Search

Background Treatment outcomes of incidental gallbladder cancer generally stem from tertiary referral centres, while many patients are initially diagnosed and managed in secondary care centres. Referral patterns of patients with incidental gallbladder cancer are poorly reported. This study aimed to evaluate incidental gallbladder cancer treatment in secondary centres, rates of referral to tertiary centres and its impact on survival. Methods Medical records of patients with incidental gallbladder cancer diagnosed between 2000 and 2019 in 27 Dutch secondary centres were retrospectively reviewed. Patient characteristics, surgical treatment, tumour characteristics, referral pattern and survival were assessed. Predictors for overall survival were determined using multivariable Cox regression. Results In total, 382 patients with incidental gallbladder cancer were included. Of 243 patients eligible for re-resection (pT1b–pT3, M0), 131 (53.9%) were referred to a tertiary centre. The reason not to refer, despite indication for re-resection, was not documented for 52 of 112 non-referred patients (46.4%). In total, 98 patients underwent additional surgery with curative intent (40.3%), 12 of these in the secondary centre. Median overall survival was 33 months (95% c.i. 24 to 42 months) in referred patients versus 17 months (95% c.i. 3 to 31 months) in the non-referred group (P = 0.019). Referral to a tertiary centre was independently associated with improved survival after correction for age, ASA classification, tumour stage and resection margin (HR 0.60, 95% c.i. 0.38 to 0.97; P = 0.037). Conclusion Poor incidental gallbladder cancer referral rates were associated with worse survival. Age, performance status, resection margin or tumour stage should not preclude referral of a patient with incidental gallbladder cancer to a tertiary centre. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-targeting therapeutics have shown efficacy in the treatment of colorectal cancer patients. Clinical studies have revealed that activating mutations in the KRAS protooncogene predict resistance to EGFR-targeted therapy. However, the causality between mutant KRAS and resistance to EGFR inhibition has so far not been demonstrated. Here, we show that deletion of the oncogenic KRAS allele from colorectal tumor cells resensitizes those cells to EGFR inhibitors. Resensitization was accompanied by an acquired dependency on the EGFR for maintaining basal extracellular signal-regulated kinase (ERK) activity. Deletion of oncogenic KRAS not only resensitized tumor cells to EGFR inhibition but also promoted EGF-induced NRAS activation, ERK and AKT phosphorylation, and c-FOS transcription. The poor responsiveness of mutant KRAS tumor cells to EGFR inhibition and activation was accompanied by a reduced capacity of these cells to bind and internalize EGF and by a failure to retain EGFR at the plasma membrane. Of 16 human colorectal tumors with activating mutations in KRAS, 15 displayed loss of basolateral EGFR localization. Plasma membrane localization of the EGFR could be restored in vitro by suppressing receptor endocytosis through Rho kinase inhibition. This caused an EGFR-dependent increase in basal and EGF-stimulated ERK phosphorylation but failed to restore tumor cell sensitivity to EGFR inhibition. Our results demonstrate a causal role for oncogenic KRAS in desensitizing tumor cells not only to EGFR inhibitors but also to EGF itself. [ABSTRACT FROM AUTHOR]

Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling. Methods: K-ras mutant colorectal tumor cell lines C26, HCT116 and L169 were used. K-ras or components of the MEK/ERK and p38 pathway were suppressed by RNA interference (RNAi). MEK was inhibited by U0126. p38 was inhibited by SB203850. Results: MEK inhibition, or suppression of MEK1/2 or ERK1/2 by RNA interference, reduced the proliferation rate of all colorectal cancer cell lines. However, cell proliferation returned to normal after two weeks of chronic inhibition, despite the continued suppression of MEK or ERK. In contrast, K-ras-suppressed tumor cells entered an irreversible senescent-like state following ERK pathway inhibition. MEK inhibition or ERK1/2 suppression caused activation of p38α in a K-ras-dependent manner. Inhibition or suppression of p38α prevented the recovery of K-ras mutant tumor cells during prolonged MEK inhibition. Conclusion: Oncogenic K-ras activates p38α to maintain cell proliferation during MEK inhibition. MEK-targeting therapeutics can create an acquired tumor cell dependency on p38α. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BrCa) is a predominant malignancy, with metastasis occurring in one in eight patients, nearly half of which target the bone, leading to serious complications such as pain, fractures, and compromised mobility. Structural rigidity, crucial for bone strength, becomes compromised with osteolytic lesions, highlighting the vulnerability and increased fracture risk in affected areas. Historically, two-dimensional radiographs have been employed to predict these fracture risks; however, their limitations in capturing the three-dimensional structural and material changes in bone have raised concerns. Recent advances in CT-based Structural Rigidity Analysis (CTRA), offer a promising, more accurate non-invasive 3D approach. This study aims to assess the efficacy of CTRA in monitoring osteolytic lesions' progression and response to therapy, suggesting its potential superiority over existing methodologies in guiding treatment strategies., Methods: Twenty-seven female nude rats underwent femoral intra-medullary inoculation with MDA-MB-231 human breast cancer cells or saline control. They were divided into Control, Cancer Control, Ibandronate, and Paclitaxel groups. Osteolytic progression was monitored weekly using biplanar radiography, quantitative computed tomography (QCT), and dual-energy X-ray absorptiometry (DEXA). CTRA was employed to predict fracture risk, normalized using the contralateral femur. Statistical analyses, including Kruskal-Wallis and ANOVA, assessed differences in outcomes among groups and over time., Results: Biplanar radiographs showed treatment benefits over time; however, only certain time-specific differences between the Control and other treatment groups were discernible. Notably, observer subjectivity in X-ray scoring became evident, with significant inter-operator variations. DEXA measurements for metaphyseal Bone Mineral Content (BMC) did not exhibit notable differences between groups. Although diaphyseal BMC highlighted some variance, it did not reveal significant differences between treatments at specific time points, suggesting a limited ability for DEXA to differentiate between treatment effects. In contrast, the CTRA consistently demonstrated variations across different treatments, effectively capturing bone rigidity changes over time, and the axial- (EA), bending- (EI), and torsional rigidity (GJ) outcomes from the CTRA method successfully distinguished differences among treatments at specific time points., Conclusion: Traditional approaches, such as biplanar radiographs and DEXA, have exhibited inherent limitations, notably observer bias and time-specific inefficacies. Our study accentuates the capability of CTRA in capturing real-time, progressive changes in bone structure, with the potential to predict fractures more accurately and provide a more objective analysis. Ultimately, this innovative approach may bridge the existing gap in clinical guidelines, ushering in enhanced Clinical Decision Support Tool (CDST) for both surgical and non-surgical treatments., (© 2024. The Author(s).)

Background: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB., Methods: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan., Results: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions., Discussion: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors., (Copyright © 2024 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Treatment outcomes of incidental gallbladder cancer generally stem from tertiary referral centres, while many patients are initially diagnosed and managed in secondary care centres. Referral patterns of patients with incidental gallbladder cancer are poorly reported. This study aimed to evaluate incidental gallbladder cancer treatment in secondary centres, rates of referral to tertiary centres and its impact on survival., Methods: Medical records of patients with incidental gallbladder cancer diagnosed between 2000 and 2019 in 27 Dutch secondary centres were retrospectively reviewed. Patient characteristics, surgical treatment, tumour characteristics, referral pattern and survival were assessed. Predictors for overall survival were determined using multivariable Cox regression., Results: In total, 382 patients with incidental gallbladder cancer were included. Of 243 patients eligible for re-resection (pT1b-pT3, M0), 131 (53.9%) were referred to a tertiary centre. The reason not to refer, despite indication for re-resection, was not documented for 52 of 112 non-referred patients (46.4%). In total, 98 patients underwent additional surgery with curative intent (40.3%), 12 of these in the secondary centre. Median overall survival was 33 months (95% c.i. 24 to 42 months) in referred patients versus 17 months (95% c.i. 3 to 31 months) in the non-referred group (P = 0.019). Referral to a tertiary centre was independently associated with improved survival after correction for age, ASA classification, tumour stage and resection margin (HR 0.60, 95% c.i. 0.38 to 0.97; P = 0.037)., Conclusion: Poor incidental gallbladder cancer referral rates were associated with worse survival. Age, performance status, resection margin or tumour stage should not preclude referral of a patient with incidental gallbladder cancer to a tertiary centre., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Objectives: Patients with pancreatic disease(s) have a high risk of developing diabetes mellitus (DM). Diabetes mellitus is associated with adverse postoperative outcomes. This study aimed to investigate the prevalence and effects of DM on postoperative outcomes in pancreatic surgery., Methods: Subgroup analysis of a prospective cohort study conducted at an academic hospital. Patients undergoing pancreatoduodenectomy between January 2019 and November 2022 were included and screened for DM preoperatively using glycated hemoglobin (HbA1c). New-onset DM was diagnosed based on HbA1c ≥ 6.5% (48 mmol/mol). Postoperative outcomes were compared between patients with and without DM., Results: From 117 patients, 29 (24.8%) were given a diagnosis of DM, and of those, 5 (17.2%) were diagnosed with new-onset DM, and 15 (51.8%) displayed poorly controlled preoperative DM (HbA 1c ≥ 7% [53 mmol/mol]). The incidence of surgical site infections (48.3% vs 27.3% in the non-DM group; P = 0.04) was higher for patients with DM. This association remained significant after adjusting for confounders (odds ratio, 2.60 [95% confidence interval, 1.03-6.66]; P = 0.04)., Conclusions: One-quarter of the patients scheduled for pancreatoduodenectomy had DM; over half of them had poor glycemic control. The association between DM status and surgical site infections revealed in this study emphasizes the importance of adequate preoperative glycemic control., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Most data on the treatment and outcomes of intrahepatic cholangiocarcinoma (iCCA) derives from expert centers. This study aimed to investigate the treatment and outcomes of all patients diagnosed with iCCA in a nationwide cohort., Methods: Data on all patients diagnosed with iCCA between 2010 and 2018 were obtained from the Netherlands Cancer Registry., Results: In total, 1747 patients diagnosed with iCCA were included. Resection was performed in 292 patients (17%), 548 patients (31%) underwent palliative systemic treatment, and 867 patients (50%) best supportive care (BSC). The OS median and 1-, and 3-year OS were after resection: 37.5 months (31.0-44.0), 79.2%, and 51.6%,; with systemic therapy, 10.0 months (9.2-10.8), 38.4%, and 5.1%, and with BSC 2.2 months (2.0-2.5), 10.4%, and 1.3% respectively. The resection rate for patients who first presented in academic centers was 33% (96/292) compared to 13% (195/1454) in non-academic centers (P < 0.001)., Discussion: Half of almost 1750 patients with iCCA over an 8 year period did not receive any treatment with a 1-year OS of 10.4%. Three-year survival was about 50% after resection, while long-term survival was rare after palliative treatment. The resection rate was higher in academic centers compared to non-academic centers., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of prehabilitation is to improve postoperative outcomes by increasing patients' resilience against the stress of surgery. This study investigates the effect of personalized multimodal prehabilitation on patients undergoing pancreatoduodenectomy., Methods: Included patients were screened for six modifiable risk factors: (1) low physical fitness, (2) malnutrition, (3) low mental resilience, (4) anemia and hyperglycemia, (5) frailty, and (6) substance abuse. Interventions were performed as needed. Using 1:1 propensity score matching (PSM), patients were compared to a historical cohort., Results: From 120 patients, 77 (64.2%) performed a cardiopulmonary exercise test to assess their physical fitness and provide them with a preoperative training advice. Furthermore, 88 (73.3%) patients received nutritional support, 15 (12.5%) mental support, 17 (14.2%) iron supplementation to correct for iron deficiency, 18 (15%) regulation support for hyperglycemia, 14 (11.7%) a comprehensive geriatric assessment, and 19 (15.8%) substance abuse support. Of all patients, 63% required ≥2 prehabilitation interventions. Fewer cardiopulmonary complications were observed in the prehabilitation cohort (9.2% versus 23.3%; p = 0.002). In surgical outcomes and length of stay no differences were observed., Conclusion: Our prehabilitation program is effective in detecting risk factors in patients; most patients required multiple interventions. Consequently, a reduction in cardiopulmonary complications was observed., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Currently, no practical definition of potentially resectable, borderline or unresectable perihilar cholangiocarcinoma (pCCA) is available. Aim of this study was to define criteria to categorize patients for use in a future neoadjuvant or induction therapy study., Method: Using the modified DELPHI method, hepatobiliary surgeons from all tertiary referral centers in the Netherlands were invited to participate in this study. During five online meetings, predefined factors determining resectability and additional factors regarding surgical resectability and operability were discussed., Results: The five online meetings resulted in 52 statements. After two surveys, consensus was reached in 63% of the questions. The main consensus included a definition regarding potential resectability. 1) Clearly resectable: no vascular involvement (≤90°) of the future liver remnant (FLR) and expected feasibility of radical biliary resection. 2) Clearly unresectable: non-reconstructable venous and/or arterial involvement of the FLR or no feasible radical biliary resection. 3) Borderline resectable: all patients between clearly resectable and clearly unresectable disease., Conclusion: This DELPHI study resulted in a practical and applicable resectability, or more accurate, an explorability classification, which can be used to categorize patients for use in future neoadjuvant therapy studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lynn Nooijen reports financial support was provided by Amsterdam Gastroenterology Endocrinology Metabolism., (© 2023 Published by Elsevier Ltd.)

Background: Evaluation of morbidity and mortality after hepatic resection often lacks stratification by extent of resection or diagnosis. Although a liver resection for different indications may have technical similarities, postoperative outcomes differ. The aim of this systematic review and meta-analysis was to determine the risk of major complications and mortality after resection of intrahepatic cholangiocarcinoma., Methods: Meta-analysis was performed to assess postoperative mortality (in-hospital, 30-, and 90-day) and major complications (Clavien-Dindo grade ≥III)., Results: A total of 32 studies that reported on 19,503 patients were included. Pooled in-hospital, 30-day, and 90-day mortality were 5.9% (95% confidence interval 4.1-8.4); 4.6% (95% confidence interval 4.0-5.2); and 6.1% (95% confidence interval 5.0-7.3), respectively. Pooled proportion of major complications was 22.2% (95% confidence interval 17.7-27.5) for all resections. The pooled 90-day mortality was 3.1% (95% confidence interval 1.8-5.2) for a minor resection, 7.4% (95% confidence interval 5.9-9.3) for all major resections, and 11.4% (95% confidence interval 6.9-18.7) for extended resections (P = .001). Major complications were 38.8% (95% confidence interval 29.5-49) after a major hepatectomy compared to 11.3% (95% confidence interval 5.0-24.0) after a minor hepatectomy (P = .001). Asian studies had a pooled 90-day mortality of 4.4% (95% confidence interval 3.3-5.9) compared to 6.8% (95% confidence interval 5.6-8.2) for Western studies (P = .02). Cohorts with patients included before 2000 had a pooled 90-day mortality of 5.9% (95% confidence interval 4.8-7.3) compared to 6.8% (95% confidence interval 5.1-9.1) after 2000 (P = .44)., Conclusion: When informing patients or comparing outcomes across hospitals, postoperative mortality rates after liver resection should be reported for 90-days with consideration of the diagnosis and the extent of liver resection., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/purpose: Intraductal papillary neoplasm of the bile duct (IPNB) is a rare disease in Western countries. The main aim of this study was to characterize current surgical strategies and outcomes in the mainly European participating centers., Methods: A multi-institutional retrospective series of patients with a diagnosis of IPNB undergoing surgery between 1 January 2010 and 31 December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association. The textbook outcome (TO) was defined as a non-prolonged length of hospital stay plus the absence of any Clavien-Dindo grade at least III complications, readmission, or mortality within 90 postoperative days., Results: A total of 28 centers contributed 85 patients who underwent surgery for IPNB. The median age was 66 years (55-72), 49.4% were women, and 87.1% were Caucasian. Open surgery was performed in 72 patients (84.7%) and laparoscopic in 13 (15.3%). TO was achieved in 54.1% of patients, reaching 63.8% after liver resection and 32.0% after pancreas resection. Median overall survival was 5.72 years, with 5-year overall survival of 63% (95% CI: 50-82). Overall survival was better in patients with Charlson comorbidity score 4 or less versus more than 4 ( P =0.016), intrahepatic versus extrahepatic tumor ( P =0.027), single versus multiple tumors ( P =0.007), those who underwent hepatic versus pancreatic resection ( P =0.017), or achieved versus failed TO ( P =0.029). Multivariable Cox regression analysis showed that not achieving TO (HR: 4.20; 95% CI: 1.11-15.94; P =0.03) was an independent prognostic factor of poor overall survival., Conclusions: Patients undergoing liver resection for IPNB were more likely to achieve a TO outcome than those requiring a pancreatic resection. Comorbidity, tumor location, and tumor multiplicity influenced overall survival. TO was an independent prognostic factor of overall survival., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions., Methods: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases., Results: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001)., Conclusion: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients' postoperative course negatively., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons., Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC., Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers., Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001)., Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surgical resection is the only potentially curative treatment for pancreatic neuroendocrine tumors. The choice for the type of procedure is influenced by the expected oncological benefit and the anticipated risk of procedure-specific complications. Few studies have focused on complications in these patients. This cohort study aimed to assess complications and risk factors after resections of pancreatic neuroendocrine tumors., Methods: Patients undergoing resection of a pancreatic neuroendocrine tumor were identified within 2 centers of excellence. Complications were assessed according to the Clavien-Dindo classification and the comprehensive complication index. Logistic regression was performed to compare surgical procedures with adjustment for potential confounders (Clavien-Dindo ≥3)., Results: The cohort comprised 123 patients, including 12 enucleations, 50 distal pancreatectomies, 51 pancreatoduodenectomies, and 10 total/combined pancreatectomies. Mortality was 0.8%, a severe complication occurred in 41.5%, and the failure-to-rescue rate was 2.0%. The median comprehensive complication index was 22.6 (0-100); the comprehensive complication index increased after more extensive resections. After adjustment, a pancreatoduodenectomy, as compared to a distal pancreatectomy, increased the risk for a severe complication (odds ratio 3.13 [95% confidence interval 1.32-7.41]). Of the patients with multiple endocrine neoplasia type 1 or von Hippel-Lindau, 51.9% developed a severe complication vs 38.5% with sporadic disease. After major resections, morbidity was significantly higher in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau (comprehensive complication index 45.1 vs 28.9, P = .029)., Conclusion: Surgery for pancreatic neuroendocrine tumors is associated with a high rate of complications but low failure-to-rescue in centers of excellence. Complications are procedure-specific. Major resections in patients with multiple endocrine neoplasia type 1/von Hippel-Lindau appear to increase the risk of complications., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors., Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence., Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80)., Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic., Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave., Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37)., Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making., Lay Summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes., Competing Interests: SM.-M.: Speaker fees from Bayer and travel funding from 10.13039/100004326Bayer and 10.13039/501100014382Eisai. V.S.: Travel grants from 10.13039/100004326Bayer. A.F.: Lecture fees from Bayer, Gilead and MSD; consultancy fees from Bayer, AstraZeneca, Roche and Guerbert. J-C.N.: Received research grant from 10.13039/100004326Bayer for Inserm UMR1138. L.R.: Reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, 10.13039/100004325AstraZeneca, BeiGene, 10.13039/501100003769Eisai, 10.13039/100010544Exelixis, 10.13039/100006591Fibrogen, Incyte, 10.13039/501100014382Ipsen, 10.13039/100004312Lilly, 10.13039/100007054MSD, 10.13039/100004337Roche. B.S.: Reports consultancy fees from Adaptimmune, AstraZeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; and research grants from 10.13039/100002491BMS and Sirtex Medical. J. Bruix: Consultancy: AbbVie, ArQule, Astra, Basilea, Bayer, BMS, Daiichi Sankyo, GlaxoSmithKline, Gilead, Kowa, Lilly, Medimune, Novartis, Onxeo, Polaris, Quirem, Roche, Sanofi-Aventis, Sirtex, Terumo/Grants: 10.13039/100004326Bayer and 10.13039/501100014382Ipsen. M.S.Z.: Received speaker fees and travel grants from 10.13039/100004326Bayer and 10.13039/100014869BTG, 10.13039/100007054MSD. M.B.: Consultant and Advisory Board for: Bayer Pharma, Ipsen, BMS, Eisai, Roche, AstraZeneca, Sirtex Medical. D.J.P.: Received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and AstraZeneca; received research funding (to institution) from MSD and BMS. T.M.: Consultancy: Eisai, Roche, BTG, Ipsen, Bayer, Adaptimmune. Research funding: Bayer, BTG. H.W.: Served as speaker for Bayer, Eisai, and Ipsen, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. B.M.: Consultancy: Bayer-Shering Pharma /Speaker fees: Eisai, MSDG. C. Consultancy fees from Bayer, Ipsen. P.R.G.: Bayer, BMS, MSD, AstraZeneca, Adaptimmune, Sirtex, Lilly Ipsen, Roche, Eisai. M.R.A.S.: Has received Research grants, advisory board or speaker fees for 10.13039/100006483AbbVie, 10.13039/100004326Bayer, Biolab, Intercept, 10.13039/501100014382Ipsen, 10.13039/100008799Gilead, 10.13039/100009947MSD, 10.13039/100004336Novartis, and 10.13039/100004337Roche. J.T.: Has received research grants from 10.13039/100004337Roche and 10.13039/501100014382Ipsen. He has received speaker and consulting honoraria from AstraZeneca, Amgen, Bayer Healthcare, Bristol Myers-Squibb, Eisai, Ipsen, Merck Serono, Merck Sharp & Dome, Lilly Imclone, and Roche. J. Bridgewater: Consultancy Bayer, BMS, Incyte, Taiho, Roche, MSD and Merck Serono. Research funding from Incyte. G.C.: Consultancy fees from Bayer, Ipsen. A.L.: Consultancy CAScination, Advisory Board Neuwave and Histosonics. H.T.: Speaker fees from AbbVie, Gilead, MSD, and Bayer. R.V.: Research grant from 10.13039/100006483Abbvie. A.M.M.P.: Speaker honorarium from Bayer, BMS, Boston Scientific and EISAI. Consulting honorarium from Bayer, AstraZeneca and EISAI. Advisory honorarium from Bayer, AstraZeneca and EISAI. Grants from 10.13039/100004326Bayer and 10.13039/100008497Boston Scientific. M.D.: Has received consulting and training fees from Bayer and Eisai. B.B.: Reports Consultancy for GenMab (paid to Institution); Advisory Boards for Roche (paid to Institution), Eisai Europe Limited (paid to Institution), research grant from 10.13039/100006436Celgene Ltd (paid to Institution), Speakers Bureau for Eisai Europe Limited (paid to Institution), Travel and registration for Congress from Bayer. L.d.F.: Lectures fees from BMS, Roche and Bayer. B.M.M.: Advisory/Speaker: Amgen, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Merck, Roche, Sanoffi Genzyme, Taiho. Expert Testimony: Eisai, Roche. Travel: Eisai, Merck. Research: Sillajen (Individual); AstraZeneca, H3/Eisai, Galera, GSK, Exelixis (Institution). M.S.: Travel/ accommodation/meeting expenses: Bayer. Eisai. Speaker fees: Bayer. C.R.L.: Travel grants from 10.13039/100004326Bayer. M.R-G.: Reports grants from Intercept, grants from 10.13039/100005564Gilead-Sciences, personal fees from Shionogi, personal fees from Alfa-Wasserman, personal fees from Prosciento, personal fees from Kaleido, personal fees from Novonrdisk, personal fees from MSD, personal fees from BMS, personal fees from Allergan, personal fees from Boehriger-Ingelheim, personal fees from Zydus, personal fees from Intercept Pharma, personal fees from Gilead-Sciences, outside the submitted work. F.P.: Disclosures: Received speaker honoraria from Bayer, Roche, LKM-Biotoscana, RAFFO. Research Grants from INC Argentinean 10.13039/100013137National Institute of Corrections, 10.13039/100004337Roche. V.M.: Lectures sponsored by Bayer. G.B.: Advisory board Eli-Lilly and Incyte. M. Vergara: Travel grants from 10.13039/100004326Bayer, 10.13039/100008799Gilead, 10.13039/100009947MSD and 10.13039/100006483Abbvie. Lectures sponsored by Gilead, Abbvie, Intercept, and MSD. M.L.: Lectures and educational presentations: Abbvie. Travel/accommodation, meeting expenses covered by Bayer, Gilead, Abbvie. M.I.: Received speaker honoraria from Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, EISAI, and was consultant for BTG-Boston Scientific, Bayer, and Guerbet. M.R.: Consultancy: Bayer-Schering Pharma, BMS, Roche, Ipsen, AstraZeneca, Lilly, BTG/Paid conferences: Bayer-Schering Pharma, BMS, Gilead, Lilly/Research Grants: 10.13039/100004326Bayer-Schering Pharma, 10.13039/501100014382Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Purpose: To determine diagnostic performance of preoperative CT in differentiating between benign and malignant suspicious gallbladder lesions and to develop a preoperative risk score., Method: All patients referred between January 2007 and September 2018 for suspicion of gallbladder cancer (GBC) or incidentally found GBC were retrospectively analyzed. Patients were excluded when preoperative CT or histopathologic examination was lacking. Two radiologists, blinded to histopathology results, independently reviewed CT images to differentiate benign disease from GBC. Multivariable analysis and internal validation were used to develop a risk score for GBC. Model discrimination, calibration, and diagnostic performance were assessed., Results: In total, 118 patients with 39 malignant (33 %) and 79 benign (67 %) lesions were included. Sensitivity of CT for diagnosing GBC was 90 % (95 % confidence interval [CI]: 76-97). Specificity rates were 61 % (95 % CI: 49-72) and 59 % (95 % CI: 48-70). Three predictors of GBC (irregular lesion aspect, absence of fat stranding, and locoregional lymphadenopathy) were included in the risk score ranging from -1 to 4. Adequate performance was found (AUC: 0.79, calibration slope: 0.89). In patients allocated >0 points, the model showed higher performance in excluding GBC than the radiologists (sensitivity 92 % [95 % CI: 79-98]). Moreover, when allocated >3 points, the risk score was superior in diagnosing GBC (specificity 99 % [95 % CI: 93-100])., Conclusions: Sensitivity rates of CT for differentiation between benign and malignant gallbladder lesions are high, however specificity rates are relatively low. The proposed risk score may facilitate differentiation between benign and malignant suspicious gallbladder lesions., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs., Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size., Results: In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3-160) and 21 (4-200) mm, respectively. Mean bias between radiological and pathological tumor size was -0.2 mm and LoA ranged from -12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from -9.6 to 10.9, -15.9 to 15.8, and -13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively., Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality., (© 2020 S. Karger AG, Basel.)

Background: Hepatopancreatoduodenectomy (HPD) is an aggressive operation for treatment of advanced bile duct and gallbladder cancer associated with high perioperative morbidity and mortality, and uncertain oncological benefit in terms of survival. Few reports on HPD from Western centers exist. The purpose of this study was to evaluate safety and efficacy for HPD in European centers., Method: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients operated with HPD for bile duct or gallbladder cancer between January 2003 and January 2018. The patient and tumor characteristics, perioperative and survival outcomes were analyzed., Results: In total, 66 patients from 19 European centers were included in the analysis. 90-day mortality rate was 17% and 13% for bile duct and gallbladder cancer respectively. All factors predictive of perioperative mortality were patient and disease-specific. The three-year overall survival excluding 90-day mortality was 80% for bile duct and 30% for gallbladder cancer (P = 0.013). In multivariable analysis R0-resection had a significant impact on overall survival., Conclusion: HPD, although being associated with substantial perioperative mortality, can offer a survival benefit in patient subgroups with bile duct cancer and gallbladder cancer. To achieve negative resection margins is paramount for an improved survival outcome., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off ≥0.2mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size ≥3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p < 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Background: The peritoneal cancer index (PCI) calculated during exploratory laparotomy is a strong prognostic factor for overall survival (OS) in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Progression of the PCI between diagnostic laparoscopy (DLS) and potential CRS + HIPEC (ΔPCI) might be a more dynamic prognostic factor for OS after CRS + HIPEC., Materials and Methods: Between 2012 and 2018, all colorectal PM patients who underwent an exploratory laparotomy for potential CRS + HIPEC after DLS were retrospectively identified from a prospectively maintained database. Patients were divided into stable disease (ΔPCI 0-3), mild progression (ΔPCI 4-9), or severe progression (ΔPCI ≥10). Kaplan-Meier analysis and a multivariate Cox regression were performed., Results: Eighty-four patients (ΔPCI 0-3, n = 35; ΔPCI 4-9, n = 34; and ΔPCI ≥10, n = 15) were analysed. Median OS after CRS + HIPEC was significantly decreased in patients with a ΔPCI of 4-9 (35.1 [95% CI 25.5-44.6]) or ΔPCI ≥10 (24.1 [95% CI 11.7-36.5]) compared to patients with a ΔPCI of 0-3 (47.9 [95% CI 40.0-55.7], p = 0.004). In multivariate regression analysis, ΔPCI remained an independent risk factor for OS: ΔPCI 4-9 HR 3.1 (95% CI 1.4-7.2, p = 0.007) and ΔPCI ≥10 HR 4.4 (95% CI 1.5-13.1, p = 0.007)., Conclusion: A high ΔPCI is an independent dynamic prognostic factor for OS and might reflect a more aggressive tumour biology in patients with colorectal PM. HIPEC surgeons should be aware of a high-ΔPCI-associated diminished prognosis and should reconsider CRS + HIPEC when confronted with a ΔPCI ≥10., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)