Next-generation study databases require FAIR, EHR-integrated, and scalable Electronic Data Capture for medical documentation and decision support.

Structured patient data play a key role in all types of clinical research. They are often collected in study databases for research purposes. In order to describe characteristics of a next-generation study database and assess the feasibility of its implementation a proof-of-concept study in a German university hospital was performed. Key characteristics identified include FAIR access to electronic case report forms (eCRF), regulatory compliant Electronic Data Capture (EDC), an EDC with electronic health record (EHR) integration, scalable EDC for medical documentation, patient generated data, and clinical decision support. In a local case study, we then successfully implemented a next-generation study database for 19 EDC systems (n = 2217 patients) that linked to i.s.h.med (Oracle Cerner) with the local EDC system called OpenEDC. Desiderata of next-generation study databases for patient data were identified from ongoing local clinical study projects in 11 clinical departments at Heidelberg University Hospital, Germany, a major tertiary referral hospital. We compiled and analyzed feature and functionality requests submitted to the OpenEDC team between May 2021 and July 2023. Next-generation study databases are technically and clinically feasible. Further research is needed to evaluate if our approach is feasible in a multi-center setting as well.

Surgery for intraductal papillary mucinous neoplasms in young patients: High-risk population.

BACKGROUND: Intraductal papillary mucinous neoplasms of the pancreas are uncommon in young individuals. Management of these patients is challenging because the risk of malignancy and recurrence after surgery remains unclear. The aim of the present study was to assess the long-term risk for intraductal papillary mucinous neoplasm recurrence after surgery for intraductal papillary mucinous neoplasms in patients ≤50 years of age. METHODS: Perioperative and long-term follow-up data of patients who had undergone surgery for intraductal papillary mucinous neoplasms between 2004 and 2020 were extracted from a prospective unicentric database and retrospectively analyzed. RESULTS: Seventy-eight patients underwent surgical treatment for benign intraductal papillary mucinous neoplasms (low-grade n = 22 and intermediate-grade n = 21) and malignant intraductal papillary mucinous neoplasms (high-grade n = 16 and intraductal papillary mucinous neoplasm-associated carcinoma n = 19). Severe postoperative morbidity (Clavien-Dindo ≥III) was found in 14 patients (18%). The median length of hospital stay was 10 days. No perioperative mortality was observed. The median length of follow-up was 72 months. Recurrence of intraductal papillary mucinous neoplasm-associated carcinoma was found in 6 patients (19%) with malignant intraductal papillary mucinous neoplasm and 1 patient (3%) with benign intraductal papillary mucinous neoplasm. CONCLUSION: Surgery for intraductal papillary mucinous neoplasm is safe and can be performed with low morbidity and potentially no mortality in young patients. Given the high rate of malignancy (45%), these patients with intraductal papillary mucinous neoplasms represent a high-risk population, and prophylactic surgical treatment should be considered in these patients with long life expectancies. Regular clinical and radiologic follow-up examinations are important to rule out disease recurrence, which is high, especially in patients with intraductal papillary mucinous neoplasm-associated carcinoma.

Perioperative Drug Treatment in Pancreatic Surgery-A Systematic Review and Meta-Analysis.

INTRODUCTION: Pancreatic resections for malignant or benign diseases are associated with major morbidity and changes in physiology. To reduce perioperative complications and enhance recovery, many types of perioperative medical management have been introduced. The aim of this study was to provide an evidence-based overview on the best perioperative drug treatment. METHODS: The electronic bibliographic databases Medline, Embase, CENTRAL, and Web of Science were systematically searched for randomized controlled trials (RCT) evaluating perioperative drug treatments in pancreatic surgery. The investigated drugs were somatostatin analogues, steroids, pancreatic enzyme replacement therapy (PERT), prokinetic therapy, antidiabetic drugs, and proton pump inhibitors (PPI). Targeted outcomes in each drug category were meta-analyzed. RESULTS: A total of 49 RCT were included. The analysis of somatostatin analogues showed a significantly lower incidence of postoperative pancreatic fistula (POPF) in the somatostatin group compared to the control group (OR 0.58, 95% CI: 0.45 to 0.74). The comparison of glucocorticoids versus placebo showed significantly less POPF in the glucocorticoid group (OR 0.22, 95% CI: 0.07 to 0.77). There was no significant difference in DGE when erythromycin was compared to placebo (OR 0.33, 95% CI: 0.08 to 1.30). The other investigated drug regimens could only be analyzed qualitatively. CONCLUSION: This systematic review provides a comprehensive overview on perioperative drug treatment in pancreatic surgery. Some often-prescribed perioperative drug treatments lack high quality evidence and further research is needed.

Middle Segment-Preserving Pancreatectomy to Avoid Pancreatic Insufficiency: Individual Patient Data Analysis of All Published Cases from 2003-2021.

Middle segment-preserving pancreatectomy (MPP) can treat multilocular diseases in the pancreatic head and tail while avoiding impairments caused by total pancreatectomy (TP). We conducted a systematic literature review of MPP cases and collected individual patient data (IPD). MPP patients (N = 29) were analyzed and compared to a group of TP patients (N = 14) in terms of clinical baseline characteristics, intraoperative course, and postoperative outcomes. We also conducted a limited survival analysis following MPP. Pancreatic functionality was better preserved following MPP than TP, as new-onset diabetes and exocrine insufficiency each occurred in 29% of MPP patients compared to near-ubiquitous prevalence among TP patients. Nevertheless, POPF Grade B occurred in 54% of MPP patients, a complication avoidable with TP. Longer pancreatic remnants were a prognostic indicator for shorter and less eventful hospital stays with fewer complications, whereas complications of endocrine functionality were associated with older patients. Long-term survival prospects after MPP appeared strong (median up to 110 months), but survival was lower in cases with recurring malignancies and metastases (median < 40 months). This study demonstrates MPP is a feasible treatment alternative to TP for selected cases because it can avoid pancreoprivic impairments, but at the risk of perioperative morbidity.

A Multicenter, Randomized, Double-Blinded, Clinical Trial Comparing Cattell-Warren and Blumgart Anastomoses Following Partial Pancreatoduodenectomy: PANasta Trial.

Whether a Blumgart anastomosis (BA) is superior to Cattell-Warren anastomosis (CWA) in terms of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy. Importance: Complications driven by POPF following pancreatic cancer resection may hinder adjuvant therapy, shortening survival. BA may reduce complications compared to CWA, improving the use of adjuvant therapy and prolonging survival. Methods: A multicenter double-blind, controlled trial of patients undergoing resection for suspected pancreatic head cancer, randomized during surgery to a BA or CWA, stratified by pancreatic consistency and duct diameter. The primary end point was POPF, and secondary outcome measures were adjuvant therapy use, specified surgical complications, quality of life, and survival from the date of randomization. For a 10% POPF reduction, 416 patients were required, 208 per arm (two-sided α = 0·05; power = 80%). Results: Z-score at planned interim analysis was 0.474 so recruitment was held to 238 patients; 236 patients were analyzed (112 BA and 124 CWA). No significant differences in POPF were observed between BA and CWA, odds ratio (95% confidence interval [CI]) 1·04 (0.58-1.88), P = 0.887, nor in serious adverse events. Adjuvant therapy was delivered to 98 (62%) of 159 eligible patients with any malignancy; statistically unrelated to arm or postoperative complications. Twelve-month overall survival, hazard ratio (95% CI), did not differ between anastomoses; BA 0.787 (0.713-0.868) and CWA 0.854 (0.792-0.921), P = 0.266, nor for the 58 patients with complications, median (IQR), 0.83 (0.74-0.91) compared to 101 patients without complications 0.82 (0.76-0.89) (P = 0.977). Conclusions: PANasta represents the most robust analysis of BA versus CWA to date.

SmartPAN: In vitro and in vivo proof-of-safety assessments for an intra-operative predictive indicator of postoperative pancreatic fistula.

Pancreatic surgery is complicated by untreated fluid leakage, but no tenable techniques exist to detect and close leakage sites during surgery. A novel hydrogel called SmartPAN has been developed to meet this need and is here assessed for safety before trials on human patients. First, resazurin assays were used to test the cytotoxic effects of SmartPAN's active bromothymol blue (BTB) indicator and its solution of phosphate-buffered saline (PBS) on normal (HPDE: human pancreatic duct epithelial) or carcinomic (FAMPAC) human pancreatic cells. Cells incubated with BTB showed no significant reduction in cell viability below threshold safety levels. However, PBS had a mild cytotoxic effect on FAMPAC cells. Second, SmartPAN's pathological effects were evaluated in vivo by applying 4-ml SmartPAN to a porcine (Sus scrofa domesticus) model of pancreatic resection. There were no significant differences in macroscopic and microscopic pathologies between pigs treated with SmartPAN or saline. Third, measurements using HPLC-MS/MS demonstrate that BTB does not cross into the bloodstream and was eliminated from the body within 2 days of surgery. Overall, SmartPAN appears safe in the short term and ready for first-in-human trials because its components are either biocompatible or quickly neutralized by dilution and drainage.

Intraoperative visualisation of pancreatic leakage (ViP): study protocol for an IDEAL Stage I Post Market Clinical Study.

INTRODUCTION: Pancreatic resections are an important field of surgery worldwide to treat a variety of benign and malignant diseases. Postoperative pancreatic fistula (POPF) remains a frequent and critical complication after partial pancreatectomy and affects up to 50% of patients. POPF increases mortality, prolongs the postoperative hospital stay and is associated with a significant economic burden. Despite various scientific approaches and clinical strategies, it has not yet been possible to develop an effective preventive tool. The SmartPAN indicator is the first surgery-ready medical device for direct visualisation of pancreatic leakage already during the operation. Applied to the surface of pancreatic tissue, it detects sites of biochemical leak via colour reaction, thereby guiding effective closure and potentially mitigating POPF development. METHODS AND ANALYSIS: The ViP trial is a prospective single-arm, single-centre first in human study to collect data on usability and confirm safety of SmartPAN. A total of 35 patients with planned partial pancreatectomy will be included in the trial with a follow-up of 30 days after the index surgery. Usability endpoints such as adherence to protocol and evaluation by the operating surgeon as well as safety parameters including major intraoperative and postoperative complications, especially POPF development, will be analysed. ETHICS AND DISSEMINATION: Following the IDEAL-D (Idea, Development, Exploration, Assessment, and Long term study of Device development and surgical innovation) framework of medical device development preclinical in vitro, porcine in vivo, and human ex vivo studies have proven feasibility, efficacy and safety of SmartPAN. After market approval, the ViP trial is the IDEAL Stage I trial to investigate SmartPAN in a clinical setting. The study has been approved by the local ethics committee as the device is used exclusively within its intended purpose. Results will be published in a peer-reviewed journal. The study will provide a basis for a future randomised controlled interventional trial to confirm clinical efficacy of SmartPAN. TRIAL REGISTRATION NUMBER: German Clinical Trial Register DRKS00027559, registered on 4 March 2022.

Survival Benefit of Resection Surgery for Pancreatic Ductal Adenocarcinoma with Liver Metastases: A Propensity Score-Matched SEER Database Analysis.

Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III-IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials.

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo. Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation.