[Impact of the COVID pandemic on treatment of bariatric patients in Germany-An analysis of the national StuDoQ/MBE register]. / Auswirkungen der COVID-Pandemie auf die Versorgung bariatrischer Patienten in Deutschland ­ eine Analyse des nationalen StuDoQ/MBE-Registers.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic the standard inpatient care of patients was restricted to increase overall and intensive care capacity reserves for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected persons. OBJECTIVE: This article presents the impact of the COVID-19 pandemic on the surgical and postoperative care of bariatric patients in Germany. MATERIAL AND METHODS: A statistical analysis of the national StuDoQ/MBE register data for the period from 1 May 2018 until 31 May 2022 was performed. RESULTS: Throughout the entire study period there was a continuous increase in documented operations, which continued even during the COVID-19 pandemic. A significant intermittent decline in surgery performed was observed only during the imposition of first lockdown in the months of March to May 2020, with a minimum number of 194 cases performed monthly in April 2020. The pandemic had no measurable effect on the surgically treated patient population, the type of surgical procedure, the perioperative and postoperative outcomes and follow-up care. CONCLUSION: Based on the results of the StuDoQ data and the current literature, it can be deduced that bariatric surgery can be carried out with no increased risk during the COVID-19 pandemic and the quality of postoperative care is not impaired.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Variation in pancreatoduodenectomy as delivered in two national audits.

BACKGROUND: Nationwide audits facilitate quality and outcome assessment of pancreatoduodenectomy. Differences may exist between countries but studies comparing nationwide outcomes of pancreatoduodenectomy based on audits are lacking. This study aimed to compare the German and Dutch audits for external data validation. METHODS: Anonymized data from patients undergoing pancreatoduodenectomy between 2014 and 2016 were extracted from the German Society for General and Visceral Surgery StuDoQ|Pancreas and Dutch Pancreatic Cancer Audit, and compared using descriptive statistics. Univariable and multivariable risk analyses were undertaken. RESULTS: Overall, 4495 patients were included, 2489 in Germany and 2006 in the Netherlands. Adenocarcinoma was a more frequent indication for pancreatoduodenectomy in the Netherlands. German patients had worse ASA fitness grades, but Dutch patients had more pulmonary co-morbidity. Dutch patients underwent more minimally invasive surgery and venous resections, but fewer multivisceral resections. No difference was found in rates of grade B/C postoperative pancreatic fistula, grade C postpancreatectomy haemorrhage and in-hospital mortality. There was more centralization in the Netherlands (1·3 versus 13·3 per cent of pancreatoduodenectomies in very low-volume centres; P < 0·001). In multivariable analysis, both hospital stay (difference 2·49 (95 per cent c.i. 1·18 to 3·80) days) and risk of reoperation (odds ratio (OR) 1·55, 95 per cent c.i. 1·22 to 1·97) were higher in the German audit, whereas risk of postoperative pneumonia (OR 0·57, 0·37 to 0·88) and readmission (OR 0·38, 0·30 to 0·49) were lower. Several baseline and surgical characteristics, including hospital volume, but not country, predicted mortality. CONCLUSION: This comparison of the German and Dutch audits showed variation in case mix, surgical technique and centralization for pancreatoduodenectomy, but no difference in mortality and pancreas-specific complications.

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

[Quality indicators for pancreatic surgery : Scientific derivation and clinical relevance]. / Qualitätsindikatoren für die Pankreaschirurgie : Wissenschaftliche Herleitung und klinische Relevanz.

Quality indicators are by definition indirect measures of quality. The selection for the field of pancreatic surgery was based on the clinical relevance and controllability, scientific evidence and the practicability of data acquisition. In terms of outcome quality, hospital mortality, the composite endpoint MTL30 (mortality-transfer-length of stay), and major complications (Clavien-Dindo classification grades 3b and 4) were chosen as being essential. With respect to structural quality, the presence of interventional radiology with constant availability was considered essential. To evaluate target values two strategies were used: a systematic literature search and evaluation of the current numbers from the German Society for General and Visceral Surgery (DGAV) StuDoQ|Pancreas registry for the years 2014-2016. The results are presented in the following consensus statement.

The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: a meta-analysis for the 5-year survival.

PURPOSE: To assess the available evidence on the prognostic factors for the 5-year survival for patients with distal cholangiocarcinoma (DCC) following surgical resection. METHODS: We performed a comprehensive search of abstracts included in databases where relevant studies were published between January 2000 and August 2015. Risk ratios (RRs), 95 % confidence intervals (95 % CIs), and random-effects model were calculated using RevMan 5.3 software. RESULTS: A total of 23 observational studies involving 2063 patients with DCC were analyzed. The meta-analysis showed that postoperative adjuvant chemotherapy was not confirmed as a prognostic factor, with similar 5-year survival rates between those receiving and not receiving chemotherapy (RR 0.71; 95 % CI 0.21-2.36; P = 0.57). Perineural invasion (RR 0.51; 95 % CI 0.40-0.64; P < 0.00001), lymph node metastasis (RR 0.51; 95 % CI 0.38-0.70; P < 0.0001), positive resection margin status (RR 2.11; 95 % CI 1.36-3.30; P = 0.001), and not-well-differentiated adenocarcinoma (RR 1.77; 95 % CI 1.39-2.25; P < 0.00001) were associated with shorter survival. CONCLUSIONS: Perineural invasion, lymph node metastasis, resection margin status, and tumor differentiation were the significant prognostic factors for the 5-year survival.

[Pancreaticogastrostomy: when and how?] / Pankreatogastrostomie: wann und wie?

BACKGROUND: Pancreaticojejunostomy and pancreaticogastrostomy are the two techniques for pancreatic anastomosis that are widely established for the reconstruction after pancreaticoduodenectomy. Pancreaticogastrostomy is the most recent and to date less frequently performed method, the history, techniques and indications of which are presented. METHOD: Review of the literature and current evidence. RESULTS: Current evidence from randomized controlled trials and meta-analyses does not demonstrate significant differences in complication rates or pancreatic function after pancreaticogastrostomy versus pancreaticojejunostomy. CONCLUSION: Pancreaticogastrostomy is the technically less demanding procedure, offering at least the same level of safety as pancreaticojejunostomy. Minimally invasive and parenchyma-sparing procedures provide new areas of application for this anastomotic technique.

Fibroblast activation protein-α, a stromal cell surface protease, shapes key features of cancer associated fibroblasts through proteome and degradome alterations.

Cancer associated fibroblasts (CAFs) constitute an abundant stromal component of most solid tumors. Fibroblast activation protein (FAP) α is a cell surface protease that is expressed by CAFs. We corroborate this expression profile by immunohistochemical analysis of colorectal cancer specimens. To better understand the tumor-contextual role of FAPα, we investigate how FAPα shapes functional and proteomic features of CAFs using loss- and gain-of function cellular model systems. FAPα activity has a strong impact on the secreted CAF proteome ("secretome"), including reduced levels of anti-angiogenic factors, elevated levels of transforming growth factor (TGF) ß, and an impact on matrix processing enzymes. Functionally, FAPα mildly induces sprout formation by human umbilical vein endothelial cells. Moreover, loss of FAPα leads to a more epithelial cellular phenotype and this effect was rescued by exogenous application of TGFß. In collagen contraction assays, FAPα induced a more contractile cellular phenotype. To characterize the proteolytic profile of FAPα, we investigated its specificity with proteome-derived peptide libraries and corroborated its preference for cleavage carboxy-terminal to proline residues. By "terminal amine labeling of substrates" (TAILS) we explored FAPα-dependent cleavage events. Although FAPα acts predominantly as an amino-dipeptidase, putative FAPα cleavage sites in collagens are present throughout the entire protein length. In contrast, putative FAPα cleavage sites in non-collagenous proteins cluster at the amino-terminus. The degradomic study highlights cell-contextual proteolysis by FAPα with distinct positional profiles. Generally, our findings link FAPα to key aspects of CAF biology and attribute an important role in tumor-stroma interaction to FAPα.

Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

[Internal hernias after bariatric surgery]. / Innere Hernien nach bariatrischer Chirurgie.

Hernias are among the most common long-term complications after bariatric surgery. Besides incisional hernias, which occur very often after conventional open bariatric surgery, internal hernias after bariatric surgery constitute a special challenge. The incidence of internal hernias after bariatric surgery is more common than for other upper gastrointestinal tract operations. Internal hernias are not limited to laparoscopic procedures but are also observed after conventional open gastric bypass surgery. As the incidence is significantly increased after laparoscopic interventions, there seems to be a close association with minimally invasive procedures. The clinical symptoms of internal hernias without complete obstruction are non-specific and the correct diagnosis is often not straightforward. In addition to the aspects of prevention of internal hernias in laparoscopic surgery, this article discusses the diagnosis and treatment, taking into account the various forms of internal hernia after bariatric operations.

Quantitative proteomic analysis of formalin-fixed, paraffin-embedded clear cell renal cell carcinoma tissue using stable isotopic dimethylation of primary amines.

BACKGROUND: Formalin-fixed, paraffin-embedded (FFPE) tissues represent the most abundant resource of archived human specimens in pathology. Such tissue specimens are emerging as a highly valuable resource for translational proteomic studies. In quantitative proteomic analysis, reductive di-methylation of primary amines using stable isotopic formaldehyde variants is increasingly used due to its robustness and cost-effectiveness. RESULTS: In the present study we show for the first time that isotopic amine dimethylation can be used in a straightforward manner for the quantitative proteomic analysis of FFPE specimens without interference from formalin employed in the FFPE process. Isotopic amine dimethylation of FFPE specimens showed equal labeling efficiency as for cryopreserved specimens. For both FFPE and cryopreserved specimens, differential labeling of identical samples yielded highly similar ratio distributions within the expected range for dimethyl labeling. In an initial application, we profiled proteome changes in clear cell renal cell carcinoma (ccRCC) FFPE tissue specimens compared to adjacent non-malignant renal tissue. Our findings highlight increased levels of glyocolytic enzymes, annexins as well as ribosomal and proteasomal proteins. CONCLUSION: Our study establishes isotopic amine dimethylation as a versatile tool for quantitative proteomic analysis of FFPE specimens and underlines proteome alterations in ccRCC.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

Postpancreatectomy hemorrhage--incidence, treatment, and risk factors in over 1,000 pancreatic resections.

BACKGROUND: Postpancreatectomy hemorrhage is a rare but often severe complication after pancreatic resection. The aim of this retrospective study was to define incidence and risk factors of postpancreatectomy hemorrhage and to evaluate treatment options and outcome. PATIENTS AND METHODS: Clinical data was extracted from a prospectively maintained database. Descriptive statistics, univariate and multivariate risk factor analysis by binary logistic regression were performed with SPSS software at a significance level of p = 0.05. RESULTS: N = 1,082 patients with pancreatic resections between 1994 and 2012 were included. Interventional angiography was successful in about half of extraluminal bleeding. A total of 78 patients (7.2 %) had postpancreatectomy hemorrhage (PPH), and 29 (2.7 %) were grade C PPH. Multivariate modeling disclosed a learning effect, age, BMI, male sex, intraoperative transfusion, portal venous and multivisceral resection, pancreatic fistula and preoperative biliary drainage as independent predictors of severe postpancreatectomy hemorrhage. High-risk histopathology, age, transfusion, pancreatic fistula, postpancreatectomy hemorrhage and pancreatojejunostomy in pancreatoduodenectomies were independent predictors of mortality. CONCLUSIONS: Our study identifies clinically relevant risk factors for postpancreatectomy hemorrhage and mortality. Interventional treatment of extraluminal hemorrhage is successful in about half of the cases and if unsuccessful constitutes a valuable adjunct to operative hemostasis. Based on our observations, we propose a treatment scheme for PPH. Risk factor analysis suggests appropriate patient selection especially for extended resections and pancreatogastrostomy for reconstruction in pancreatoduodenectomy.

[Tumour stem cells and metastasis]. / Tumorstammzellen und Metastasierung.

The underlying mechanisms of cancer development, invasion and metastasis are still only partly unraveled. Cancer stem cells (CSC) and the so-called epithelial-mesenchymal transition (EMT) seem to contribute to these oncological phenomena. Cancer stem cells which, according to our present knowledge, play an important role in tumour development and persistence, are operationally defined. The embryonic programme of EMT is activated aberrantly in cancer cells at the invasive front and seems to contribute to tumour invasion and metastasis. Recent observations suggest that the EMT and CSC traits are closely related. This provides new explanatory models for cancer development and metastasis.

[Liver metastases: pathogenesis and oncogenesis]. / Lebermetastasen: Pathogenese und Onkogenese.

Liver metastases are most often caused by colorectal cancer, followed by pancreatic and breast cancer. Metastasis constitutes the last step of malignant tumor progression. Molecular investigations point towards an important role of the epithelial-mesenchymal transition (EMT) as a mechanism of local invasion and distant metastasis formation. Furthermore, the existence of a subpopulation of cancer stem cells (CSC) could be demonstrated in solid tumors. Recent observations show a dynamic induction of CSC properties by EMT. Therefore, theoretically migrating cancer stem cells (MCSC) can be induced which form the basis for the development of distant metastases.