tumor therapy to reduce tumor growth, inflammation, edema, and other side effects. Controversially, GCs may also cause the progression of highly aggressive pancreatic ductal adenocarcinoma (PDAC). Because microRNA (miR) and autophagy signaling support the invasive growth of PDAC, we asked whether these mechanisms may be targeted by GCs. Six established human PDAC cell lines, tissue from patients who received GC medication (n = 35) prior to surgery, or not (n = 35), and tumor xenografts were examined by RT‒qPCR, transmission electron microscopy (TEM), monodansylcadaverine (MDC) staining, immunohistochemistry, in situ hybridization, gene array and Kaplan‒Meier analysis with bioinformatics, and MTT, western blot, colony, spheroid, migration, and invasion assays. We found that various GCs, including dexamethasone (DEX), induced typical features of macroautophagy with the appearance of autolysosomes, enhanced LC3-II, decreased SQSTM1/p62 expression and induced epithelial-mesenchymal transition (EMT) and gemcitabine resistance. The GC receptor (GR) antagonist mifepristone (RU486) counteracted DEX-induced autophagy features, suggesting that the GC-GR complex is involved in the induction of autophagy. The autophagy-related miR-378i and miR-378a-3p were selected as the top upregulated candidates, and their high expression in PDAC patient tissue correlated with low survival. siRNA-mediated downregulation of miR-378 inhibited DEX-induced autophagy, and tumor progression. Bioinformatics confirmed the contribution of miR-378 to the regulation of signaling networks involved in GC-induced autophagy and tumor progression. The construction of a molecular docking model revealed stable binding of miR-378 to the DEX-GR complex, suggesting direct regulation. These substantial, novel, in-depth data reveal that GCs favor autophagy-mediated cancer progression by inducing miR-378 and GR binding and implicate GR and miR-378 as new therapeutic targets.

Tumor and stroma COL8A1 secretion induces autocrine and paracrine progression signaling in pancreatic ductal adenocarcinoma.

Several collagen subtypes are involved in pancreatic ductal adenocarcinoma (PDAC) desmoplasia, which constrains therapeutic efficacy. We evaluated collagen type VIII alpha 1 chain (COL8A1), whose function in PDAC is currently unknown. We identified COL8A1 expression in 7 examined PDAC cell lines by microarray analysis, western blotting, and RT‒qPCR. Higher COL8A1 expression occurred in 2 gemcitabine-resistant PDAC cell lines; pancreas tissue (n=15) from LSL-KrasG12D/+; p48-Cre mice with advanced PDAC predisposition; and PDAC parenchyma and stroma of a patient tissue microarray (n=82). Bioinformatic analysis confirmed higher COL8A1 expression in PDAC patient tissue available from TCGA (n=183), GTEx (n=167), and GEO (n=261) databases. siRNA or lentiviral sh-mediated COL8A1 inhibition in PDAC cells reduced migration, invasion and gemcitabine resistance and resulted in lower cytidine deaminase and thymidine kinase 2 expression and was rescued by COL8A1-secreting cancer-associated fibroblasts (CAFs). The activation of COL8A1 expression involved cJun/AP-1, as demonstrated by CHIP assay and siRNA inhibition. Downstream of COL8A1, activation of ITGB1 and DDR1 receptors and PI3K/AKT and NF-κB signaling occurred, as detected by expression, adhesion and EMSA binding studies. Orthotopic transplantation of PDAC cells with downregulated COL8A1 expression resulted in reduced tumor xenograft growth and lower gemcitabine resistance but was prevented by cotransplantation of COL8A1-secreting CAFs. Most importantly, COL8A1 expression in PDAC patient tissues from our clinic (n=84) correlated with clinicopathological data, and we confirmed these findings by the use of patient data (n=177) from the TCGA database. These findings highlight COL8A1 expression in tumor and stromal cells as a new biomarker for PDAC progression.