The Relevance of Radial Margin Status in Perihilar Cholangiocarcinoma: A State-of-the-Art Narrative Review.

BACKGROUND: Prognosis of perihilar cholangiocarcinoma (PHCC) is poor, and curative-intent resection is the most effective treatment associated with long-term survival. Surgery is technically demanding since it involves a major hepatectomy with en bloc resection of the caudate lobe and extrahepatic bile duct. Furthermore, to achieve negative margins, it may be necessary to perform concomitant vascular resection or pancreatoduodenectomy. Despite this aggressive approach, recurrence is often observed, considering 5-year recurrence-free survival below 15% and 5-year overall survival that barely exceeds 40%. SUMMARY: The literature reports that survival rates are better in patients with negative margins, and surprisingly, R0 resections range between 19% and 95%. This variability is probably due to different surgical strategies and the pathologist's expertise with specimens. In fact, a proper pathological examination of residual disease should take into consideration both the ductal and the radial margin (RM) status. Currently, detailed pathological reports are lacking, and there is a likelihood of misinterpreting residual disease status due to the missing of RM description and the utilization of various definitions for surgical margins. KEY MESSAGES: The aim of PHCC surgery is to achieve negative margins including RM. More clarity in reporting on RM is needed to define true radical resection and consistent design of oncological studies for adjuvant treatments.

Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Endoscopic ultrasound fine-needle biopsy to assess DAXX/ATRX expression and alternative lengthening of telomeres status in non-functional pancreatic neuroendocrine tumors.

BACKGROUND/OBJECTIVES: Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens. METHODS: Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading. RESULTS: Forty-one NF-PanNETs (mean diameter 36.1 ± 26.5 mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (κ = 0.828; p < 0.001), 92.7% (κ = 0.626; p < 0.001), and 100% (κ = 1; p < 0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p < 0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss + ALT-positivity + grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k = 0.573; p < 0.001). CONCLUSION: DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.

Current Role and Future Perspectives of Immunotherapy and Circulating Factors in Treatment of Biliary Tract Cancers.

Biliary tract cancers (BTCs) are a heterogenous group of malignancies arising from the epithelial cells of the biliary tree and the gallbladder. They are often locally advanced or already metastatic at the time of the diagnosis and therefore prognosis remains dismal. Unfortunately, the management of BTCs has been limited by resistance and consequent low response rate to cytotoxic systemic therapy. New therapeutic approaches are needed to improve the survival outcomes for these patients. Immunotherapy, one of the newest therapeutic options, is changing the approach to the oncological treatment. Immune checkpoint inhibitors are by far the most promising group of immunotherapeutic agents: they work by blocking the tumor-induced inhibition of the immune cellular response. Immunotherapy in BTCs is currently approved as second-line treatment for patients whose tumors have a peculiar molecular profile, such as high levels of microsatellites instability, PD-L1 overexpression, or high levels of tumor mutational burden. However, emerging data from ongoing clinical trials seem to suggest that durable responses can be achieved in other subsets of patients. The BTCs are characterized by a highly desmoplastic microenvironment that fuels the growth of cancer tissue, but tissue biopsies are often difficult to obtain or not feasible in BTCs. Recent studies have hence proposed to use liquid biopsy approaches to search the blood circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to use as biomarkers in BTCs. So far studies are insufficient to promote their use in clinical management, however trials are still in progress with promising preliminary results. Analysis of blood samples for ctDNA to research possible tumor-specific genetic or epigenetic alterations that could be linked to treatment response or prognosis was already feasible. Although there are still few data available, ctDNA analysis in BTC is fast, non-invasive, and could also represent a way to diagnose BTC earlier and monitor tumor response to chemotherapy. The prognostic capabilities of soluble factors in BTC are not yet precisely determined and more studies are needed. In this review, we will discuss the different approaches to immunotherapy and tumor circulating factors, the progress that has been made so far, and the possible future developments.

A machine learning analysis of difficulty scoring systems for laparoscopic liver surgery.

INTRODUCTION: In the last decade, several difficulty scoring systems (DSS) have been proposed to predict technical difficulty in laparoscopic liver resections (LLR). The present study aimed to investigate the ability of four DSS for LLR to predict operative, short-term, and textbook outcomes. METHODS: Patients who underwent LLR at a single tertiary referral center from January 2014 to June 2020 were included in the present study. Four DSS for LLR (Halls, Hasegawa, Kawaguchi, and Iwate) were investigated to test their ability to predict operative and postoperative complications. Machine learning algorithms were used to identify the most important DSS associated with operative and short-term outcomes. RESULTS: A total of 346 patients were included in the analysis, 28 (8.1%) patients were converted to open surgery. A total of 13 patients (3.7%) had severe (Clavien-Dindo ≥ 3) complications; the incidence of prolonged length of stay (> 5 days) was 39.3% (n = 136). No patients died within 90 days after the surgery. According to Halls, Hasegawa, Kawaguchi, and Iwate scores, 65 (18.8%), 59 (17.1%), 57 (16.5%), and 112 (32.4%) patients underwent high difficulty LLR, respectively. In accordance with a random forest algorithm, the Kawaguchi DSS predicted prolonged length of stay, high blood loss, and conversions and was the best performing DSS in predicting postoperative outcomes. Iwate DSS was the most important variable associated with operative time, while Halls score was the most important DSS predicting textbook outcomes. No one of the DSS investigated was associated with the occurrence of complication. CONCLUSIONS: According to our results DDS are significantly related to surgical complexity and short-term outcomes, Kawaguchi and Iwate DSS showed the best performance in predicting operative outcomes, while Halls score was the most important variable in predicting textbook outcome. Interestingly, none of the DSS showed any correlation with or importance in predicting overall and severe postoperative complications.

Effect of Diameter and Number of Hepatocellular Carcinomas on Survival After Resection, Transarterial Chemoembolization, and Ablation.

INTRODUCTION: Most studies predicting survival after resection, transarterial chemoembolization (TACE), and ablation analyzed diameter and number of hepatocellular carcinomas (HCCs) as dichotomous variables, resulting in an underestimation of risk variation. We aimed to develop and validate a new prognostic model for patients with HCC using largest diameter and number of HCCs as continuous variables. METHODS: The prognostic model was developed using data from patients undergoing resection, TACE, and ablation in 645 Japanese institutions. The model results were shown after balanced using the inverse probability of treatment-weighted analysis and were externally validated in an international multi-institution cohort. RESULTS: Of 77,268 patients, 43,904 patients, including 15,313 (34.9%) undergoing liver resection, 13,375 (30.5%) undergoing TACE, and 15,216 (34.7%) undergoing ablation, met the inclusion criteria. Our model (http://www.u-tokyo-hbp-transplant-surgery.jp/about/calculation.html) showed that the 5-year overall survival (OS) in patients with HCC undergoing these procedures decreased with progressive incremental increases in diameter and number of HCCs. For patients undergoing resection, the inverse probability of treatment-weighted-adjusted 5-year OS probabilities were 10%-20% higher compared with patients undergoing TACE for 1-6 HCC lesions <10 cm and were also 10%-20% higher compared with patients undergoing ablation when the HCC diameter was 2-3 cm. For patients undergoing resection and TACE, the model performed well in the external cohort. DISCUSSION: Our novel prognostic model performed well in predicting OS after resection and TACE for HCC and demonstrated that resection may have a survival benefit over TACE and ablation based on the diameter and number of HCCs.

Simultaneous Sigmoid Colectomy, Bilobar Liver Resection and Lung Metastasectomy via a Transdiaphragmatic Approach for Stage IV Colonic Adenocarcinoma.

BACKGROUND: Current evidence supports the curative resection of colorectal cancer and synchronous liver and lung metastases in selected patients.1,2 This video shows simultaneous left colectomy, bilobar liver resection, and lung metastasectomy via a transdiaphragmatic approach for stage IV colorectal cancer.3 PATIENT: A 57-year-old man with a stage IV colonic adenocarcinoma was considered for simultaneous resection of primary, liver, and lung metastases without thoracic incision. The tumor mutational status was KRAS, NRAS, and BRAF wild-type, and the patient underwent preoperative chemotherapy. TECHNIQUE: After performing a midline laparotomy, atypical liver resection of segments 8/4a was performed under the guidance of intraoperative ultrasonography and intermittent Pringle maneuver using the two-surgeon's technique. A small capsular lesion in segment 3 also was intraoperatively detected and resected. Lung metastasectomy of the right lower lobe was performed via a transdiaphragmatic approach using an endoscopic stapler. Sigmoid colectomy with transanal circular-stapled anastomosis was performed. Duration of surgery and blood loss were 358 min and 400 ml, respectively. Histopathological examination showed metastatic colonic adenocarcinoma with negative surgical margins and final stage was T3N2aM1b. The patient was discharged on postoperative day 6 without complication. He was alive and free of disease at 90-day follow-up. CONCLUSIONS: Simultaneous colon, liver, and lung resection via a transdiaphragmatic approach is a feasible and safe surgical strategy in selected patients with peripheral lung metastases and favorable tumor biology.4 This surgical strategy avoids thoracic incision, multiple operations, and may reduce the healthcare costs and the recovery time to early implement postoperative therapy.

Conditional Recurrence-Free Survival after Oncologic Extended Resection for Gallbladder Cancer: An International Multicenter Analysis.

BACKGROUND: Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC. PATIENTS AND METHODS: Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000-2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free. RESULTS: Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3-T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49-3.13, P < 0.001], 12-month recurrence-free (HR 3.42, 95% CI 1.88-6.23, P < 0.001), and 24-month recurrence-free (HR 2.71, 95% CI 1.11-6.62, P = 0.029). Of the 125 patients without these risk factors, only 2 had recurrence after 36 months. CONCLUSION: C-RFS improves over time, and only T3-T4 disease remains a risk factor for recurrence at 24 months after OER for GBC. For all recurrence-free survivors after 36 months, the probability of recurrence is similar regardless of T category or disease stage.

Hepatopancreatoduodenectomy for Multifocal Cholangiocarcinoma in the Setting of Biliary Papillomatosis.

BACKGROUND: Hepatopancreatoduodenectomy is performed to achieve curative resection of malignant biliary tumors.1 However, the morbidity and mortality associated with this challenging surgical procedure remain high, and optimal indications remain unclear.2-4 Biliary papillomatosis (BP) is a precursor lesion of cholangiocarcinoma. This video shows hepatopancreatoduodenecomy for multifocal cholangiocarcinoma in the setting of BP. PATIENT: A 75-year-old man with a medical history of cholecystectomy presented with obstructive jaundice. Magnetic resonance colangiopancreatography and computed tomography scan showed diffuse biliary dilation with mild enhancing nodularities in the whole extrahepatic bile duct. Cholangioscopy with biopsies proved cholangiocarcinoma arising from BP at the prepapillary common bile duct (CBD) and the biliary confluence. The second-order right ducts were free of disease. The patient underwent nasobiliary drainage and was considered for hepatopancreatoduodenecomy. TECHNIQUE: A right subcostal incision was performed. Intraoperative ultrasound showed BP of the intrapancreatic CBD spreading only to the left bile duct. En bloc resection of the left liver, caudate lobe, and CBD was performed together with pylorus-preserving pancreatoduodenectomy. The reconstruction phase was performed on a single-loop by duct-to-mucosa pancreatojejunostomy, two-duct biliojejunostomy with mucosa-to-mucosa alignment, and duodenojejunostomy. Transanastomotic external stents were used for biliary and pancreatic drainage. Histopathologic examination confirmed foci of cholangiocarcinoma arising from BP. Resection margins were negative. Lymph node metastasis, microvascular invasion, perineural invasion, and mucin secretion were absent. The patient was discharged on postoperative day 14 without complications. At the 2-year follow-up assessment, he was alive and free of disease. CONCLUSION: Cholangiocarcinoma arising from BP is a proper indication for hepatopancreatoduodenectomy. The long-term oncologic benefits might outweigh the possible perioperative complications.5,6.

Pancreatic resections in patients who refuse blood transfusions. The application of a perioperative protocol for a true bloodless surgery.

BACKGROUND: The refusal of blood transfusions compels surgeons to face ethical and clinical issues. A single-institution experience with a dedicated perioperative blood management protocol was reviewed to assess feasibility and short-term outcomes of true bloodless pancreatic surgery. METHODS: The institutional database was reviewed to identify patients who refused transfusion and were scheduled for elective pancreatic surgery from 2010 through 2018. A protocol to optimize the hemoglobin values by administration of drugs stimulating erythropoiesis was systematically used. RESULTS: Perioperative outcomes of 32 Jehovah's Witnesses patients were included. Median age was 67 years (range, 31-77). Nineteen (59.4%) patients were treated with preoperative erythropoietin. Twenty-four (75%) patients underwent pylorus-preserving pancreaticoduodenectomy, 4 (12.5%) distal pancreatectomy (DP) with splenectomy, 3 (9.4%) spleen-preserving DP, and 1 (3.1%) total pancreatectomy. Median estimated blood loss and surgical duration were 400 mL (range, 100-1000) and 470 min (range, 290-595), respectively. Median preoperative hemoglobin was 13.9 g/dL (range, 11.7-15.8) while median postoperative nadir hemoglobin was 10.5 g/dL (range, 7.1-14.1). The most common histological diagnosis (n = 15, 46.9%) was pancreatic ductal adenocarcinoma. Clavien-Dindo grade I-II complications occurred in fourteen (43.8%) patients while one (3.1%) patient had a Clavien-Dindo grade IIIa complication wich was an abdominal collection that required percutaneous drainage. Six (18.8%) patients presented biochemical leak or postoperative pancreatic fistula grade B. Median hospital stay was 16 days (range, 8-54) with no patient requiring transfusion or re-operation and no 90-day mortality. CONCLUSIONS: A multidisciplinary approach and specific perioperative management allowed performing pancreatic resections in patients who refused transfusion with good short-term outcomes.

How to identify patients who are less likely to have metachronous neoplasms after a colon cancer: a predictive model.

BACKGROUND: Patients with prior colon cancer have increased risk of metachronous colorectal neoplasms; therefore, endoscopic surveillance is indicated. Current recommendations are not risk-stratified. We investigated predictive factors for colorectal neoplasms to build a model to spare colonoscopies for low-risk patients. METHODS: This was a multicenter, retrospective study including patients who underwent surgery for colon cancer in 2001 - 2008 (derivation cohort) and 2009 - 2013 (validation cohort). A predictive model for neoplasm occurrence at second surveillance colonoscopy was developed and validated. RESULTS: 421 and 203 patients were included in derivation and validation cohort, respectively. At second surveillance colonoscopy, 112 (26.6 %) and 55 (27.1 %) patients had metachronous neoplasms in derivation and validation groups; three cancers were detected in the latter. History of left-sided colon cancer (OR 1.64, 95 %CI 1.02 - 2.64), ≥ 1 advanced adenoma at index colonoscopy (OR 1.90, 95 %CI 1.05 - 3.43), and ≥ 1 adenoma at first surveillance colonoscopy (OR 2.06, 95 %CI 1.29 - 3.27) were independently predictive of metachronous colorectal neoplasms at second surveillance colonoscopy. For patients without such risk factors, diagnostic accuracy parameters were: 89.3 % (95 %CI 82.0 %-94.3 %) and 78.2 % (95 %CI 65.0 %-88.2 %) sensitivity, and 28.5 % (95 %CI 23.5 %-33.9 %) and 33.8 % (95 %CI 26.2 %-42.0 %) specificity in derivation and validation group, respectively. No cancer would be missed. CONCLUSIONS: Patients with prior left-sided colon cancer or ≥ 1 advanced adenoma at index colonoscopy or ≥ 1 adenoma at first surveillance colonoscopy had a significantly higher risk of neoplasms at second surveillance colonoscopy; patients without such factors had much lower risk and could safely skip the second surveillance colonoscopy. A prospective, multicenter validation study is needed.

Characteristics of atypical large well-differentiated hepatocellular carcinoma: a specific subtype of hepatocellular carcinoma?

BACKGROUND: Hepatocellular carcinoma (HCC) de-differentiation is thought to correlate with size, therefore well-differentiated HCC ≥3 cm are considered rare and not fully understood. METHODS: Patients who underwent hepatectomy for HCC between 1998-2016 were retrospectively analyzed. Patient's characteristics and recurrence-free (RFS) and overall (OS) survival were compared between those with atypical- (well-differentiated-HCC ≥3 cm) and typical-HCC (moderate-to-poorly-differentiated HCC ≥3 cm). RESULTS: Of 176 patients included in this study, 37 (21%) had atypical-HCC. Patients with atypical-HCC were less likely to be Asian ethnicity (3% vs. 17%, p = 0.062), have lower rate of viral infection (14% vs. 43%, p = 0.003), cirrhosis (8% vs. 27%, p = 0.015). The tumors were less likely to demonstrate vascular invasion (30% vs. 59%, p = 0.002), and were associated with a lower alpha-fetoprotein level (3.5 ng/ml vs. 33.2 ng/ml, p < 0.001). Patients with atypical-HCC had a longer RFS (5-y RFS: 58.3% vs. 35.7%, p = 0.016) and OS (5-y OS: 79.1% vs 53.3%, p = 0.029) as compared to those with typical-HCC following univariate analysis, however this did not appear following multivariate analysis. CONCLUSION: Patients with atypical-HCC have different characteristic in terms of epidemiology, etiology, cirrhosis and vascular invasion as compared to typical-HCC. The etiology of atypical-HCC may be non-alcoholic fatty liver disease-related and/or malignant transformation of hepatocellular adenoma.

Periendoscopic management of direct oral anticoagulants: a prospective cohort study.

OBJECTIVE: To assess the frequency of adverse events associated with periendoscopic management of direct oral anticoagulants (DOACs) in patients undergoing elective GI endoscopy and the efficacy and safety of the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) recommendations (NCT02734316). DESIGN: Consecutive patients on DOACs scheduled for elective GI endoscopy were prospectively included. The timing of DOAC interruption and resumption before and after the procedures were recorded, along with clinical and procedural data. Procedures were stratified into low-risk and high-risk for GI-related bleeding, and patients into low-risk and high-risk for thromboembolic events. Patients were followed-up for 30 days for major and clinically relevant non-major bleeding events (CRNMB), arterial and venous thromboembolism and death. RESULTS: Of 529 patients, 38% and 62% underwent high-risk and low-risk procedures, respectively. There were 45 (8.5%; 95% CI 6.3% to 11.2%) major or CRNMB events and 2 (0.4%; 95% CI 0% to 1.4%) thromboembolic events (transient ischaemic attacks). Overall, the incidence of bleeding events was 1.8% (95% CI 0.7% to 4%) and 19.3% (95% CI 14.1% to 25.4%) in low-risk and high-risk procedures, respectively. For high-risk procedures, the incidence of intraprocedural bleeding was similar in patients who interrupted anticoagulation according to BSG/ESGE guidelines or earlier (10.3%vs10.8%, p=0.99), with a trend for a lower risk as compared with those who stopped anticoagulation later (10.3%vs25%, p=0.07). The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6%vs7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.4%vs6.6%, p=0.27). The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.6%vs5.9%, p=0.017). CONCLUSION: High-risk procedures in patients on DOACs are associated with a substantial risk of bleeding, further increased by heparin bridging. Adoption of the BSG/ESGE guidelines in periendoscopic management of DOACs seems to result in a favourable benefit/risk ratio. TRIAL REGISTRATION NUMBER: NCT02734316; Pre-results.

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Percutaneous ablation therapy of hepatocellular carcinoma with irreversible electroporation: MRI findings.

OBJECTIVE: Irreversible electroporation is a new ablation modality. Our purpose was to describe the MRI findings after irreversible electroporation treatment of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: In an 18-month period, we treated 24 HCC lesions in 20 patients who were not candidates for surgery. MRI was performed before and 1 month after irreversible electroporation. We used the liver-specific contrast medium gadoxetic acid. We evaluated the size, shape, signal intensity (T1-weighted, T2-weighted, and diffusion-weighted imaging), dynamic contrast enhancement pattern, and signal behavior during the liver-specific phase. Changes in the perilesional parenchyma, perfusion abnormalities, and complications were also recorded. RESULTS: According to the modified Response Evaluation Criteria in Solid Tumors system, 22 of 24 lesions had a complete response, and two lesions showed a partial response and were retreated. The lesions showed a mean size increase of 10%, with a round or oval shape. On the T1-weighted images, we observed a hyperintense core and a hypointense rim. On the T2-weighted sequences, the signal was heterogeneously hypointense. On diffusion-weighted images, 83% of lesions showed restricted diffusion, with b values of 0-800 s/mm(2), whereas in 17% of the lesions, the signal was not clearly discernible for different b values. The apparent diffusion coefficient values did not show statistically significant differences between the baseline (800-1020 × 10(-3) mm(2)/s) and the reassessment after 1 month (900-1100 × 10(-3) mm(2)/s). The necrotic area did not show a signal increase after contrast material injection. Perfusion abnormalities, such as areas of transient hepatic intensity difference, were present in the tissue adjacent to six treated lesions. In two patients, a reduced or absent concentration of the contrast medium was observed during the liver-specific phase around the ablation zone. One patient had an arteriovenous shunt and another had biliary duct dilatation. CONCLUSION: MRI detects characteristic morphologic and functional changes after irreversible electroporation treatment.

The Role of Three-Dimensional Modeling to Improve Comprehension of Liver Anatomy and Tumor Characteristics for Medical Students and Surgical Residents.

OBJECTIVE: Studying liver anatomy can be challenging for medical students and surgical residents due to its complexity. Three-dimensional visualization technology (3DVT) allows for a clearer and more precise view of liver anatomy. We sought to assess how 3DVT can assist students and surgical residents comprehend liver anatomy. DESIGN: Data from 5 patients who underwent liver resection for malignancy at our institution between September 2020 and April 2022 were retrospectively reviewed and selected following consensus among the investigators. Participants were required to complete an online survey to investigate their understanding of tumor characteristics and vascular variations based on patients' computed tomography (CT) and 3DVT. SETTING: The study was carried out at the General and Hepato-Biliary Surgery Department of the University of Verona. PARTICIPANTS: Among 32 participants, 13 (40.6%) were medical students, and 19 (59.4%) were surgical residents. RESULTS: Among 5 patients with intrahepatic lesions, 4 patients (80.0%) had at least 1 vascular variation. Participants identified number and location of lesions more correctly when evaluating the 3DVT (84.6% and 80.9%, respectively) compared with CT scans (61.1% and 64.8%, respectively) (both p ≤ 0.001). The identification of any vascular variations was more challenging using the CT scans, with only 50.6% of correct answers compared with 3DVT (72.2%) (p < 0.001). Compared with CT scans, 3DVT led to a 23.5%, 16.1%, and 21.6% increase in the correct definition of number and location of lesions, and vascular variations, respectively. 3DVT allowed for a decrease of 50.8 seconds (95% CI 23.6-78.0) in the time needed to answer the questions. All participants agreed on the usefulness of 3DVT in hepatobiliary surgery. CONCLUSIONS: The 3DVT facilitated a more precise preoperative understanding of liver anatomy, tumor location and characteristics.

Portal vein stenting in recurrent or locally advanced peri-hilar cholangiocarcinoma.

BACKGROUND: Recurrent or locally advanced peri-hilar cholangiocarcinoma (PHCC) usually involves the portal vein (PV) leading to significant stenosis. With disease progression, clinical symptoms such as ascites, bleeding, and hepatic insufficiency are usually observed. Little is know about the benefit of PV stenting in relieving the symptoms associated to portal hypertension and allowing anticancer therapies. The aim of this study is to review our experience in PV stenting for PHCC patients. METHODS: From 2014 to 2022, data from PHCC patients underwent PV stenting at Verona University Hospital, Italy, were reviewed. The indications were: gastrointestinal bleeding from esophagus-gastric varices, ascites not responsive to medical therapy, severe thrombocytopenia, liver insufficiency (hepatic jaundice, coagulopathy, and/or hyperammoniemia), or asymptomatic high-grade PV stenosis. Cavernous transformation and intrahepatic thrombosis in both sides of the liver were considered contraindication. Systematic anticoagulation therapy was not administered. RESULTS: Technical success was achieved in all 16 (100 %) patients. The improvement of clinical symptoms were observed in 12 (75 %) patients. Anticancer therapy was administrated in 11 (69 %) patients. 2 (13 %) complications were observed: 1 biliary injury and 1 recurrent cholangitis that required a percutaneous trans-hepatic biliary drainage placement. Stent occlusion for tumor progression occurred in 1 patient and a re-stenting procedure was successfully performed. No case of thrombotic stent occlusion was observed during follow up. The 1-year stent patency was 86 % and the median patency period was 8 months (IQR, 4-12). CONCLUSION: PV stenting is a feasible and safe palliative treatment that improves clinical condition, allow anticancer therapies, and provide a better quality of life.