The impact of intra- and postoperative fluid balance in pancreatic surgery - A retrospective cohort study.

BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the impact of perioperative fluid administration in pancreatic surgery. METHODS: Patients who underwent pancreatic resections were identified from our institution's prospectively maintained database. Fluid balances were recorded intraoperatively and at 24hr postoperatively. Patients were stratified into tertiles of fluid administration (low, medium, high). Adjusted multivariable analysis was performed and outcome measures were postoperative complications. RESULTS: A total of 211 patients were included from 2012 to 2017. Complication rates were POPF(B/C) 19.4%, DGE(B/C) 14.7%, PPH(C) 10.0% and CDC ≥ IIIb 26.1%. In multivariable analysis, high perioperative fluid balance was an independent risk factor associated with POPF (OR = 10.5, 95%CI 2.7-40.7, p = .001), CDC (OR = 2.5, 95%CI 1.2-5.3, p < .002), DGE (OR = 2.3, 95%CI 1.0-5.2, p = .017), PPH (OR = 6.7 95%CI 2.2-20.0, p = .038) and reoperation (OR = 3.1, 95%CI 1.6-6.2, p = .006). In multivariable analysis with intraoperative and postoperative fluid balances as separate predictors, intraoperative (OR = 2,5, 95%CI 1.2-5.5, p = .04) and postoperative fluid balance (OR = 2.5, 95%CI 1.2-5.5, p = .02) were predictors of POPF. Postoperative fluid balance was the only predictor for mortality (OR = 4.5, 95%CI 1.0-18.9, p = .041) and predictor for CDC (OR = 2.0, 95%CI 1.0-4.0, p = .043) and OHS days (OR = 6.9, 95%CI 0.03-13.7, p = .038). CONCLUSIONS: High postoperative fluid balance in particular is associated with postoperative morbidity. Maintaining a fluid-restrictive strategy postoperatively should be recommended for patients undergoing pancreatic surgery.

[Incidence, Treatment and Survival in Pancreatic Cancer- Data of the Nationwide Oncological Quality Conference from a Surgical Perspective]. / Inzidenz, Behandlung und Überleben beim Pankreaskarzinom ­ Daten der bundesweiten onkologischen Qualitätskonferenz aus chirurgischer Perspektive.

BACKGROUND: In recent years, there have been changes in the treatment of ductal pancreatic carcinoma with regard to multimodal therapy and also surgical therapy. These changes have not yet been explored in large nationwide studies in Germany. The present work gives an initial overview from a surgical perspective of the developments in diagnosis, therapy and survival of pancreatic cancer within the last 19 years in Germany. METHODS: In this cohort of 18 clinical cancer registries in Germany, patients with a diagnosis of ductal pancreatic cancer from 2000-2018 were included. The patients were categorised according to the years of diagnosis (2000-2009 vs. 2010-2018) and treatment modalities and compared. RESULTS: In the cohort of approx. 48000 patients with ductal pancreatic cancer, the number of newly diagnosed cases increased from approx. 18000 to 30000 patients in the two ten-year periods. The median overall survival increased slightly but statistically significantly from 7.1 to 7.9 months (p < 0.001). The resection rate increased from 25% to 32%, with the proportion of patients for whom no specific therapy was reported decreased by 11%. The rate of palliative chemotherapy and neoadjuvant chemotherapy also increased from 16% to 20% of the patients and from less than 1% to 2% of the patients, respectively. The median survival in the curatively treated subgroups was up to 24 months. SUMMARY: The cancer registry data appear to confirm the known increase in the incidence of pancreatic cancer in the western world. Resection rates and the rates of treatment with neoadjuvant and palliative intent also increased. The overall survival of all patients with ductal pancreatic cancer only increased marginally. In the subgroups of patients who were treated with curative intent, however, significantly longer survival times were found.

The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model.

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.

Form follows function: Morphological and immunohistological insights into epithelial-mesenchymal transition characteristics of tumor buds.

In cancer biology, the architectural concept "form follows function" is reflected by cell morphology, migration, and epithelial-mesenchymal transition protein pattern. In vivo, features of epithelial-mesenchymal transition have been associated with tumor budding, which correlates significantly with patient outcome. Hereby, the majority of tumor buds are not truly detached but still connected to a major tumor mass. For detailed insights into the different tumor bud types and the process of tumor budding, we quantified tumor cells according to histomorphological and immunohistological epithelial-mesenchymal transition characteristics. Three-dimensional reconstruction from adenocarcinomas (pancreatic, colorectal, lung, and ductal breast cancers) was performed as published. Tumor cell morphology and epithelial-mesenchymal transition characteristics (represented by zinc finger E-box-binding homeobox 1 and E-Cadherin) were analyzed qualitatively and quantitatively in a three-dimensional context. Tumor buds were classified into main tumor mass, connected tumor bud, and isolated tumor bud. Cell morphology and epithelial-mesenchymal transition marker expression were assessed for each tumor cell. Epithelial-mesenchymal transition characteristics between isolated tumor bud and connected tumor bud demonstrated no significant differences or trends. Tumor cell count correlated significantly with epithelial-mesenchymal transition and histomorphological characteristics. Regression curve analysis revealed initially a loss of membranous E-Cadherin, followed by expression of cytoplasmic E-Cadherin and subsequent expression of nuclear zinc finger E-box-binding homeobox 1. Morphologic changes followed later in this sequence. Our data demonstrate that connected and isolated tumor buds are equal concerning immunohistochemical epithelial-mesenchymal transition characteristics and histomorphology. Our data also give an insight in the process of tumor budding. While there is a notion that the epithelial-mesenchymal transition zinc finger E-box-binding homeobox 1-E-Cadherin cascade is initiated by zinc finger E-box-binding homeobox 1, our results are contrary and outline other possible pathways influencing the regulation of E-Cadherin.

Hybrid minimally invasive esophagectomy vs. open esophagectomy: a matched case analysis in 120 patients.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001). There was no difference between the groups with respect to surgical complications (37 vs. 37%, p = 0.575), but the patients undergoing hybrid technique showed more delayed gastric emptying (23 vs. 10%, p = 0.042). Pulmonary morbidity was significantly reduced after HMIE (20 vs. 42%, p = 0.009). This affected both the occurrence of pneumonia and pleural effusions. The difference in the overall complication rate was not significant (50 vs. 60%, p = 0.179), but life-threatening complications (Clavien/Dindo 4/5) were less frequent (2 vs. 12%, p = 0.031). Overall, there was significantly less need for transfusion after HMIE (18 vs. 50%, p < 0.001), and hospital (and IMC) stay was significantly shorter (14 (6) vs. 18 (7) days, p = 0.002 (0.003)). The multivariate analysis confirms the surgical procedure as an independent risk factor for the development of pulmonary complications (OR 3.2, p = 0.011). Furthermore, preexisting pulmonary conditions were identified as a risk factor (OR 3.6, p = 0.006). CONCLUSION: Our retrospective analysis shows that reduction of postoperative pulmonary morbidity, perioperative blood loss, and shortening of hospital stay can be achieved by HMIE. The procedure is safe, and the rate of surgical complications and oncological radicality is comparable to the conventional procedure.

Management and outcome of esophageal stenting for spontaneous esophageal perforations.

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.

Postoperative fluid overload is a risk factor for adverse surgical outcome in patients undergoing esophagectomy for esophageal cancer: a retrospective study in 335 patients.

BACKGROUND: Restrictive intraoperative fluid management is increasingly recommended for patients undergoing esophagectomy. Controversy still exists about the impact of postoperative fluid management on perioperative outcome. METHODS: We retrospectively examined 335 patients who had undergone esophagectomy for esophageal cancer at the University Hospital Freiburg between 1996 and 2014 to investigate the relation between intra- and postoperative fluid management and postoperative morbidity after esophagectomy. RESULTS: Perioperative morbidity was 75%, the in-hospital mortality 8%. A fluid balance above average on the operation day was strongly associated with a higher rate of postoperative mortality (21% vs 3%, p < 0.001) and morbidity (83% vs 66%, p = 0.001). Univariate analysis for risk factors for adverse surgical outcome (Clavien ≥ III) identified ASA-score (p = 0.002), smoking (p = 0.036), reconstruction by colonic interposition (p = 0.036), cervical anastomosis (p = 0.017), blood transfusion (p = 0.038) and total fluid balance on the operation day and on POD 4 (p = 0.001) as risk factors. Multivariate analysis confirmed only ASA-score (p = 0.001) and total fluid balance (p = 0.001) as independent predictors of adverse surgical outcome. CONCLUSION: Intra- and postoperative fluid overload is strongly associated with increased postoperative morbidity. Our results suggest restrictive intra- and especially postoperative fluid management to optimize the outcome after esophagectomy.

KRAS mutations in pancreatic circulating tumor cells: a pilot study.

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.

The degree of local inflammatory response after colonic resection depends on the surgical approach: an observational study in 61 patients.

BACKGROUND: Clinical data indicate that laparoscopic surgery reduces postoperative inflammatory response and benefits patient recovery. Little is known about the mechanisms involved in reduced systemic and local inflammation and the contribution of reduced trauma to the abdominal wall and the parietal peritoneum. METHODS: Included were 61 patients, who underwent elective colorectal resection without intraabdominal complications; 17 received a completely laparoscopic, 13 a laparoscopically- assisted procedure and 31 open surgery. Local inflammatory response was quantified by measurement of intraperitoneal leukocytes and IL-6 levels during the first 4 days after surgery. RESULTS: There was no statistical difference between the groups in systemic inflammatory parameters and intraperitoneal leukocytes. Intraperitoneal interleukin-6 was significantly lower in the laparoscopic group than in the laparoscopically-assisted and open group on postoperative day 1 (26.16 versus 43.25 versus 40.83 ng/ml; p = 0.001). No difference between the groups was recorded on POD 2-4. Intraperitoneal interleukin-6 showed a correlation with duration of hospital stay on POD 1 (0.233, p = 0.036), but not on POD 2-4. Patients who developed a surgical wound infection showed higher levels of intraperitoneal interleukin-6 on postoperative day 2-4 (POD 2: 42.56 versus 30.02 ng/ml, p = 0.03), POD 3: 36.52 versus 23.62 ng/ml, p = 0.06 and POD 4: 34.43 versus 19.99 ng/ml, p = 0.046). Extraabdominal infections had no impact. CONCLUSION: The analysis shows an attenuated intraperitoneal inflammatory response on POD 1 in completely laparoscopically-operated patients, associated with a quicker recovery. This effect cannot be observed in patients, who underwent a laparoscopically-assisted or open procedure. Factors inflicting additional trauma to the abdominal wall and parietal peritoneum promote the intraperitoneal inflammation process.

Multimodal treatment of locally advanced esophageal adenocarcinoma: which regimen should we choose? Outcome analysis of perioperative chemotherapy versus neoadjuvant chemoradiation in 105 patients.

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 = 58) or periCTX (n = 47) 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 = 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 (P < 0.01). 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; P < 0.01). CONCLUSION: 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.

Impact of intraoperative temperature and humidity on healing of intestinal anastomoses.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Covered self-expanding stent treatment for anastomotic leakage: outcomes in esophagogastric and esophagojejunal anastomoses.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Searching for the molecular benchmark of physiological intestinal anastomotic healing in rats: an experimental study.

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.

Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasm of the Pancreas.

Intraductal papillary mucinous neoplasm (IPMN) is the most common pancreatic cyst and a precursor of pancreatic cancer (PDAC). Since PDAC has a devastatingly high mortality rate, the early diagnosis and treatment of any precursor lesion are rational. The safety of the existing guidelines on the clinical management of IPMN has been criticized due to unsatisfactory sensitivity and specificity, showing the need for further markers. Blood obtained from patients with IPMN was therefore subjected to size-based isolation of circulating epithelial cells (CECs). We isolated CECs and evaluated their cytological characteristics. Additionally, we compared Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CECs and the primary IPMN tissue, since KRAS mutations are very typical for PDAC. Samples from 27 IPMN patients were analyzed. In 10 (37%) patients, CECs were isolated and showed a hybrid pattern of surface markers involving both epithelial and mesenchymal markers, suggesting a possible EMT process of the cells. Especially, patients with high-grade dysplasia in the main specimen were all CEC-positive. KRAS mutations were also present in CECs but less common than in IPMN tissue. The existence of CEC in IPMN patients offers additional blood-based research possibilities for IMPN biology.

Cancer-associated Macrophage-like Cells in Patients with Non-metastatic Adenocarcinoma of the Esophagus - Cytomorphological Heterogeneity.

Introduction: Esophageal adenocarcinoma (EAC) often recurs systemically despite therapy with a curative aim. New diagnostic and therapeutic approaches are urgently needed. A promising field is liquid biopsy, meaning the investigation of tumor-associated cells in the peripheral blood, for example cancer-associated macrophage-like cells (CAML). The aim of this multicentric study was to investigate the presence and cytomorphological appearance of CAML in patients with non-metastatic and operable esophageal cancer. Methods: Blood samples from 252 patients with locally advanced EAC were obtained before starting curative treatment including surgery, and then processed using ScreenCell® filtration devices. Cytological analysis was performed via May-Grünwald-Giemsa staining. CAML were defined by their morphological characteristics. We also performed immunofluorescence staining with the mesenchymal marker vimentin on a subset of our study cohort. Results: We detected cytomorphologically heterogeneous CAML in 31.8% (n=80) patients. Their presence and cell count did not correlate significantly with pretherapeutic cTNM. Even in patients with small tumors and no lymph-node infiltration, cell counts were high. CAML showed heterogenous staining patterns for vimentin. Conclusion: This is one of the first studies demonstrating the presence and phenotype of CAML in a uniquely broad cohort of EAC patients. As they are believed to be representatives of the inflammatory tumor microenvironment shed into the bloodstream, their presence in non-metastatic EAC is a promising finding.

Prognostic factors after resection of locally advanced non-functional pancreatic neuroendocrine neoplasm: an analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

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 < 0.001) and lymphangiosis (HR 2.35, 95% CI 1.20-4.59, 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.

The Glasgow Prognostic Score Predicts Survival Outcomes in Neuroendocrine Neoplasms of the Gastro-Entero-Pancreatic (GEP-NEN) System.

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.

Three-dimensional stomach analysis with computed tomography after laparoscopic sleeve gastrectomy: sleeve dilation and thoracic migration.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Dual Inhibition of mTORC1/2 Reduces Migration of Cholangiocarcinoma Cells by Regulation of Matrixmetalloproteinases.

Cholangiocarcinoma (CCA) is a rare but highly aggressive tumor entity for which systemic therapies only showed limited efficacy so far. As OSI-027-a dual kinase inhibitor targeting both mTOR complexes, mTORC1 and mTORC2 - showed improved anti-cancer effects, we sought to evaluate its impact on the migratory and metastatic capacity of CCA cells in vitro. We found that treatment with OSI-027 leads to reduced cell mobility and migration as well as a reduced surviving fraction in colony-forming ability. While neither cell viability nor proliferation rate was affected, OSI-027 decreased the expression of MMP2 and MMP9. Moreover, survival as well as anti-apoptotic signaling was impaired upon the use of OSI-027 as determined by AKT and MAPK blotting. Dual targeting of mTORC1/2 might therefore be a viable option for anti-neoplastic therapy in CCA.

Resection of Non-Functional Pancreatic Neuroendocrine Neoplasms-A Single-Center Retrospective Outcome Analysis.

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.