Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by an aggressive biology and poor prognosis. Experimental evidence has suggested a role for the transcriptional repressor Zinc ...finger E-box binding homeobox 1 (ZEB1) in epithelial-mesenchymal transition, invasion, and metastasis in PDAC. ZEB1 expression has been observed in cancer cells as well as stromal fibroblasts. Our study aimed to evaluate the prognostic value of ZEB1 expression in PDAC tissue. Methods Patient baseline and follow-up data were extracted from a prospectively maintained database. After clinicopathologic re-review, serial sliced tissue slides were immunostained for ZEB1, E-cadherin, vimentin, and pan-cytokeratin. ZEB1 expression in cancer cells and adjacent stromal fibroblasts was graded separately and correlated to routine histopathologic parameters and survival after resection. Results A total of 117 cases of PDAC were included in the study. High ZEB1 expression in cancer cells and in stromal cancer-associated fibroblasts was associated with poor prognosis. There was also a trend for poor prognosis with a lymph node ratio of greater than 0.10. In line with its role as an inducer of epithelial-mesenchymal transition, ZEB1 expression in cancer cells was positively correlated with Vimentin expression and negatively with E-Cadherin expression. In multivariate analysis, stromal ZEB1 expression grade was the only independent factor of survival after resection. Conclusion Our data suggest that ZEB1 expression in cancer cells as well as in stromal fibroblasts are strong prognostic factors in PDAC. Stromal ZEB1 expression is identified for the first time as an independent predictor of survival after resection of PDAC. This observation suggests that therapies targeting ZEB1 and its downstream pathways could hit both cancer cells and supporting cancer-associated fibroblasts.
We are in great need of specific biomarkers to detect pancreatic ductal adenocarcinoma (PDAC) at an early stage, ideally before invasion. Plectin-1 (Plec1) was recently identified as one such ...biomarker. However, its suitability as a specific biomarker for human pancreatic cancer, and its usability as an imaging target, remain to be assessed.
Specimens of human PDAC, chronic pancreatitis, and normal pancreata were evaluated by immunohistochemistry and Western blot analysis. To validate Plec1 as an imaging target, Plec1-targeting peptides (tPTP) were used as a contrast agent for single photon emission computed tomography in an orthotopic and liver metastasis murine model of PDAC.
Plec1 expression was noted to be positive in all PDACs but negative in benign tissues. Plec1 expression increases during pancreatic carcinogenesis. It was found to be misexpressed in only 0% to 3.85% of early PDAC precursor lesions (PanIN I/II) but in 60% of PanIN III lesions. Plec1 expression was further noted to be retained in all metastatic foci assayed and clearly highlighted these metastatic deposits in lymph nodes, liver, and peritoneum. In vivo imaging using tPTP specifically highlighted the primary and metastatic tumors. Biodistribution studies performed after imaging show that the primary pancreatic tumors and liver metastases retained 1.9- to 2.9-fold of tPTP over normal pancreas and 1.7-fold over normal liver.
Plec1 is the first biomarker to identify primary and metastatic PDAC by imaging and may also detect preinvasive PanIN III lesions. Strategies designed to image Plec1 could therefore improve detection and staging.
In this retrospective study, we analyzed the association between tumor budding and perineural invasion as well as their prognostic role in pancreatic ductal adenocarcinoma. A total of
N
= 119 ...patients resected for pancreatic ductal carcinoma from 1996 to 2015 were included. Clinical and standard histopathological parameters were retrieved from the patient’s records. One representative hematoxylin and eosin section from the tumor region was examined for perineural invasion and tumor budding using light microscopy. Tumor budding was assessed independently using two different methods: in the first approach, the number of buds was counted over three fields of 0.237 mm
2
at 40-fold magnification; in the second approach, tumor budding was quantified according to the recommendation of the International Tumor Budding Consensus Conference (ITBCC) over a field of 0.785 mm
2
at 20-fold magnification. Linear and logistic regression was applied to delineate association between perineural invasion, tumor budding, and other parameters; Kaplan-Meier and Cox regression were used in the survival analysis. Regardless of the quantification approach, high tumor budding was a significant negative prognostic factor in the univariable Cox regression (> 5 buds/0.237 mm
2
, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.06–2.61,
p
= 0.027; ≥ 10 buds/0.785 mm
2
, HR 1.68, 95% CI 1.07–2.64,
p
= 0.024). In the multivariable model adjusting for stage and standard histopathological parameters, lymph vessel invasion (HR = 2.43, 95% CI 1.47–4.03,
p
= 0.001) and tumor budding > 5 buds/0.237 mm
2
(HR = 1.70, 95% CI 1.07–2.7,
p
= 0.026) were independent negative prognostic factors, while adjuvant therapy was a positive prognostic factor (HR = 0.54, 95% CI 0.33–0.86,
p
= 0.009). No significant prognostic value could be delineated for perineural invasion. In conclusion, tumor budding is an independent negative prognostic factor in pancreatic ductal adenocarcinoma associated with lymph node metastasis. The prognostic role of perineural invasion remains uncertain.
Background and Aim
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biology and poor prognosis even after resection. Long‐term survival is very rare and cannot be reliably ...predicted. Experimental data suggest an important role of epithelial‐mesenchymal transition (EMT) in invasion and metastasis of PDAC. Tumor budding is regarded as the morphological correlate of local invasion and cancer cell dissemination. The aim of this study was to evaluate the biological and prognostic implications of EMT and tumor budding in PDAC of the pancreatic head.
Methods
Patients were identified from a prospectively maintained database, and baseline, operative, histopathological, and follow‐up data were extracted. Serial tissue slices stained for Pan‐Cytokeratin served for analysis of tumor budding, and E‐Cadherin, Beta‐Catenin, and Vimentin staining for analysis of EMT. Baseline, operative, standard pathology, and immunohistochemical parameters were evaluated for prediction of long‐term survival (≥ 30 months) in uni‐ and multivariate analysis.
Results
Intra‐ and intertumoral patterns of EMT marker expression and tumor budding provide evidence of partial EMT induction at the tumor–host interface. Lymph node ratio and E‐Cadherin expression in tumor buds were independent predictors of long‐term survival in multivariate analysis.
Conclusions
Detailed immunohistochemical assessment confirms a relationship between EMT and tumor budding at the tumor–host interface. A small group of patients with favorable prognosis can be identified by combined assessment of lymph node ratio and EMT in tumor buds.
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.
The impact of preoperative biliary stenting (PBS) before pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) is controversial.
Patients undergoing PD with or without PBS for PDAC ...were identified from the German DGAV-StuDoQlPancreas registry. The impact of PBS on perioperative complications was analyzed.
1133 patients undergoing PD for PDAC were identified from the registry. After matching, 480 PBS patients vs. 480 patients without PBS were analyzed. Postoperative complications Clavien-Dindo classification (CDC) grade IIIa-IVb were higher in PBS patients (PBS 27% vs. no PBS 22%, p = 0.027). 320 PBS patients (66%) had no history of jaundice. In these patients, PBS was associated with higher morbidity. In contrast, PBS was not associated with higher complication rates in patients with history of jaundice. Serum bilirubin levels of 15 mg/dl and higher lead to more CDC IIIa-IVb (24% vs. 28%, p = 0.053) and higher mortality (3% vs. 7%, p < 0.001). PBS in patients with serum bilirubin levels of >15 mg/dl increased CDC IIa-IVb complications (21% vs. 50%, p = 0.001), mortality was equivalent.
Most PBS procedures were performed in patients with no history of jaundice and increased morbidity. Serum bilirubin levels >15 mg/dl lead to higher morbidity and mortality. PBS correlated with higher complication rates in these patients.
Background A “step-up” approach is currently the treatment of choice for acute necrotizing pancreatitis. Our aim was to evaluate the outcome of minimally invasive retroperitoneal necrosectomy (MINE) ...and endoscopic transgastric necrosectomy (ETG) and to compare it to open necrosectomy (ONE). Methods Patients with acute pancreatitis admitted to our institution from 1998 to 2010 ( n = 334) were identified. From these, patients who underwent either ONE, MINE, or ETG were selected for further analysis. Statistical analysis employed 2-sided Fisher's exact test and Mann–Whitney U -test. Results From 2002 to 2010, 32 patients with acute necrotizing pancreatitis were treated by minimally invasive procedures including MINE ( n = 14) and ETG ( n = 18) or with the classic technique of ONE ( n = 30). Time from onset of symptoms to intervention was less for ONE than for MINE or ETG (median, 11 vs 39 vs 54 days; P < .05). The rate of critically ill patients with sepsis or septic shock was greatest in ONE (93%) and MINE (71%) compared with ETG (17%; P < .05). Problems after ONE and MINE were ongoing sepsis (ONE 73% vs MINE 29% vs ETG 11%) and bleeding requiring intervention (ONE 26% vs MINE 21% vs ETG 17%). A specific complication of ETG was gastric perforation into the peritoneal cavity during the procedure (28%), requiring immediate open pseudocystogastrostomy. Laparotomy was necessary in 21% after MINE and 28% after ETG owing to specific complications or persistent infected necrosis. Overall mortality was greatest after ONE (ONE 63% vs MINE 21% vs ETG 6%; P < .05). Conclusion Morbidity and mortality remains high in acute necrotizing pancreatitis. Operative procedures should be delayed as long as possible to decrease morbidity and mortality. Minimally invasive procedures can avoid laparotomy, but also introduce specific complications requiring immediate or secondary open operative treatment. Minimally invasive procedures require unique expertise and therefore should only be performed at specialized centers.
Borderline resectability in pancreatic cancer (PDAC) is currently debated.
Patients undergoing pancreatic resections for PDAC were identified from a prospectively maintained database. As new ...borderline criteria, the presence of any superior mesenterico-portal vein alteration (SMPV) and perivascular stranding of the superior mesenteric artery (SMA) was evaluated in preoperative imaging. The accuracy of established radiological borderline criteria as compared to the new borderline criteria in predicting R status (sensitivity/negative predictive value) and overall survival was assessed. (3)
118 patients undergoing pancreatic resections for PDAC from 2013 to 2018 were identified. Forty-three (36.4%) had radiological perivascular SMA stranding and 55 (46.6%) had SMPV alterations. Interrater reliability was 90% for SMA stranding and 87% for SMPV alterations. The new borderline definition including SMPV alterations and perivascular SMA stranding was the best predictor of conventional R status (
= 0.040, sensitivity 53%, negative predictive value 81%) and Leeds/Wittekind circumferential margin status (
= 0.050, sensitivity 73%, negative predictive value 79%) as compared to established borderline resectability definition criteria. Perivascular SMA stranding qualified as an independent negative prognostic parameter (HR 3.066, 95% CI 1.078-5.716,
= 0.036).
: The radiological evaluation of any SMPV alteration and perivascular SMA stranding predicts R status and overall survival in PDAC patients, and may serve to identify potential candidates for neoadjuvant therapy.
Purpose
Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from ...western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma.
Methods
Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival.
Results
N
= 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51–19.22,
p
= 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13–12.35,
p
= 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25–14.72,
p
= 0.038), and advanced age (OR 4.00, 95%CI 1.12–14.03,
p
= 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29–3.33,
p
= 0.003), high tumor grade (HR 1.71, 95%CI 1.13–2.58,
p
= 0.010), lymph node (HR 1.68, 95%CI 1.13–2.51,
p
= 0.011), and distant metastases (HR 2.70, 95%CI 1.21–5.58,
p
= 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04–2.58,
p
= 0.033) were independent negative prognostic factors for survival in multivariable analysis.
Conclusion
Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.
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