Lymph node examination and survival in resected pancreatic ductal adenocarcinoma: retrospective study.

BACKGROUND: The minimum number of examined lymph nodes (ELN) required for adequate staging and best prediction of survival has not been established in pancreatic ductal adenocarcinoma (PDAC). The aim of the study was to investigate the influence of ELN on staging and survival in PDAC. METHODS: Patients undergoing partial or total pancreatectomy for PDAC at two European university hospitals between 2007 and 2018 were retrospectively reviewed. Multivariate Cox regression model and survival analyses were performed to verify adequate staging. RESULTS: Overall 341 (73 per cent) patients showed lymph node metastasis (N1/N2), whereas 125 (27 per cent) patients had no lymph node involvement (N0). With increasing number of ELN, the proportion of positive lymph nodes increased. The minimum number of ELN needed to detect lymph node involvement was 21. In multivariate analysis, examination of <21 lymph nodes was a significant negative predictor for survival. Examination of ≥21 ELN reversed this effect and ruled out possible misclassification. CONCLUSION: The number of ELN affects survival in PDAC. Possible misclassification was identified when <21 lymph nodes were examined. Therefore, at least 21 lymph nodes must be examined to avoid false lymph node classification in all types of resection.

Continuous irrigation after pancreatectomy: a systematic review.

PURPOSE: Prevention and management of postoperative pancreatic fistula (POPF) after pancreatic resections is still an unresolved issue. Continuous irrigation of the peripancreatic area is frequently used to treat necrotizing pancreatitis, but its use after elective pancreatic surgery is not well-known. With this systematic review, we sought to evaluate the current knowledge and expertise regarding the use of continuous irrigation in the surgical area to prevent or treat POPF after elective pancreatic resections. METHODS: A systematic search of the literature was conducted according to the PRISMA 2020 guidelines, screening the databases of Pubmed, Scopus, Web of Science, and Ovid MEDLINE. Because of the heterogeneity of the included articles, a statistical inference could not be performed and the literature was reviewed only descriptively. The study was pre-registered online (OSF Registry). RESULTS: Nine studies were included. Three studies provided data regarding the prophylactic use of continuous irrigation after distal and limited pancreatectomies. Here, patients after irrigation showed a lower rate of clinically relevant POPF, related complications, lengths of stay, and mortality. Six other papers reported the use of local lavage to treat clinically relevant POPF and subsequent fluid collections, with successful outcomes. CONCLUSION: In the current literature, only a few publications are focused on the use of continuous irrigation after pancreatic resection to prevent or manage POPF. The included studies showed promising results, and this technique may be useful in patients at high risk of POPF. Further investigations and randomized trials are needed.

Bacterial content of the human pancreatic duct: An observational study.

Background: Pancreatic fistula/PF is a challenging surgical complication. We could recently show that intestinal bacteria such as Enterobacterales colonize the PF fluid even after a "sterile" operation like distal pancreatectomy/DP. Therefore, we explored the bacterial flora of the human pancreatic duct in a patient collective undergoing pancreatic surgery. Methods: In this observational study, upon transection of the pancreas during surgery, a swab was inserted into the main duct, and the micro-organismal content was correlated with clinical characteristics. Results: Between February 2017 and February 2020, an intraoperative swab from the pancreatic duct was obtained from a total of 54 patients who underwent pancreatico-duodenectomy/PD or DP. The swabs were sterile in 39 cases (72.2%), detected intestinal bacteria in 10 cases (18.5%), and other bacteria in 5 cases (9.3%). There was no correlation of the micro-organismal content of the pancreatic duct swab with bacteria detected in the PF fluid or bile. Preoperative ERCP was associated with a higher frequency of bacterial colonization of the pancreatic duct (33.3% vs. 6.7%, p = 0.005). There was no correlation of the pancreatic duct swabs with postoperative complications. Discussion: The human main pancreatic duct is usually sterile, and its bacterial colonization does not correlate with the occurrence of PF. Therefore, the mechanisms leading to infection of PF warrant in-depth, mechanistic investigation.

Regulatory T Cells in Pancreatic Cancer: Of Mice and Men.

Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of αSMA+ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8+ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.

The Effect of Celiac Neurolysis and Splanchnicectomy on Survival in Unresectable Pancreatic Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Intractable pancreatic pain is one of the most common symptoms of patients with pancreatic ductal adenocarcinoma (PDAC). Celiac neurolysis (CN) and splanchnicectomy were already described as effective methods to manage abdominal pain in unresectable PDAC, but their impact on overall survival (OS) has not yet been established. OBJECTIVE: We aimed to investigate the impact of CN and splanchnicectomy on the survival of patients with unresectable pancreatic cancer. METHODS: A systematic review of PubMed and Cochrane Library according to predefined searching terms was conducted in March 2020. Hazard ratios (HR) of OS data were calculated using the Mantel-Haenszel model for random effects or fixed effects. RESULT: Four randomized-controlled trials (RCTs) and 2 non-RCTs with a total of 2,507 patients were identified. The overall pooled HR did not reveal any relevant effect of CN and splanchnicectomy on OS (HR: 1.03; 95% CI: 0.81-1.32), which was also underlined by the sensitivity analysis of RCTs (HR: 1.0; 95% CI: 0.72-1.39) and non-RCTs (HR: 1.07; 95% CI: 0.71-1.63). However, subgroup analyses depending on tumor stage revealed that CN or splanchnicectomy was associated with a worsened OS in AJCC (American Joint Committee on Cancer) stage III patients with unresectable PDAC (HR: 1.22; 95% CI: 1.03-1.45), but nor for AJCC stage IV patients (HR: 1.27; 95% CI: 0.9-1.80). CONCLUSION: Although only few data are currently available, this systematic review with meta-analysis showed that in unresectable PDAC, CN or splanchnicectomy is associated with a worsened survival in stage III PDAC patients, with no effect on stage IV PDAC patients. These data call for caution in the usage of CN or splanchnicectomy in stage III PDAC and for further studies addressing this observation.

INR and not bilirubin levels predict postoperative morbidity in patients with malignant obstructive jaundice.

BACKGROUND: There are no established predictors for deciding between upfront surgery and PBD in pancreatic head malignancy. Once PBD is present, the ideal drainage-time remains elusive. The aim was, to identify predictors in jaundiced patients and ideal PBD-duration. METHODS: Analysis of 304 patients with pancreatic head malignancy (56% with PBD, n = 170) undergoing pancreaticoduodenectomy was performed. Postoperative morbidity and survival were analyzed. RESULTS: Postoperative complications increased after PBD (98.2% vs. 88.8%; p < 0.001). Patients with PBD received more postoperative antibiotics (42.4% vs. 21.6%; p < 0.001) and wound infections were increased (21.4% vs. 9.4%; p = 0.006). INR predicted postoperative morbidity (p = 0.026), whereas serum-bilirubin (p = 0.708), leucocytes (p = 0.158) and MELD-score (p = 0.444) had no impact. Complications were not different between long (>4 weeks) and short (<4 weeks) PBD-duration (p = 0.608). No life-threatening complications (CDIV + V) occurred after long drainage (0.0% vs. 8.9%; p = 0.028) and long-term survival was not compromised. CONCLUSIONS: INR is a suitable predictor for postoperative outcome, while serum-bilirubin levels had no predictive value. The INR can help deciding between PBD and upfront surgery. If PBD is inevitable, drainage duration of >4 weeks reduced major complications. CATEGORY: Clinical study.

Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation.

BACKGROUND: Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. METHODS: We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. RESULTS: We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. CONCLUSION: For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.

Do somatostatin-analogues have the same impact on postoperative morbidity and pancreatic fistula in patients after pancreaticoduodenectomy and distal pancreatectomy? - A systematic review with meta-analysis of randomized-controlled trials.

OBJECTIVE: Postoperative pancreatic fistula/POPF is the most feared complication in pancreatic surgery. Although several systematic reviews investigated the impact of somatostatin analogues on POPF, no stratification was performed regarding type of pancreatic resection (pancreaticoduodenectomy/PD; distal pancreatectomy/DP) and different somatostatin analogues. METHODS: This study was planed according to the Preferred-Reporting-Items-for-Systematic -Review-and-Meta-Analysis/PRISMA-guidelines. After screening databases for randomized controlled trials/RCT, studies were stratified into pancreatic resection techniques and data were pooled in meta-analyses containing subgroups of octreotide, somatostatin, lanreotide, pasireotide and vapreotide. RESULTS: The meta-analysis of studies with a mixed cohort of patients after pancreatic resection revealed a protective effect of somatostatin analogues for morbidity (RR: 0.71, p < .00001) but not for mortality (RR: 1.07, = 0.78) or intra-abdominal abscesses (RR: 1.00, p = 1.00). Moreover, no effect was visible for mortality (RR: 1.57, p = .15), morbidity (RR: 0.87, p = .15) and intra-abdominal abscesses (RR: 0.92, p = .48) after PD. The meta-analysis of patients after PD revealed no impact of somatostatin analogues on POPF (RR: 0.87, p = .19) and clinically relevant POPF (RR: 0.69, p = .30). However, treatment with somatostatin analogues in the mixed cohort showed less POPF (RR: 0.60, p < .00001) and clinically relevant POPF (RR: 0.47, p = .02), which was also the case after DP (RR: 0.41, p = .03). CONCLUSION: Somatostatin analogues did not affect POPF and clinically relevant POPF after PD, but seemed to be associated with less POPF after DP. As no sufficiently powered RCT could be identified by the systematic review, further RCTs are urgently needed to investigate the effect of somatostatin analogues after DP. STUDY REGISTRATION: CRD42018099808.