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Introduction Survival after surgery of pancreatic cancer is still poor, even after curative resection. Some prognostic factors like the status of the resection margin, lymph node (LN) status, or tumor grading have been identified. However, only few data have been published regarding the prognostic influence of the LN ratio (number of LN involved to number of examined LN). We, therefore, evaluated potential prognostic factors in 182 patients after resection of pancreatic cancer including assessment of LN ratio. Methods Since 1994, 204 patients underwent pancreatic resection for ductal pancreatic adenocarcinoma. Survival was evaluated in 182 patients with complete follow-up evaluations. Of those 182 patients, 88% had cancer of the pancreatic head, 5% of the body, and 7% of the pancreatic tail. Patients underwent pancreatoduodenectomy (85%), distal resection (12%), or total pancreatectomy (3%). Survival was analyzed by the Kaplan–Meier and Cox methods. Results In all 204 resected patients, operative mortality was 3.9% ( n  = 8). In the 182 patients with follow-up, 70% had free resection margins, 62% had G1- or G2-classified tumors, and 70% positive LN. Median tumor size was 30 (7–80) mm. The median number of examined LN was 16 and median number of involved LN 1 (range 0–22). Median LN ratio was 0.1 (0–0.79). Cumulative 5-year survival (5-year SV) in all patients was 15%. In univariate analysis, a LN ratio ≥ 0.2 (5-year SV 6% vs. 19% with LN ratio < 0.2; p  = 0.003), LN ratio ≥ 0.3 (5-year SV 0% vs. 18% with LN ratio < 0.3; p  < 0.001), a positive resection margin ( p  < 0.01) and poor differentiation (G3/G4; p  < 0.03) were associated with poorer survival. In multivariate analysis, a LN ratio ≥ 0.2 ( p  < 0.02; relative risk RR 1.6), LN ratio ≥ 0.3 ( p  < 0.001; RR 2.2), positive margins ( p  < 0.02; RR 1.7), and poor differentiation ( p  < 0.03; RR 1.5) were independent factors predicting a poorer outcome. The conventional nodal status or the number of examined nodes (in all patients and in the subgroups of node positive or negative patients) had no significant influence on survival. Patients with one metastatic LN had the same outcome as patients with negative nodes, but prognosis decreased significantly in patients with two or more LN involved. Conclusions Not the lymph node involvement per se but especially the LN ratio is an independent prognostic factor after resection of pancreatic cancers. In our series, the LN ratio was even the strongest predictor of survival. The routine estimation of the LN ratio may be helpful not only for the individual prediction of prognosis but also for the indication of adjuvant therapy and herein related outcome and therapy studies.

Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT‐activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR‐203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR‐203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism‐based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer. Synopsis Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells. Strategy to counteract the well‐known cancer‐promoting functions of the EMT inducer ZEB1. Identification of the stemness‐inhibiting microRNA miR‐203 as major ZEB1 target inducing drug sensitivity. Identification of the class I HDAC inhibitor mocetinostat as drug to interfere with ZEB1 function and overcome ZEB1‐associated drug resistance. Mocetinostat has better effects in combination with chemotherapeutics compared to other HDACis, such as SAHA. Blueprint for further drug screens with reduction in ZEB1 function as major readout. Graphical Abstract Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells.

Background The aim of this single-center randomized trial was to compare the perioperative outcome of pancreatoduodenectomy with pancreatogastrostomy (PG) vs pancreaticojejunostomy (PJ). Methods Randomization was done intraoperatively. PG was performed via anterior and posterior gastrotomy with pursestring and inverting seromuscular suture; control intervention was PJ with duct–mucosa anastomosis. The primary endpoint was postoperative pancreatic fistula (POPF). Results From 2006 to 2011, n  = 268 patients were screened and n  = 116 were randomized to n  = 59 PG and n  = 57 PJ. There was no statistically significant difference regarding the primary endpoint (PG vs PJ, 10 % vs 12 %, p  = 0.775). The subgroup of high-risk patients with a soft pancreas had a non-significantly lower pancreatic fistula rate with PG (PG vs PJ, 14 vs 24 %, p  = 0.352). Analysis of secondary endpoints demonstrated a shorter operation time (404 vs 443 min, p  = 0.005) and reduced hospital stay for PG (15 vs 17 days, p  = 0.155). Delayed gastric emptying (DGE; PG vs PJ, 27 vs 17 %, p  = 0.246) and intraluminal bleeding (PG vs PJ, 7 vs 2 %, p  = 0.364) were more frequent with PG. Mortality was low in both groups (<2 %). Conclusions Our randomized controlled trial shows no difference between PG and PJ as reconstruction techniques after partial pancreatoduodenectomy. POPF rate, DGE, and bleeding were not statistically different. Operation time was significantly shorter in the PG group.

Introduction 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. Methods Clinicopathologic, perioperative, and survival data of patients undergoing pancreatic head resection (PHR) for PDAC 1994–2014 were reviewed from a prospective database. Results 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. Conclusion 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.

Background Like many other cancer patients, most pancreatic carcinoma patients suffer from severe weight loss. As shown in numerous studies with fish oil (FO) supplementation, a minimum daily intake of 1.5 g n-3-fatty acids (n-3-FA) contributes to weight stabilization and improvement of quality of life (QoL) of cancer patients. Given n-3-FA not as triglycerides (FO), but mainly bound to marine phospholipids (MPL), weight stabilization and improvement of QoL has already been seen at much lower doses of n-3-FA (0,3 g), and MPL were much better tolerated. The objective of this double-blind randomized controlled trial was to compare low dose MPL and FO formulations, which had the same n-3-FA amount and composition, on weight and appetite stabilization, global health enhancement (QoL), and plasma FA-profiles in patients suffering from pancreatic cancer. Methods Sixty pancreatic cancer patients were included into the study and randomized to take either FO- or MPL supplementation. Patients were treated with 0.3 g of n-3-fatty acids per day over six weeks. Since the n-3-FA content of FO is usually higher than that of MPL, FO was diluted with 40% of medium chain triglycerides (MCT) to achieve the same capsule size in both intervention groups and therefore assure blinding. Routine blood parameters, lipid profiles, body weight, and appetite were measured before and after intervention. Patient compliance was assessed through a patient diary. Quality of life and nutritional habits were assessed with validated questionnaires (EORTC-QLQ-C30, PAN26). Thirty one patients finalized the study protocol and were analyzed (per-protocol-analysis). Results Intervention with low dose n-3-FAs, either as FO or MPL supplementation, resulted in similar and promising weight and appetite stabilization in pancreatic cancer patients. MPL capsules were slightly better tolerated and showed fewer side effects, when compared to FO supplementation. Conclusion The similar effects between both interventions were unexpected but reliable, since the MPL and FO formulations caused identical increases of n-3-FAs in plasma lipids of included patients after supplementation. The effects of FO with very low n-3-FA content might be explained by the addition of MCT. The results of this study suggest the need for further investigations of marine phospholipids for the improvement of QoL of cancer patients, optionally in combination with MCT.

The role of superior mesenteric−portal vein resection (SM-PVR) for vein invasion or tumor adherence during pancreatoduodenectomy (PD) is still under debate. We investigated morbidity, mortality, and long-term survival in patients who underwent PD with or without SM-PVR. Between July 1994 and December 2004, 222 PD (78% pylorus preserving, 19% Whipple, and 3% total pancreatectomy) were performed for malignant disease. Fifty-three patients (24%) had PD with SM-PVR. Sixty-eight percent of the venous resections were performed as wedge excisions and 32% as segmental resections. Long-term survival was analyzed in 165 patients with pancreatic (n = 110), ampullary (n = 33), or distal bile (n = 22) duct cancer using univariate (log-rank) and multivariate (Cox regression) methods. In patients undergoing PD with SM-PVR and conclusive histologic examination of the resected vein specimen (n = 42), 60% had true tumor involvement of the venous wall, whereas 40% had no proven tumor infiltration. In the complete study group, negative resection margins were obtained in 69% of patients with SM-PVR and in 79% of patients without SM-PVR ( P = 0.09). Median duration of surgery was 500 minutes (SM-PVR) versus 440 minutes (no SM-PVR; P < 0.001). Volume of intraoperatively transfused blood was 600 ml (median) in both groups. Postoperative surgical complications/mortality occurred in 23%/3.8% (SM-PVR) versus 35%/4.1% (no SM-PVR); P = 0.09/0.9. Analysis of long-term survival in all 165 patients included 41 with SM-PVR. Five-year survival rates were 15% in cancer of the pancreatic head, 22% in ampullary cancer, and 24% in distal bile duct cancer ( P = 0.02). Long-term survival was not influenced by the need for SM-PVR in any of the different tumor entities. In multivariate analysis, a positive resection margin ( P < 0.01, relative risk [RR]: 1.8, 95% confidence interval [CI]: 1.2−2.7), a histologically undifferentiated tumor ( P = 0.01, RR: 1.7, 95% CI: 1.1−2.5), and the tumor entity ( P < 0.01) were significant predictors of survival. Univariate survival analysis of the 110 patients with cancer of the pancreatic head revealed that a histologically undifferentiated tumor ( P = 0.05) and positive resection margins ( P = 0.02) were associated with a poorer survival. In multivariate analysis, the resection margin ( P = 0.02, RR: 5.1, 95% CI: 1.1−2.8) and a histologically undifferentiated tumor ( P = 0.05, RR: 3.8, 95% CI: 1.0−2.5) significantly influenced survival. After PD, perioperative morbidity and long-term survival in patients with SM-PVR were similar to those of patients without vein resection. In case of tumor adherence or infiltration, combined resection of the pancreatic head and the vein should always be considered in the absence of other contraindications for resection.

PurposeModern chemotherapy (CTX) increases survival in stage IV colorectal cancer. In colorectal liver metastases (CLM), neoadjuvant (neo) CTX may increase resectability and improve survival. Due to widespread use of CTX in CLM, recent studies assessed the role of the hepatic margin after CTX, with conflicting results. We evaluated the outcome after resection of CLM in relation to CTX and hepatic resection status.MethodsSince 2000, 334 patients with first hepatic resection for isolated CLM were analyzed. Thirty-two percent had neoadjuvant chemotherapy (targeted therapy in 42%). Sixty-eight percent never had CTX before hepatectomy or longer than 6 months before resection. The results were gained by analysis of our prospective database.ResultsPositive hepatic margins occurred in 8% (independent of neoCTx). Patients after neoCTX had higher numbers of CLM (p < 0.01) and a longer duration of surgery (p < 0.03). After hepatectomy, 5-year survival was 45% and correlated strongly with the margin status (47% in R-0 and 21% in R-1; p < 0.001). Survival also correlated with margin status in the subgroups with neoCTX (p < 0.01) or without neoCTx (p < 0.01). In multivariate analysis of the entire group, hepatic margin status (RR 3.2; p < 0.001) and age > 65 years (RR 1.6; p < 0.01) were associated with poorer survival. In the subgroup of patients after neoCTX (n = 106), only the resection margin was an independent predictor of survival (p < 0.001).ConclusionIn patients with isolated colorectal liver metastases undergoing resection, the hepatic margin status was the strongest independent prognostic factor. This effect was also present after neoadjuvant chemotherapy for CLM.

Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R. Male Wistar-Kyoto rats (age: 6-8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK-activation and Hippo-YAP signaling was determined by Western blot. Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling. VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK-activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated.

Organ complications like biliary or duodenal stenosis as well as intractable pain are current indications for surgery in patients with chronic pancreatitis (CP). We present here our experience with pancreatic resection for CP and focus on the long-term outcome after surgery regarding pain, exocrine/endocrine pancreatic function, and the control of organ complications in 224 patients with a median postoperative follow-up period of 56 months. During 11 years 272 pancreatic resections were performed in our institution for CP. Perioperative mortality was 1%. Follow-up data using at least standardized questionnaires were available in 224 patients. The types of resection in these 224 patients were Whipple (9%), pylorus-preserving pancreato-duodenectomy (PD) (PPPD; 40%), duodenum-preserving pancreatic head resection (DPPHR; 41%, 50 Frey, 42 Beger), distal (9%) and two central pancreatic resections. Eighty-six of the patients were part of a randomized study comparing PPPD and DPPHR. The perioperative and follow-up (f/up) data were prospectively documented. Exocrine insufficiency was regarded as the presence of steatorrhea and/or the need for oral enzyme supplementation. Multivariate analysis was performed using binary logistic regression. Perioperative surgical morbidity was 28% and did not differ between the types of resection. At last f/up 87% of the patients were pain-free (60%) or had pain less frequently than once per week (27%). Thirteen percent had frequent pain, at least once per week (no difference between the operative procedures). A concomitant exocrine insufficiency and former postoperative surgical complications were the strongest independent risk factors for pain and frequent pain at follow-up. At the last f/up 65% had exocrine insufficiency, half of them developed it during the postoperative course. The presence of regional or generalized portal hypertension, a low preoperative body mass index, and a longer preoperative duration of CP were independent risk factors for exocrine insufficiency. Thirty-seven percent of the patients without preoperative diabetes developed de novo diabetes during f/up (no risk factor identified). Both, exocrine and endocrine insufficiencies were independent of the type of surgery. Median weight gain was 2 kg and higher in patients with preoperative malnutrition and in patients without abdominal pain. After PPPD, 8% of the patients had peptic jejunal ulcers, whereas 4% presented with biliary complications after DPPHR. Late mortality was analyzed in 233 patients. Survival rates after pancreatic resection for CP were 86% after 5 years and 65% after 10 years. Pancreatic resection leads to adequate pain control in the majority of patients with CP. Long-term outcome does not depend on the type of surgical procedure but is in part influenced by severe preoperative CP and by postoperative surgical complications (regarding pain). A few patients develop procedure-related late complications. Late mortality is high, probably because of the high comorbidity (alcohol, smoking) in many of these patients.

Introduction Multimodal therapies (especially surgery of metastases and “aggressive” chemotherapy) in patients with metastases of colorectal cancers (CRC) are increasingly performed and may provide long-term survival in selected patients with more than one location of metastases. In the current literature, there are only few studies with relatively low patient numbers reporting on the outcome after resection of both hepatic and pulmonary metastases of CRC. We therefore evaluated survival of patients who underwent sequential resection of hepatic and pulmonary metastases under potentially curative intention. Material and Methods From 1987 until 2006, 44 patients (32% female; median age, 58 years) with hepatic and pulmonary CRC metastases underwent resections at both metastatic sites. The primary CRCs were in 50% rectal and in 50% colonic carcinomas (61% node positive, all with free resection margins). Metastases occurred synchronously (regarding primary CRC) in 32% of the patients. In 86%, liver resection was performed prior to pulmonary resection. The first resection of metastases was performed a median of 16 months after resection of the primary CRC; the median interval between the first and the second resection of metastases was 7 months. Forty-seven percent of the patients also underwent at least a third metastasectomy. During resection of the first and second site of metastases, free margins were achieved in 98% and 95%, respectively. Survival analysis was performed using Kaplan–Meier and Cox regression methods. Results The 5-year survival rates (SV) were 64% after initial surgery of CRC, 42% after the first resection of metastases, and 27% after the last metastasectomy. Patients with synchronous metastases had a 5-year SV after first metastasectomy of 43% and in patients with metachronous metastases of 41% (n.s.). The location of the primary tumor (20% 5-year SV in rectal vs. 57% in colonic cancer; p  < 0.02) and the lung as primary site of metastatic disease (5-year SV 0% vs. 60% in patients with primarily hepatic metastases only; p  < 0.001) significantly influenced survival in univariate analysis. Patients with rectal cancer had a significantly higher frequency of the lung as first metastatic site (46%) compared to patients with colonic cancer (14%; p  < 0.03). Multivariate survival analysis revealed the lung as first metastatic site and as the sole significant independent factor for the outcome ( p  < 0.001; relative risk vs. liver first metastases 4.7). Conclusion In selected patients with metastasized CRC resection of both hepatic and pulmonary metastases may improve survival rates or even provide long-term survival. Patients with lung as the first site of metastatic disease (either lung only or in combination with hepatic metastases) have a significantly worse outcome than patients with metastases primarily confined to the liver.