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Predicting R status before surgery for pancreatic cancer (PDAC) patients with upfront surgery and neoadjuvant therapy.Negative surgical margins (R0) are a key predictor of long-term outcomes in PDAC.Patients undergoing pancreatic resection with curative intent for PDAC were identified. Using the CT scans from the time of diagnosis, the 2019 NCCN borderline resectability criteria were compared to novel criteria: presence of any alteration of the superior mesenteric-portal vein (SMPV) and perivascular stranding of the superior mesenteric artery (SMA). Accuracy of predicting R status was evaluated for both criteria. Patient baseline characteristics, surgical, histopathological parameters, and long-term overall survival (OS) after resection were evaluated.A total of 593 patients undergoing pancreatic resections for PDAC between 2010 and 2018 were identified. Three hundred and twenty-five (54.8%) patients underwent upfront surgery, whereas 268 (45.2%) received neoadjuvant therapy. In upfront resected patients, positive SMA stranding was associated with 56% margin positive resection rates, whereas positive SMA stranding and SMPV alterations together showed a margin positive resection rate of 75%. In contrast to these criteria, the 2019 NCCN borderline criteria failed to predict margin status. In patients undergoing neoadjuvant therapy, only perivascular SMA stranding remained a predictor of margin positive resection, leading to a rate of 33% R+ resections. Perivascular SMA stranding was related to higher clinical T stage (P = 0.003) and clinical N stage (P = 0.043) as well as perineural invasion (P = 0.022). SMA stranding was associated with worse survival in both patients undergoing upfront surgery (36 vs 22 months, P = 0.002) and neoadjuvant therapy (47 vs 34 months, P = 0.050).The novel criteria were accurate predictors of R status in PDAC patients undergoing upfront resection. After neoadjuvant treatment, likelihood of positive resection margins is approximately halved, and only perivascular SMA stranding remained a predictive factor.

Introduction: There are limited numbers of high-volume centers performing minimally invasive pancreatoduodenectomy (MIPD) routinely. Several approaches to MIPD have been described. Aim of this analysis was to show the learning curve of three different approaches to MIPD. Focus was on determining the number of cases necessary to obtain proficient level in MIPD. Patients and methods: Retrospective study wherein outcomes of 300 consecutive patients at three centers—at each center the initial 100 consecutive patients undergoing MIPD for malignant and benign tumors of the head of the pancreas and perimpullary area, performed by three experienced surgeons were collected and analyzed. Results: Overall, 300 patients after MIPD were included: the three different cohorts (laparoscopic n = 100, hybrid n = 100, robotic n = 100). CUSUM analysis of operating time in each center demonstrated that the plateau for laparoscopic PD was n = 61, for hybrid PDes was n = 32 and for robotic PD was n = 68. Median operative time for laparoscopic, hybrid, and robotic approaches was 395 min, 404 min, 510 min, respectively. Intraoperative blood loss for laparoscopic PD, hybrid PD, and robotic PD was 250 ml, 250 ml, and 413 ml, respectively. Delayed gastric emptying occurred 12% in laparoscopic cohort, 10% in hybrid, and 53% in robotic cohort. Major complications (Clavien-Dindo III/IV) rate for laparoscopic PD, hybrid PD, and robotic PD was 32%, 37%, and 22% with 5% death in each cohorts, respectively. Conclusion: This analysis of the learning curve of three European centers found a shorter learning curve with hybrid PD as compared to laparoscopic and robotic PD. In implementation of a MIPD program, a stepwise approach might be beneficial.

© 2022 Wolters Kluwer Health, Inc. All rights reserved.Objective: To assess postoperative 90-day outcomes after minimally invasive (laparoscopic/robot-assisted) total pancreatectomy (MITP) in selected patients versus open total pancreatectomy (OTP) among European centers. Background: Minimally invasive pancreatic surgery is becoming increasingly popular but data on MITP are scarce and multicenter studies comparing outcomes versus OTP are lacking. It therefore remains unclear if MITP is a valid alternative. Methods: Multicenter retrospective propensity-score matched study including consecutive adult patients undergoing MITP or OTP for all indications at 16 European centers in 7 countries (2008-2017). Patients after MITP were matched (1:1, caliper 0.02) to OTP controls. Missing data were imputed. The primary outcome was 90-day major morbidity (Clavien-Dindo ≥3a). Secondary outcomes included 90-day mortality, length of hospital stay, and survival. Results: Of 361 patients (99MITP/262 OTP), 70 MITP procedures (50 laparoscopic, 15 robotic, 5 hybrid) could be matched to 70 OTP controls. After matching, MITP was associated with a lower rate of major morbidity (17% MITP vs. 31% OTP, P = 0.022). The 90-day mortality (1.4% MITP vs. 7.1% OTP, P = 0.209) and median hospital stay (17 [IQR 11-24] MITP vs. 12 [10-23] days OTP, P = 0.876) did not differ significantly. Among 81 patients with PDAC, overall survival was 3.7 (IQR 1.7-N/A) versus 0.9 (IQR 0.5-N/ A) years, for MITP versus OTP, which was nonsignificant after stratification by T-stage. Conclusion: This international propensity score matched study showed that MITP may be a valuable alternative to OTP in selected patients, given the associated lower rate of major morbidity.

GEP-NETs are heterogeneous tumors originating from the pancreas (panNET) or the intestinal tract. Only a few patients with NETs are amenable to curative tumor resection, and for most patients, only palliative treatments to successfully control the disease or manage symptoms remain, such as with synthetic somatostatin (SST) analogs (SSAs), such as octreotide (OCT) or lanreotide (LAN). However, even cells expressing low levels of SST receptors (SSTRs) may exhibit significant responses to OCT, which suggests the possibility that SSAs signal through alternative mechanisms, e.g., transforming growth factor (TGF)-β. This signaling mode has been demonstrated in the established panNET line BON but not yet in other permanent (i.e., QGP) or primary (i.e., NT-3) panNET-derived cells. Here, we performed qPCR, immunoblot analyses, and cell counting assays to assess the effects of SST, OCT, LAN, and TGF-β1 on neuroendocrine marker expression and cell proliferation in NT-3, QGP, and BON cells. SST and SSAs were found to regulate a set of neuroendocrine genes in all three cell lines, with the effects of SST, mainly LAN, often differing from those of OCT. However, unlike NT-3 cells, BON cells failed to respond to OCT with growth arrest but paradoxically exhibited a growth-stimulatory effect after treatment with LAN. As previously shown for BON, NT-3 cells responded to TGF-β1 treatment with induction of expression of SST and SSTR2/5. Of note, the ability of NT-3 cells to respond to TGF-β1 with upregulation of the established TGF-β target gene SERPINE1 depended on cellular adherence to a collagen-coated matrix. Moreover, when applied to NT-3 cells for an extended period, i.e., 14 days, TGF-β1 induced growth suppression as shown earlier for BON cells. Finally, next-generation sequencing-based identification of microRNAs (miRNAs) in BON and NT-3 revealed that SST and OCT impact positively or negatively on the regulation of specific miRNAs. Our results suggest that primary panNET cells, such as NT-3, respond similarly as BON cells to SST, SSA, and TGF-β treatment and thus provide circumstantial evidence that crosstalk of SST and TGF-β signaling is not confined to BON cells but is a general feature of panNETs.

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

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

Background: Total pancreatectomy has high morbidity and mortality and differences among countries are currently unknown. This study compared the use and postoperative outcomes of total pancreatec-tomy among 4 Western countries. Methods: Patients who underwent one-stage total pancreatectomy were included from registries in the United States, Germany, the Netherlands, and Sweden (2014-2018). Use of total pancreatectomy was assessed by calculating the ratio total pancreatectomy to pancreatoduodenectomy. Primary outcomes were major morbidity (Clavien Dindo >3) and in-hospital mortality. Predictors for the primary outcomes were assessed in multivariable logistic regression analyses. Sensitivity analysis assessed the impact of volume (low-volume 40 pancreatoduodenectomies annually; data available for the Netherlands and Germany). Results: In total, 1,579 patients underwent one-stage total pancreatectomy. The relative use of total pancreatectomy to pancreatoduodenectomy varied up to fivefold (United States 0.03, Germany 0.15, the Netherlands 0.03, and Sweden 0.15; P < .001). Both the indication and several baseline characteristics differed significantly among countries. Major morbidity occurred in 423 patients (26.8%) and differed (22.3%, 34.9%, 38.3%, and 15.9%, respectively; P < .001). In-hospital mortality occurred in 85 patients (5.4%) and also differed (1.8%, 10.2%, 10.8%, 1.9%, respectively; P < .001). Country, age >75, and vascular resection were predictors for in-hospital mortality. In-hospital mortality was lower in high-volume centers in the Netherlands (4.9% vs 23.1%; P = .002), but not in Germany (9.8% vs 10.6%; P = .733). Conclusion: Considerable differences in the use of total pancreatectomy, patient characteristics, and postoperative outcome were noted among 4 Western countries with better outcomes in the United States and Sweden. These large, yet unexplained, differences require further research to ultimately improve patient outcome. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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.

Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare malignancy and its pathophysiology is poorly understood. Sparse clinical data suggest that clinical outcome and overall survival is worse in comparison to common pancreatic ductal adenocarcinoma (PDAC). Methods: We evaluated clinical outcome and prognostic factors for overall survival of patients with ASCP in comparison to patients with PDAC recorded between 2000 and 2019 in 17 population-based clinical cancer registries at certified cancer centers within the Association of German Tumor Centers (ADT). Results: We identified 278 (0.5%) patients with ASCP in the entire cohort of 52,518 patients with pancreatic cancer. Significantly, more patients underwent surgical resection in the cohort of ASCP patients in comparison to patients with PDAC (p < 0.001). In the cohort of 142 surgically resected patients with ASCP, the majority of patients was treated by pancreatoduodenectomy (44.4%). However, compared to the cohort of PDAC patients, significantly more patients underwent distal pancreatectomy (p < 0.001), suggesting that a significantly higher proportion of ASCP tumors was located in the pancreatic body/tail. ASCPs were significantly more often poorly differentiated (G3) (p < 0.001) and blood vessel invasion (V1) was detected more frequently (p = 0.01) in comparison with PDAC. Median overall survival was 6.13 months (95% CI 5.20–7.06) for ASCP and 8.10 months (95% CI 7.93–8.22) for PDAC patients, respectively (p = 0.094). However, when comparing only those patients who underwent surgical resection, overall survival of ASCP patients was significantly shorter (11.80; 95% CI 8.20–15.40 months) compared to PDAC patients (16.17; 95% CI 15.78–16.55 months) (p = 0.007). ASCP was a highly significant prognostic factor for overall survival in univariable regression analysis (p = 0.007) as well as in multivariable Cox regression analysis (HR 1.303; 95% CI 1.013–1.677; p = 0.039). Conclusions: In conclusion, ASCP showed poorer differentiation and higher frequency of blood vessel invasion indicative of a more aggressive tumor biology. ASCP was a significant prognostic factor for overall survival in a multivariable analysis. Overall survival of resected ASCP patients was significantly shorter compared to resected PDAC patients. However, surgical resection still improved survival significantly.

OBJECTIVE: This analysis aimed to compare failure to rescue (FTR) after pancreatoduodenectomy across the Atlantic. SUMMARY BACKGROUND DATA: FTR, or mortality after development of a major complication, is a quality metric originally created to compare hospital results. FTR has been studied in North American and Northern European patients undergoing pancreatoduodenectomy (PD). However, a direct comparison of FTR after PD between North America and Northern Europe has not been performed. METHODS: Patients who underwent PD in North America, the Netherlands, Sweden and Germany (GAPASURG dataset) were identified from their respective registries (2014-17). Patients who developed a major complication defined as Clavien-Dindo ≥3 or developed a grade B/C postoperative pancreatic fistula (POPF) were included. Preoperative, intraoperative, and postoperative variables were compared between patients with and without FTR. Variables significant on univariable analysis were entered into a logistic regression for FTR. RESULTS: Major complications occurred in 6188 of 22,983 patients (26.9%) after PD, and 504 (8.1%) patients had FTR. North American and Northern European patients with complications differed, and rates of FTR were lower in North America (5.4% vs 12%, P < 0.001). Fourteen factors from univariable analysis contributing to differences in patients who developed FTR were included in a logistic regression. On multivariable analysis, factors independently associated with FTR were age, American Society of Anesthesiology ≥3, Northern Europe, POPF, organ failure, life-threatening complication, nonradiologic intervention, and reoperation. CONCLUSIONS: Older patients with severe systemic diseases are more difficult to rescue. Failure to rescue is more common in Northern Europe than North America. In stable patients, management of complications by interventional radiology is preferred over reoperation.

Purpose Postoperative pancreatic fistulae (POPF) present a serious and life-threatening complication after pancreatic head resections (PD). Therefore, reliable risk stratification to identify those at risk is urgently needed. The aim of this study was to identify postoperative laboratory parameters for the prediction of POPF in the early postoperative period. Methods One hundred eighty-two patients who underwent PD from 2012 until 2017 were retrospectively analyzed. Multivariate logistic regression was performed using the GLM (general linear model) method for model building. Two nomograms were created based on the GLM models of postoperative day one and postoperative day one to five. A cohort of 48 patients operated between 2018 and 2019 served as internal validation. Results Clinically relevant pancreatic fistulae (CR-POPF) were present in 16% (n = 29) of patients. Patients with CR-POPF experienced significantly more insufficiencies of gastroenterostomies, delayed gastric emptying, and more extraluminal bleeding than patients without CR-POPF. Multivariate analysis revealed multiple postoperative predictive models, the best one including ASA, main pancreatic duct diameter, operation time, and serum lipase as well as leucocytes on day one. This model was able to predict CR-POPF with an accuracy of 90% and an AUC of 0.903. Two nomograms were created for easier use. Conclusion Clinically relevant fistula can be predicted using simple laboratory and clinical parameters. Not serum amylase, but serum lipase is an independent predictor of CR-POPF. Our simple nomograms may help in the identification of patients for early postoperative interventions.

Objectives The postoperative quality of life (QoL) after pancreatic surgery is frequently impaired. The aim of this study was to evaluate the QoL after pancreatic surgery and its influencing risk factors. Furthermore, an age-adjusted comparison with the normal population of Germany was performed. Methods A total of 94 patients were surveyed. The Short Form-36 questionnaire was sent to all patients undergoing pancreatic surgery between 2013 and 2017. All pathologies and types of pancreatic resections were included. Statistical analyses were performed, and an analysis by the Robert Koch-Institute to determine the health-related age-adjusted QoL in Germany served as control group. Results Response rate was 29%. Median time of survey was 28 months. As compared with a normative population, QoL after pancreaticoduodenectomy was significantly impaired. Distal pancreatic resection showed no significant differences. Univariate and Lasso analyses showed that the following factors had a negative impact: coronary artery disease, chronic pancreatitis, and open access. Postoperative enzyme supplementation seemed to have a positive impact. Conclusions Pancreatic surgery leads to long-lasting negative effect on QoL. Distal pancreatic resections and laparoscopic access seemed to be the best tolerated. Complications seems to have less impact, whereas maintaining exocrine and endocrine function seems to have a positive effect.

ZusammenfassungDas Pankreaskarzinom im Bereich des Korpus und linksseitig der mesenterikoportalen Achse wird wegen der unspezifischen oder gar fehlenden klinischen Symptome häufig erst in späten Stadien erkannt, wobei in etwa 20% der Fälle bereits eine Infiltration der umliegenden arteriellen oder venösen Gefäße vorliegt. Trotz eines lokal fortgeschrittenen Wachstums (T4, UICC-Stadium III) weisen 30% der Patienten keine Fernmetastasen auf und würden sich potenziell für eine lokale Resektion qualifizieren. Arterielle Resektionen mit Anastomosierung und Gefäßrekonstruktion sind einschränkend mit einer fast 9-fach erhöhten Mortalität des Eingriffs im Vergleich zu Resektionen ohne Gefäßrekonstruktion verbunden. Die Appleby-Operation stellt eine komplexe Operationstechnik dar, die ursprünglich für das fortgeschrittene Magenkarzinom entwickelt wurde. Die Adaptation der Technik wurde für Patienten mit fortgeschrittenen Pankreaskorpus- und Pankreasschwanztumoren mit einer Infiltration des Truncus coeliacus weiterentwickelt. Der Vorteil der Operation besteht darin, dass technisch keine Rekonstruktion der resezierten Arterien erfolgen muss, da man sich eine natürliche interne Anastomose im Pankreaskopf zwischen der A. mesenterica superior und der A. hepatica über Äste der A. gastroduodenalis zum Erhalt der Leberperfusion und der Magendurchblutung zu Nutze macht. Das Operationsverfahren ist jedoch ebenso mit einer hohen Morbidität und Mortalität verbunden mit vergleichbar schlechten onkologischen Ergebnissen (R0-Raten ca. 60%), sodass das Verfahren bis vor einigen Jahren nicht empfohlen wurde und die Patienten als inoperabel galten. Im Zuge der Entwicklung neoadjuvanter Therapieverfahren beim Pankreaskarzinom wird die Appleby-Operation wieder häufiger durchgeführt, da der Bedarf an lokal radikal resezierenden Operationsverfahren und Techniken im Kontext der multimodalen Behandlung gestiegen ist. Im Zuge der derzeitigen Etablierung der Robotik in der Viszeralchirurgie könnten bisherige Limitationen der minimalinvasiven Pankreaschirurgie überwunden werden und deutlich mehr Patienten die Vorteile der minimalinvasiven Chirurgie – wie eine schnellere Rekonvaleszenz – ermöglicht werden. Der Einsatz robotischer Operationsverfahren ermöglicht die Erweiterung minimalinvasiver Techniken in den Bereich der komplexen Gefäßresektion und Rekonstruktion. Im vorliegenden Videobeitrag beschreiben wir eine robotisch assistierte modifizierte Appleby-Operation mit dem Einsatz des Da Vinci Xi Surgical System bei einer Patientin mit einem fortgeschrittenen Pankreaskorpuskarzinom nach neoadjuvanter Therapie.

Die minimal-invasive Pankreaschirurgie hangt der Entwicklung anderer Einsatzgebiete der minimal-invasiven Chirurgie hinterher. Nach sehr zogerlicher Entwicklung uber die letzten zwei Dekaden werden minimal-invasive Operationstechniken aktuell verstarkt in Zentren angewendet. Dies liegt nicht zuletzt in der zunehmenden Verfugbarkeit robotischer Assistenzsysteme begrundet, welche abwinkelbare Instrumente und dreidimensionale und vergroserte Sicht bieten. Inzwischen konnte die technische Machbarkeit („feasability“) auch komplexester Pankreasresektionen gezeigt werden. Somit stellt sich die Frage, ob laparoskopische und robotische Operationen gleichwertige oder gar bessere Ergebnisse (Evidenz) hinsichtlich der perioperativen Morbiditat, des Uberlebens nach onkologischen Resektionen und der Lebensqualitat bieten konnen. Wie bei allen innovativen Techniken, die in die Chirurgie Einzug halten, muss auch die Anwendbarkeit in der Breite, Lehrmethoden, Volumen-Outcome-Effekte sowie die Kosteneffektivitat evaluiert werden. Wir stellen die aktuelle wissenschaftliche Evidenz zur laparoskopischen und robotischen Pankreaskopf- und Pankreaslinksresektion vor.

Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy characterized by early loco-regional invasion. Portal vein resection (PVR) during pancreatoduodenectomy (PD) for PDAC is performed if tumor cell invasion to the venous wall (PVI) is suspected. The aim of this study is to evaluate radiological criteria for predicting PVR and PVI. Methods Patients undergoing PD for PDAC were identified from a prospectively maintained database. On the basis of CT- and MRI-based imaging portal vein tumor contact (PV), stranding of the superior mesenteric artery (SMA) and any alterations of the superior mesenterico-portal vein (SMPV) were evaluated. The accuracy of PVI and PVR prediction based on the radiological parameters was calculated. Results 143 patients were included in the study. 48 patients underwent PVR (34%), PVI was diagnosed in 23 patients (16%). Median overall survival was 22 months. Prediction of PVR (sensitivity 79%, negative predictive value 88%, p = 0.010) and PVI (sensitivity 95%, negative predictive value 99%, p = 0.002) was most accurate for any SMPV alterations as compared to the other radiological parameters. SMPV alterations qualified as an independent prognostic parameter (26.5 months vs. 33.5months, p = 0.034). Conclusion Radiological evaluation of any SMPV alterations is a simple preoperative method to accurately predict PVI. Assessing SMPV alterations may help to identify candidates for neoadjuvant therapy.

ZusammenfassungDie chronische Pankreatitis stellt eine über die Jahre rezidivierende Erkrankung mit wiederkehrenden Entzündungsschüben der Bauchspeicheldrüse und gürtelförmigen Oberbauchschmerzen dar. Unbehandelt führt die chronische Pankreatitis zu rezidivierenden Schmerzen, die letztendlich häufig eine Therapie mit Opiaten erfordern. Die chronische Pankreatitis führt zu rezidivierenden Krankenhausaufenthalten der Betroffenen sowie zu sozioökonomischen Nachteilen für die Patienten. Im Verlauf kann es zu lokalen Folgen der chronischen Pankreatitis kommen wie Pseudozystenbildung, Gallengangstenose, Duodenalobstruktion oder portaler Hypertension. Ziel dieses Artikels ist die Darstellung der Indikationen zur chirurgischen Therapie für die chronische Pankreatitis. Zugrunde liegend ist eine systematische Literaturrecherche und Bewertung, die Erstellung von Schlüsselfragen nach dem PICO-Prinzip und die Evaluation der Indikationen in einem 3-stufigen Delphi-Verfahren unter den Mitgliedern der Arbeitsgruppe Pankreas und der Arbeitsgruppe Indikationsqualität der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie. Die chirurgische Resektion des entzündlichen Pankreaskopftumors nach einem primär konservativen Therapieversuch stellt eine hocheffiziente Therapie zur Kontrolle der Schmerzen und zur Vermeidung von Komplikationen bei der chronischen Pankreatitis dar. Hierfür stehen gut evaluierte duodenumerhaltende (Operationen nach Frey, Bern, Beger) und duodenumresezierende Verfahren (pyloruserhaltende Pankreaskopfresektion, Whipple-Operation) sowie Drainageoperationen zur Verfügung. Protrahierung der chirurgischen Therapie bei Versagen eines initialen konservativen Therapieversuchs kann zur Chronifizierung von Schmerzen, Kachexie und Malnutrition des Patienten und zur Erhöhung der Komplikationen bei der chirurgischen Therapie führen.

Zusammenfassung Hintergrund Die Zahl der Operationen für Pankreaskarzinome in Deutschland nimmt kontinuierlich zu. Das entspricht der steigenden Inzidenz dieser Erkrankung in der Bevölkerung. Diese Übersichtsarbeit fasst die evidenzbasierten aktuellen Operationsindikationen bei Patienten mit Pankreaskarzinom zusammen. Methode Als DGAV-Initiative wurde eine Arbeitsgruppe von Pankreasexperten eingerichtet. Diese formulierte konkrete Schlüsselfragen nach dem PICO-Schema, führte eine systematische Literatursuche in Medline und Cochrane Library (1989 – 2019) zu Studien und Leitlinien mit Aussagen zu Operationsindikationen bei Pankreaskarzinom durch und erstellte daraus resultierende evidenzbasierte Empfehlungen. Diese wurden innerhalb der CALGP im Rahmen eines Delphi-Verfahrens abgestimmt. Ergebnisse Die Operationsindikation bei Pankreaskarzinom soll im Tumorboard von erfahrenen Pankreaschirurgen leitliniengerecht und unter Berücksichtigung der individuellen Besonderheiten der Patienten gestellt werden. Fortgeschrittene Infiltration der großen Viszeralgefäße, multiple Fernmetastasen und schwere Komorbiditäten, die einen Eingriff in Vollnarkose verbieten, stellen die häufigsten Kontraindikationen zur Operation dar. Die Therapie von Borderline-resektablen und primär resektablen oligometastatischen Patienten sowie solchen mit sekundärer Resektabilität nach neoadjuvanter Behandlung soll bevorzugt an Zentren und im Rahmen von Studien erfolgen. Die Behandlung an Pankreaszentren reduziert die Mortalität und verbessert das Überleben. Die palliative Bypasschirurgie kann bei endoskopisch nicht therapierbaren Gallenwegs- und Duodenalobstruktionen indiziert sein. Bei diagnostischen Schwierigkeiten kann die Staging-Laparoskopie mit histologischer Sicherung eingesetzt werden. Schlussfolgerung Unabhängig von der Entwicklung erfolgversprechender multimodaler Behandlungskonzepte bleibt die chirurgische Resektion weiterhin der einzig kurative Therapieeinsatz. Wegen des hohen Anteils von primär fortgeschrittenen und metastasierten Pankreaskarzinomen spielt auch die palliative Chirurgie weiterhin eine wichtige Rolle in der komplexen Versorgung dieses Patientenkollektivs.

Background/aim FOLFIRINOX [fluorouracil (5-FU), irinotecan, oxaliplatin] and gemcitabine plus nab-paclitaxel are standard treatments for patients with pancreatic ductal adenocarcinoma (PDAC). Despite efficacy rates of less than 32%, evidence is lacking to guide the use of one drug over the other. Herein, we compared the sensitivity of patient-derived PDAC cell lines to each of these regimens. Materials and methods Changes in the growth of 19 low-passage patient-derived PDAC cell lines were evaluated in response to treatment with FOLFIRINOX and gemcitabine plus paclitaxel (Gem-Pac). Results Six cell lines exhibited optimal sensitivity (high EMax and low GI50) to FOLFIRINOX and three cell lines exhibited optimal sensitivity to Gem-Pac. Several cell lines that were optimally sensitive to one drug regimen exhibited very poor response to the other. Conclusion Further characterization of cancer cells exhibiting preferential sensitivity to each of these regimens may allow the identification of biomarkers to guide the selection of appropriate chemotherapy for a given patient.

Zusammenfassung Hintergrund Bei 15 – 20% der Patienten mit akuter Pankreatitis entwickelt sich eine nekrotisierende Form. Die Mortalität beträgt bis zu 20%. Entscheidende Säulen der Behandlung sind die intensivmedizinische Therapie sowie chirurgische und interventionelle Maßnahmen. Methoden Diese Übersichtsarbeit zur Indikationsstellung von chirurgischen und interventionellen Maßnahmen bei der nekrotisierenden Pankreatitis wurde auf der Basis einer systematischen Literaturrecherche verfasst. In der Analyse wurden 85 Artikel ausgewertet. Die Ergebnisse wurden im Delphi-Befragungsverfahren der Qualitätskommission der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV) und Experten auf einer Sitzung des Viszeralmedizin-Kongresses in Wiesbaden 2019 vorgestellt. Bei der abschließenden Formulierung der Empfehlungen wurde ein starker Konsensus von 84% bei den Befragten erreicht. Ergebnisse Bei Nachweis oder Verdacht auf eine Infektion der Pankreasnekrosen besteht eine Indikation zur chirurgischen und interventionellen Behandlung (Empfehlungsgrad: stark; Evidenzstärke: schwach). In Ausnahmefällen stellen auch sterile Nekrosen eine Indikation zur Intervention dar. Wenn es der klinische Zustand erlaubt, sollte die Intervention bis in die 4. Krankheitswoche geschoben werden. Als Therapiestrategie wird mit hohem Evidenz- und Empfehlungsgrad der „step-up approach“ empfohlen. Diese Strategie der Therapieeskalation beinhaltet als 1. Maßnahme eine Drainagebehandlung und bei Erfolglosigkeit die minimalinvasive chirurgische oder endoskopische Nekrosektomie. Sind die minimalinvasiven Techniken nicht effektiv, ist die offene Nekrosektomie indiziert. Nach primärer Drainagebehandlung kann bei 35 – 50% der Patienten die 2. Therapiestufe der Nekrosektomie vermieden werden. Indikationen zur Notfalloperation sind Organperforation, Darmischämie, interventionell nicht stillbare Blutungen und das abdominelle Kompartmentsyndrom bei erfolgloser konservativer Therapie. Spätabszesse und symptomatische Pseudozysten sind Indikationen für eine interventionelle Drainagebehandlung. Bei der biliären Pankreatitis ist die Cholezystektomie indiziert, bei der milden Form frühelektiv und bei schwerem Verlauf frühestens nach 6 – 8 Wochen. Schlussfolgerung Die vorliegenden Empfehlungen enthalten Kriterien für die Indikationsstellung zur chirurgischen und interventionellen Behandlung der akuten Pankreatitis. Sie sollen als Referenzstandards für die Entscheidungsfindung in einem multidisziplinären Team dienen.

ZusammenfassungEine stetige Verbesserung der modernen Bildgebung sowie ein steigendes Alter in der Gesellschaft haben dazu geführt, dass zunehmend häufiger zystische Pankreastumoren detektiert werden. Zystische Pankreasraumforderungen stellen eine klinisch herausfordernde Entität dar, da sie ein breites biologisches Spektrum umfassen und ihre Differenzierung untereinander vor allem bei kleinen Tumoren häufig schwierig ist. Sie bedingen daher eine differenzierte Operationsindikationsstellung. Zur Bestimmung von Empfehlungen zur Operationsindikation bei zystischen Tumoren des Pankreas wurde von einer Qualitätskommission für Pankreaserkrankungen der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie eine systematische Literaturrecherche durchgeführt und daraus resultierend folgende Übersichtsarbeit erstellt. Auf Grundlage der aktuellen Evidenz besteht bei Vorliegen von Malignitätszeichen oder Hochrisikokriterien (Ikterus bei Obstruktion des Ductus choledochus durch die zystische Pankreasläsion, kontrastmittelaufnehmende intramurale Knoten ≥ 5 mm oder solide Komponenten in der Zyste oder Pankreashauptgang ≥ 10 mm) sowie bei Symptomen unabhängig von der Zystenentität (ausgenommen Pankreaspseudozysten) eine Operationsindikation. Ist die Entität der Pankreaszyste mittels bildgebender Diagnostik eruierbar, so sollten alle intraduktalen papillär-muzinösen Neoplasien (IPMN) vom Hauptgang und vom Mischtyp, alle muzinös-zystischen Neoplasien (MCN) > 4 cm sowie alle soliden pseudopapillären Neoplasien (SPN) reseziert werden. Serös-zystische Neoplasien (SCN) und Seitengang-IPMN ohne Risikokriterien stellen primär keine Operationsindikation dar. Die Operationsindikationsstellung bei Seitengang-IPMN mit relativen Risikokriterien und MCN

Zusammenfassung Einführung Der Einsatz von Robotern in der minimalinvasiven Chirurgie hat in den letzten Jahren immer weiter zugenommen. Die roboterunterstützte Pankreaschirurgie hat gegenüber der laparoskopischen Pankreaschirurgie den Vorteil einer besseren Handhabung und verbesserten Angulation durch die größere Flexibilität der Instrumente. Darüber hinaus besteht durch die 3-D-Technik eine verbesserte Sicht und durch eine softwarebasierte Tremorkontrolle eine exakte Instrumentenführung. Die körperliche Belastung des Chirurgen durch die sitzende Position ist bei langen Eingriffen geringer. Methoden und Ergebnisse Dieser Artikel liefert einen Ansatz für die Einrichtung eines Roboter-Pankreas-Programms und eine detaillierte Anleitung im Sinne von SOPs für die robotergestützte Pankreaslinksresektion und robotergestützte Pankreatoduodenektomie. Ergebnisse In unserem standardisierten SOP-Ansatz verwenden wir sowohl bei der Pankreaslinksresektion als auch bei der Pankreatduodenektomie jeweils 5 Trokare – 4 Da-Vinci-Trokare und einen laparoskopischen Hilfstrokar. Wir bevorzugen die Position der Robotertrokare auf einer geraden horizontalen Linie mit einem Abstand von etwa 20 cm vom Operationsfeld. Die Operation wird in standardisierten Arbeitsschritten durchgeführt. Bei der Pankreaslinksresektion sind dies: Zugang und Visualisierung des Pankreas, Mobilisierung der linken Dickdarmflexur und des Pankreasunterrandes, Präparation der V. lienalis und der mesenterikoportalen Achse, Präparation des Pankreasoberrandes mit Lymphadenektomie und Darstellung der A. lienalis, Durchtrennung des Pankreas, retrograde Präparation des Pankreas und der Milz (bei onkologischen Eingriffen). Bergung, Einlage von Drainagen und Wundverschluss. Bei der Pankreatoduodenektomie sind es folgende Schritte: Zugang und Visualisierung des Pankreas, erweitertes Kocher-Manöver, Darstellung der Unterkante und der mesenterikoportalen Achse, Darstellung des Pankreasoberrandes und des Lig. hepatoduodenale, Präparation des Pankreashalses, Darstellung der Mesenterialwurzel und Pars IV duodeni, Präparation des Mesopankreas, Durchführung der Pankreasanastomose und der biliodigestiven Anastomose, Naht der dudenojejunalen Anastomose, Einlage von Drainagen und schichtweiser Wundverschluss. Der graduelle Aufbau unseres Roboter-Pankreas-Programms und der strukturierte Ansatz für komplexe Pankreasresektionen werden erläutert. Zusammenfassung Zusammenfassend beschreiben wir den Ansatz der robotischen Bauchspeicheldrüsenchirurgie in einem minimalinvasiven Exzellenzzentrum und Bauchspeicheldrüsenzentrum auf struktureller und verfahrenstechnischer Ebene, um die Einrichtung derartiger Programme an anderen Standorten zu unterstützen.

Zusammenfassung Einleitung Die robotisch assistierte Chirurgie ist eine vielversprechende Technik zur Überwindung der Grenzen der laparoskopischen Chirurgie – insbesondere bei komplexen chirurgischen Eingriffen in der Oberbauchchirurgie. Im Folgenden beschreiben wir die Etablierung komplexer robotisch assistierter Oberbauchchirurgie in unserem Zentrum für minimalinvasive Chirurgie und präsentieren die Ergebnisse aus den ersten 100 Eingriffen. Material und Methoden Die robotisch assistierte Chirurgie wurde mit dem Da Vinci® Xi Surgical System™ durchgeführt. Die Eingriffe wurden von 2 Chirurgen durchgeführt, die Spezialisten auf dem Gebiet der minimalinvasiven Chirurgie sind. Die robotisch assistierte Oberbauchchirurgie wurde in 3 Schritten etabliert. Step 1: Zunächst wurden robotisch assistierte Eingriffe mit leichterem Schwierigkeitsgrad durchgeführt (Cholezystektomien, atypische Magenresektionen und Fundoplikationen). Step 2: Anschließend wurden linksseitige Pankreasresektionen, Adrenalektomien und Lebersegment- bzw. atypische Leberresektionen als Verfahren mit mittlerem Schwierigkeitsgrad durchgeführt. Step 3: Schließlich wurden fortgeschrittene und hochkomplexe Verfahren durchgeführt (Hemihepatektomien, komplexe Pankreasresektionen, Gastrektomien und Ösophagektomien). Die von Juli 2017 bis Oktober 2018 erhobenen Daten wurden retrospektiv hinsichtlich Konversionsrate, Morbidität (Clavien-Dindo > 2) und Mortalität analysiert. Ergebnisse Der 1. Schritt der Etablierung unseres Roboterprogramms umfasste 26 Eingriffe. Hier betrugen die Konversionsrate, die Morbidität und die Mortalität jeweils 0%. Im 2. Schritt wurden 23 Eingriffe durchgeführt. Die Konversionsrate, Morbidität und Mortalität lagen bei 28, 8 und 0%. Der letzte Schritt umfasste 51 hochkomplexe operative Verfahren. Diese Verfahren hatten eine Konversionsrate 43%, eine Morbidität von 41% und eine Mortalität von 4%. Schlussfolgerung Unser Stepwise Approach ermöglicht eine sichere Etablierung robotisch assistierter Oberbauchchirurgie mit vergleichbaren Morbiditäts- und Mortalitätsraten – auch bei hochkomplexen operativen Eingriffen. Hochkomplexe Eingriffe erforderten jedoch vergleichsweise häufig eine Konversion, was durch die geringen Erfahrungswerte und durch die Lernkurve beeinflusst sein könnte.

The benefit of adjuvant therapy in ampullary cancer (AMPAC) patients following pancreatoduodenectomy (PD) is debated. The aim of this study was to determine the role of adjuvant therapy after pancreatoduodenectomy (PD) in histological subtypes of AMPAC.Patients undergoing PD for AMPAC at 5 high-volume European surgical centers from 1996 to 2017 were identified. Patient baseline characteristics, surgical and histopathological parameters, and long-term overall survival (OS) after resection were evaluated.214 patients undergoing PD for AMPAC were included. ASA score (ASA1-2 149 vs. ASA 3-4 82 months median OS, p = 0.002), preoperative serum CEA (CEA0.5 ng/ml 128 vs. CEA0.5 ng/ml 62 months, p = 0.013), preoperative serum CA19-9 (CA19-9 40 IU/ml 147 vs. CA19-940IU/ml 111 months, p = 0.042), T stage (T1-2 163 vs. T3-4 98 months, p 0.001), N stage (N0 159 vs. N+ 110 months, p 0.001), grading (G1-2 145 vs. G3-4 113 months, p = 0.026), R status (R0 136 vs. R+ 38 months, p = 0.031), and histological subtype (intestinal subtype 156 vs. PB/M subtype 118 months, p = 0.003) qualified as prognostic parameters. In multivariable analysis, ASA score (HR 1.784, 95%CI 0.997-3.193, p = 0.050) and N stage (HR 1.831, 95%CI 0.904-3.707, p = 0.033) remained independent prognostic factors. In PB/M subtype AMPAC, patients undergoing adjuvant therapy showed an improved median overall survival (adjuvant therapy 85 months vs. no adjuvant therapy 65 months, p = 0.005), and adjuvant therapy remained an independent prognostic parameter in multivariate analysis (HR 0.351, 95%CI 0.151-0.851, p = 0.015). There was no significant benefit of adjuvant therapy in intestinal subtype AMPAC patients.Adjuvant treatment seems indicated in pancreatobiliary or mixed type AMPAC.

(1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers—Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone.

Background: Evidence on the optimal pancreatic anastomosis during pancreatoduodenectomy is inconclusive. Large multicenter and nationwide registries may provide additional insights. The study compared the practice and outcome of different pancreatic anastomoses during pancreatoduodenectomy, focusing on the rate of postoperative pancreatic fistula, in two large audits of pancreatic surgery.Methods: Posthoc analysis of patients after pancreatoduodenectomy in the Dutch Pancreatic Cancer Audit and the German DGAV StuDoQ vertical bar Pancreas registries (January 2014 to December 2017). Postoperative pancreatic fistula (International Study Group of Pancreatic Surgery B/C), postpancreatectomy hemorrhage (International Study Group of Pancreatic Surgery B/C) and Clavien-Dindo >= 3 complications rates were compared for the three most common anastomoses: duct-to-mucosa pancreatojejunostomy, non-duct-to-mucosa pancreatojejunostomy, and non-duct-to-mucosa pancreatogastrostomy. Multivariable adjustment for potential confounders was performed.Results: Overall, 6,149 patients were included. The most common anastomosis was duct-to-mucosa pancreatojejunostomy (duct-to-mucosa pancreatojejunostomy 59.8%, non-duct-to-mucosa pancreatojejunostomy 21.1%, non-duct-to-mucosa pancreatogastrostomy 12.4%). The overall postoperative pancreatic fistula rate was 14%: duct-to-mucosa pancreatojejunostomy 12.9%, non-duct-to-mucosa pancreatojejunostomy 14.4% (P = .162), non-duct-to-mucosa pancreatogastrostomy 18.3% (P < .001). The rate of postpancreatectomy hemorrhage was the lowest after duct-to-mucosa pancreatojejunostomy: duct-to-mucosa pancreatojejunostomy 6.9%, non-duct-to-mucosa pancreatojejunostomy 10% (P < .001), non-duct-to-mucosa pancreatogastrostomy 17.9% (P < .001). The rate of Clavien-Dindo >= 3 complications was the lowest after duct-to-mucosa pancreatojejunostomy: duct-to-mucosa pancreatojejunostomy 28%, non-duct-to-mucosa pancreatojejunostomy 32.7% (P = .002), non-duct-to-mucosa pancreatogastrostomy 43.1% (P < .001). In the multivariable analysis, the risk of postoperative pancreatic fistula did not differ significantly between the three anastomoses. The risk of hemorrhage (odds ratio 2.4, 95% confidence interval 1.6-3.5, P < .001) and Clavien-Dindo >= 3 (odds ratio 1.6, 95% confidence interval 1.2-2.1, P = .001) remained significantly higher only for non-duct-to-mucosa pancreatogastrostomy.Conclusion: Data from two national audits showed no difference in the risk-adjusted postoperative pancreatic fistula rate among the three most used pancreatic anastomoses during pancreatoduodenectomy. Pancreatogastrostomy was inferior to pancreatojejunostomy regarding bleeding and overall major complications. (C) 2021 Elsevier Inc. All rights reserved.

Pancreatic neuroendocrine neoplasms (pNENs) account for approximately 5% of all pancreatic tumors; thus, they constitute the second most common tumor type in the pancreas [...]

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer types with the quasi-mesenchymal (QM) subtype of PDAC having the worst prognosis. De-differentiation of the ductal tumor cells to a mesenchymal phenotype occurs as a result of epithelial–mesenchymal transition (EMT), a process associated with the acquisition of stem cell traits. While QM tumor cells are highly metastatic and drug-resistant, their increased plasticity opens a window of opportunity for trans-differentiation into non-malignant pancreatic cells. In this study we compared established PDAC-derived cell lines of either epithelial (E) or QM phenotype for their potential to be differentiated to pancreatic endocrine cells. We found that QM cells responded more strongly than E cells with transcriptional activation of a pancreatic progenitor or pancreatic β cell-specific program. Our results bear strong implications for a novel type of targeted therapy, namely EMT-based trans-differentiation of highly metastatic PDAC cells in vivo to non-malignant endocrine cells. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or β cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5′-aza-2′-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic β cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells.

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

Background Distal cholangiocarcinoma (DCC) is a rare malignancy and validated prognostic markers remain scarce. We aimed to evaluate the role of serum CA19-9 as a potential biomarker in DCC. Methods Patients operated for DCC at 6 high-volume surgical centers from 1994 to 2015 were identified from prospectively maintained databases. Patient baseline characteristics, surgical and histopathological parameters, as well as overall survival after resection were assessed for correlation with preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 (CA19-9). Preoperative CA19-9 to bilirubin ratio (CA19-9/BR) was classified as elevated (≥ 25 U/ml/mg/dl) according to the upper serum normal values of CA19-9 (37 U/ml) and bilirubin (1.5 mg/dl) giving a cut-off at ≥ 25 U/ml/mg/dl. Results In total 179 patients underwent resection for DCC during the study period. High preoperative CA19-9/BR was associated with advanced age and regional lymph node metastases. Median overall survival after resection was 27 months. Elevated preoperative serum CA19-9/bilirubin ratio (HR 1.6, p = 0.025), T3/4 stage (HR 1.8, p = 0.022), distant metastasis (HR 2.5, p = 0.007), tumor grade (HR 1.9, p = 0.001) and R status (HR 1.7, p = 0.023) were identified as independent negative prognostic factors following multivariable analysis. Conclusion Elevated preoperative bilirubin-adjusted serum CA19-9 correlates with regional lymph node metastases and constitutes a negative independent prognostic factor after resection of DCC.

Background: Surgery is seldom used for palliation in advanced lung cancer and the published data on this issue are very limited. We aimed to assess the results of palliative lung resections and identify criteria to guide surgical therapy in this situation. Methods: This is a retrospective single-institution analysis of patients with palliative intended lung cancer resection. Survival analysis was performed by Kaplan-Meier method, log-rank test and Cox proportional hazards regression at a statistical significance level of P=0.05. Results: Forty-eight patients received palliative intended lung resections (31 lobectomies, 4 bilobectomies, 13 pneumonectomies) with acceptable rates of severe complications (Clavien-Dindo >IIIa 29%) and 30-day mortality (4%). The most frequent indications were infection and hemoptysis. The median survival for the entire group was 12 months (95% CI: 6.9–17.1 months). Due to unexpectedly favorable histopathologic tumor stage, a switch to curative treatment in 17 completely resected patients resulted in a 2-year survival rate of 46%. In a subgroup of 20 patients with favorable prognostic factors as identified by uni- and multivariable analysis, a median survival of 26 months was observed. Conclusions: In well selected patients with lung cancer, resection in palliative intent can offer symptom relief and even a survival benefit with acceptable morbidity and low mortality. Prognostic factors were identified and can be used to guide operative treatment. Due to the low specificity of CT and FDG-PET/CT in the presence of inflammation or centrally located lung tumors, a large proportion of patients with lung resection in palliative intent experience a down-staging and frequently also a switch from palliative to curative treatment with additional survival benefit. Factors like expected complete resection, a squamous cell type and the ability to receive adjuvant therapy are useful to support the decision to perform palliative tumor resection.

Background/Objective The impact of preoperative biliary stenting (PBS) before pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) is controversial. Methods Patients undergoing PD with or without PBS for PDAC were identified from the German DGAV-StuDoQlPancreas registry. The impact of PBS on perioperative complications was analyzed. Results 1133 patients undergoing PD for PDAC were identified from the registry. After matching, 480 PBS patients vs. 480 patients without PBS were analyzed. Postoperative complications Clavien-Dindo classification (CDC) grade IIIa-IVb were higher in PBS patients (PBS 27% vs. no PBS 22%, p = 0.027). 320 PBS patients (66%) had no history of jaundice. In these patients, PBS was associated with higher morbidity. In contrast, PBS was not associated with higher complication rates in patients with history of jaundice. Serum bilirubin levels of 15 mg/dl and higher lead to more CDC IIIa-IVb (24% vs. 28%, p = 0.053) and higher mortality (3% vs. 7%, p 15 mg/dl increased CDC IIa-IVb complications (21% vs. 50%, p = 0.001), mortality was equivalent. Conclusion Most PBS procedures were performed in patients with no history of jaundice and increased morbidity. Serum bilirubin levels >15 mg/dl lead to higher morbidity and mortality. PBS correlated with higher complication rates in these patients.

Postoperative local infection is a major complication after pancreatic surgery. The aim of this prospective clinical trial was to assess the potential of moxifloxacin (MXF) to treat pancreatic infections from a pharmacokinetic (PK)/pharmacodynamic (PD) perspective. The PK of MXF in serum and pancreatic juice, via an inserted tube in the pancreatic duct, was determined in 19 patients up to day 7 after pancreatoduodenectomy. PK data in both specimens was analyzed with NONMEM 7.3. Intraoperative swipes were performed for microbiological examination. PK/PD target attainment was assessed in both matrices using unbound area under the plasma concentration-time curve/minimum inhibitory concentration (MIC) targets of ≥30 and ≥100, for gram-positive and gram-negative pathogens, respectively. A 2-compartment population PK model in which the measurements in pancreatic juice were assigned to a scaled peripheral compartment best described the PK in both specimens simultaneously. Median (10th-90th percentile) area under the plasma concentration-time curve values after the third dose were 28.9 mg · h/L (18.6-42.0) in serum and 55.8 mg · h/L (23.7-81.4) in pancreatic juice. Target attainment rate for the intraoperatively isolated bacterial strains was ≥0.88 after the third MXF dose. For gram-negatives, high probability of target attainment ≥0.84 was observed in serum for MIC ≤ 0.125 mg/L and in pancreatic juice for MIC ≤ 0.25 mg/L. For gram-positives, the probability of target attainment was 0.84-1 in serum for MIC ≤ 0.5 mg/L and in pancreatic juice for MIC ≤ 1 mg/L. In conclusion, penetration of MXF into pancreatic juice was substantial. The PK/PD analysis indicated that treatment of pancreatic infections by isolates with MIC ≤ 0.25 mg/L (gram-negative) and ≤1 mg/L (gram-positive) should be evaluated in further studies.

Background: Registries of pancreatic surgery have become increasingly popular as they facilitate both quality improvement and clinical research. We aimed to compare registries for design, variables collected, patient characteristics, treatment strategies, clinical outcomes, and pathology. Methods: Registered variables and outcomes of pancreatoduodenectomy (2014–2017) in 4 nationwide or multicenter pancreatic surgery registries from the United States of America (American College of Surgeons National Surgical Quality Improvement Program), Germany (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie - Studien-, Dokumentations- und Qualitätszentrum), the Netherlands (Dutch Pancreatic Cancer Audit), and Sweden (Swedish National Pancreatic and Periampullary Cancer Registry) were compared. A core registry set of 55 parameters was identified and evaluated using relative and absolute largest differences between extremes (smallest versus largest). Results: Overall, 22,983 pancreatoduodenectomies were included (15,224, 3,558, 2,795, and 1,406 in the United States of America, Germany, the Netherlands, and Sweden). Design of the registries varied because 20 out of 55 (36.4%) core parameters were not available in 1 or more registries. Preoperative chemotherapy in patients with pancreatic ductal adenocarcinoma was administered in 27.6%, 4.9%, 7.0%, and 3.4% (relative largest difference 8.1, absolute largest difference 24.2%, P < .001). Minimally invasive surgery was performed in 7.8%, 4.5%, 13.5%, and unknown (relative largest difference 3.0, absolute largest difference 9.0%, P < .001). Median length of stay was 8.0, 16.0, 12.0, and 11.0 days (relative largest difference 2.0, absolute largest difference 8.0, P < .001). Reoperation was performed in 5.7%, 17.1%, 8.7%, and 11.2% (relative largest difference 3.0, absolute largest difference 11.4%, P < .001). In-hospital mortality was 1.3%, 4.7%, 3.6%, and 2.7% (relative largest difference 3.6, absolute largest difference 3.4%, P < .001). Conclusion: Considerable differences exist in the design, variables, patients, treatment strategies, and outcomes in 4 Western registries of pancreatic surgery. The absolute largest differences of 24.3% for the use of preoperative chemotherapy, 9.0% for minimally invasive surgery, 11.4% for reoperation rate, and 3.4% for in-hospital mortality require further study and improvement. This analysis provides 55 core parameters for pancreatic surgery registries.

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.

Realistic preclinical models of primary pancreatic cancer and metastasis are urgently needed to test the therapy response ex vivo and facilitate personalized patient treatment. However, the absence of tumor-specific microenvironment in currently used models, e.g., patient-derived cell lines and xenografts, only allows limited predictive insights. Organotypic slice cultures (OTSCs) comprise intact multicellular tissue, which can be rapidly used for the spatially resolved drug response testing. This protocol describes the generation and cultivation of viable tumor slices of pancreatic cancer and its metastasis. Briefly, tissue is casted in low melt agarose and stored in cold isotonic buffer. Next, tissue slices of 300 µm thickness are generated with a vibratome. After preparation, slices are cultured at an air-liquid interface using cell culture inserts and an appropriate cultivation medium. During cultivation, changes in cell differentiation and viability can be monitored. Additionally, this technique enables the application of treatment to viable human tumor tissue ex vivo and subsequent downstream analyses, such as transcriptome and proteome profiling. OTSCs provide a unique opportunity to test the individual treatment response ex vivo and identify individual transcriptomic and proteomic profiles associated with the respective response of distinct slices of a tumor. OTSCs can be further explored to identify therapeutic strategies to personalize treatment of primary pancreatic cancer and metastasis.

Background The present study aimed to examine the impact of microscopically tumour-infiltrated resection margins (R1) in pancreatic ductal adenocarcinoma (PDAC) patients with advanced lymphonodular metastasis (pN1–pN2) on overall survival (OS). Methods This retrospective, multi-institutional analysis included patients undergoing surgical resection for PDAC at three tertiary university centres between 2005 and 2018. Subcohorts of patients with lymph node status pN0–N2 were stratified according to the histopathological resection status using Kaplan-Meier survival analysis. Results The OS of the entire cohort (n = 620) correlated inversely with the pN status (26 [pN0], 18 [pN1], 11.8 [pN2] months, P < 0.001) and R status (21.7 [R0], 12.5 [R1] months, P < 0.001). However, there was no statistically significant OS difference between R0 versus R1 in cases with advanced lymphonodular metastases: 19.6 months (95% CI: 17.4–20.9) versus 13.6 months (95% CI: 10.7–18.0) for pN1 stage and 13.7 months (95% CI: 10.7–18.9) versus 10.1 months (95% CI: 7.9–19.1) for pN2, respectively. Accordingly, N stage–dependent Cox regression analysis revealed that R status was a prognostic factor in pN0 cases only. Furthermore, there was no significant survival disadvantage for patients with R0 resection but circumferential resection margin invasion (≤ 1 mm; CRM+; 10.7 months) versus CRM-negative (13.7 months) cases in pN2 stages (P = 0.5). Conclusions An R1 resection is not associated with worse OS in pN2 cases. If there is evidence of advanced lymph node metastasis and a re-resection due to an R1 situation (e.g. at venous or arterial vessels) may substantially increase the perioperative risk, margin clearance in order to reach local control might be avoided with respect to the OS.

Background Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) can be associated with severe postoperative morbidity. This study aims to develop a preoperative POPF risk calculator that can be easily implemented in clinical routine. Methods Patients undergoing PD were identified from a prospectively-maintained database. A total of 11 preoperative baseline and CT-based radiological parameters were used in a binominal logistic regression model. Parameters remaining predictive for grade B/C POPF were entered into the risk calculator and diagnostic accuracy measures and ROC curves were calculated for a training and a test patient cohort. The risk calculator was transformed into a simple nomogram. Results A total of 242 patients undergoing PD in the period from 2012 to 2018 were included. CT-imaging-based maximum main pancreatic duct (MPD) diameter (p = 0.047), CT-imaging-based pancreatic gland diameter at the anticipated resection margin (p = 0.002) and gender (p = 0.058) were the parameters most predictive for grade B/C POPF. Based on these parameters, a risk calculator was developed to identify patients at high risk of developing grade B/C POPF. In a training cohort of PD patients this risk calculator was associated with an AUC of 0.808 (95%CI 0.726–0.874) and an AUC of 0.756 (95%CI 0.669-0-830) in the independent test cohort. A nomogram applicable as a visual risk scale for quick assessment of POPF grade B/C risk was developed. Conclusion The preoperative POPF risk calculator provides a simple tool to stratify patients planned for PD according to the risk of developing postoperative grade B/C POPF. The nomogram visual risk scale can be easily integrated into clinical routine and may be a valuable model to select patients for POPF-preventive therapy or as a stratification tool for clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer–stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer–CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. Implications: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor–stroma cross-talk as a potential therapeutic avenue.

Autocrine transforming growth factor (TGF)&beta, has been implicated in epithelial-mesenchymal transition (EMT) and invasion of several cancers including pancreatic ductal adenocarcinoma (PDAC) as well as triple-negative breast cancer (TNBC). However, the precise mechanism and the upstream inducers or downstream effectors of endogenous TGFB1 remain poorly characterized. In both cancer types, the small GTPase RAC1B inhibits cell motility induced by recombinant human TGF&beta, 1 via downregulation of the TGF&beta, type I receptor, ALK5, but whether RAC1B also impacts autocrine TGF&beta, signaling has not yet been studied. Intriguingly, RNA interference-mediated knockdown (RNAi-KD) or CRISPR/Cas-mediated knockout of RAC1B in TGF&beta, 1-secreting PDAC-derived Panc1 cells resulted in a dramatic decrease in secreted bioactive TGF&beta, 1 in the culture supernatants and TGFB1 mRNA expression, while the reverse was true for TNBC-derived MDA-MB-231 cells ectopically expressing RAC1B. Surprisingly, the antibody-mediated neutralization of secreted bioactive TGF&beta, or RNAi-KD of the endogenous TGFB1 gene, was associated with increased rather than decreased migratory activities of Panc1 and MDA-MB-231 cells, upregulation of the promigratory genes SNAI1, SNAI2 and RAC1, and downregulation of the invasion suppressor genes CDH1 (encoding E-cadherin) and SMAD3. Intriguingly, ectopic re-expression of SMAD3 was able to rescue Panc1 and MDA-MB-231 cells from the TGFB1 KD-induced rise in migratory activity. Together, these data suggest that RAC1B favors synthesis and secretion of autocrine TGF&beta, 1 which in a SMAD3-dependent manner blocks EMT-associated gene expression and cell motility.