Bert A. Bonsing

Background: Complete surgical resection is the cornerstone of curative treatment for pancreatic ductal adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (eCCA). Distinguishing tumor margins intraoperatively from fibrosis or inflammation remains challenging, contributing to incomplete resections and poorer outcomes. Near-infrared (NIR) fluorescence imaging enables real-time tumor identification and margin assessment. Antibody-based NIR fluorescent probes show favorable tumor-to-background ratios (TBRs) but are limited by prolonged circulation and hepatic clearance, which increases background signal. Peptide-based probes, such as cRGD-ZW800-1 (cyclic pentapeptide (cRGD) conjugated to an 800 nm fluorophore ZW800-1), which target integrins upregulated in these cancers, have shorter half-lives, enabling administration closer to surgery than with antibody-based probes while achieving high tumor contrast. This study evaluates the safety and feasibility of cRGD-ZW800-1 for fluorescence-guided surgery in PDAC and eCCA. Methods: In this open-label phase II trial, 21 patients undergoing pancreatectomy received cRGD-ZW800-1 (0.025 or 0.05 mg/kg) 2–4 or 18–24 hours preoperatively in four cohorts. Feasibility was predefined as ex vivo visualization with a TBR ≥ 1.5. Intraoperative imaging assessed tumor delineation, margins, vascular involvement, and suspected metastases. Findings were correlated with histopathology and integrin expression. Results: No probe-related adverse events occurred. All evaluable tumors met the feasibility criteria, with a median TBR of 3.0. A trend toward higher contrast was observed with the 0.025 mg/kg dose administered 18–24 hours before surgery. Fluorescence remained detectable after neoadjuvant therapy. Intraoperative imaging confirmed all irradicable vascular margins and provided surgically relevant information in over half of the patients, including confirmation of metastatic disease. Fluorescence imaging contributed to an intraoperative change in surgical management in two patients. Pathological analyses showed co-localization of fluorescence with integrin expression. Conclusions: cRGD-ZW800-1 was safe and reliably enabled visualization of PDAC and eCCA. The results demonstrate feasibility and suggest potential clinical utility in supporting surgical assessment, warranting further investigation in prospective, multicentre trials of intraoperative margin assessment, surgical radicality, and oncological outcomes.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of venous thromboembolism (VTE), which is burdensome and associated with decreased survival. Although neoadjuvant treatment is increasingly used in patients with PDAC, data on VTE in this setting remain scarce. This study evaluated VTE incidence during (neo)adjuvant therapy for resectable and borderline resectable PDAC and its relation to survival. METHODS: This study included patients from the investigator-initiated, multicenter, randomized controlled phase III PREOPANC-2 trial. Patients were randomly assigned to neoadjuvant 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin followed by surgery (FFX arm) or neoadjuvant gemcitabine-based chemoradiotherapy (CRT), followed by surgery and adjuvant gemcitabine (CRT arm). VTE was defined as both incidental and symptomatic lower- or upper-extremity deep vein thrombosis, pulmonary embolism (PE), splanchnic vein thrombosis, and catheter-related thrombosis. VTE occurrence was retrospectively evaluated from random assignment to 12 months after random assignment. The association with overall survival (OS) was analyzed using Cox regression analysis. RESULTS: VTE was diagnosed in 28 of 325 patients (9%): nine (3%) preoperatively and 19 (8%) postoperatively. Most VTEs were symptomatic (54%). Although a higher proportion of patients developed postoperative VTE in the CRT arm (FFX 3% v CRT 12%, P = .02), the 12-month cumulative incidence did not differ between arms (6% v 11%, P = .06). Two patients died from PE-related causes in the CRT arm. VTE was independently associated with reduced OS (adjusted time-varying hazard ratio, 2.13, P = .002). CONCLUSION: VTE occurred in 9% of patients with (borderline) resectable PDAC undergoing (neo)adjuvant treatment in the year after random assignment and was associated with decreased OS. These results underscore the need for standardized reporting of thromboembolic events in clinical trials and future studies assessing the potential benefits of thromboprophylaxis during neoadjuvant therapy.

Background: Preoperative planning of patients diagnosed with pancreatic head cancer is difficult and requires specific expertise. This pilot study assesses the added value of three-dimensional (3D) patient models and computer-aided detection (CAD) algorithms in determining the resectability of pancreatic head tumors. Methods: This study included 14 hepatopancreatobiliary experts from eight hospitals. The participants assessed three radiologically resectable and three radiologically borderline resectable cases in a simulated setting via crossover design. Groups were divided in controls (using a CT scan), a 3D group (using a CT scan and 3D models), and a CAD group (using a CT scan, 3D and CAD). For the perceived fulfillment of preoperative needs, the quality and confidence of clinical decision-making were evaluated. Results: A higher perceived ability to determine degrees and the length of tumor–vessel contact was reported in the CAD group compared to controls (p = 0.022 and p = 0.003, respectively). Lower degrees of tumor–vessel contact were predicted for radiologically borderline resectable tumors in the CAD group compared to controls (p = 0.037). Higher confidence levels were observed in predicting the need for vascular resection in the 3D group compared to controls (p = 0.033) for all cases combined. Conclusions: “CAD (including 3D) improved experts’ perceived ability to accurately assess vessel involvement and supports the development of evolving techniques that may enhance the diagnosis and treatment of pancreatic cancer”.

Background: Composite outcome measures aim to provide a more holistic view when determining the effectiveness and safety of surgical interventions. Recently, ‘Ideal Outcome’ (IO) harmonized the European and American composite outcome of pancreatic surgery. The rate of IO after pancreatoduodenectomy was 54% but is unknown after left pancreatectomy(LP). Methods: This transatlantic analysis included patients after LP from the audits in North America (NSQIP), Germany (StuDoQ), the Netherlands (DPCA), and Sweden (SNPPCR) (2014 – 2020). IO is obtained in the absence of (1)in-hospital mortality, (2)severe complications (Clavien-Dindo≥3), (3)postoperative pancreatic fistula (ISGPS grade B/C), (4)reoperation, (5)hospital stay exceeding the 75^th-percentile, and (6)readmission. Clinical predictors of IO were identified using a multivariable logistic regression. Results: Overall, 20,126 patients after LP were included (37.8% minimally invasive). The rate of IO after LP was 59.1%. The rate of IO varied among the four audits: North America 58.5%, Germany 53.4%, the Netherlands 56.9%, and Sweden 61.7% (PPP<0.001) compared to open LP. No difference in the IO was observed between robot-assisted and laparoscopic LP. Conclusion: The new composite outcome measure IO was reached in 59% patients after LP and varied between four transatlantic audits. Minimally invasive LP was associated with higher rates of IO. IO can be used for evaluating, comparing, and improving patient outcomes between the four audits, especially regarding postoperative pancreatic fistula.

INTRODUCTION: Refractory pain is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). New, effective therapies to reduce pain are urgently needed. Intravenous lidocaine is used in clinical practice in patients with PDAC and CP, but its efficacy has not been studied prospectively. METHODS: Multicenter prospective nonrandomized pilot study included patients with moderate or severe pain (Numeric Rating Scale ≥ 4) associated with PDAC or CP in 5 Dutch centers. An intravenous lidocaine bolus of 1.5 mg/kg was followed by continuous infusion at 1.5 mg/kg/hr. The dose was raised every 15 minutes until treatment response (up to a maximum 2 mg/kg/hr) and consecutively administered for 2 hours. Primary outcome was the mean difference in pain severity, preinfusion, and the first day after (Brief Pain Inventory [BPI] scale 1–10). A BPI decrease ≥1.3 points was considered clinically relevant. RESULTS: Overall, 30 patients were included, 19 with PDAC (63%) and 11 with CP (37%). The mean difference in BPI at day 1 was 1.1 (SD ± 1.3) points for patients with PDAC and 0.5 (SD ± 1.7) for patients with CP. A clinically relevant decrease in BPI on day 1 was reported in 9 of 29 patients (31%), and this response lasted up to 1 month. No serious complications were reported, and only 3 minor complications (vertigo, nausea, and tingling of mouth). Treatment with lidocaine did not impact quality of life. DISCUSSION: Intravenous lidocaine in patients with painful PDAC and CP did not show an overall clinically relevant reduction of pain. However, this pilot study shows that the treatment is feasible in this patient group and had a positive effect in a third of patients which lasted up to a month with only minor side effects. To prove or exclude the efficacy of intravenous lidocaine, the study should be performed in a study with a greater sample size and less heterogeneous patient group.