When Should Lymphadenectomy Be Performed in Non-Metastatic Pancreatic Neuroendocrine Tumors? A Population-Based Analysis of the German Clinical Cancer Registry Group.

BACKGROUND: Patient selection for lymphadenectomy remains a controversial aspect in the treatment of pancreatic neuroendocrine tumors (pNETs), given the growing importance of parenchyma-sparing resections and minimally invasive procedures. METHODS: This population-based analysis was derived from the German Cancer Registry Group during the period from 2000 to 2021. Patients with upfront resected non-functional non-metastatic pNETs were included. RESULTS: Out of 5520 patients with pNET, 1006 patients met the inclusion criteria. Fifty-three percent of the patients were male. The median age was 64 ± 17 years. G1, G2, and G3 pNETs were found in 57%, 37%, and 7% of the patients, respectively. Lymph node metastasis (LNM) was present in 253 (24%) of all patients. LNM was an independent prognostic factor (HR 1.79, CI 95% 1.21-2.64, p = 0.001) for disease-free survival (DFS). The 3-, 5-, and 10-year disease-free survival in nodal negative tumors compared to nodal positive was 82% vs. 53%, 75% vs. 38%, and 48% vs. 16%. LNM was present in 5% of T1 tumors, 25% of T2 tumors, and 49% of T3-T4 tumors. In T1 tumors, G1 was the most predominant tumor grade (80%). However, in T2 tumors, G2 and G3 represented 44% and 5% of all tumors. LNM was associated with tumors located in the pancreatic head (p < 0.001), positive resection margin (p < 0.001), tumors larger than 2 cm (p < 0.001), and higher tumor grade (p < 0.001). The multivariable analysis showed that tumor size, tumor grade, and location were independent prognostic factors associated with LNM that could potentially be used to predict LNM preoperatively. CONCLUSION: LNM is an independent negative prognostic factor for DFS in pNETs. Due to the low incidence of LNM in T1 tumors (5%), parenchyma-sparing surgery seems oncologically adequate in small G1 pNETs, while regional lymphadenectomy should be recommended in T2 or G2/G3 pNETs.

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.

TAp73 Inhibits EMT and Cell Migration in Pancreatic Cancer Cells through Promoting SMAD4 Expression and SMAD4-Dependent Inhibition of ERK Activation.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease due to early metastatic spread, late diagnosis and the lack of efficient therapies. A major driver of cancer progression and hurdle to successful treatment is transforming growth factor (TGF)-ß. Recent data from pancreatic cancer mouse models showed that transcriptionally active p73 (TAp73), a p53 family member, inhibits tumor progression through promoting tumor suppressive canonical TGF-ß/Smad signaling, while preventing non-canonical TGF-ß signaling through extracellular signal-regulated kinases (ERK)1/2. Here, we studied whether this mechanism also operates in human PDAC. Using the PDAC-derived tumor cell lines PANC-1, HPAFII and L3.6pl, we showed that TAp73 induces the expression of the epithelial marker and invasion suppressor E-cadherin and the common-mediator Smad, SMAD4, while at the same time suppressing expression of the EMT master regulator SNAIL and basal and TGF-ß1-induced activation of ERK1 and ERK2. Using dominant-negative and RNA interference-based inhibition of SMAD4 function, we went on to show that inhibition of ERK activation by TAp73 is mediated through SMAD4. Intriguingly, both SMAD4 and the α isoform of TAp73-but not the ß isoform-interfered with cell migration, as shown by xCELLigence technology. Our findings highlighted the role of TAp73-SMAD4 signaling in tumor suppression of human PDAC and identified direct inhibition of basal and TGF-ß-stimulated pro-invasive ERK activation as an underlying mechanism.

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.

Gastrointestinal stromal tumors of the upper GI tract: population-based analysis of epidemiology, treatment and outcome based on data from the German Clinical Cancer Registry Group.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors. They are most frequently located in the stomach but are also found in the esophagus and the gastroesophageal junction (GEJ). Information regarding the prognostic factors associated with upper gastrointestinal GIST is still scarse. METHODS: In this study, datasets provided by the German Clinical Cancer Registry Group, including a total of 93,069 patients with malignant tumors in the upper GI tract (C15, C16) between 2000 and 2016 were analyzed to investigate clinical outcomes of GIST in the entire upper GI tract. RESULTS: We identified 1361 patients with GIST of the upper GI tract. Tumors were located in the esophagus in 37(2.7%) patients, at the GEJ in 70 (5.1%) patients, and in the stomach in 1254 (91.2%) patients. The incidence of GIST increased over time, reaching 5% of all UGI tumors in 2015. The median age was 69 years. The incidence of GIST was similar between males and females (53% vs 47%, respectively). However, the proportion of GIST in female patients increased continuously with advancing age, ranging from 34.7% (41-50 years) to 71.4% (91-100 years). Male patients were twice as likely to develop tumors in the esophagus and GEJ compared to females (3.4% vs. 1.9% and 6.7% vs. 3.4%, respectively). The median overall survival of upper gastrointestinal GIST was 129 months. The 1-year, 5-year, and 10-year OS was 93%, 79%, and 52% respectively. Nevertheless, tumors located in the esophagus and GEJ were associated with shorter OS compared to gastric GIST (130 vs. 111 months, p = 0.001). The incidence of documented distant metastasis increased with more proximal location of GIST (gastric vs. GEJ vs. esophagus: 13% vs. 16% vs. 27%) at presentation. CONCLUSION: GIST of the esophagus and GEJ are rare soft tissue sarcomas with increasing incidence in Germany. They are characterized by worse survival outcomes and increased risk of metastasis compared to gastric GIST.

Elucidation of the Role of SMAD4 in Epithelial-Mesenchymal Plasticity: Does It Help to Better Understand the Consequences of DPC4 Inactivation in the Malignant Progression of Pancreatic Ductal Adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related mortality worldwide, with a 5-year-survival rate below 10% that is the lowest of all cancer types [...].

Establishment and Molecular Characterization of Two Patient-Derived Pancreatic Ductal Adenocarcinoma Cell Lines as Preclinical Models for Treatment Response.

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is exceedingly poor. Although surgical resection is the only curative treatment option, multimodal treatment is of the utmost importance, as only about 20% of tumors are primarily resectable at the time of diagnosis. The choice of chemotherapeutic treatment regimens involving gemcitabine and FOLFIRINOX is currently solely based on the patient's performance status, but, ideally, it should be based on the tumors' individual biology. We established two novel patient-derived primary cell lines from surgical PDAC specimens. LuPanc-1 and LuPanc-2 were derived from a pT3, pN1, G2 and a pT3, pN2, G3 tumor, respectively, and the clinical follow-up was fully annotated. STR-genotyping revealed a unique profile for both cell lines. The population doubling time of LuPanc-2 was substantially longer than that of LuPanc-1 (84 vs. 44 h). Both cell lines exhibited a typical epithelial morphology and expressed moderate levels of CK7 and E-cadherin. LuPanc-1, but not LuPanc-2, co-expressed E-cadherin and vimentin at the single-cell level, suggesting a mixed epithelial-mesenchymal differentiation. LuPanc-1 had a missense mutation (p.R282W) and LuPanc-2 had a frameshift deletion (p.P89X) in TP53. BRCA2 was nonsense-mutated (p.Q780*) and CREBBP was missense-mutated (p.P279R) in LuPanc-1. CDKN2A was missense-mutated (p.H83Y) in LuPanc-2. Notably, only LuPanc-2 harbored a partial or complete deletion of DPC4. LuPanc-1 cells exhibited high basal and transforming growth factor (TGF)-ß1-induced migratory activity in real-time cell migration assays, while LuPanc-2 was refractory. Both LuPanc-1 and LuPanc-2 cells responded to treatment with TGF-ß1 with the activation of SMAD2; however, only LuPanc-1 cells were able to induce TGF-ß1 target genes, which is consistent with the absence of DPC4 in LuPanc-2 cells. Both cell lines were able to form spheres in a semi-solid medium and in cell viability assays, LuPanc-1 cells were more sensitive than LuPanc-2 cells to treatment with gemcitabine and FOLFIRINOX. In summary, both patient-derived cell lines show distinct molecular phenotypes reflecting their individual tumor biology, with a unique clinical annotation of the respective patients. These preclinical ex vivo models can be further explored for potential new treatment strategies and might help in developing personalized (targeted) therapy regimens.

Specifics of Young Gastric Cancer Patients: A Population-Based Analysis of 46,110 Patients with Gastric Cancer from the German Clinical Cancer Registry Group.

Introduction: 2−8% of all gastric cancer occurs at a younger age, also known as early-onset gastric cancer (EOGC). The aim of the present work was to use clinical registry data to classify and characterize the young cohort of patients with gastric cancer more precisely. Methods: German Cancer Registry Group of the Society of German Tumor Centers­Network for Care, Quality and Research in Oncology (ADT)was queried for patients with gastric cancer from 2000−2016. An approach that stratified relative distributions of histological subtypes of gastric adenocarcinoma according to age percentiles was used to define and characterize EOGC. Demographics, tumor characteristics, treatment and survival were analyzed. Results: A total of 46,110 patients were included. Comparison of different groups of age with incidences of histological subtypes showed that incidence of signet ring cell carcinoma (SRCC) increased with decreasing age and exceeded pooled incidences of diffuse and intestinal type tumors in the youngest 20% of patients. We selected this group with median age of 53 as EOGC. The proportion of female patients was lower in EOGC than that of elderly patients (43% versus 45%; p < 0.001). EOGC presented more advanced and undifferentiated tumors with G3/4 stages in 77% versus 62%, T3/4 stages in 51% versus 48%, nodal positive tumors in 57% versus 53% and metastasis in 35% versus 30% (p < 0.001) and received less curative treatment (42% versus 52%; p < 0.001). Survival of EOGC was significantly better (five-years survival: 44% versus 31% (p < 0.0001), with age as independent predictor of better survival (HR 0.61; p < 0.0001). Conclusion: With this population-based registry study we were able to objectively define a cohort of patients referred to as EOGC. Despite more aggressive/advanced tumors and less curative treatment, survival was significantly better compared to elderly patients, and age was identified as an independent predictor for better survival.

The Quasimesenchymal Pancreatic Ductal Epithelial Cell Line PANC-1-A Useful Model to Study Clonal Heterogeneity and EMT Subtype Shifting.

Intratumoral heterogeneity (ITH) is an intrinsic feature of malignant tumors that eventually allows a subfraction of resistant cancer cells to clonally evolve and cause therapy failure or relapse. ITH, cellular plasticity and tumor progression are driven by epithelial-mesenchymal transition (EMT) and the reverse process, MET. During these developmental programs, epithelial (E) cells are successively converted to invasive mesenchymal (M) cells, or back to E cells, by passing through a series of intermediate E/M states, a phenomenon termed E-M plasticity (EMP). The induction of MET has clinical potential as it can block the initial EMT stages that favor tumor cell dissemination, while its inhibition can curb metastatic outgrowth at distant sites. In pancreatic ductal adenocarcinoma (PDAC), cellular models with which to study EMP or MET induction are scarce. Here, we have generated single cell-derived clonal cultures of the quasimesenchymal PDAC-derived cell line, PANC-1, and found that these differ strongly with respect to cell morphology and EMT marker expression, allowing for their tentative classification as E, E/M or M. Interestingly, the different EMT phenotypes were found to segregate with differences in tumorigenic potential in vitro, as measured by colony forming and invasive activities, and in circadian clock function. Moreover, the individual clones the phenotypes of which remained stable upon prolonged culture also responded differently to treatment with transforming growth factor (TGF)ß1 in regard to regulation of growth and individual TGFß target genes, and to culture conditions that favour ductal-to-endocrine transdifferentiation as a more direct measure for cellular plasticity. Of note, stimulation with TGFß1 induced a shift in parental PANC-1 cultures towards a more extreme M and invasive phenotype, while exposing the cells to a combination of the proinflammatory cytokines IFNγ, IL1ß and TNFα (IIT) elicited a shift towards a more E and less invasive phenotype resembling a MET-like process. Finally, we show that the actions of TGFß1 and IIT both converge on regulating the ratio of the small GTPase RAC1 and its splice isoform, RAC1b. Our data provide strong evidence for dynamic EMT-MET transitions and qualify this cell line as a useful model with which to study EMP.

[Robotic-assisted Enucleation of a Cystic Neoplasm in the Head of the Pancreas]. / Robotisch gestützte Enukleation einer zystischen Neoplasie des Pankreaskopfes.

According to current revised Fukuoka guidelines, there is an indication for resection of BD-IPMN of the pancreas with "worrisome features", as there is a risk of malignant degeneration of up to 30%. This can be performed as a non-anatomical local excision in the absence of clinical, radiological and laboratory signs of malignancy.Robotic enucleation for benign tumours of the pancreas is a very good alternative to resecting procedures, especially those using open techniques. This surgical treatment option is recommended by the "International consensus statement on robotic pancreatic surgery" in a case of a minimum distance to the main pancreatic duct of at least 2 mm.In addition to the known advantages of minimally invasive surgery, this parenchyma-sparing approach results in preservation of endo- and exocrine function (ca. 90%) and 10-year progression-free survival of ca. 75% with slightly increased morbidity (ca. 60%) compared with resecting procedures.The following video article presents the surgical video of a robotic cyst enucleation (for suspected BD-IPMN with "worrisome features") in the pancreatic head and uncinate process in a 62-year-old female patient with special emphasis on the most important vascular landmarks, special features of the approach and advantages of the robotic technique.

[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.

Risk Stratification for the Intensive Care Unit Following Pancreaticoduodenectomy. / Risikostratifizierung für intensivmedizinische Betreuung nach Pankreatoduodenektomie.

INTRODUCTION: In view of the limited capacities in intensive care units and the increasing economic burden, identification of risk factors could allow better and more efficient planning. Therefore, the aim of this study was to assess independent risk factors for the duration of intensive care unit stay after pancreatoduodenectomy (PD). METHODS: 147 patients who underwent pancreatoduodenectomy in the time period from 2013 to 2015 were identified from a prospective database and a retrospective analysis was performed. The primary endpoint was length of time spent in the ICU. A retrograde analysis was performed using univariate and multivariate regression analysis. All pre-, intra- and postoperative parameters were considered in the analysis. RESULTS: The median time spent in the intensive care unit (ICU) is one day. The univariate analysis demonstrated increased pack years, cerebrovascular events, anticoagulation, elevated creatinine and CA 19-9 as preoperative risk factors. In multivariate analysis, antihypertensive medication (AHT; OR 2.46; 95% CI 1.57 - 3.87; p = 0.05), operation time (OR 1.01; 95% CI 1.00 - 1.01; p = 0.03), extended LAD (OR 5.46; 95% CI 2.77 - 10.75; p = 0.01) and severe PPH (OR 4.01; 95% CI 2.07 - 7.76; p = 0.04) are significant risk factors for longer ICU stay. DISCUSSION: Patients with cardiovascular risk factors and elevated preoperative creatinine level are at greater risk for a prolonged ICU stay. Risk and benefit of an extended LAD should be weighed during the operation. Median duration on ICU/IMC after PD is one day or less for patients without risk factors. Whether routine monitoring in the ICU/IMC after PD is necessary must be clarified in further studies.

Survival Outcome and Prognostic Factors for Pancreatic Acinar Cell Carcinoma: Retrospective Analysis from the German Cancer Registry Group.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a distinct type of pancreatic cancer with low prevalence. We aimed to analyze prognostic factors and survival outcome for PACC in comparison to pancreatic ductal adenocarcinoma (PDAC), based on data from the German Cancer Registry Group. METHODS: Patients with PACC and PDAC were extracted from pooled data of the German clinical cancer registries (years 2000 to 2019). The distribution of demographic parameters, tumor stage and therapy modes were compared between PACC and PDAC. The Kaplan-Meier method and Cox regression analysis were used to delineate prognostic factors for PACC. Propensity score matching was used to compare survival between PACC and PDAC. RESULTS: There were 233 (0.44%) patients with PACC out of 52,518 patients with pancreatic malignancy. Compared to PDAC, patients with PACC were younger (median age 66 versus 70, respectively, p < 0.001) and the percentage of males was higher (66.1% versus 53.3%, respectively, p < 0.001). More patients were resected with PACC than with PDAC (56.2% versus 38.9%, respectively, p < 0.001). The estimated overall median survival in PACC was 22 months (95% confidence interval 15 to 27), compared to 12 months (95% confidence interval 10 to 13) in the matched PDAC cohort (p < 0.001). Surgical resection was the strongest positive prognostic factor for PACC after adjusting for sex, age, and distant metastases (hazard ratio 0.34, 95% confidence interval 0.22 to 0.51, p < 0.001). There was no survival benefit for adjuvant therapy in PACC. CONCLUSIONS: PACC has overall better prognosis than PDAC. Surgical resection is the best therapeutic strategy for PACC and should be advocated even in advanced tumor stages.

Activation of a Ductal-to-Endocrine Transdifferentiation Transcriptional Program in the Pancreatic Cancer Cell Line PANC-1 Is Controlled by RAC1 and RAC1b through Antagonistic Regulation of Stemness Factors.

Epithelial-mesenchymal transition (EMT) is a driving force for tumor growth, metastatic spread, therapy resistance, and the generation of cancer stem cells (CSCs). However, the regained stem cell character may also be exploited for therapeutic conversion of aggressive tumor cells to benign, highly differentiated cells. The PDAC-derived quasimesenchymal-type cell lines PANC-1 and MIA PaCa-2 have been successfully transdifferentiated to endocrine precursors or insulin-producing cells; however, the underlying mechanism of this increased plasticity remains elusive. Given its crucial role in normal pancreatic endocrine development and tumor progression, both of which involve EMT, we analyzed here the role of the small GTPase RAC1. Ectopic expression in PANC-1 cells of dominant negative or constitutively active mutants of RAC1 activation blocked or enhanced, respectively, the cytokine-induced activation of a ductal-to-endocrine transdifferentiation transcriptional program (deTDtP) as revealed by induction of the NEUROG3, INS, SLC2A2, and MAFA genes. Conversely, ectopic expression of RAC1b, a RAC1 splice isoform and functional antagonist of RAC1-driven EMT, decreased the deTDtP, while genetic knockout of RAC1b dramatically increased it. We further show that inhibition of RAC1 activation attenuated pluripotency marker expression and self-renewal ability, while depletion of RAC1b dramatically enhanced stemness features and clonogenic potential. Finally, rescue experiments involving pharmacological or RNA interference-mediated inhibition of RAC1 or RAC1b, respectively, confirmed that both RAC1 isoforms control the deTDtP in an opposite manner. We conclude that RAC1 and RAC1b antagonistically control growth factor-induced activation of an endocrine transcriptional program and the generation of CSCs in quasimesenchymal PDAC cells. Our results have clinical implications for PDAC patients, who in addition to eradication of tumor cells have a need for replacement of insulin-producing cells.

[Preoperative diagnostics in periampullary adenocarcinomas]. / Präoperative Diagnostik bei periampullären Adenokarzinomen.

BACKGROUND: Approximately 30-40% of pancreatoduodenectomies for adenocarcinomas result in nonpancreatic periampullary adenocarcinoma as the final diagnosis. Depending on the origin, a distinction is made between four different carcinomas with histomorphological subtypes. OBJECTIVE: Carcinoma location and subtype are of prognostic and therapeutic relevance; however, the preoperative differentiation is often incorrect despite modern diagnostics. MATERIAL AND METHODS: Overview of the current literature on the classification and preoperative diagnostics of periampullary adenocarcinomas. RESULTS: A precise knowledge of the papillary anatomy is necessary for the correct classification of diagnostic findings. Current studies demonstrate diagnostically valuable information from the anamnesis, imaging and endoscopy. CONCLUSION: In ca. 70-80% of cases a correct diagnosis of the type of periampullary adenocarcinoma is possible on the basis of interdisciplinary diagnostics. This potentially enables a correspondingly individualized treatment planning in the preoperative phase.

Surgeon vs Pathologist for Prediction of Pancreatic Fistula: Results from the Randomized Multicenter RECOPANC Study.

BACKGROUND: Surgically assessed pancreatic texture has been identified as the strongest predictor of postoperative pancreatic fistula. However, texture is a subjective parameter with no proven reliability or validity. Therefore, a more objective parameter is needed. In this study, we evaluated the fibrosis level at the pancreatic neck resection margin and correlated fibrosis and all clinico-pathologic parameters collected over the course of the Pancreatogastrostomy vs Pancreatojejunostomy for RECOnstruction (RECOPANC) study. STUDY DESIGN: The RECOPANC trial was a multicenter randomized prospective trial of patients undergoing pancreatoduodenectomy. There were 261 hematoxylin and eosin-stained slides allocated for histopathologic analyses. Pancreatic fibrosis was scored from 0 to III (no fibrosis up to severe fibrosis) by 2 blinded independent pathologists. All variables possibly associated with POPF were entered into a generalized linear model for multivariable analysis. RESULTS: The fibrosis grade and pancreatic texture were scored in all 261 patients. In POPF B/C (postoperative pancreatic fistula grade B or C) patients, 71% had a soft pancreas, and fibrosis grades were distributed as follows: 48% with score 0, 28% with score I, 20% with score II, and 7% with score III, respectively. Fibrosis grading showed substantial inter-rater reliability (kappa = 0.74) and correlated positively with hard pancreatic texture (p < 0.05). In univariable analysis, area under the curve (AUC) for POPF B/C prediction was higher for fibrosis grade than for pancreatic texture (0.71 vs 0.59). In multivariate analysis, the following predictors were selected: sex, surgeon volume, pancreatic texture, and fibrosis grade. However, the addition of pancreatic texture only led to an incremental improvement (AUC 0.794 vs 0.819). CONCLUSIONS: Histologically evaluated pancreatic fibrosis is an easily applicable and highly reproducible POPF predictor and superior to surgically evaluated pancreatic texture. Future studies might use fibrosis grade for risk stratification in pancreatoduodenectomy.

[Robot-assisted Distal Pancreatectomy with En Bloc Celiac Axis Resection (Modified Appleby Procedure) after Neoadjuvant Therapy]. / Robotisch assistierte Resektion eines zentralen neoadjuvant behandelten Pankreaskarzinoms mit En-bloc-Resektion des Truncus coeliacus (modifizierte Appleby-Operation).

Pancreatic carcinoma in the body and on the left side of the mesentericoportal axis is often only detected in late stages owing to unspecific or even missing clinical symptoms. In approximately 20% of the cases, there is already infiltration of the tumour into the surrounding arteries or veins. Despite locally advanced growth, 30% of patients do not have distant metastases and would potentially qualify for local resection. Arterial resections and vascular reconstruction are associated with an almost 9-fold increase in postoperative mortality compared with resections without vascular reconstruction. The Appleby procedure is a complex surgical technique originally developed for advanced gastric cancer. The technique has been further developed for patients with advanced pancreatic body and tail tumours with infiltration of the coeliac trunk (modified Appleby procedure). The advantage of the procedure is that technically, no reconstruction of the resected arteries is required. This is because a natural internal anastomosis in the pancreatic head between the A. mesenterica superior and the A. hepatica via branches of the A. gastroduodenalis is used to maintain liver perfusion and gastric blood flow. However, the surgical procedure is also associated with high morbidity and mortality, with comparably poor oncological results (R0 rates of approximately 60%). Therefore, the procedure was not recommended until a few years ago, and patients were considered inoperable. With developments in neoadjuvant therapy for pancreatic carcinoma, the Appleby procedure is being performed more frequently, with the goal of improving oncological outcomes in the context of multimodal treatment. With developments in robotics in visceral surgery, the previous limitations of minimally invasive pancreatic surgery can be overcome, and significantly more patients may benefit from the advantages of this minimally invasive surgery, such as faster convalescence. The use of robotic surgical techniques allows the extension of minimally invasive techniques into the field of complex vessel resection and reconstruction. In this video contribution, we describe a robot-assisted modified Appleby procedure using the Da Vinci Xi Surgical System in a patient with advanced pancreatic carcinoma of the pancreatic body, after neoadjuvant therapy.

Prognostic impact of tumor budding and EMT in periampullary adenocarcinoma: a quantitative approach.

The presence of invasive cell clusters known as tumor budding and the closely related epithelial mesenchymal transition (EMT) have a prognostic impact on cancer patients' overall survival. Interestingly, data quantitatively analyzing and correlating the amount of tumor buds and patient overall survival as well as the impact of expression of epithelial phenotype markers are missing. Periampullary carcinoma samples of 171 patients were immunohistochemically stained for E-Cadherin (ECad). Tumor cell clusters (TCC, defined from one to 50 cells) were manually quantified comprising tumor cell number and subcellular localization of ECad expression (membranous, cytoplasmic or mixed). Data analyses were performed using elastic net feature selection. Hereby, five distinct intervals of TCC sizes and corresponding fractions of cells with distinct ECad expression were identified. Prognostic features of the defined budding categories were entered into a subsequent Cox regression model together with standard clinicopathological parameters and, based on the model prediction, cases were categorized into "low and high budding" grades. Overall median TCC size was 16 cells (range: 2-36 cells). The median number of TCCs per tumor was 42 (range: 3-283). Elastic net feature selection identified TCCs of 6-10 and 31-35 cells as prognostically most relevant negative and positive features, respectively. Regarding ECad expression, cytoplasmic ECad expression in TCCs of 11-15 as well as of 26-30 cells revealed prognostic relevance. Combining TCC numbers and ECad expression, budding grade qualified as independent prognostic factor for patient overall survival (p<0.001) in a multivariable clinicopathologic Cox model. Applying an advanced modelling by machine learning on a cohort of periampullary cancers, we show that not the smallest TCCs (1-5 cells) but tumor cell nests containing 6-10 cells display the strongest negative prognostic relevance. Moreover, we demonstrate that larger TCCs might have a strong positive prognostic impact in periampullary adenocarcinomas, contributing to establishing an advanced grading system.

[Indications for Surgical Therapy in Chronic Pancreatitis]. / Operationsindikationen bei der chronischen Pankreatitis.

Chronic pancreatitis is a recurrent disease with repeating exacerbations of inflammation of the pancreatic gland - associated with belt-like back pain. Without treatment, recurrent chronic pancreatitis leads to development of opioid-dependent pain. The chronic pancreatitis leads to recurrent hospital stays for the affected patient and socioeconomic challenges. In progress it can lead to local complications of chronic pancreatitis, such as formation of pseudocysts, biliary duct obstruction, duodenal obstruction or portal hypertension. The aim of this article is a detailed description of the indication for surgical therapy in chronic pancreatitis. The underlying analysis was a systematic literature research and evaluation, the formulation of key questions according to the PICO system and the evaluation of indications and key statements and questions, as implemented in a three level Delphi process among the members of the pancreas research group and the indications for the surgery group of the German Society of General and Visceral Surgery (DGAV). Surgical resection of the inflammatory pancreatic head pseudotumour, after initial conservative therapy, is a highly efficient therapy for the control of pain and the avoidance of complications in chronic pancreatitis. For this purpose, well evaluated surgical strategies are available. Delay in surgical therapy can lead to chronic pain, kachexia and malnutrition and increase complications of surgical therapy.

[Indications for Surgery in Pancreatic Ductal Adenocarcinoma - Consensus Recommendations by the German Society for General and Visceral Surgery]. / Von der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie konsentierte Operationsindikationen beim duktalen Pankreasadenokarzinom.

BACKGROUND: Surgery for pancreatic cancer in Germany is increasing due to the climbing incidence of this cancer in the population. This review presents a summary of modern evidence-based indications for surgery in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The German Society for General and Visceral Surgery (DGAV) authorised a task force to define evidence based indications for surgery in patients with PDAC. A systematic literature search in Medline and Cochrane Library databases (1989 - 2019) was performed. Recommendations were summarised on the basis of the most relevant and recent guidelines and clinical studies and then voted by members of the Working Group on Hepato-Biliary and Pancreatic Diseases (CALGP) in a Delphi procedure. RESULTS: Indications for surgery in patients with PDAC should be set by experienced pancreatic surgeons within a tumour board. Decisions should consider the guidelines as well as the individual patient characteristics. Large vessel infiltration, metastatic disease and severe comorbidities are the most common contraindications for surgery. Borderline-resectable, primary resectable oligometastatic and secondary resectable PDAC should be preferably managed at high-volume centres as a part of clinical studies. Centralisation of pancreatic surgery reduces mortality and improves survival. Palliative bypass surgery as well as staging laparoscopy are still indicated in a large proportion of patients with PDAC. CONCLUSION: Irrespective of the recent development of multimodal therapeutic concepts, surgical resection remains the sole chance of long-term cure for patients with PDAC. Due to the significant proportion of patients in advanced stages of the disease, palliative surgery still plays an important role in the complex management of this cancer.