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Objective The available literature regarding outcome after pancreatic resection in locally advanced non-functional pNEN (LA-pNEN) is sparse. Therefore, this study evaluates the current survival outcomes and prognostic factors in after resection of LA-pNEN. Materials and methods This population-based analysis was derived from 17 German cancer registries from 2000 to 2019. Patients with upfront resected non-functional non-metastatic LA-pNEN were included. Results Out of 2776 patients with pNEN, 277 met the inclusion criteria. 137 (45%) of the patients were female. The median age was 63 ± 18 years. Lymph node metastasis was present in 45%. G1, G2 and G3 pNEN were found in 39%, 47% and 14% of the patients, respectively. Resection of LA-pNEN resulted in favorable 3-, 5- and 10-year overall survival of 79%, 74%, and 47%. Positive resection margin was the only potentially modifiable independent prognostic factor for overall survival (HR 1.93, 95% CI 1.71–3.69, p value = 0.046), whereas tumor grade G3 (HR 5.26, 95% CI 2.09–13.25, p value p value = 0.012) were the only independent prognostic factors for disease-free survival. Conclusion Resection of LA-pNEN is feasible and associated with favorable overall survival. G1 LA-pNEN with negative resection margins and absence of lymph node metastasis and lymphangiosis might be considered as cured, while those not fulfilling these criteria might be considered as a high-risk group for disease progression. Herein, negative resection margins represent the only potentially modifiable prognostic factor in LA-pNEN but seem to be influenced by tumor grade.

Zusammenfassung Hintergrund In den letzten Jahren haben sich Veränderungen in der Behandlung des duktalen Pankreaskarzinoms bezüglich der multimodalen Therapie und auch der chirurgischen Therapie ergeben. Diese Veränderungen sind bisher noch nicht in großen landesweiten Studien in Deutschland untersucht worden. Die vorliegende Arbeit gibt einen ersten Überblick aus chirurgischer Perspektive über die Entwicklungen in Diagnose, Therapie und Überleben des Pankreaskarzinoms innerhalb der letzten 19 Jahre in Deutschland. Methoden In dieser Kohorte aus 18 klinischen Krebsregistern Deutschlands wurden Patienten mit Diagnose eines duktalen Pankreaskarzinoms von 2000–2018 eingeschlossen. Die Patienten wurden nach Diagnosejahren (2000–2009 vs. 2010–2018) und nach Behandlungsmodalitäten aufgeteilt und verglichen. Ergebnisse In der Kohorte von ca. 48000 Patienten mit duktalem Pankreaskarzinom zeigte sich eine Erhöhung der Zahl der Neuerkrankungen von ca. 18000 auf 30000 Patienten in den beiden 10-Jahres-Abschnitten. Das mediane Gesamtüberleben stieg marginal, aber statistisch signifikant von 7,1 auf 7,9 Monate (p Zusammenfassung Die Krebsregisterdaten scheinen den bekannten Anstieg der Inzidenz des Pankreaskarzinoms in der westlichen Welt zu bestätigen. Resektionsraten sowie die Raten an Behandlung in neoadjuvanter sowie palliativer Intention erhöhten sich ebenfalls. Das Gesamtüberleben aller Patienten mit einem duktalen Pankreaskarzinom verlängerte sich allerdings nur marginal. In Subgruppen von Patienten, die in kurativer Intention behandelt wurden, zeigten sich jedoch mitunter deutlich längere Überlebenszeiten.

Background/aim The impact of venous resections and reconstruction techniques on morbidity after surgery for pancreatic cancer (PDAC) remains controversial. Patients and methods A total of 143 patients receiving pancreatoduodenectomy (PD) for PDAC between 2013 and 2018 were identified from a prospective database. Morbidity and mortality after PD with tangential resection versus end-to-end reconstruction were assessed. Results Fifty-two of 143 (36.4%) patients underwent PD with portal venous resection (PVR), which was associated with longer operation times [398 (standard error (SE) 12.01) vs. 306 (SE 13.09) min, p 0.99) were not different. Tangential venous resection was associated with similar CDC grade IIIa-IV (42.9% vs. 50.0%, p=0.781) and 30-day mortality rates (3.5% vs. 4.1%, p=0.538) as segmental resection and end-to-end venous reconstruction. Conclusion Both tangential and segmental PVR appear feasible and can be safely performed to achieve negative resection margins.

Background: Across a variety of solid tumors, prognostic implications of nutritional and inflammation-based risk scores have been identified as a complementary resource of risk stratification. Methods: In this retrospective study, we performed a comparative analysis of several established risk scores and ratios, such as the Glasgow Prognostic Score (GPS), in neuroendocrine neoplasms of the gastro–entero–pancreatic (GEP-NEN) system with respect to their prognostic capabilities. Clinicopathological and treatment-related data for 102 GEP-NEN patients administered to the participating institutions between 2011 and 2021 were collected. Scores/ratios significantly associated with overall or progression-free survival (OS, PFS) upon univariate analysis were subsequently included in a Cox-proportional hazard model for the multivariate analysis. Results: The median age was 62 years (range 18–95 years) and the median follow-up period spanned 51 months. Pancreatic or intestinal localization at the initial diagnosis were present in 41 (40.2%) and 44 (43.1%) cases, respectively. In 17 patients (16.7%), the primary manifestation could not be ascertained (NNUP; neuroendocrine neoplasms of unknown primary). Histological grading (HG) revealed 24/102 (23.5%) NET/NEC (poorly differentiated; high grade G3) and 78/102 (76.5%) NET (highly or moderately differentiated; low–high grade G1–G2). In total, 53/102 (51.9%) patients presented with metastatic disease (UICC IV), 11/102 (10.7%) patients presented with multifocal disease, and 56/102 (54.9%) patients underwent a primary surgical or endoscopic approach, whereas 28 (27.5%) patients received systemic cytoreductive treatment. The univariate analysis revealed the GPS and PI (prognostic index), as well as UICC-stage IV, HG, and the Charlson comorbidity index (CCI) to predict both the PFS and OS in GEP-NEN patients. However, the calculation of the survival did not separate GPS subgroups at lower risk (GPS 0 versus GPS 1). Upon the subsequent multivariate analysis, GPS was the only independent predictor of both OS (p < 0.0001; HR = 3.459, 95% CI = 1.263–6.322) and PFS (p < 0.003; HR = 2.119, 95% CI = 0.944–4.265). Conclusion: In line with previous results for other entities, the present study revealed the GPS at baseline to be the only independent predictor of survival across all stages of GEP-NEN, and thus supports its clinical utility for risk stratification in this group of patients.

Surgery remains the only curative treatment of pancreatic neuroendocrine neoplasms (pNEN). Here, we report the outcome after surgery for non-functional pNEN at a European Neuroendocrine Tumor Society (ENETS) center in Germany between 2000 and 2019, cases were analyzed for surgical (Clavien–Dindo classification, CDc) and oncological outcomes. Forty-nine patients (tumor grading G1 n = 25, G2 n = 22, G3 n = 2), with a median age of 56 years, were included. Severe complications (CDc ≥ grade 3b) occurred in 11 patients (22.4%) and type B/C pancreatic fistulas (POPFs) occurred in 5 patients (10.2%), in-hospital mortality was 2% (n = 1). Six of seven patients with tumor recurrence (14.3%) had G2 tumors in the pancreatic body/tail. The median survival was 5.7 years (68 months, [1–228 months]). Neither the occurrence (p = 0.683) nor the severity of complications had an influence on the relapse behavior (p = 0.086). This also applied for a POPF (≥B, p = 0.609). G2 pNEN patients (n = 22) with and without tumor recurrence had similar median tumor sizes (4 cm and 3.9 cm, respectively). Five of the six relapsed G2 patients (83.3%) had tumor-positive lymph nodes (N+), all G2 pNEN patients with recurrence had initially been treated with distal pancreatic resection. Pancreatic resections for pNEN are safe but associated with relevant postoperative morbidity. Future studies are needed to evaluate suitable resection strategies for G2 pNEN.

Background/aim The presence of circulating tumor cells (CTC) has been reported to have an impact on prognosis in different tumor entities. Little is known about CTC morphology and heterogeneity. Patients and methods In a multicenter setting, pre-therapeutic peripheral blood specimens were drawn from patients with non-metastatic esophageal adenocarcinoma (EAC). CTCs were captured by size-based filtration (ScreenCell®), subsequently Giemsa-stained and evaluated by two trained readers. The isolated cells were categorized in groups based on morphologic criteria. Results Small and large single CTCs, as well as CTC-clusters, were observed in 69.2% (n=81) of the 117 specimens; small CTCs were observed most frequently (59%; n=69), followed by large CTCs (40%; n=47) and circulating cancer-associated macrophage-like cells (CAMLs; 34.2%, n=40). Clusters were rather rare (12%; n=14). CTC/CAML were heterogeneous in the cohort, but also within one specimen. Neither the presence of the CTC subtypes/CAMLs nor the exact cell count were associated with the primary clinical TNM stage. Conclusion Morphologically heterogenic CTCs and CAMLs are present in patients with non-metastatic, non-pretreated EAC.

The impact of venous resections and reconstruction techniques on morbidity after surgery for pancreatic cancer (PDAC) remains controversial.A total of 143 patients receiving pancreatoduodenectomy (PD) for PDAC between 2013 and 2018 were identified from a prospective database. Morbidity and mortality after PD with tangential resection versus end-to-end reconstruction were assessed.Fifty-two of 143 (36.4%) patients underwent PD with portal venous resection (PVR), which was associated with longer operation times [398 (standard error (SE) 12.01) vs. 306 (SE 13.09) min, p0.001]. PVR was associated with longer intensive-care-unit stay (6.3 vs. 3.8 days, p=0.054); morbidity (Clavien-Dindo classification (CDC) grade IIIa-V 45.8% vs. 35.8%, p=0.279) and 30-day mortality (4.1% vs. 4.2%, p0.99) were not different. Tangential venous resection was associated with similar CDC grade IIIa-IV (42.9% vs. 50.0%, p=0.781) and 30-day mortality rates (3.5% vs. 4.1%, p=0.538) as segmental resection and end-to-end venous reconstruction.Both tangential and segmental PVR appear feasible and can be safely performed to achieve negative resection margins.

Objective To examine pasireotide’s effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation. Material and methods Forty-five male Wistar rats received an ileoileal end-to-end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined. Results Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R-SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R-SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups. Conclusion Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect.

BACKGROUND Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332–340. © 2017 American Cancer Society.

Background: Carcinoembryonic antigen cell adhesion molecule (CEA) is a commonly immunohistochemically used antibody in pathological routine diagnostics with an overexpression in different cancers. We aimed to examine the immunohistochemically detectable CEA level in ampullary cancer and to correlate it with clinico-pathological data. Methods: Shot-gun proteomics revealed CEA in undifferentiated ampullary cancer cell lines. Next, tumor tissue of 40 ampullary cancers of a retrospective single center cohort of 40 patients was stained immunohistochemically for CEA; CEA expression was determined and correlated with clinico-pathological data. Results: Thirty-six patient specimens were included in statistical analysis. CEA expression and lymph node ratio (LNR) were the only independent predictors of overall survival in multivariate analysis. Conclusion: To our knowledge, cell line and patient cohorts are the largest and characterized cohorts examined for CEA so far. Hereby, CEA expression in ampullary cancer cells permits an estimation of outcome and suggests an opportunity for individualized CEA-directed therapy. Further trials with larger cohorts are needed to verify our results and to integrate CEA immunohistochemistry into clinical routine.

In esophageal surgery, total minimally invasive techniques compete with hybrid and robot-assisted procedures. The benefit of the individual techniques for the patient remains vague. At our institution, the hybrid minimally invasive laparoscopic-thoracotomic esophagectomy (HMIE) has been routinely applied since 2013. We conducted this retrospective study to analyze the perioperative outcome. Since 2013, 60 patients were operated in HMIE technique for esophageal cancer. Each of these patients was paired according to the criteria of gender, BMI, age, tumor histology, pulmonary preexisting conditions, and a history of smoking with a patient treated by open esophagectomy (OE). Perioperative parameters were extracted from our prospectively maintained database and compared among the groups. The HMIE and OE groups were homogeneous in terms of patient- and tumor-related data. There was no difference in lymph nodes harvested (22 vs. 20, p = 0.459) and R0-resection rate (95 vs. 93%, p = 0.500). The operation time for the HMIE was significantly shorter (329 vs. 407 min, p

BACKGROUND Obesity is generally considered to be associated with worse surgical outcome and impaired oncological prognosis. The impact of pre-therapeutic body mass index (BMI) in patients with oesophagogastric cancer on the surgical outcome is controversially discussed. METHODS We retrospectively examined 730 patients who had undergone curative treatment for oesophagogastric cancer at the Medical Center of the University of Freiburg (1996-2015). Patients were divided in groups according to pre-therapeutic BMI (underweight (UW): 30 kg/m2 ). RESULTS Median BMI was 24.7 kg/m2 . Forty-two patients were UW, 337 NW, 263 OW and 84 OB. No significant differences between the groups (UW/NW/OW/OB) in operating time, hospital stay, perioperative complication rate and in-hospital mortality were found. Pre-therapeutic BMI was significantly associated with 5-year survival (UW: 22%, NW: 37%, OW: 51%, OB: 50%, P

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

A disintegrin and a metalloprotease (ADAM)‐9 is a metzincin cell‐surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss‐of‐function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage‐independent growth. In AsPC1 cells, but not in MiaPaCa‐2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post‐translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro‐angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin‐binding EGF‐like growth factor (HB‐EGF). Finally, we carried out orthotopic seeding of either wild‐type AsPC‐1 cells or AsPC‐1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro‐angiogenic impact.

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.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic tumor spread. Blood obtained from healthy donors and patients with PDAC was therefore subject to size-based CTC-isolation. We additionally compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in pancreatic CTC and corresponding tumors, and evaluated their significance as prognostic markers. Samples from 68 individuals (58 PDAC patients, 10 healthy donors) were analyzed; CTCs were present in patients with UICC stage IA-IV tumors and none of the controls (p 0.001). Patients with3 CTC/ml had a trend for worse median overall survival (OS) than patients with 0.3–3 CTC/ml (P = 0.12). Surprisingly, CTCs harbored various KRAS mutations in codon 12 and 13. Patients with a KRAS G12V mutation in their CTC (n = 14) had a trend to better median OS (24.5 months) compared to patients with other (10 months), or no detectable KRAS mutations (8 months; P = 0.04). KRAS mutations in CTC and corresponding tumor were discordant in 11 of 26 “tumor-CTC-pairs” (42%), while 15 (58%) had a matching mutation; survival was similar in both groups (P = 0.36). Genetic characterization, including mutations such as KRAS, may prove useful for prognosis and understanding of tumor biology.

Esophageal cancer (EC) is mostly diagnosed due to clinical symptoms such as dysphagia or anemia. Depending on the staging and the histological subtype, squamous cell carcinoma or adenocarcinoma, patients with non-metastasized disease mostly undergo neoadjuvant chemoradiation or perioperative chemotherapy followed by esophageal resection. Nearly 50% of the curatively treated patients develop distant metastasis within 5 years, although no metastases were clinically evident at time of treatment. More recently, the concept of circulating tumor cells (CTC) has also been introduced for EC. CTC are thought to be the means of systemic tumor spread, with the ability to set up metastases in distant organs. Much effort has been made to capture, enrich and detect these very rare cells from the blood stream of EC patients. CTC have been found to be independent risk factors for worse prognosis in patients with EC. Pre- and intra-therapeutic CTC enrichment and detection has the potential to improve preoperative staging, and provide a differential indication for neoadjuvant therapeutic modality and an indication for adjuvant therapy.

Clinical data indicate that laparoscopic surgery has a beneficial effect on intestinal wound healing and is associated with a lower incidence of anastomotic leakage. This observation is based on weak evidence, and little is known about the impact of intraoperative parameters during laparoscopic surgery, e.g., temperature and humidity.A small-bowel anastomosis was formed in rats inside an incubator, in an environment of stable humidity and temperature. Three groups of ten Wistar rats were operated: a control group (G1) in an open surgical environment and two groups (G2 and G3) in the incubator at a humidity of 60 % and a temperature of 30 and 37 °C (G2 and G3, respectively). After 4 days, bursting pressure and hydroxyproline concentration of the anastomosis were analyzed. The tissue was histologically examined. Serum levels of C-reactive-protein (CRP) were measured.No significant changes were seen in the evaluation of anastomotic stability. Bursting pressure was very similar among the groups. Hydroxyproline concentration in G3 (36.3 μg/g) was lower by trend (p = 0.072) than in G1 (51.7 μg/g) and G2 (46.4 μg/g). The histological evaluation showed similar results regarding necrosis, inflammatory cells, edema, and epithelization for all groups. G3 (2.56) showed a distinctly worse score for submucosal bridging (p = 0.061) than G1 (1.68). A highly significant increase (p = 0.008) in CRP was detected in G3 (598.96 ng/ml) compared to G1 (439.49 ng/ml) and G2 (460 ng/ml).A combination of high temperature and humidity during surgery induces an increased systemic inflammatory response and seems to be attenuating the early regeneration process in the anastomotic tissue.

Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin.Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test.No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor.CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017 American Cancer Society.

Background: The study was done to compare treatment and long‐term outcomes of neoadjuvant chemoradiation (neoCRT) and perioperative chemotherapy (periCTX) in patients with surgically treated esophageal adenocarcinoma. Methods: An analysis of 105 patients with esophageal adenocarcinoma undergoing neoCRT (n ¼58) or periCTX (n ¼47) and esophagectomy between 2000 and 2012 was carried out. Results: The overall median survival was 5.97 years. Postoperative morbidity and in‐hospital mortality occurred in 74%/7% of the patients the neoCRT group and in 53%/0% of the patients in the periCTX group (P ¼0.03/P ¼0.08). Total or subtotal histological tumor response after neoadjuvant treatment and esophagectomy was found in 59% after neoCRT and 30% after periCTX (P

It has been shown that crystalloid fluid-overload promotes anastomotic instability. As physiologic anastomotic healing requires the sequential infiltration of different cells, we hypothesized this to be altered by liberal fluid regimes and performed a histomorphological analysis.36 Wistar rats were randomized into 4 groups (n=8-10 rats/group) and treated with either liberal (+) or restrictive (-) perioperative crystalline (Jonosteril = Cry) or colloidal fluid (Voluven = Col). Anastomotic samples were obtained on postoperative day 4, routinely stained and histophathologically reviewed. Anastomotic healing was assessed using a semiquantitative score, assessing inflammatory cells, anastomotic repair and collagenase activity.Overall, the crystalloid overload group (Cry (+)) showed the worst healing score (P0.01). A substantial increase of lymphocytes and macrophages was found in this group compared to the other three (P0.01). Both groups that received colloidal fluid (Col (+) and Col (-)) as well as the group that received restricted crystalloid fluid resuscitation (Cry (-)) had better intestinal healing. Collagenase activity was significantly higher in the Cry (+) group.Intraoperative infusion of high-volume crystalloid fluid leads to a pathological anastomotic inflammatory response with a marked infiltration of leukocytes and macrophages resulting in accelerated collagenolysis.

The study was done to determine long-term outcomes of surgically treated esophageal cancer and to identify trends in epidemiology, oncological therapy, and oncological prognosis over the last two decades.Overall survival in 304 patients undergoing esophagectomy was analyzed. Fifty-three percent had squamous cell carcinoma and 46 % had adenocarcinoma (AC). A total of 161 patients received neoadjuvant chemoradiation, 38 received neoadjuvant chemotherapy, and 105 were treated with surgery alone.Median survival (MS) increased significantly from 18.0 months (1988-1994) to 26.6 months (1995-2001) and to 59.3 months (2002-2011; p 0.001). The proportion of AC (22 vs 35 vs 65 %; p 0.001) and the proportion of patients treated with neoadjuvant therapy (neoT; 15.9 vs 85.3 vs 77.8 %; p 0.001) increased during the treatment period. After neoT, a beneficial outcome with a MS of 45.6 vs. 20.4 months (p = 0.003) was found. Lymph node ratio [LNR; relative risk (RR), 5.4; p 0.001], response to neoT (RR, 1.6; p 0.004), and histological subtype (RR, 1.7; p 0.003) were identified as independent parameters of survival.Since 1988, the outcome of surgically resected esophageal cancer strongly improved. Besides tumorbiological factors like histological type and LNR, the outcome is also affected by the increasing use of neoT towards favorable survival rates.

Treatment of spontaneous esophageal perforation (SEP) consists of different conservative, surgical and endoscopic treatment modalities. In this study, we evaluated the clinical efficacy and the outcome of covered self-expanding stent (CSES) treatment of SEP. All patients with SEP treated by CSES at our institution between 2005 and 2014 were included in this prospective single-center study. The data were collected from a prospective database based on clinical, endoscopic and operative reports. Follow-up data were procured by contacting the patients or their family doctors. The patient data were analyzed concerning course of treatment, leakage sealing rate, complications, and mortality. Patients with iatrogenic or malignant perforations were excluded. In total, 16 patients underwent endoscopic CSES placement for SEP between 2005 and 2014. Sealing of the leakage was immediately successful in 50% (8 patients). A second stent was placed in 5 patients, but did not achieve sealing of the perforation in any case, requiring a switch in treatment to a surgical procedure (n=4) or drainage of the persisting leakage (n=4). In-hospital mortality was 13%. Only delayed treatment was identified as a risk factor for inferior outcome. Patients with successful CSES treatment had a shorter ICU- and hospital stay and had a reduced risk of developing esophageal stenosis (RR: 0.4) or persisting dysphagia despite treatment (RR: 0.33). Endoscopic treatment of SEP is beneficial to the patient if immediately successful, but in our experience, failure rates are higher than described in the literature. Secondary placement of CSES was not successful when initial stent treatment failed, while both surgical intervention and drainage of the perforation showed good results in sealing the leakage.

Proteins of the pregnancy specific β-1 glycoprotein (PSG) family are renowned for their elevated expression during pregnancy. Only few reports have investigated their expression in adenocarcinomas. We studied the expression of PSG1 in pancreatic adenocarcinoma (PDAC). In a cohort of 104 patient samples, immunohistochemical analysis determined PSG1 expression in every specimen. PSG1 was found at apical and cytoplasmic localization or solely at cytoplasmic localization, with the latter case being correlated to shortened median survival (25 vs 11 months, logrank p-value < 0.001). At the same time, enzyme linked immunosorbent assay (ELISA) did not detect elevated PSG1 levels in the plasma of PDAC patients as opposed to the plasma of healthy, non-pregnant control individuals. We also probed the impact of PSG1 expression in a murine tumor model system, using subcutaneous injection of Colo-26 cells into immunocompetent BALB/c mice. Here, tumor growth was not affected by the expression of human PSG1. Our study reaffirms interest into the tumor-contextual biology of PSG proteins.

Pancreatic ductal adenocarcinoma (PDAC) is most often diagnosed in a metastatic stage. Circulating tumor cells (CTC) in the blood are hypothesized as the means of systemic dissemination. We aimed to isolate and characterize CTC to evaluate their significance as prognostic markers in PDAC. Blood obtained from healthy donors and patients with PDAC before therapy was filtered with ScreenCell® filtration devices for size-based CTC isolation. Captured cells were analyzed by immunofluorescence for an epithelial to mesenchymal transition (EMT) marker (zinc finger E-box binding homebox 1 (ZEB1)) and an epithelial antigen (cytokeratin (CK)). Molecular analysis of parallel specimens evaluated the KRAS mutation status of the CTC. The survival of each patient after study was recorded. As demonstrated by either cytology or finding of a KRAS mutation, CTC were detected in 18 of 21 patients (86 %) with proven PDAC: 8 out of 10 patients (80 %) with early stage (UICC IIA/IIB) and 10 out of 11 (91 %) with late stage (UICC III/IV) disease. CTC were not found in any of the 10 control patients (p 0.001). The presence of CTC did not adversely affect median survival: 16 months in CTC-positive (n = 18) vs. 10 months in CTC-negative (n = 3) patients. Neither ZEB1 nor cytological characteristics correlated with overall survival, although ZEB1 was found almost exclusively in CTC of patients with established metastases. Patients with a CTC KRAS mutation (CTC-KRAS (mut)) had a substantially better survival, 19.4 vs. 7.4 months than patients with wild type KRAS (p = 0.015). With ScreenCell filtration, CTC are commonly found in PDAC (86 %). Molecular and genetic characterization, including mutations such as KRAS, may prove useful for prognosis.

To examine bowel wall edema development in laparoscopic and open major visceral surgery. In a prospective study, 47 consecutively operated patients with gastric and pancreatic resections were included. Twenty-seven patients were operated in a conventional open procedure (open group) and 20 in a laparoscopic fashion (lap group). In all procedures, a small jejunal segment was resected during standard preparation, of which we measured the dry-wet ratio. Furthermore, HE staining was performed for measuring of bowel wall thickness and edema assessment. Mean value (±std) of dry-wet ratio was significantly lower in the open than in the lap group (0.169 ± 0.017 versus 0.179 ± 0.015; p = 0.03) with the same amount of fluid administration in both groups and a longer infusion interval during laparoscopic surgery. Subgroup analyses (only pancreatic resections) still showed similar results. Histologic examination depicted a significantly larger bowel wall thickness in the open group. Laparoscopic surgery does not seem to lead to the bowel wall edema observed to occur in open surgery regardless of the degree of intravenous fluid administration, thus supporting its use even in major visceral surgery.

The aim of the article is to investigate a new anastomotic technique compared with standardized intestinal anastomotic procedures.A total of 32 male Wistar rats were randomized to three groups. In the Experimental Group (n = 10), the new double 90 degrees inversely rotated anastomosis was used, in the End Group (n = 10) a single-layer end-to-end anastomosis, and in the Side Group (n = 12) a single-layer side-to-side anastomosis. All anastomoses were done using interrupted sutures. On postoperative day 4, rats were relaparotomized. Bursting pressure, hydroxyproline concentration, a semiquantitative adhesion score and two histological anastomotic healing scores (mucosal healing according to Chiu and overall anastomotic healing according to Verhofstad) were collected. Most data are presented as median (range). p0.05 was considered significant.Anastomotic insufficiency occurred only in one rat of the Side Group. Median bursting pressure in the Experimental Group was 105 mm Hg (range = 72-161 mm Hg), significantly higher in the End Group (164 mm Hg; range = 99-210 mm Hg; p = 0.021) and lower in the Side Group by trend (81 mm Hg; range = 59-122 mm Hg; p = 0.093). Hydroxyproline concentration did not differ significantly in between the groups. The adhesion score was 2.5 (range = 1-3) in the Experimental Group, 2 (range = 1-2) in the End Group, but there were significantly more adhesions in the Side Group (range = 3-4); p = 0.020 versus Experimental Group, p0.001 versus End Group. The Chiu Score showed the worst mucosal healing in the Experimental Group. The overall Verhofstad Score was significantly worse (mean = 2.032; standard deviation [SD] = 0.842) p = 0.031 and p = 0.002 in the Experimental Group, compared with the Side Group (mean = 1.729; SD = 0.682) and the End Group (mean = 1.571; SD = 0.612).The new anastomotic technique is feasible and did not show any relevant complication. Even though it was superior to the side-to-side anastomosis by trend with respect to functional stability, mucosal healing surprisingly showed the worst results. Classical end-to-end anastomosis still seems to be the best choice regarding structural and functional anastomotic stability.

Purpose: This investigation focuses on the physiological characteristics of gene transcription of intestinal tissue following anastomosis formation. Methods: In eight rats, end-to-end ileo-ileal anastomoses were performed (n = 2/group). The healthy intestinal tissue resected for this operation was used as a control. On days 0, 2, 4 and 8, 10-mm perianastomotic segments were resected. Control and perianastomotic segments were examined with an Affymetrix microarray chip to assess changes in gene regulation. Microarray findings were validated using real-time PCR for selected genes. In addition to screening global gene expression, we identified genes intensely regulated during healing and also subjected our data sets to an overrepresentation analysis using the Gene Ontology (GO) and Kyoto Encyclopedia for Genes and Genomes (KEGG). Results: Compared to the control group, we observed that the number of differentially regulated genes peaked on day 2 with a total of 2,238 genes, decreasing by day 4 to 1,687 genes and to 1,407 genes by day 8. PCR validation for matrix metalloproteinases-3 and -13 showed not only identical transcription patterns but also analogous regulation intensity. When setting the cutoff of upregulation at 10-fold to identify genes likely to be relevant, the total gene count was significantly lower with 55, 45 and 37 genes on days 2, 4 and 8, respectively. A total of 947 GO subcategories were significantly overrepresented during anastomotic healing. Furthermore, 23 overrepresented KEGG pathways were identified. Conclusion: This study is the first of its kind that focuses explicitly on gene transcription during intestinal anastomotic healing under standardized conditions. Our work sets a foundation for further studies toward a more profound understanding of the physiology of anastomotic healing.

Gastroenterology 2014;146:618–621 Question: A 45year-old man presented in our surgical department with progressive dysphagia for solids and liquids and weight loss over the last 6 month, he had a long history of tobacco abuse (25 pack-years), but no history of trauma or alcohol use. Physical examination showed his cachexia, but was otherwise unremarkable without palpable lymphadenopathy. He had been treated with long-term bouginage over 4 years for a long segment esophageal stenosis starting 30 cm distal to the dental arch. Repeatedly performed biopsies over that time course had been nondiagnostic, with only chronic inflammation and hyperkeratosis. He presented in our institution owing to shorter bouginage intervals and weight loss. Upper endoscopy showed a thickened, white, contact-vulnerable, exophytic, and lumen-constricting polypoid mass in the esophagus over a distance of 15 cm (Figure A; star 1⁄4 esophageal lumen). Multiple deep biopsies were taken; they revealed keratosis and chronic inflammation but no evidence of malignancy. The subsequent computed tomography with contrast enhancement revealed a long-segment thickening of the thoracic esophagus (Figure B, arrows) without any lymphadenopathy or metastases. What is the most likely diagnosis? Look on page 871 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

The study was done to compare treatment and long-term outcomes of neoadjuvant chemoradiation (neoCRT) and perioperative chemotherapy (periCTX) in patients with surgically treated esophageal adenocarcinoma.An analysis of 105 patients with esophageal adenocarcinoma undergoing neoCRT (n = 58) or periCTX (n = 47) and esophagectomy between 2000 and 2012 was carried out.The overall median survival was 5.97 years. Postoperative morbidity and in-hospital mortality occurred in 74%/7% of the patients the neoCRT group and in 53%/0% of the patients in the periCTX group (P = 0.03/P = 0.08). Total or subtotal histological tumor response after neoadjuvant treatment and esophagectomy was found in 59% after neoCRT and 30% after periCTX (P0.01). Three- and five-year survival rates were 52%/45% for neoCRT and 68%/63% for periCTX (P = 0.05). PeriCTX was identified as an independent predictor of survival (RR2.6; 95% CI 1.3-5.1; P0.01).A higher rate of histologic response to neoCRT compared to histologic response following the preoperative cycles of periCTX does not translate to a benefit in overall survival. PeriCTX offers a decreased incidence of treatment-related morbidity and mortality and at least equal results in terms of survival compared to neoCRT in patients with locally advanced esophageal adenocarcinoma.

Anastomotic leakage of esophagogastric and esophagojejunal anastomoses is a severe complication after esophagectomy and gastrectomy associated with a high mortality. We conducted this non-randomized observational study to evaluate the outcomes and clinical effectiveness of covered self-expanding stents (CSESs) in treating esophageal anastomotic leakage. From 2002 to 2013, consecutive patients with anastomotic leakage after esophagogastrostomy or esophagojejunostomy who received CSESs were analyzed concerning leakage characteristics, leakage sealing rate, success and failure rates of CSES treatment, stent-related complications, and mortality. In 35 patients, anastomotic leakage originating from 5 cervical esophagogastrostomies, 6 thoracic esophagogastrostomies, 12 mediastinal esophagojejunostomies and 12 abdominal esophagojejunostomies were treated with 48 CSESs (16 fully CSES, 32 partially CSES). Of 35 patients, 24 received one stent, 9 received two consecutive stents, and 2 received three consecutive stents. Stent-related complications occurred in 71 % of patients (25/35). The most frequent complications were leakage persistence (44 %) and stent dislocation (19 %). Sealing of the anastomotic leakage was achieved in 24 (69 %) patients after a median (range) stenting time of 19 (1–78) days. Sealing rates differed significantly with 20 % (cervical esophagogastrostomies), 50 % (thoracic esophagogastrostomies), 92 % (mediastinal esophagojejunostomies) and 67 % (abdominal esophagojejunostomies) of patients (p = 0.023). Moreover, clinical success rates differed among these groups (60 vs. 67 vs. 92 vs. 58 %; p = 0.247). Clinical failure of stent treatment was more likely to be recognized in early postoperative leakage (median postoperative day 3 vs. 8; p = 0.098) compared with successful treatment, whereas no difference for clinical success rates was found comparing leakage ≤10 versus >10 mm (68 vs. 64 %; p = 0.479). CSESs are an effective treatment for anastomotic leakage in patients with esophagogastrostomies and esophagojejunostomies. Best results can be achieved in patients with anastomotic leakages following mediastinal esophagojejunostomy, and in leakages occurring after the very early postoperative phase.

To analyze our experience in patients with duodenal gastrointestinal stromal tumors (GIST) and review the appropriate surgical approach.We retrospectively reviewed the medical records of all patients with duodenal GIST surgically treated at our medical institution between 2002 and 2011. Patient files, operative reports, radiological charts and pathology were analyzed. For surgical therapy open and laparoscopic wedge resections and segmental resections were performed for limited resection (LR). For extended resection pancreatoduodenectomy was performed. Age, gender, clinical symptoms of the tumor, anatomical localization, tumor size, mitotic count, type of resection resectional status, neoadjuvant therapy, adjuvant therapy, risk classification and follow-up details were investigated in this retrospective study.Nine patients (5 males/4 females) with a median age of 58 years were surgically treated. The median follow-up period was 45 mo (range 6-111 mo). The initial symptom in 6 of 9 patients was gastrointestinal bleeding (67%). Tumors were found in all four parts of the duodenum, but were predominantly located in the first and second part of the duodenum with each 3 of 9 patients (33%). Two patients received neoadjuvant medical treatment with 400 mg imatinib per day for 12 wk before resection. In one patient, the GIST resection was done by pancreatoduodenectomy. The 8 LRs included a segmental resection of pars 4 of the duodenum, 5 wedge resections with primary closure and a wedge resection with luminal closure by Roux-Y duodeno-jejunostomy. One of these LRs was done minimally invasive; seven were done in open fashion. The median diameter of the tumors was 54 mm (14-110 mm). Using the Fletcher classification scheme, 3/9 (33%) tumors had high risk, 1/9 (11%) had intermediate risk, 4/9 (44%) had low risk, and 1/9 (11%) had very low risk for aggressive behaviour. Seven resections showed microscopically negative transsection margins (R0), two showed positive margins (R1). No patient developed local recurrence during follow-up. The one patient who underwent pancreatoduodenectomy died due to progressive disease with hepatic metastasis but without evidence of local recurrence. Another patient died in complete remission due to cardiac disease. Seven of the nine patients are alive disease-free.In patients with duodenal GIST, limited surgical resection with microscopically negative margins, but also with microscopically positive margins, lead to very good local and systemic disease-free survival.

AIM: To investigate the influence of remote ischemic preconditioning (RIPC) on anastomotic integrity. METHODS: Sixty male Wistar rats were randomized to six groups. The control group (n = 10) had an end-to-end ileal anastomosis without RIPC. The preconditioned groups (n = 34) varied in time of ischemia and time of reperfusion. One group received the amino acid L-arginine before constructing the anastomosis (n = 9). On postoperative day 4, the rats were re-laparotomized, and bursting pressure, hydroxyproline concentration, intra-abdominal adhesions, and a histological score concerning the mucosal ischemic injury were collected. The data are given as median (range). RESULTS: On postoperative day 4, median bursting pressure was 124 mmHg (60-146 mmHg) in the control group. The experimental groups did not show a statistically significant difference (P > 0.05). Regarding the hydroxyproline concentration, we did not find any significant variation in the experimental groups. We detected significantly less mucosal injury in the RIPC groups. Furthermore, we assessed more extensive intra-abdominal adhesions in the preconditioned groups than in the control group. CONCLUSION: RIPC directly before performing small bowel anastomosis does not affect anastomotic stability in the early period, as seen in ischemic preconditioning.

Laparoscopic sleeve gastrectomy (LSG) is frequently performed as a definitive bariatric procedure today. Quantitative data on the detailed anatomy of the stomach after LSG are yet sparse. Thirty-two multislice computed tomography (MSCT) data sets acquired in 27 LSG patients (22 female, 5 male) with a dedicated examination protocol and post-processing were evaluated for gastric volume, stomach length, sleeve length, antrum length, staple line length, and maximum cross-sectional sleeve area. Obtained parameters were compared to time after surgery, weight loss, and the occurrence of postsurgical regurgitation. Mean gastric volume was 186.5 ± 88.4 ml. Gastric volume correlated significantly with the time interval after surgery. Sleeve sizes of 105.3 ± 30.2 ml during early follow-up confirmed correct primary sizing of the sleeve, whereas marked dilation to 196.8 ± 84.3 ml was found in patients with a follow-up of 6 months and longer (p = 0.038). Sleeve area and staple line length were also positively correlated with time after surgery. No correlation was found between gastric volume and excess weight loss. In ten patients an intrathoracic migration of the staple line could be noted, with four of these patients developing persistent regurgitation after LSG. Regurgitation was present in only 2 of 17 patients without sleeve herniation. Multislice computed tomography allows for a comprehensive and quantitative evaluation of the anatomy after LSG and thus provides new insights in the process of sleeve dilation. Intrathoracic migration of the staple line could be identified as a possible cause of persistent regurgitation.

Background A 23-year-old woman who 2 weeks before visiting our institution swallowed a plastic fork while attempting to induce vomiting during a party presented with progressive abdominal pain. Various techniques for removing foreign bodies from the intestinal tract have been described. We present the laparoscopic retrieval of a 15-cm fork from the duodenal bulb.