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Abstract Prostate-specific membrane antigen (PSMA) targeted tracers show increased uptake in several malignancies, indicating a potential for peptide radioligand therapy. Intra-arterial injection of radiotracers can increase the therapeutic window. This study aimed to evaluate the feasibility of intra-arterial injection of [68Ga]Ga-PSMA-11 for intrahepatic cholangiocarcinoma and compare tracer uptake after intrahepatic arterial injection and intravenous injection. Three patients with intrahepatic cholangiocarcinoma received [68Ga]Ga-PSMA-11 through a hepatic arterial infusion pump, followed by positron emission tomography/computed tomography (PET/CT). Two-three days later, patients underwent PET/CT after intravenous [68Ga]Ga-PSMA-11 injection. All tumours showed higher uptake on the intra-arterial scan compared with the intravenous scan: the intra-arterial / intravenous standardised uptake value normalised by lean body mass ratios were 1.40, 1.46, and 1.54. Local intra-arterial PSMA injection is possible in patients with intrahepatic cholangiocarcinoma. Local injection increases tumour-to-normal tissue ratios, increasing the therapeutic window for theranostic applications. Relevance statement Intra-arterial Prostate specific membrane antigen (PSMA) injection increases the therapeutic window for potential theranostic application in intrahepatic cholangiocarcinoma. Key Points Three patients with intrahepatic cholangiocarcinoma underwent PET/CT after intra-arterial and intravenous injection of [68Ga]Ga-PSMA-11. Intra-arterial injection showed higher uptake than intravenous injection. PSMA-targeted imaging could be valuable for a subset of intrahepatic cholangiocarcinoma patients. Graphical Abstract

Introduction Postoperative pancreatic fistula (POPF) occurs in 25% of patients undergoing a high-risk pancreatoduodenectomy (PD) and is a driving cause of major morbidity, mortality, prolonged hospital stay and increased costs after PD. There is a need for perioperative methods to decrease these risks. In recent studies, preoperative chemoradiotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) reduced the rate of POPF seemingly due to radiation-induced pancreatic fibrosis. However, patients with a high risk of POPF mostly have a non-pancreatic periampullary tumour and do not receive radiotherapy. Prospective studies using radiotherapy specifically to reduce the risk of POPF have not been performed. We aim to assess the safety, feasibility and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the rate of POPF.Methods and analysis In this multicentre, single-arm, phase II trial, we aim to assess the feasibility and safety of a single fraction of preoperative stereotactic radiotherapy (12 Gy) to a 4 cm area around the future pancreatic neck transection margin in patients at high risk of developing POPF after PD aimed to reduce the risk of grade B/C POPF. Adult patients scheduled for PD for malignant and premalignant periampullary tumours, excluding PDAC, with a pancreatic duct diameter ≤3 mm will be included in centres participating in the Dutch Pancreatic Cancer Group. The primary outcome is the safety and feasibility of single-dose preoperative stereotactic radiotherapy before PD. The most relevant secondary outcomes are grade B/C POPF and the difference in the extent of fibrosis between the radiated and non-radiated (uncinate margin) pancreas. Evaluation of endpoints will be performed after inclusion of 33 eligible patients.Ethics and dissemination Ethical approval was obtained by the Amsterdam UMC’s accredited Medical Research Ethics Committee (METC). All included patients are required to have provided written informed consent. The results of this trial will be used to determine the need for a randomised controlled phase III trial and submitted to a high-impact peer-reviewed medical journal regardless of the study outcome.Trial registration number NL72913 (Central Committee on Research involving Human Subjects Registry) and NCT05641233 (ClinicalTrials).

Background & Aims: Patients with intrahepatic cholangiocarcinoma can now be managed with targeted therapies directed against specific molecular alterations. Consequently, tissue samples submitted to the pathology department must produce molecular information in addition to a diagnosis or, for resection specimens, staging information. The pathologist’s role when evaluating these specimens has therefore changed to accommodate such personalised approaches. Methods: We developed recommendations and guidance for pathologists by conducting a systematic review of existing guidance to generate candidate statements followed by an international Delphi process. Fifty-nine pathologists from 28 countries in six continents rated statements mapped to all elements of the specimen pathway from receipt in the pathology department to authorisation of the final written report. A separate survey of ‘end-users’ of the report including surgeons, oncologists, and gastroenterologists was undertaken to evaluate what information should be included in the written report to enable appropriate patient management. Results: Forty-eight statements reached consensus for inclusion in the guidance including 10 statements about the content of the written report that also reached consensus by end-user participants. A reporting proforma to allow easy inclusion of the recommended data points was developed. Conclusions: These guiding principles and recommendations provide a framework to allow pathologists reporting on patients with intrahepatic cholangiocarcinoma to maximise the informational yield of specimens required for personalised patient management. Impact and Implications: Biopsy or resection lesional tissue from intrahepatic cholangiocarcinoma must yield information about the molecular abnormalities within the tumour that define suitability for personalised therapies in addition to a diagnosis and staging information. Here, we have developed international consensus guidance for pathologists that report such cases using a Delphi process that sought the views of both pathologists and ‘end-users of pathology reports. The guide highlights the need to report cases in a way that preserves tissue for molecular testing and emphasises that reporting requires interpretation of histological characteristics within the broader clinical and radiological context. The guide will allow pathologists to report cases of intrahepatic cholangiocarcinoma in a uniform manner that maximises the value of the tissue received to facilitate optimal multidisciplinary patient management.

Background: Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. This study aims to explore the potential of a multi-omics biomarker for predicting early PDAC progression by employing an in-depth mathematical modeling approach. Methods: Blood samples were collected from 58 PDAC patients undergoing FOLFIRINOX before and after the first cycle. These samples underwent gene (GEP) and inflammatory protein expression profiling (IPEP). We explored the predictive potential of exclusively IPEP through Stepwise (Backward) Multivariate Logistic Regression modeling. Additionally, we integrated GEP and IPEP using Bayesian Kernel Regression modeling, aiming to enhance predictive performance. Ultimately, the FOLFIRINOX IPEP (FFX-IPEP) signature was developed. Results: Our findings revealed that proteins exhibited superior predictive accuracy than genes. Consequently, the FFX-IPEP signature consisted of six proteins: AMN, BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8. The signature effectively identified patients transitioning from disease control to progression early during FOLFIRINOX, achieving remarkable predictive accuracy with an AUC of 0.89 in an independent test set. Importantly, the FFX-IPEP signature outperformed the conventional CA19-9 tumor marker. Conclusions: Our six-protein FFX-IPEP signature holds solid potential as a liquid biomarker for the early prediction of PDAC progression during toxic FOLFIRINOX chemotherapy. Further validation in an external cohort is crucial to confirm the utility of the FFX-IPEP signature. Future studies should expand to predict progression under different chemotherapies to enhance the guidance of personalized treatment selection in PDAC.

Abstract Background Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery needs to be confirmed. To guide safe implementation of MIPD, large-scale international randomized trials comparing MIPD and OPD in experienced high-volume centers are needed. We hypothesize that MIPD is non-inferior in terms of overall complications, but superior regarding time to functional recovery, as compared to OPD. Methods/design The DIPLOMA-2 trial is an international randomized controlled, patient-blinded, non-inferiority trial performed in 14 high-volume pancreatic centers in Europe with a minimum annual volume of 30 MIPD and 30 OPD. A total of 288 patients with an indication for elective pancreatoduodenectomy for pre-malignant and malignant disease, eligible for both open and minimally invasive approach, are randomly allocated for MIPD or OPD in a 2:1 ratio. Centers perform either laparoscopic or robot-assisted MIPD based on their surgical expertise. The primary outcome is the Comprehensive Complication Index (CCI®), measuring all complications graded according to the Clavien-Dindo classification up to 90 days after surgery. The sample size is calculated with the following assumptions: 2.5% one-sided significance level (α), 80% power (1-β), expected difference of the mean CCI® score of 0 points between MIPD and OPD, and a non-inferiority margin of 7.5 points. The main secondary outcome is time to functional recovery, which will be analyzed for superiority. Other secondary outcomes include post-operative 90-day Fitbit™ measured activity, operative outcomes (e.g., blood loss, operative time, conversion to open surgery, surgeon-reported outcomes), oncological findings in case of malignancy (e.g., R0-resection rate, time to adjuvant treatment, survival), postoperative outcomes (e.g., clinically relevant complications), healthcare resource utilization (length of stay, readmissions, intensive care stay), quality of life, and costs. Postoperative follow-up is up to 36 months. Discussion The DIPLOMA-2 trial aims to establish the safety of MIPD as the new standard of care for this selected patient population undergoing pancreatoduodenectomy in high-volume centers, ultimately aiming for superior patient recovery. Trial registration ISRCTN27483786. Registered on August 2, 2023

Abstract Background Malignant gastric outlet obstruction (GOO) is a debilitating condition that frequently occurs in patients with malignancies of the distal stomach and (peri)ampullary region. The standard palliative treatment for patients with a reasonable life expectancy and adequate performance status is a laparoscopic surgical gastrojejunostomy (SGJ). Recently, endoscopic ultrasound-guided gastroenterostomy (EUS-GE) emerged as a promising alternative to the surgical approach. The present study aims to compare these treatment modalities in terms of efficacy, safety, and costs. Methods The ENDURO-study is a multicentre, open-label, parallel-group randomized controlled trial. In total, ninety-six patients with gastric outlet obstruction caused by an irresectable or metastasized malignancy will be 1:1 randomized to either SGJ or EUS-GE. The primary endpoint is time to tolerate at least soft solids. The co-primary endpoint is the proportion of patients with persisting or recurring symptoms of gastric outlet obstruction for which a reintervention is required. Secondary endpoints are technical and clinical success, quality of life, gastroenterostomy dysfunction, reinterventions, time to reintervention, adverse events, quality of life, time to start chemotherapy, length of hospital stay, readmissions, weight, survival, and costs. Discussion The ENDURO-study assesses whether EUS-GE, as compared to SGJ, results in a faster resumption of solid oral intake and is non-inferior regarding reinterventions for persistent or recurrent obstructive symptoms in patients with malignant GOO. This trial aims to guide future treatment strategies and to improve quality of life in a palliative setting. Trial registration International Clinical Trials Registry Platform (ICTRP): NL9592. Registered on 07 July 2021.

Abstract Purpose The role of locoregional therapy compared to systemic chemotherapy (SYS) for unresectable intrahepatic cholangiocarcinoma (IHC) remains controversial. The importance of hepatic disease control, either as initial or salvage therapy, is also unclear. We compared overall survival (OS) in patients treated with resection, hepatic arterial infusion pump (HAIP) chemotherapy, or SYS as it relates to hepatic recurrence or progression. We also evaluated recurrence after resection to determine the efficacy of locoregional salvage therapy. Patients and Methods In this single‐institution retrospective analysis, patients with biopsy‐proven IHC treated with either curative‐intent resection, HAIP (with or without SYS), or SYS alone were analyzed. Propensity score matching (PSM) was used to compare patients with liver‐limited, advanced disease treated with HAIP versus SYS. The impact of locoregional salvage therapies in patients with liver‐limited recurrence was analyzed in the resection cohort. Results From 2000 to 2017, 714 patients with IHC were treated, 219 (30.7%) with resectable disease, 316 (44.3%) with locally advanced disease, and 179 (25.1%) with metastatic disease. Resected patients were less likely to recur or progress in the liver (hazard ratio [HR] 0.41, 95% CI 0.34–0.45) versus those that received HAIP or SYS (HR 0.58, 95% CI 0.50–0.65 vs. HR 0.63, 95% CI 0.57–0.69, respectively). In resected patients, 161 (64.4%) recurred, with 65 liver‐only recurrences. Thirty of these patients received subsequent locoregional therapy. On multivariable analysis, locoregional therapy was associated with improved OS after isolated liver recurrence (HR 0.46, 95% CI 0.29–0.75; p = 0.002). In patients with locally advanced unresectable or multifocal liver disease (with or without distant organ metastases), PSM demonstrated improved hepatic progression‐free survival in patients treated with HAIP versus SYS (HR 0.65; 95% CI 0.46–0.91; p = 0.01), which correlated with improved OS (HR 0.59, 95% CI 0.43–0.80; p

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.

Abstract Background Disseminated disease (DD) is often found at (re-)exploration in gallbladder cancer (GBC) patients. We aimed to assess the yield of staging laparoscopy (SL) and identify predictors for DD. Methods This retrospective study included patients from all Dutch academic centres with primary GBC (pGBC) and incidentally diagnosed GBC (iGBC) planned for (re-)resection. The yield of SL was determined. In iGBC, predictive factors for DD were assessed. Results In total, 290 patients were included. Of 183 included pGBC patients, 143 underwent laparotomy without SL, and 42 (29%) showed DD perioperatively. SL, conducted in 40 patients, identified DD in eight. DD was found in nine of 32 patients who underwent laparotomy after SL. Of 107 included iGBC patients, 100 underwent laparotomy without SL, and 19 showed DD perioperatively. SL, conducted in seven patients, identified DD in one. Cholecystitis (OR = 4.25; 95% CI 1.51–11.91) and primary R1/R2 resection (OR = 3.94; 95% CI 1.39–11.19) were independent predictive factors for DD. Conclusions In pGBC patients, SL may identify DD in up to 20% of patients and should be part of standard management. In iGBC patients, SL is indicated after primary resection for cholecystitis and after initial R1/R2 resection due to the association of these factors with DD.

Summary: Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of −7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI −6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0–30.0] vs 23.0 [14.0–32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0–30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5–5.5] vs 5 [95% CI 4.7–5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67–1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Background: Floxuridine’s high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine. Methods: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed. Results: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472–0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470–0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463–0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257–0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation.The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %−37.8 %) over a period of 15 days (n = 18). Conclusion: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

Summary: Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p

Abstract Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin‐stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour–liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo‐naïve versus 67% for preoperatively treated patients (p 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

Background and study aims Accurate assessment of the lymph node (LN) status is crucial in resectable perihilar cholangiocarcinoma (pCCA) to prevent major surgery in patients with extraregional metastatic LNs (MLNs). This study investigates the added value of preoperative endoscopic ultrasound (EUS) with or without tissue acquisition (TA) for the detection of MLNs in patients with resectable pCCA. Patients and methods In this retrospective, multicenter cohort study, patients with potentially resectable pCCA who underwent EUS preoperatively between 2010–2020, were included. The clinical impact of EUS-TA was defined as the percentage of patients who did not undergo surgical resection due to MLNs found with EUS-TA. Findings of cross-sectional imaging were compared with EUS-TA findings and surgery. Results EUS was performed on 141 patients, of whom 107 (76 %) had suspicious LNs on cross-sectional imaging. Surgical exploration was prevented in 20 patients (14 %) because EUS-TA detected MLNs, of which 17 (85 %) were extraregional. Finally, 74 patients (52 %) underwent surgical exploration followed by complete resection in 40 (28 %). MLNs were identified at definitive pathology in 24 (33 %) patients, of which 9 (38 %) were extraregional and 15 (63 %) regional. Conclusions EUS-TA may be of value in patients with potentially resectable pCCA based on preoperative cross-sectional imaging, regardless of lymphadenopathy at cross-sectional imaging. A prospective study in which a comprehensive EUS investigation with LN assessment and EUS-TA of LNs is performed routinely should confirm this promise.

BackgroundThe diagnostic process of patients with suspect pancreatic lesions is often lengthy and prone to repeated diagnostic procedures due to inconclusive results. Targeted Next-Generation Sequencing (NGS) performed on cytological material obtained with fine needle aspiration (FNA) or biliary duct brushing can speed up this process. Here, we study the incremental value of NGS for establishing the correct diagnosis, and subsequent treatment plan in patients with inconclusive diagnosis after regular diagnostic work-up for suspect pancreatic lesions.MethodsIn this prospective cross-sectional cohort study, patients were screened for inclusion in four hospitals. NGS was performed with AmpliSeq Cancer Hotspot Panel v2 and v4b in patients with inconclusive cytology results or with an uncertain diagnosis. Diagnostic results were evaluated by the oncology pancreatic multidisciplinary team. The added value of NGS was determined by comparing diagnosis (malignancy, cystic lesion or benign condition) and proposed treatment plan (exploration/resection, neoadjuvant chemotherapy, follow-up, palliation or repeated FNA) before and after integration of NGS results. Final histopathological analysis or a 6-month follow-up period were used as the reference standard in case of surgical intervention or non-invasive treatment, respectively.ResultsIn 50 of the 53 included patients, cytology material was sufficient for NGS analysis. Diagnosis before and after integration of NGS results differed in 24% of the patients. The treatment plan was changed in 32% and the diagnosis was substantiated by the NGS data in 44%. Repetition of FNA/brushing was prevented in 14% of patients. All changes in treatment plan were correctly made after integration of NGS. Integration of NGS increased overall diagnostic accuracy from 68% to 94%.InterpretationThis study demonstrates the incremental diagnostic value of NGS in patients with an initial inconclusive diagnosis. Integration of NGS results can prevent repeated EUS/FNA, and can also rigorously change the final diagnosis and treatment plan.

Abstract Background Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP. Methods/design DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin ≥ 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-β), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively. Discussion The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting. Trial registration ISRCTN registry ISRCTN44897265 . Prospectively registered on 16 April 2018.

BackgroundBiomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS).MethodsSerum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX.ResultsPatients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25, P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14, P=0.010), IL-18 (HR 2.00, P=0.020), and MIP-1β (HR 0.51, P=0.025) after one cycle of FOLFIRINOX showed correlations with OS.ConclusionsCirculating IL-1RA, IL-7, IL-18, and MIP-1β concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.

Abstract Background Growing evidence for the advantages of robotic pancreatoduodenectomy (RPD) has been demonstrated internationally. However, there has been no structured training program for RPD in Japan. Herein, we present the surgical training model of RPD and a standardized protocol for surgical technique. Methods The surgical training model and surgical technique were standardized in order to implement RPD safely, based on the Dutch training system collaborated with the University of Pittsburgh Medical Center. Results The surgical training model included various trainings such as basic robotic training, simulation training, biotissue training, and a surgical video review. Furthermore, a standardized protocol on the surgical technique was established to understand the tips, tricks, and pitfalls of RPD. Conclusions Safe implementation of RPD can be achieved through the completion of a structured training program and learning surgical technique. A nationwide structured training system should be developed to implement the program safely in Japan.

BackgroundBiological sex, gender and age have an impact on the incidence and outcome in patients with metastatic pancreatic cancer. The aim of this study is to investigate whether biological sex, gender and age are associated with treatment allocation and overall survival (OS) of patients with metastatic pancreatic cancer in a nationwide cohort.MethodsPatients with synchronous metastatic pancreatic cancer diagnosed between 2015 and 2019 were selected from the Netherlands Cancer Registry (NCR). The association between biological sex and the probability of receiving systemic treatment were examined with multivariable logistic regression analyses. Kaplan Meier analyses with log-rank test were used to describe OS.ResultsA total of 7470 patients with metastatic pancreatic cancer were included in this study. Fourty-eight percent of patients were women. Women received less often systemic treatment (26% vs. 28%, P=0.03), as compared to men. Multivariable logistic regression analyses with adjustment for confounders showed that women ≤55 years of age, received more often systemic treatment (OR 1.82, 95% CI 1.24-2.68) compared to men of the same age group. In contrast, women at >55 years of age had a comparable probability to receive systemic treatment compared to men of the same age groups. After adjustment for confounders, women had longer OS compared to men (HR 0.89, 95% CI 0.84-0.93).ConclusionThis study found that women in general had a lower probability of receiving systemic treatment compared to men, but this can mainly be explained by age differences. Women had better OS compared to men after adjustment for confounders.

Background and AimsFailing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients’ body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC.MethodsPatients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected.ResultsA total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (≥900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes.ConclusionThis study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients’ survival outcomes.

Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control ( n = 30) or progressive disease ( n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.

Abstract Aim Evidence of nutritional therapies in pancreatoduodenectomy (PD) has been shown. However, few studies focus on the association between different nutritional therapies and outcomes. The aim of this review was to summarize the current evidence of nutritional therapies such as enteral nutrition (EN), immunonutrition, and synbiotics on postoperative outcomes after PD. Methods A systematic literature search of Embase, Medline Ovid, and Cochrane CENTRAL was done to summarize the available evidence, including randomized controlled trials, meta‐analyses and reviews, regarding nutritional therapy in PD. Results A total of 20 randomized controlled trials were included in this review. Safety and tolerability of EN in PD was shown. Giving postoperative EN can shorten length of stay compared to parenteral nutrition; however, the effect of EN on postoperative complications remains controversial. Postoperative EN should be given only on selective indications rather than routinely used, and preoperative EN is indicated only in patients with severe malnutrition. Giving preoperative immunonutrition is considered to reduce the incidence of infectious complications; however, evidence level is moderate and recommendation grade is weak. The beneficial effect of perioperative synbiotics on postoperative infectious complications is limited. Furthermore, the effectiveness of other nutritional supplements remains unclear. Conclusion Recently, evidence of enhanced recovery after surgery (ERAS) in PD has been increasing. Early oral intake with systematic nutritional support is an important aspect of the ERAS concept. Future well‐designed studies should investigate the impact of systematic nutritional therapies on outcomes following PD.

Introduction: There is a pressing demand for the development of cancer-specific diagnostic imaging tools, particularly for staging of pancreatic-, gastric- or cholangiocarcinoma, as current diagnostic imaging techniques, including CT, MRI and PET using FDG, are not fully adequate. The novel PET-tracer “FAPI” has the potential to visualize even small tumour deposits employing the tumour-specific expression of fibroblast-activating protein (FAP) in malignant cells. Methods: We performed a systematic review to select studies investigating the use of FAPI PET for staging pancreatic-, gastric- and cholangiocarcinoma (PROSPERO CRD42022329512). Patient-wise and lesion-wise comparisons were performed for primary tumour (T), lymph nodes (N), organ metastases (M) and peritoneal carcinomatosis (PC). Maximum standardized uptake values (SUVmax) and tumour-to-background ratios (TBR) were compared between PET using FAPI versus FDG (if reported). Results: Ten articles met the inclusion criteria. In all studies, FAPI PET showed superiority over FDG-PET/CT/MRI for the detection of T, N, M and PC, both in the patient-wise and in lesion-wise comparisons (when performed). Additionally, higher SUVmax and TBRmax values were reported for use of FAPI compared to FDG. Conclusions: The positive results of this review warrant prospective clinical studies to investigate the accuracy and clinical value of FAPI PET for diagnosing and staging patients with pancreatic-, gastric- and cholangiocarcinoma.

Approximately 20% of pancreatic ductal adenocarcinoma (PDAC) patients have (borderline) resectable pancreatic cancer [(B)RPC] at diagnosis. Upfront resection with adjuvant chemotherapy has long been the standard of care for these patients. However, although surgical quality has improved, still about 50% of patients never receive adjuvant treatment. Therefore, recent developments have focused on a neoadjuvant approach. Directly comparing results from neoadjuvant and adjuvant regimens is challenging due to differences in patient populations that influence outcomes. Neoadjuvant trials include all patients who have (B)RPC on imaging, while adjuvant-only trials include patients who underwent a complete resection and recovered to a good performance status without any evidence of residual disease. Guidelines recommend neoadjuvant treatment for BRPC patients mainly to improve negative resection margin (R0) rates. For resectable PDAC, upfront resection is still considered the standard of care. However, theoretical advantages of neoadjuvant treatment, including the increased R0 resection rate, early delivery of systemic therapy to all patients, directly addressing occult metastatic disease, and improved patient selection for resection, may also apply to these patients. A systematic review by intention-to-treat showed a superior median overall survival (OS) for any neoadjuvant approach (19 months) compared to upfront surgery (15 months) in (B)RPC patients. A neoadjuvant approach was recently supported by three randomized controlled trials (RCTs). For resectable PDAC, neoadjuvant treatment was superior in a Japanese RCT of neoadjuvant gemcitabine with S-1 vs. upfront surgery, with adjuvant S-1 in both arms (median OS: 37 vs. 27 months, p = 0.015). A Korean trial of neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront resection in BRPC patients was terminated early due to superiority of the neoadjuvant group (median OS: 21 vs. 12 months, p = 0.028; R0 resection: 52 vs. 26%, p = 0.004). The PREOPANC-1 trial for (B)RPC patients also showed favorable outcome for neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront surgery (median OS: 17 vs. 14 months, p = 0.07; R0 resection: 63 vs. 31%, p < 0.001). FOLFIRINOX is likely a better neoadjuvant regimen, because of superiority compared to gemcitabine in both the metastatic and adjuvant setting. Currently, five RCTs evaluating neoadjuvant modified or fulldose FOLFIRINOX are accruing patients.

Abstract Background Data from observational studies suggest that minimally invasive pancreatoduodenectomy (MIPD) is superior to open pancreatoduodenectomy regarding intraoperative blood loss, postoperative morbidity, and length of hospital stay, without increasing total costs. However, several case-matched studies failed to demonstrate superiority of MIPD, and large registry studies from the USA even suggested increased mortality for MIPDs performed in low-volume (

In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.

Abstract Background Observational cohort studies have suggested that minimally invasive distal pancreatectomy (MIDP) is associated with better short-term outcomes compared with open distal pancreatectomy (ODP), such as less intraoperative blood loss, lower morbidity, shorter length of hospital stay, and reduced total costs. Confounding by indication has probably influenced these findings, given that case-matched studies failed to confirm the superiority of MIDP. This accentuates the need for multicenter randomized controlled trials, which are currently lacking. We hypothesize that time to functional recovery is shorter after MIDP compared with ODP even in an enhanced recovery setting. Methods LEOPARD is a randomized controlled, parallel-group, patient-blinded, multicenter, superiority trial in all 17 centers of the Dutch Pancreatic Cancer Group. A total of 102 patients with symptomatic benign, premalignant or malignant disease will be randomly allocated to undergo MIDP or ODP in an enhanced recovery setting. The primary outcome is time (days) to functional recovery, defined as all of the following: independently mobile at the preoperative level, sufficient pain control with oral medication alone, ability to maintain sufficient (i.e. >50%) daily required caloric intake, no intravenous fluid administration and no signs of infection. Secondary outcomes are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life and costs. Discussion The LEOPARD trial is designed to investigate whether MIDP reduces the time to functional recovery compared with ODP in an enhanced recovery setting. Trial registration Dutch Trial Register, NTR5188 . Registered on 9 April 2015

Low skeletal muscle mass is associated with poor postoperative outcomes in cancer patients. Furthermore, it is associated with increased healthcare costs in the United States. We investigated its effect on hospital expenditure in a Western-European healthcare system, with universal access.Skeletal muscle mass (assessed on CT) and costs were obtained for patients who underwent curative-intent abdominal cancer surgery. Low skeletal muscle mass was defined based on pre-established cut-offs. The relationship between low skeletal muscle mass and hospital costs was assessed using linear regression analysis and Mann-Whitney U-tests.452 patients were included (median age 65, 61.5% males). Patients underwent surgery for colorectal cancer (38.9%), colorectal liver metastases (27.4%), primary liver tumours (23.2%), and pancreatic/periampullary cancer (10.4%). In total, 45.6% had sarcopenia. Median costs were €2,183 higher in patients with low compared with patients with high skeletal muscle mass (€17,144 versus €14,961; P