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Background Tumor growth encompasses multiple immunologic processes leading to impaired immunity. Regarding cancer surgery, the perioperative period is characterized by an additional immunosuppression that may contribute to poor outcomes. In this exploratory study, we assessed plasma parameters, characterizing the perioperative immunity with a particular focus on their prognostic value. Patients and methods 31 patients undergoing pancreatoduodenectomy were enrolled (adenocarcinoma of the pancreatic head and its periampullary region: n=24, benign pancreatic diseases n=7). Abundance and function of circulating immune cells and the plasma protein expression were analyzed in blood samples taken pre- and postoperatively using flow cytometry, ELISA and Proximity Extension Assay. Results Prior to surgery, an increased population of Tregs, a lower frequency of intermediate monocytes, a decreased portion of activated T-cells and a reduced response of T-cells to stimulation in vitro were associated with cancer. On the first postoperative day, both groups showed similar dynamics. The preoperative alterations did not persist six weeks postoperatively. Moreover, several preoperative parameters correlated with the postoperative survival. Conclusion Our data suggest systemic immunologic changes in adenocarcinoma patients, which are reversible six weeks after tumor resection. Additionally, the preoperative immune status affects the postoperative survival. In summary, our results implicate prognostic and therapeutic potential, justifying further trials on the perioperative tumor immunity to maximize the benefit of surgical tumor therapy.

Background Minimally invasive surgery is a field of rapid development. Evidence from randomized controlled trials in visceral surgery however still falls short of attesting unequivocal superiority to laparoscopic procedures over conventional open approaches with regard to postoperative outcome. The aim of this study was to explore the perioperative immune status of patients undergoing hybrid minimally invasive or conventional open pancreatoduodenectomy in a prospective cohort study. Material and methods Subtyping, quantification and functional analysis of circulating immune cells and determination of cytokine-levels in blood samples from patients receiving either hybrid minimally invasive (laPD) or conventional open pancreatoduodenectomy (oPD) was performed. Samples were taken from 29 patients (laPD: n = 14, oPD: n = 15) prior, during and up to six weeks after surgery. Cells were analyzed by flow cytometry, cytokines/chemokines were measured by proximity extension and enzyme-linked immunoassays. Results Open surgery induced higher levels of circulating inflammatory CD14++CD16+ intermediate monocytes. In contrast, hybrid minimally invasive resection was accompanied by increased numbers of circulating regulatory CD4+CD25+CD127low T-cells and by a reduced response of peripheral blood CD3+CD4+ T-cell populations to superantigen stimulation. Yet, rates of postoperative morbidity and infectious complications were similar. Conclusions In summary, the results of this exploratory study may suggest a more balanced postoperative inflammatory response and a better-preserved immune regulation after hybrid minimally invasive pancreatoduodenectomy when compared to open surgery. Whether these results may translate to or be harnessed for improved patient outcome needs to be determined by future studies including larger cohorts and fully laparoscopic or robotic procedures.

Purpose Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. Methods One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. Results Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p Conclusion Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

Introduction Pancreatic trauma (PT) involving the main pancreatic duct is rare, but represents a challenging clinical problem with relevant morbidity and mortality. It is generally classified according to the American Association for the Surgery of Trauma (AAST) and often presents as concomitant injury in blunt or penetrating abdominal trauma. Diagnosis may be delayed because of a lack of clinical or radiological manifestation. Treatment options for main pancreatic duct injuries comprise highly complex surgical procedures. Patients and Methods We retrospectively analyzed clinical data from 12 patients who underwent surgery in two tertiary centers in Germany during 2003–2016 for grade III-V PT with affection of the main pancreatic duct, according to the AAST classification. Results The median age was 23 (range: 7-44) years. In nine patients blunt abdominal trauma was the reason for PT, whereas penetrating trauma only occurred in three patients. MRI outperformed classical trauma CT imaging with regard to detection of duct involvement. Complex procedures as i.e. an emergency pancreatic head resection, distal pancreatectomy or parenchyma sparing pancreatogastrostomy were performed. Compared to elective pancreatic surgery the complication rate in the emergency setting was higher. Yet, parenchyma-sparing procedures demonstrated safety. Conclusions Often extension of diagnostics including MRI and/or ERP at an early stage is necessary to guide clinical decision-making. If, due to main duct injuries, surgical therapy for PT is required, we suggest consideration of an organ preservative pancreatogastrostomy in grade III/IV trauma of the pancreatic body or tail.

Objective We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs). Summary background data An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis. Methods Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice. Results Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice. Conclusions Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.

Detection and quantification of tumor-derived KRAS and NRAS mutations in plasma cell-free DNA (cfDNA) holds great potential for cancer diagnostics and treatment response monitoring. Because of high sensitivity, specificity, robustness, and affordability, digital droplet PCR (ddPCR) is ideally suited for this application but requires discriminatory multiplexing when used as screening assay. We therefore designed, optimized, and clinically validated mutation-specific locked nucleic acid–based ddPCR assays for 14 commonly occurring KRAS and NRAS mutations and assembled these assays into seven discriminatory multitarget screening assays covering two to six single-nucleotide variants each. Limit of detection, limit of blank, and interassay accuracy were determined. Assay performance and suitability for screening in cfDNA were validated with plasma samples from a clinically fully characterized cohort of pancreatic cancer patients and healthy controls. Limits of detection for single-target assays were between 0.0015% and 0.069% variant allele fraction, and between 0.022% and 0.16% for multitarget assays. Dilution linearity and interassay accuracy were excellent throughout (r2 > 0.99). Multitarget assay screening of cfDNA extracted from pancreatic cancer patients with unknown KRAS mutational status correctly identified single-nucleotide variants in 45 of 45 (100%) of tumor-derived cell-free DNA–positive samples. In summary, we herein present and clinically validate generic single-target and discriminatory multitarget ddPCR assays for KRAS and NRAS hot spot mutations with broad applicability for clinical and translational research.

Summary: Background: Many techniques have been developed to prevent postoperative pancreatic fistula (POPF) after distal pancreatectomy, but POPF rates remain high. The aim of our study was to analyze POPF occurrence after closure of the pancreatic remnant by different operative techniques. Methods: Between 2006 and 2017, 284 patients underwent distal pancreatectomy in our institution. For subgroup analysis the patients were divided into hand-sewn (n = 201) and stapler closure (n = 52) groups. The hand-sewn closure was performed in three different ways (fishmouth-technique, n = 27; interrupted transpancreatic U-suture technique, n = 77; common interrupted suture, n = 97). All other techniques were summarized in a separate group (n = 31). Results were gained by analysis of our prospective pancreatic database. Results: The median age was 63 (range 23–88) years. 74 of 284 patients (26%) were operated with spleen preservation (similar rates in subgroups). ASA-classes, median BMI as well as frequencies of malignant diseases, chronic pancreatitis, alcohol and nicotine abuse were also comparable in the subgroups. Neither the rates of overall POPF (fishmouth-technique 30%, common interrupted suture 40%, stapler closure 33% and interrupted U-suture 38%) nor the rates of POPF grades B and C showed significant differences in the subgroups. However is shown to be associated with pancreatic function and parenchymal texture. Conclusion: In our experience the technique of pancreatic stump closure after distal resection did not influence postoperative pancreatic fistula rate. As a consequence patient specific reasons rather than surgical techniques may be responsible for POPF formation after distal pancreatectomy. Keywords: Distal pancreatectomy, Postoperative pancreatic fistula, Hand-sewn, Stapler closure

Background Distal cholangiocarcinoma (DCC) is a rare malignancy and validated prognostic markers remain scarce. We aimed to evaluate the role of serum CA19-9 as a potential biomarker in DCC. Methods Patients operated for DCC at 6 high-volume surgical centers from 1994 to 2015 were identified from prospectively maintained databases. Patient baseline characteristics, surgical and histopathological parameters, as well as overall survival after resection were assessed for correlation with preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 (CA19-9). Preoperative CA19-9 to bilirubin ratio (CA19-9/BR) was classified as elevated (≥ 25 U/ml/mg/dl) according to the upper serum normal values of CA19-9 (37 U/ml) and bilirubin (1.5 mg/dl) giving a cut-off at ≥ 25 U/ml/mg/dl. Results In total 179 patients underwent resection for DCC during the study period. High preoperative CA19-9/BR was associated with advanced age and regional lymph node metastases. Median overall survival after resection was 27 months. Elevated preoperative serum CA19-9/bilirubin ratio (HR 1.6, p = 0.025), T3/4 stage (HR 1.8, p = 0.022), distant metastasis (HR 2.5, p = 0.007), tumor grade (HR 1.9, p = 0.001) and R status (HR 1.7, p = 0.023) were identified as independent negative prognostic factors following multivariable analysis. Conclusion Elevated preoperative bilirubin-adjusted serum CA19-9 correlates with regional lymph node metastases and constitutes a negative independent prognostic factor after resection of DCC.

Background This study evaluated the outcome and survival of patients with radiologically suspected intraductal papillary mucinous neoplasms (IPMNs). Methods IPMN management was reviewed according to Fukuoka risk factors and IPMN localization, differentiating main‐duct (MD), mixed‐type (MT) and branch‐duct (BD) IPMNs. Perioperative results were compared with those of patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) over the same interval (2010–2014). Overall (OS) and disease‐specific (DSS) survival rates were calculated and subgroups compared. Results Of 142 patients with IPMNs, 26 had MD‐IPMN, eight had MT‐IPMN and 108 had BD‐IPMN. Some 74 per cent of patients with MD‐ and MT‐IPMN were managed by primary resection, whereas this was used in only 27·8 per cent of those with BD‐IPMN. The risk of secondary resection and malignant transformation for BD‐IPMNs smaller than 20 mm was 8 and 2 per cent respectively during follow‐up. Pancreatic head resection of IPMNs was associated with an increased risk of postoperative pancreatic fistula grade B/C compared with resection of PDAC (12 of 33 (36 per cent) versus 41 of 221 (18·6 per cent) respectively; P = 0·010), and greater morbidity and mortality (Clavien–Dindo grade III: 15 of 33 (45 per cent) versus 56 of 221 (25·3 per cent) respectively; grade IV: 1 (3 per cent) versus 7 (3·2 per cent); grade V: 2 (6 per cent) versus 2 (0·9 per cent); P = 0·008). Five‐year OS and DSS rates in patients with MD‐IPMN were worse than those for MT‐ and BD‐IPMN (OS: 44, 86 and 97·4 per cent respectively, P

Postoperative local infection is a major complication after pancreatic surgery. The aim of this prospective clinical trial was to assess the potential of moxifloxacin (MXF) to treat pancreatic infections from a pharmacokinetic (PK)/pharmacodynamic (PD) perspective. The PK of MXF in serum and pancreatic juice, via an inserted tube in the pancreatic duct, was determined in 19 patients up to day 7 after pancreatoduodenectomy. PK data in both specimens was analyzed with NONMEM 7.3. Intraoperative swipes were performed for microbiological examination. PK/PD target attainment was assessed in both matrices using unbound area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) targets of ≥30 and ≥100, for gram-positive and gram-negative pathogens, respectively. A 2-compartment population PK model in which the measurements in pancreatic juice were assigned to a scaled peripheral compartment best described the PK in both specimens simultaneously. Median (10th-90th percentile) area under the plasma concentration-time curve values after the third dose were 28.9 mg · h/L (18.6-42.0) in serum and 55.8 mg · h/L (23.7-81.4) in pancreatic juice. Target attainment rate for the intraoperatively isolated bacterial strains was ≥0.88 after the third MXF dose. For gram-negatives, high probability of target attainment ≥0.84 was observed in serum for MIC ≤ 0.125 mg/L and in pancreatic juice for MIC ≤ 0.25 mg/L. For gram-positives, the probability of target attainment was 0.84-1 in serum for MIC ≤ 0.5 mg/L and in pancreatic juice for MIC ≤ 1 mg/L. In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies.

Background Bio‐absorbable sealants are widely used to reduce the rate and severity of postoperative pancreatic fistulas after distal pancreatectomy. However, numerous clinical trials have failed to demonstrate their clinical benefit. We therefore investigated stability and bio‐compatibility of absorbable sealants in vitro and in vivo. Methods In vitro, polymerized compounds were incubated in pancreatic juice before their stability was tested. In vivo, two compounds were used to seal the pancreatic stump after distal pancreatectomy in nine pigs. Burst pressure of the pancreatic stump, surgical outcome, histology of the pancreatic stump, systemic inflammation, and drain fluid was examined. Results Products based on fibrin or collagen were unstable in the presence of active pancreatic enzymes and completely dissolved within 2 h. Sealants using chemical cross‐linking of proteins showed improved stability for 7 days. In vivo, application of polyethylenglycol‐based sealant leads to complete closure of the pancreatic duct after 5 days, while a glutaraldehyde‐based sealant prevented physiological closure of the pancreatic main duct. Conclusions Many compounds used clinically to reinforce the pancreatic stump after distal pancreatectomy are inadequate due to instability in the presence of pancreatic enzymes. While selected bio‐absorbable sealants inhibited the natural healing of the pancreatic stump, polyethylenglycol‐based sealants should be tested in further clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies with poor survival rates. Only 20% of the patients are eligible for R0-surgical resection, presenting with early relapses, mainly in the liver. PDAC patients with hepatic metastases have a worse outcome compared to patients with metastases at other sites. Early detection of hepatic spread bears the potential to improve patient outcomes. Thus, this study sought for serum-based perioperative biomarkers allowing discrimination of early (EHMS ≤ 12 months) and late hepatic metastatic spread (LHMS > 12 months). Serum samples from 83 resectable PDAC patients were divided into EHMS and LHMS and analyzed for levels of inflammatory mediators by LEGENDplexTM, which was validated and extended by Olink® analysis. CA19-9 serum levels served as control. Results were correlated with clinicopathological data. While serum CA19-9 levels were comparable, Olink® analysis confirmed distinct differences between both groups. It revealed significantly elevated levels of factors involved in chemotaxis and migration of immune cells, immune activity, and cell growth in serum of LHMS-patients. Overall, Olink® analysis identified a comprehensive biomarker panel in serum of PDAC patients that could provide the basis for predicting LHMS. However, further studies with larger cohorts are required for its clinical translation.

Background Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19–9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. Methods Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19–9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. Results Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19–9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19–9 levels outperformed either individual marker. cfKRASmut outperformed CA 19–9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. Conclusions Integrated analysis of cfKRASmut and CA 19–9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker’s specific potential.

4008 Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p

BACKGROUND: Sclerosing angiomatoid nodular transformation (SANT) is a rare benign disease of the spleen with unknown origin. Clinical symptoms are inhomogeneous, and suspicious splenic lesion often found incidentally, leading to splenectomy, as malignancy cannot securely be ruled out. Diagnosis is made histologically after resection. CASE SUMMARY: Two cases of German, white, non-smoking, and non-drinking patients of normal weight are presented. The first one is a 26-year-old man without medical history who was exhibiting an undesired weight loss of 10 kg and recurring vomiting for about 18 mo. The second one is a 65-year-old woman with hypertension who had previously undergone gynecological surgery, suffering from a lasting feeling of abdominal fullness. Both showed radiologically an inhomogeneous splenic lesion leading to splenectomy approximately 6 and 9 wk after surgical presentation. Both diagnoses of SANT were made histologically. Follow-up went well, and both were treated according to the recommendation for asplenic patients. CONCLUSION: SANT is a rare cause of splenectomy and an incidental histological finding. Further research should focus on clinical and radiological diagnosis of SANT as well as on treatment of patients with asymptomatic and small findings.

Importance Morbidity is still high in pancreatic surgery, driven mainly by gastrointestinal complications such as pancreatic fistula. Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are frequently used for pain control after pancreatic surgery. Evidence from a post hoc analysis suggests that PCIA is associated with fewer gastrointestinal complications. Objective To determine whether postoperative PCIA decreases the occurrence of gastrointestinal complications after pancreatic surgery compared with EDA. Design, Setting, and Participants In this adaptive, pragmatic, international, multicenter, superiority randomized clinical trial conducted from June 30, 2015, to October 1, 2017, 371 patients at 9 European pancreatic surgery centers who were scheduled for elective pancreatoduodenectomy were randomized to receive PCIA (n = 185) or EDA (n = 186); 248 patients (124 in each group) were analyzed. Data were analyzed from February 22 to April 25, 2019, using modified intention to treat and per protocol. Interventions Patients in the PCIA group received general anesthesia and postoperative PCIA with intravenous opioids with the help of a patient-controlled analgesia device. In the EDA group, patients received general anesthesia and intraoperative and postoperative EDA. Main Outcomes and Measures The primary end point was a composite of pancreatic fistula, bile leakage, delayed gastric emptying, gastrointestinal bleeding, or postoperative ileus within 30 days after surgery. Secondary end points included 30-day mortality, other complications, postoperative pain levels, intraoperative or postoperative use of vasopressor therapy, and fluid substitution. Results Among the 248 patients analyzed (147 men; mean [SD] age, 64.9 [10.7] years), the primary composite end point did not differ between the PCIA group (61 [49.2%]) and EDA group (57 [46.0%]) (odds ratio, 1.17; 95% CI, 0.71-1.95P = .54). Neither individual components of the primary end point nor 30-day mortality, postoperative pain levels, or intraoperative and postoperative substitution of fluids differed significantly between groups. Patients receiving EDA gained more weight by postoperative day 4 than patients receiving PCIA (mean [SD], 4.6 [3.8] vs 3.4 [3.6] kg;P = .03) and received more vasopressors (46 [37.1%] vs 31 [25.0%];P = .04). Failure of EDA occurred in 23 patients (18.5%). Conclusions and Relevance This study found that the choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding gastrointestinal complications because the 2 procedures are comparable with regard to effectiveness and safety. However, EDA was associated with several shortcomings. Trial Registration German Clinical Trials Register:DRKS00007784

Background Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. Discussion The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. Trial registration ClinicalTrials.gov : NCT02047513, 08/13/2014. Open-Access-Publikationsfonds 2018

Laparoscopic resections of the pancreatic head are increasingly performed. Several studies show that they are comparable to open operations in terms of postoperative morbidity. However, since a substantial proportion of pancreatic head resections are necessary for pancreatic adenocarcinoma the oncologic safety and outcome of minimally invasive operations is of interest. In this study we evaluated oncologic outcome and survival after laparoscopically assisted pancreatic head resection for ductal adenocarcinoma.Perioperative and oncological outcome of sixty-two laparoscopically assisted pancreatic head resections for pancreatic ductal adenocarcinoma performed between 2010 and 2016 was compared to outcome of 278 open resections between 2001 and 2016 in a retrospective study. Data was continuously collected in a prospectively maintained database.Operation time was significantly longer in the laparoscopic group (477 vs. 428 min. p 0.001). Tumor size, lymph node yield and lymph node state and need of portal vein resection were comparable. There was a higher rate of free resection margins in the laparoscopic group (87% vs. 71%, p 0.01). There was no difference in postoperative mortality and morbidity. Patients with laparoscopic resection stayed in hospital significantly shorter (median 14 vs. 16 days, p 0.003). Postoperative survival after 5 years was not different in both groups.Laparoscopically assisted resection of adenocarcinoma of the pancreatic head is equal to open resection concerning oncologic outcome and actuarial survival. However, minimally invasive resection shortened the hospital stay. However, further evaluations with a longer follow up time are needed.

Zusammenfassung Hintergrund Die Resektion großer Weichteilsarkome erfordert die Rekonstruktion mit freiem Gewebstransfer. Hierbei stellt die Selektion geeigneter Anschlussgefäße einen entscheidenden Faktor für den operativen Erfolg dar. Patienten Wir berichten über vier Fälle mit sehr großen Tumoren und mit besonders komplexem anatomischem Bezug: zwei Sarkome in der Leiste mit Infiltration der Gefäß-Nervenstraße und zwei Sarkome in der Flanke mit ausgedehnter thorakoabdomineller und viszeraler Beteiligung. In allen Fällen erfolgten interdisziplinäre Operationen innerhalb eines multimodalen Therapieansatzes. In zwei Fällen wurde ein anterolateraler Oberschenkellappen (ALT) und in zwei ein myokutaner Latissimus Dorsi (LD) Lappen zur Defektdeckung benutzt. In allen Fällen erfolgte eine epifasziale Verlagerung der tiefen inferioren epigastrischen Gefäße zum mikrochirurgischen Gefäßanschluss. Ergebnisse Die durchschnittliche Operationszeit betrug 694 ± 149 Minuten. Das mittlere Resektatgewicht war 3069 ± 1267 g. Drei Lappenplastiken heilten primär ein, in einem Fall kam es zu einer Spitzennekrose, welche operativ behandelt wurde. Schlussfolgerung Die Verlagerung der tiefen inferioren epigastrischen Gefäßen nach epifaszial stellt in dieser selektionierten Gruppe eine gute Option zum Anschluss freier Lappen dar. Aufgrund der oberflächlichen Lage ist die Durchführung der Anastomose erleichtert. Insbesondere bei großen Defekten mit bestrahltem Lager erweitert diese technische Modifikation die rekonstruktiven Optionen.

Extracellular vesicles (EVs) contain various bioactive molecules such as DNA, RNA, and proteins, and play a key role in the regulation of cancer progression. Furthermore, cancer-associated EVs carry specific biomarkers and can be used in liquid biopsy for cancer detection. However, it is still technically challenging and time consuming to detect or isolate cancer-associated EVs from complex biofluids (e.g., blood). Here, a novel EV-capture strategy based on dip-pen nanolithography generated microarrays of supported lipid membranes is presented. These arrays carry specific antibodies recognizing EV- and cancer-specific surface biomarkers, enabling highly selective and efficient capture. Importantly, it is shown that the nucleic acid cargo of captured EVs is retained on the lipid array, providing the potential for downstream analysis. Finally, the feasibility of EV capture from patient sera is demonstrated. The demonstrated platform offers rapid capture, high specificity, and sensitivity, with only a small need in analyte volume and without additional purification steps. The platform is applied in context of cancer-associated EVs, but it can easily be adapted to other diagnostic EV targets by use of corresponding antibodies.

Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed müllerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible.

BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + ( P = .030), positive M status ( P 0.1 ( P = .045) to impair overall survival. Independent prognostic factors were CAF grade ( P = .050) and positive M status ( P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = −0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation–dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.

Background Pancreatic metastasis is a rare cause for pancreas surgery and often a sign of advanced disease no chance of curative-intent treatment. However, surgery for metastasis might be a promising approach to improve patients’ survival. The aim of this study was to analyze the surgical and oncological outcome after pancreatic resection of pancreatic metastasis. Methods This is a retrospective cohort analysis of a prospectively-managed database of patients undergoing pancreatic resection at the University of Freiburg Pancreatic Center from 2005 to 2017. Results In total, 29 of 1297 (2%) patients underwent pancreatic resection due to pancreatic metastasis. 20 (69%) patients showed metastasis of renal cell carcinoma (mRCC), followed by metastasis of melanoma (n = 5, 17%), colon cancer (n = 2, 7%), ovarian cancer (n = 1, 3%) and neuroendocrine tumor of small intestine (n = 1, 3%). Two (7%) patients died perioperatively. Median follow-up was 76.4 (range 21–132) months. 5-year and overall survival rates were 82% (mRCC 89% vs. non-mRCC 67%) and 70% (mRCC 78% vs. non-mRCC 57%), respectively. Patients with mRCC had shorter disease-free survival (14 vs. 22 months) than patients with other primary tumor entities. Conclusion Despite malignant disease, overall survival of patients after metastasectomy for pancreatic metastasis is acceptable. Better survival appears to be associated with the primary tumor entity. Further research should focus on molecular markers to elucidate the mechanisms of pancreatic metastasis to choose the suitable therapeutic approach for the individual patient.

Ion mobility coupling to mass spectrometry facilitates enhanced identification certitude. Further coupling to liquid chromatography results in multi-dimensional analytical methods, especially suitable for complex matrices with structurally similar compounds. Modified nucleosides represent a large group of very similar members linked to aberrant proliferation. Besides basal production under physiological conditions, they are increasingly excreted by transformed cells and subsequently discussed as putative biomarkers for various cancer types. Here, we report a method for modified nucleosides covering 37 species. We determined collisional cross-sections with high reproducibility from pure analytical standards. For sample purification, we applied an optimized phenylboronic acid solid-phase extraction on media obtained from four different pancreatic cancer cell lines. Our analysis could discriminate different subtypes of pancreatic cancer cell lines. Importantly, they could clearly be separated from a pancreatic control cell line as well as blank medium. m1A, m27G, and Asm were the most important features discriminating cancer cell lines derived from well-differentiated and poorly differentiated cancers. Eventually, we suggest the analytical method reported here for future tumor-marker identification studies. Graphical abstract.

Background: Perioperative thoracic epidural analgesia (EDA) and patient-controlled intravenous analgesia (PCIA) are frequently used for pain control after pancreatic surgery. However, there is substantial uncertainty regarding the postoperative morbidity associated with these two strategies. Evidence from a post-hoc analysis suggests that PCIA is associated with fewer gastrointestinal complications. Therefore, we designed the multicentre PAKMAN trial to compare the occurrence of gastrointestinal complications after pancreatic surgery with PCIA versus EDA. Methods: We conducted an adaptive, pragmatic, randomised, controlled, international, multicentre, superiority trial in nine European pancreatic surgery centres. Adult patients scheduled for elective pancreatic surgery were randomised to general anaesthesia with postoperative PCIA or general anaesthesia with intra- and postoperative EDA. The primary endpoint was a composite of pancreatic fistula, bile leakage, delayed gastric emptying, gastrointestinal bleeding, or postoperative ileus within 30 days after surgery. The trial was prospectively registered (DRKS00007784). Findings: Between 30 June 2015 and 1 October 2017, 371 patients were randomly assigned to PCIA (n=185) or EDA (n=186); 248 patients (124 in each group) were analysed. The primary composite endpoint did not differ between the two groups (OR 1⋅174, 95% CI 0⋅707-1⋅949; p=0⋅536). Neither individual components of the primary endpoint nor 30-day mortality, postoperative pain levels, or intra- and postoperative substitution of fluids differed significantly. Patients with EDA gained more weight by postoperative day 4 and received more vasopressors. The failure rate of EDA was 18⋅5%. Interpretation: The choice between PCIA and EDA for pain control after pancreatic surgery should not be based on concerns regarding gastrointestinal complications. The two procedures are comparable with regard to effectiveness and safety. However, EDA was associated with several shortcomings. Trial Registration: The PAKMAN trial was registered with the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS; number DRKS00007784) on 23 March 2015. Funding Statement: Dietmar Hopp Stiftung gGmbH, Raiffeisenstr. 51, 68789 St. Leon-Rot, Germany (project number 23011217). Declaration of Interests: All authors declare that they have no conflicts of interest in relation to this trial. None of the authors has had any financial and personal relationships with funding bodies or any other people or organisations that could inappropriately influence their work within this project. Ethics Approval Statement: The PAKMAN trial protocol and other relevant documents were approved by the ethics committee of the Medical Faculty of Heidelberg University and the individual ethics committees of all other participating institutions before the first patient was enrolled. The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and the principles of Good Clinical Practice (ICH-GCP E6). Reporting of the trial complied with the recommendations of the CONSORT statement.

International audience; OBJECTIVE: The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC. METHODS: This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival. RESULTS: In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200?mL (60-400) vs 300?mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P \textless 0.001] were lower after MIDP. Clavien-Dindo grade >=3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P \textgreater 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P \textless 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P \textless 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929). CONCLUSIONS: Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

Morbidity after pancreas resection is still high with postoperative pancreatic fistulas (POPF) being the most frequent complication. However, exocrine insufficiency seems to protect from POPF. In clinical practice, patients showing increased postoperative systemic amylase concentrations appear to frequently develop POPF. We therefore retrospectively examined the occurrence of systemic amylase increase after pancreas resections and its association with the clinical course. Perioperative data from 739 consecutive pancreas resections were assessed in a prospectively maintained SPSS database. Serum and drain amylase concentrations were determined by routine clinical chemistry. POPFs were graded into A–C according to ISGPF definitions. In patients with reduced serum amylase (n = 89) on day 1 after pancreatoduodenectomy, clinically relevant POPFs were not observed. In patients with normal serum amylase concentrations, clinically relevant POPFs occurred in 9 %, while in 39 % of the patients with more than three times elevated amylase concentrations, a clinically relevant postoperative fistula was observed (p

The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas. Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome. At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP. LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

Nodal status is a strong prognostic factor after resection of pancreatic cancer. The lymph node ratio (LNR) has been shown to be superior to the pN status in several studies. The role of log odds of the ratio between positive and negative nodes (LODDS) as a suggested new indicator of prognosis, however, has been hardly evaluated in pancreatic cancer. Prognostic factors for overall survival after resection for cancer of the pancreatic head were evaluated in 409 patients from two institutions (prospectively maintained databases). The lymph node status, LNR, and LODDS were separately analyzed and independently compared in multivariate survival analysis. The median numbers of examined and positive lymph nodes were 16 and 2, respectively. Actuarial 3- and 5-year survival rates were 29 and 16 %. All three classifications of nodal disease significantly predicted survival in the entire group (n = 409), in patients with free resection margins (n = 297), and in patients with

Pancreatoduodenectomy (PD) with superior mesenteric/portal venous resection (PVR) for pancreatic ductal adenocarcinoma (PDAC) is performed routinely in case of tumor adhesion to the superior mesenteric or portal vein. True histopathological portal vein invasion (PVI) is found in a subgroup of patients. Even though this procedure has become routine in most centers for pancreatic surgery, data on prognostic factors in this situation is limited. The aim of this study was to identify prognostic factors after PD with PVR for PDAC. Retrospective analysis was performed on the basis of a prospectively maintained database, and paraffin-embedded formalin-fixed tissue slides stained for hematoxylin-eosin were re-evaluated by two independent pathologists. Statistical analysis was conducted using MedCalc software. From 2001 to 2012, 86 cases of PD with PVR for PDAC with long-term follow-up and sufficient tissue for re-assessment were identified. Histopathological re-review disclosed PVI in 39 resection specimens and adhesion without infiltration in 47. Overall median survival in all patients was 22 months. Patients with PVI versus no PVI showed comparable baseline demographic and standard histopathological parameters; however, PVI was associated with microscopic hemangiosis (p = 0.001) and positive margin status (p = 0.001). Median survival in patients with PVI was 14 months versus 25 months in patients without PVI (p = 0.042). Only lymph node ratio and PVI were independent predictors of survival after resection. The only independent factors influencing overall survival after PD with PVR for PDAC were lymph node ratio and PVI. PVI might indicate aggressive tumor biology, but the available data remains controversial.

We describe the clinical history, outcome, and toxicity of five patients with high-grade retroperitoneal soft tissue sarcoma (RSTS) who were treated with neoadjuvant low-dose radiotherapy (RT) followed by resection with or without intraoperative radiotherapy (IORT), followed by adjuvant RT. We aim to provide additional evidence for the various treatment options that exist for this rare tumor entity.Most patients presented with mild abdominal symptoms. Diagnosis was confirmed by biopsy. Additional imaging was done by sonography, magnetic resonance imaging (MRI), and/or positron emission tomography (PET)/computed tomography (CT). All patients were treated with neoadjuvant RT of 19.8 Gy in 1.8-Gy fractions followed by resection and postoperative RT up to 45 Gy with a median interval between resection and start of postoperative RT of 5 weeks. Two patients received additional IORT. Median follow-up was 61 months.One patient developed a local recurrence that was diagnosed 30 months after the start of the first therapy. He was treated with a salvage resection and had no evidence of disease at the last follow-up. Another patient developed a right-sided RSTS on the contralateral side from the primary radiation field with pelvic bone infiltration 56 months after the start of RT. He was treated again by RT and resection and was without evidence of disease at last follow-up. Radiotherapy was well tolerated without major toxicity.The treatment of RSTS by low-dose neoadjuvant RT, resection with IORT and adjuvant RT seems to be a feasible and effective treatment approach. Further studies comparing neoadjuvant with adjuvant RT are necessary to find the best treatment option.HINTERGRUND: Die vorliegende Studie beschreibt den klinischen Verlauf, die Ergebnisse und Nebenwirkungen bei fünf Patienten mit retroperitonealen „High-grade“-Weichteilsarkomen (RSTS), die mit einer neoadjuvanten Niedrigdosis-Strahlentherapie (RT) gefolgt von Resektion mit oder ohne intraoperativer Strahlentherapie (IORT) und einer adjuvanten Strahlentherapie behandelt wurden.Die meisten Patienten stellten sich mit leichten abdominellen Symptomen vor. Die Diagnose wurde durch eine Biopsie gestellt. Bildgebung wurde mittels Sonographie, Magnetresonanztomographie (MRT) und/oder Positronenemissionstomographie (PET)/Computertomographie (CT) durchgeführt. Alle Patienten wurden mit einer neoadjuvanten RT von 19,8 Gy in Fraktionen mit 1,8 Gy gefolgt von der Resektion und postoperativen RT mit 45 Gy behandelt. Das mittlere Intervall zwischen Resektion und postoperativer RT betrug 5 Wochen. Zwei Patienten erhielten eine zusätzliche IORT. Die mediane Nachbeobachtungszeit betrug 61 Monate.Bei einem Patienten kam es zum Auftreten eines Lokalrezidivs 30 Monate nach Therapiebeginn. Das Rezidiv wurde mit einer Resektion behandelt. Bei der letzten Nachsorgeuntersuchung gab es keine Anzeichen eines Rezidivs. Bei einem anderen Patienten trat ein kontralaterales Sarkom mit Knocheninfiltration 56 Monate nach Therapiebeginn auf. Es wurden eine erneute RT und Resektion durchgeführt. Bei der letzten Nachuntersuchung gab es keine Hinweise auf ein Rezidiv. Die Bestrahlung wurde insgesamt sehr gut vertragen.Die Therapie von RSTS mit neoadjuvanter Niedrigdosis-RT, Resektion mit IORT und adjuvanter RT ist eine gut verträgliche und effektive Behandlungsoption. Weitere Studien, die eine neoadjuvante mit einer adjuvanten RT vergleichen, sind notwendig.

ENETS guidelines recommend parenchyma-sparing procedures without formal lymphadenectomy, ideally with a minimally invasive laparoscopic approach for sporadic small pNENs (≤2 cm). Non-functioning (NF) small pNENs can also be observed. The aim of the study was to evaluate how these recommendations are implemented in the German surgical community. Data from the prospective StuDoQ|Pancreas registry of the German Society of General and Visceral Surgery were analyzed regarding patient’s demographics, tumor characteristics, surgical procedures, histology and perioperative outcomes. Eighty-four (29.2%) of 287 patients had sporadic pNENs ≤2 cm. Forty-three (51.2%) patients were male, and the mean age at diagnosis was 58.8 ± 15.6 years. Twenty-five (29.8%) pNENs were located in the pancreatic head. The diagnosis pNEN was preoperatively established in 53 (65%) of 84 patients. Sixty-two (73.8%) patients had formal pancreatic resections, including partial pancreaticoduodenectomy or total pancreatectomy (21.4%). Only 22 (26.2%) patients underwent parenchyma-sparing resections and 23 (27.4%) patients had minimally invasive procedures. A lymphadenectomy was performed in 63 (75.4%) patients, and lymph node metastases were diagnosed in 6 (7.2%) patients. Eighty-two (97.7%) patients had an R0 resection. Sixty (72%) tumors were classified G1, 24 (28%) tumors G2. Twenty-seven (32.2%) of 84 patients had postoperative relevant Clavien–Dindo grade ≥3 complications. Thirty- and 90-day mortalities were 2.4% and 3.6%. ENETS guidelines for surgery of small pNENs are yet not well accepted in the German surgical community, since the rate of formal resections with standard lymphadenectomy is high and the minimally invasive approach is underused. The attitude to operate small NF tumors seems to be rather aggressive.

The association between inflammation and the risk of colorectal cancer (CRC) is well documented in animal models and in humans, but the mechanistic role of inflammation in CRC is less well understood. To address this question, the induction of colon tumors was evaluated in (i) wild type (WT) and athymic BALB/c mice treated with the colon carcinogen azoxymethane (AOM) as a single agent, and (ii) in an inflammation model of colon cancer employing AOM and dextran sodium sulfate (DSS) in WT, athymic, TCRβ(-/-) , TCRδ(-/-) and TCRβ(-/-) TCRδ(-/-) C57Bl/6 mice. The athymic BALB/c mice treated with only AOM developed 90% fewer tumors than the WT mice. The difference in response was not due to metabolic activation of AOM or repair of DNA adducts. In the inflammation model using a standard sequential exposure to AOM followed by DSS treatment, the tumor incidence in WT mice was 58% with 7 adenomas and 6 adenocarcinomas. In contrast, the TCRβ(-/-) , TCRδ(-/-) and TCRβ(-/-) TCRδ(-/-) C57Bl/6 mice showed adenoma incidences of 10, 33, and 11%, respectively, and none of the immune compromised mice developed adenocarcinomas. When the DSS exposure was increased and the AOM lowered, no difference was observed between WT and TCRβ(-/-) mice due to an increase in the incidence in the TCR null mice without concomitant increase in the WT mice. No tumors were observed in mice treated with AOM or DSS alone. © 2015 Wiley Periodicals, Inc.

The value of extended resection (portal vein, multivisceral) in patients with pancreatic adenocarcinoma (PDAC) is not well defined. We analyzed the outcome after standard resection (standard pancreaticoduodenectomy (SPR)), additional portal vein (PV) and multivisceral (MV) resection in PDAC patients.Clinicopathologic, perioperative, and survival data of patients undergoing pancreatic head resection (PHR) for PDAC 1994-2014 were reviewed from a prospective database.Three hundred fifty nine patients had PHR for PDAC: 208 (58 %) underwent SPR, 131 (36 %) additional PV, and 20 (6 %) MV. The postoperative complication rate in MV (65 %) was slightly higher than in PV (56 %) or SPR (50 %; p = 0.32). MV patients had higher in-hospital mortality (10 %) than SPR (3.8 %) and PV (1.5 %) patients (p = 0.12). Nodal status was comparable, whereas more patients in PV and MV had final R0 resection (p = 0.02). Five-year survival was 7 % after MV versus 17 % in patients without MV (p = 0.07). Multivariate survival analysis identified resection margin, nodal disease, blood transfusions, and MV are set as independent risk factors for overall survival.Multivisceral pancreatic head resections for PDAC are associated with increased perioperative morbidity and mortality, without improving oncologic outcome. Portal vein resection can be performed safely to reach R0 resection and its survival benefits.

Summary Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference −2·3, 95% CI −6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. Funding German Research Foundation (DFG).