Patient-reported outcomes at three months after pancreatic surgery for benign and malignant diseases - A prospective observational study.

BACKGROUND/OBJECTIVES: Pancreatic surgery may have a long-lasting effect on patients' health status and quality of life (QoL). We aim to evaluate patient-reported outcomes (PRO) 3 months after pancreatic surgery. METHODS: Patients scheduled for pancreatic surgery were enrolled in a prospective trial at five German centers. Patients completed PRO questionnaires (EQ-5D-5L, EORTC QLQ-PAN26, patient-reported happiness, and HADS-D), we report the first follow-up 3 months after surgery as an interim analysis. Statistical testing was performed using R software. RESULTS: From 2019 to 2022 203 patients were enrolled, a three-month follow-up questionnaire was available in 135 (65.5 %). 77 (57.9 %) underwent surgery for malignant disease. Patient-reported health status (EQ-5D-5L) was impaired in 4/5 dimensions (mobility, self-care, usual activities, pain, discomfort) for patients with malignant and 3/5 dimensions (mobility, self-care, usual activities) for patients with benign disease 3 months after surgery (p < 0.05). Patients with malignant disease reported an increase in depressive symptoms, patients with benign disease had a decrease in anxiety symptoms (HADS-D; depression: 5.00 vs 6.51, p = 0.002; anxiety: 8.04 vs. 6.34, p = 0.030). Regarding pancreatic-disease-specific symptoms (EORTC-QLQ-PAN26), patients with malignant disease reported increased problems with taste, weight loss, weakness in arms and legs, dry mouth, body image and troubling side effects at three months. Patients with benign disease indicated more weakness in arms and legs, troubling side effects but less future worries at three months. CONCLUSION: Patient-reported outcomes of patients undergoing pancreatic surgery for benign vs. malignant disease show important differences. Patients with malignant tumors report more severely decreased quality of life 3 months postoperatively than patients with benign tumors.

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 surgical-oncologic textbook outcome in patients with stage I to III pancreatic ductal adenocarcinoma: A cross-validation study of two national registries.

BACKGROUND: Using national registries, we aimed to evaluate oncologic textbook outcomes in pancreatic ductal adenocarcinoma patients. METHODS: Patients with stage I to III pancreatic ductal adenocarcinoma and surgical resection from 2010 to 2020 in the US and Germany were identified using the National Cancer Database and National Cancer Registries data. The surgical-oncologic textbook outcome was defined as complete oncologic resection with no residual tumor and ≥12 harvested lymph nodes. The composite endpoint was defined as surgical-oncologic textbook outcome and receipt of perioperative systemic and/or radiation therapy. RESULTS: In total, 33,498 patients from the National Cancer Database and 14,589 patients from the National Cancer Registries were included. In the National Cancer Database, 28,931 (86%) patients had complete oncologic resection with no residual tumor, and 11,595 (79%) in the National Cancer Registries. 8,723 (26%) patients in the National Cancer Database and 556 (4%) in the National Cancer Registries had <12 lymph nodes harvested. The National Cancer Database shows 26,135 (78%) underwent perioperative therapy and 8,333 (57%) in the National Cancer Registries. Surgical-oncologic textbook outcome was achieved in 21,198 (63%) patients in the National Cancer Database and in 11,234 (77%) patients from the National Cancer Registries. 16,967 (50%) patients in the National Cancer Database and 7,878 (54%) patients in the National Cancer Registries had composite textbook outcome. Median overall survival in patients with composite textbook outcomes was 32 months in the National Cancer Database and 27 months in the National Cancer Registries (P < .001). In contrast, those with non-textbook outcomes had a median overall survival of 23 months in the National Cancer Database and 20 months in the National Cancer Registries (P < .001). CONCLUSION: Surgical-oncologic textbook outcomes were achieved in > 50% of stage I to III pancreatic ductal adenocarcinoma for both the National Cancer Database and the National Cancer Registries. Failure to achieve textbook outcomes was associated with impaired survival across both registries.

Molecular profiling and specific targeting of gemcitabine-resistant subclones in heterogeneous pancreatic cancer cell populations.

Purpose: Chemotherapy is pivotal in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC). Technical advances unveiled a high degree of inter- and intratumoral heterogeneity. We hypothesized that intratumoral heterogeneity (ITH) impacts response to gemcitabine treatment and demands specific targeting of resistant subclones. Methods: Using single cell-derived cell lines (SCDCLs) from the classical cell line BxPC3 and the basal-like cell line Panc-1, we addressed the effect of ITH on response to gemcitabine treatment. Results: Individual SCDCLs of both parental tumor cell populations showed considerable heterogeneity in response to gemcitabine. Unsupervised PCA including the 1,000 most variably expressed genes showed a clustering of the SCDCLs according to their respective sensitivity to gemcitabine treatment for BxPC3, while this was less clear for Panc-1. In BxPC3 SCDCLs, enriched signaling pathways EMT, TNF signaling via NfKB, and IL2STAT5 signaling correlated with more resistant behavior to gemcitabine. In Panc-1 SCDCLs MYC targets V1 and V2 as well as E2F targets were associated with stronger resistance. We used recursive feature elimination for Feature Selection in order to compute sets of proteins that showed strong association with the response to gemcitabine. The optimal protein set calculated for Panc-1 comprised fewer proteins in comparison to the protein set determined for BxPC3. Based on molecular profiles, we could show that the gemcitabine-resistant SCDCLs of both BxPC3 and Panc-1 are more sensitive to the BET inhibitor JQ1 compared to the respective gemcitabine-sensitive SCDCLs. Conclusion: Our model system of SCDCLs identified gemcitabine-resistant subclones and provides evidence for the critical role of ITH for treatment response in PDAC. We exploited molecular differences as the basis for differential response and used these for more targeted therapy of resistant subclones.

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.

Recent onset diabetes is associated with better survival in pancreatic ductal adenocarcinoma-An analysis of preoperative symptoms within the DGAV StuDoQ|Pancreas Registry.

BACKGROUND: This multicenter study analyzed the relationship between preoperative symptoms and postsurgical outcomes utilizing the German national DGAV StuDoQ|Pancreas database. METHODS: This retrospective study included 2,643 pancreatic ductal adenocarcinoma patients undergoing pancreatic head resection from 2013-2017 within the German pancreatic surgery registry (DGAV StuDoQ|Pancreas). The association of preoperative symptoms with overall survival was analyzed using Kaplan-Meier and Cox regression analysis. RESULTS: Preoperative symptoms were common, with 2,380 of 2,643 (90%) patients presenting with any one or more of the following symptoms: jaundice (40%), biliary obstruction treated with biliary stent (41%), pain (37%), weight loss (29%), nausea (18%), diabetes (31%), emesis (6%), and recent onset diabetes (5%). Patients were separated into 3 groups: no symptoms (n = 293), symptoms (n = 2,229), and recent onset diabetes (n = 121). The 3 groups differed in body mass index and nodal staging, where patients with recent onset diabetes had the highest values (body mass index: no symptoms: 24.5 kg/m2, symptoms: 25.1 kg/m2; recent-onset diabetes: 26.3 kg/m2, P = .007), (no symptoms: N1: 55%, N2: 10%; symptoms: N1: 53%, N2: 17%; recent-onset diabetes: N1: 56%, N2: 16%, P = .023). Other pathological characteristics, carbohydrate antigen 19-9 levels, and adjuvant chemotherapy receival did not differ between the groups. Interestingly, recent-onset diabetes was associated with better survival compared with the other groups (Median overall survival: 28 months [no symptoms at all], 22 months [symptoms] versus not reached [recent onset diabetes group], and 5-year overall survival rates of 28%, 11%, and 57%, respectively [log rank, P = .013]). Multivariable analysis revealed that recent-onset diabetes and preoperative symptoms were independently associated with overall survival (recent-onset diabetes, relative risk 0.052 P = .027, >5 symptoms relative risk 3.66, P < .001). CONCLUSION: Pancreatic ductal adenocarcinoma symptoms occured in up to 90% of patients with resectable pancreatic ductal adenocarcinoma. In addition, PDAC symptoms were associated with overall survival and might identify unique pancreatic ductal adenocarcinoma subtypes.

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.

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.

Overexpression of integrin alpha 2 (ITGA2) correlates with poor survival in patients with pancreatic ductal adenocarcinoma.

AIMS: Due to the known malignant potential and the poor overall prognosis of pancreatic ductal adenocarcinoma (PDAC), the identification of new biomarkers is of utmost importance. It has been reported that integrin alpha 2 (ITGA2), plakophilin 3 (PKP3) and adenylate kinase 4 (AK4) are associated with poor survival and more aggressive malignant behaviour in multiple cancers; however, their role in PDAC is still unknown. Therefore, the aim of this study was to investigate the correlation of ITGA2, PKP3 and AK4 expression with PDAC tumour characteristics and patient survival. METHODS: Of 105 patients undergoing oncological pancreatic resection between 2012 and 2018, tissue microarrays were prepared from formalin-fixed, paraffin-embedded PDAC tissues and immunohistochemically stained with PKP3, AK4 and ITGA2. Clinical and pathological patient data were retrieved from the electronic patient charts and correlated with biomarker staining scores. RESULTS: ITGA2 expression was high in 43% of patients with PDAC, whereas AK4 and PKP3 expressions were high in 28% and 57%, respectively. Overall survival was negatively associated with high ITGA2 expression in comparison with low expression (13 months (95% CI 10 to 18 months) vs 25 months (95% CI 20 to 30 months), p<0.001). Expression of AK4 and PKP3 did not correlate with overall survival. Multivariate Cox regression identified ITGA2 as an independent predictor of shorter overall survival in PDAC of different lymph node status and high tumour grade (G3/G4). CONCLUSIONS: ITGA2 is an independent prognostic parameter for survival in patients with resected PDAC. PKP3 and AK4 do not appear to have prognostic value for survival in PDAC.

A Tumor Microenvironment Model of Pancreatic Cancer to Elucidate Responses toward Immunotherapy.

Pancreatic cancer is a devastating malignancy with minimal treatment options. Standard-of-care therapy, including surgery and chemotherapy, is unsatisfactory, and therapies harnessing the immune system have been unsuccessful in clinical trials. Resistance to therapy and disease progression are mediated by the tumor microenvironment, which contains excessive amounts of extracellular matrix and stromal cells, acting as a barrier to drug delivery. There is a lack of preclinical pancreatic cancer models that reconstruct the extracellular, cellular, and biomechanical elements of tumor tissues to assess responses toward immunotherapy. To address this limitation and explore the effects of immunotherapy in combination with chemotherapy, a multicellular 3D cancer model using a star-shaped poly(ethylene glycol)-heparin hydrogel matrix is developed. Human pancreatic cancer cells, cancer-associated fibroblasts, and myeloid cells are grown encapsulated in hydrogels to mimic key components of tumor tissues, and cell responses toward treatment are assessed. Combining the CD11b agonist ADH-503 with anti-PD-1 immunotherapy and chemotherapy leads to a significant reduction in tumor cell viability, proliferation, metabolic activity, immunomodulation, and secretion of immunosuppressive and tumor growth-promoting cytokines.

Prediction of R Status in Resections for Pancreatic Cancer Using Simplified Radiological Criteria.

OBJECTIVE: Predicting R status before surgery for pancreatic cancer (PDAC) patients with upfront surgery and neoadjuvant therapy. SUMMARY BACKGROUND DATA: Negative surgical margins (R0) are a key predictor of long-term outcomes in PDAC. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Clinical Outcome and Prognostic Factors of Pancreatic Adenosquamous Carcinoma Compared to Ductal Adenocarcinoma-Results from the German Cancer Registry Group.

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.

Diversified Effects of Bile Contamination, Postoperative Infections, and Antimicrobial Resistance Level on the Oncologic Prognosis After Pancreatoduodenectomy for Ductal Adenocarcinoma.

BACKGROUND/AIM: Whether the presence of bacteria in the bile or postoperative infections sustained by microorganisms with different levels of drug-resistance are associated with changes in the oncologic prognosis of patients undergoing surgery for pancreatic cancer has not been thoroughly investigated. The aim was to study the association of bile contamination, postoperative infections, and multi-level resistance with long-term outcome. PATIENTS AND METHODS: Prospectively maintained databases were queried for patients who underwent pancreatoduodenectomy (PD). Patients who underwent preoperative biliary stenting prior to PD and an intraoperative bile culture were included. The levels of bacterial resistance of intraoperative bile cultures and of specimens of postoperative infections were stratified into multidrug sensitive (MDS), multidrug-resistant (MDR), and extensive drug-resistant (XDR). RESULTS: A total of 267 patients met the inclusion criteria. The Kaplan-Meier survival curves for overall survival (OS) of patients having no bacteriobilia or positive cultures with MDS versus MDR/XDR bacteria were not statistically different (log-rank=0.9). OS of patients stratified for no postoperative infection or infections by MDS was significantly better than those having MRD/XDR isolates (log-rank=0.04). A Cox multivariate model showed that having MRD/XDR postoperative infections was and independent variable for worse OS (HR=1.227; 95%CI=1.189-1.1918; p=0.036). CONCLUSION: Postoperative drug resistant infections are a significant risk factor for poor OS after pancreatoduodenectomy for ductal adenocarcinoma.

[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.

Concepts and Outcomes of Perioperative Therapy in Stage IA-III Pancreatic Cancer-A Cross-Validation of the National Cancer Database (NCDB) and the German Cancer Registry Group of the Society of German Tumor Centers (GCRG/ADT).

(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.

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.

Implications of Perineural Invasion on Disease Recurrence and Survival After Pancreatectomy for Pancreatic Head Ductal Adenocarcinoma.

OBJECTIVE: To describe PNI and to evaluate its impact on disease-free (DFS) and overall survival (OS) in patients with resected pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: Although PNI is a prognostic factor for survival in many GI cancers, there is limited knowledge regarding its impact on tumor recurrence, especially in ''early stage disease'' (PDAC ≤20 mm, R0/ N0 PDAC). METHODS: This multicenter retrospective study included patients undergoing PDAC resection between 2009 and 2014. The association of PNI with DFS and OS was analyzed using Cox proportional-hazards models. RESULTS: PNI was found in 87% of 778 patients included in the study, with lower rates in PDAC ≤20 mm (78.7%) and in R0/N0 tumors (70.6%). PNI rate did not differ between patients who underwent neoadjuvant therapy and upfront surgery (88% vs 84%, P = 0.08). Although not significant at multivariate analysis ( P = 0.07), patients with PNI had worse DFS at univariate analysis (median DFS: 20 vs 15 months, P < 0.01). PNI was the only independent predictor of DFS in R0/N0 tumors (hazard ratio [HR]: 2.2) and in PDAC ≤ 20 mm (HR: 1.8). PNI was an independent predictor of OS in the entire cohort (27 vs 50 months, P = 0.01), together with G3 tumors, pN1 status, carbohydrate antigen (CA) 19.9 >37 and pain. CONCLUSIONS: PNI represents a major determinant of tumor recurrence and patients' survival in pancreatic cancer. The role of PNI is particularly relevant in early stages, supporting the hypothesis that invasion of nerves by cancer cells has a driving role in pancreatic cancer progression.

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.

Postoperative Outcomes of Tangential versus Segmental Resection and End-to-end Reconstruction of the Superior Mesenterico-Portal Vein During Pancreatoduodenectomy for Pancreatic Adenocarcinoma: A Single-Center Experience.

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<0.001]. 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%, 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.

Outcome of pancreatic anastomoses during pancreatoduodenectomy in two national audits.

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|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.