Prognostic benefit of preoperative transarterial chemoembolization in upfront resectable large hepatocellular carcinoma: a multicentric propensity score based analysis of European high-volume centers.

BACKGROUND: Hepatocellular carcinoma (HCC) have a dismal prognosis and any effective neoadjuvant treatment has been validated to date. We aimed to investigate the role of neoadjuvant transarterial chemoembolization (TACE) in upfront resectable HCC larger than 5 cm. METHODS: This is a multicentric retrospective study comparing outcomes of large HCC undergoing TACE followed by surgery or liver resection alone before and after propensity-score matching (PSM). RESULTS: A total of 384 patients were included of whom 60 (15.6%) received TACE. This group did not differ from upfront resected cases neither in terms of disease-free survival (p = 0.246) nor in overall survival (p = 0.276). After PSM, TACE still did not influence long-term outcomes (p = 0.935 and p = 0.172, for DFS and OS respectively). In subgroup analysis, TACE improved OS only in HCC ≥10 cm (p = 0.045), with a borderline significance after portal vein embolization/ligation (p = 0.087) and in single HCC (p = 0.052). CONCLUSIONS: TACE should not be systematically performed in all resectable large HCC. Selected cases could however potentially benefit from this procedure, as patients with huge and single tumors or those necessitating of a PVE.

Management of hepatocellular carcinoma recurrence after liver surgery and thermal ablations: state of the art and future perspectives.

Despite the improvements in surgical and medical therapy for hepatocellular carcinoma (HCC), recurrence still represents a major issue. Up to 70% of patients can experience HCC recurrence after liver resection (LR), as well as 20% of them even after liver transplantation (LT). The patterns of recurrence are different according to both the time and the location. Similarly, the risk factors and the management can change not only according to these patterns, but also according to the underlying liver condition and to the first treatment performed. Deep knowledge of such correlation is fundamental, since prevention and effective management of recurrence are undoubtedly the most important strategies to improve the outcomes of HCC treatment. Without adjuvant therapy, maintaining very close monitoring during the first 2 years in order to diagnose curable recurrence and continue this monitoring beyond 5 years because late recurrences exist, remains our only possibility today. Surgery represents the cornerstone treatment for HCC, including both LT and LR. However, new interesting therapeutic opportunities are coming from immunotherapy that has shown encouraging results also in the adjuvant setting. In such a complex and evolutionary scenario, the aim of this review is to summarize current strategies for the management of HCC recurrence, focusing on the different possible scenarios, as well as on future perspectives.

International consensus guidelines on robotic pancreatic surgery in 2023.

Background: With the rapid development of robotic surgery, especially for the abdominal surgery, robotic pancreatic surgery (RPS) has been applied increasingly around the world. However, evidence-based guidelines regarding its application, safety, and efficacy are still lacking. To harvest robust evidence and comprehensive clinical practice, this study aims to develop international guidelines on the use of RPS. Methods: World Health Organization (WHO) Handbook for Guideline Development, GRADE Grid method, Delphi vote, and the AGREE-II instrument were used to establish the Guideline Steering Group, Guideline Development Group, and Guideline Secretary Group, formulate 19 clinical questions, develop the recommendations, and draft the guidelines. Three online meetings were held on 04/12/2020, 30/11/2021, and 25/01/2022 to vote on the recommendations and get advice and suggestions from all involved experts. All the experts focusing on minimally invasive surgery from America, Europe and Oceania made great contributions to this consensus guideline. Results: After a systematic literature review 176 studies were included, 19 questions were addressed and 14 recommendations were developed through the expert assessment and comprehensive judgment of the quality and credibility of the evidence. Conclusions: The international RPS guidelines can guide current practice for surgeons, patients, medical societies, hospital administrators, and related social communities. Further randomized trials are required to determine the added value of RPS as compared to open and laparoscopic surgery.

Minimally invasive versus open radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma: an entropy balancing analysis.

BACKGROUND: The safety and efficacy of minimally invasive radical antegrade modular pancreatosplenectomy (MI-RAMPS) remain to be established in pancreatic cancer (PDAC) METHODS: Eighty-five open (O)-RAMPS were compared to 93 MI-RAMPS. The entropy balance matching approach was used to compare the two cohorts, eliminating the selection bias. Three models were created. Model 1 made O-RAMPS equal to the MI-RAMPS cohort (i.e., compared the two procedures for resectable PDAC); model 2 made MI-RAMPS equal to O-RAMPS (i.e., compared the two procedures for borderline-resectable PDAC); model 3, compared robotic and laparoscopic RAMPS. RESULTS: O-RAMPS and MI-RAMPS showed "non-small" differences for BMI, comorbidity, back pain, tumor size, vascular resection, anterior or posterior RAMPS, multi-visceral resection, stump management, grading, and neoadjuvant therapy. Before reweighting, O-RAMPS had fewer clinically relevant postoperative pancreatic fistulae (CR-POPF) (20.0% vs. 40.9%; p = 0.003), while MI-RAMPS had a higher mean of lymph nodes (25.7 vs. 31.7; p = 0.011). In model 1, MI-RAMPS and O-RAMPS achieved similar results. In model 2, O-RAMPS was associated with lower comprehensive complication index scores (MD = 11.2; p = 0.038), and CR-POPF rates (OR = 0.2; p = 0.001). In model 3, robotic-RAMPS had a higher probability of negative resection margins. CONCLUSION: In patients with anatomically resectable PDAC, MI-RAMPS is feasible and as safe as O-RAMPS.

Multi-visceral resection for left-sided pancreatic ductal adenocarcinoma: a multicenter retrospective analysis from European countries.

BACKGROUND: Due to delayed diagnosis and a lower surgical indication rate, left-sided pancreatic ductal adenocarcinoma (PDAC) is often associated with a poor prognosis in comparison to pancreatic head tumors. Multi-visceral resections (MVR) associated with distal pancreatectomy could be proposed for patients presenting with locally infiltrating disease. METHODS: We retrospectively analyzed a multi-centric cohort of left-sided PDAC patients operated on from 2009 to 2020. Thirteen European high-volume HPB centers participated in this study. We analyzed patients who underwent distal pancreatectomy (DP) associated with MVR and compared them to standard DP patients. RESULTS: Among 258 patients treated curatively for PDAC of the body and tail, 28 patients successfully underwent MVR. A longer operative time was observed in the MVR group (295 min +/- 74 vs. 250 min +/- 96, p= 0.248). The post-operative complication rate was comparable between the two groups (46.4% in the MVR group vs. 62.2% in the control group, p= 0.108). The incidence of positive margin (R1) was similar between the two groups (28.6% vs. 26.6%; p=0.827). After a median follow-up of 25 (9-111) months, overall survival was comparable between the two groups (p= 0.519). CONCLUSIONS: Multi-visceral resection in left-sided pancreatic ductal adenocarcinoma is safe and feasible and should be considered in selected cases as it seems to provide acceptable surgical and oncological outcomes.

International experts consensus guidelines on robotic liver resection in 2023.

The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic surgical system, however, controversies still exist. Based on the foundation of the previous consensus statement, this new consensus document aimed to update clinical recommendations and provide guidance to improve the outcomes of RLR clinical practice. The guideline steering group and guideline expert group were formed by 29 international experts of liver surgery and evidence-based medicine (EBM). Relevant literature was reviewed and analyzed by the evidence evaluation group. According to the WHO Handbook for Guideline Development, the Guidance Principles of Development and Amendment of the Guidelines for Clinical Diagnosis and Treatment in China 2022, a total of 14 recommendations were generated. Among them were 8 recommendations formulated by the GRADE method, and the remaining 6 recommendations were formulated based on literature review and experts' opinion due to insufficient EBM results. This international experts consensus guideline offered guidance for the safe and effective clinical practice and the research direction of RLR in future.

Joint EANM/SNMMI/IHPBA procedure guideline for [99mTc]Tc-mebrofenin hepatobiliary scintigraphy SPECT/CT in the quantitative assessment of the future liver remnant function.

PURPOSE: The aim of this joint EANM/SNMMI/IHPBA procedure guideline is to provide general information and specific recommendations and considerations on the use of [99mTc]Tc-mebrofenin hepatobiliary scintigraphy (HBS) in the quantitative assessment and risk analysis before surgical intervention, selective internal radiation therapy (SIRT) or before and after liver regenerative procedures. Although the gold standard to estimate future liver remnant (FLR) function remains volumetry, the increasing interest in HBS and the continuous request for implementation in major liver centers worldwide, demands standardization. METHODS: This guideline concentrates on the endorsement of a standardized protocol for HBS elaborates on the clinical indications and implications, considerations, clinical appliance, cut-off values, interactions, acquisition, post-processing analysis and interpretation. Referral to the practical guidelines for additional post-processing manual instructions is provided. CONCLUSION: The increasing interest of major liver centers worldwide in HBS requires guidance for implementation. Standardization facilitates applicability of HBS and promotes global implementation. Inclusion of HBS in standard care is not meant as substitute for volumetry, but rather to complement risk evaluation by identifying suspected and unsuspected high-risk patients prone to develop post-hepatectomy liver failure (PHLF) and post-SIRT liver failure.

Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives.

Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.

Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery.

Background: Transarterial radioembolization (TARE) has recently been recognized as a bridging/downstaging therapy to surgery for early hepatocellular carcinomas (HCCs) with high rates of complete pathological necrosis (CPN) on liver explants. In patients with portal vein tumoral thrombus (PVTT), multifocal or large tumors, TARE has mainly a palliative role and surgery remains controversial in this poor-prognosis population. Personalized dosimetry recently proved to outperform standard dosimetry used in prior negative Y90 randomized-controlled trials. Methods: In this retrospective study, we evaluated safety, radiological and pathological response and outcomes in HCC patients with PVTT, multifocal or large tumors, who underwent surgery after downstaging using TARE with Y90-loaded glass microspheres with personalized dosimetry. Results: Between December 2015 and October 2021, 18 unresectable patients (14/18 with PVTT) had surgery (16 resections, 2 liver transplantations) 6.2 months (range, 2-14.6 months) after a single Y90 treatment. No 90-day mortality was reported. Objective modified response criteria in solid tumors (mRECIST) response were noted in all but one patient. Complete and extensive (50-99%) necrosis was observed in 36% and 45% of tumors, respectively. The post-treatment tumor-absorbed dose significantly differed depending on the extent of pathological necrosis (P=0.045). Median overall survival and progression-free survival (PFS) were respectively of 61.8 months [95% CI: 31.4 months-not reached (NR)] and 49.3 months (95% CI: 14 months-NR). PFS was longer in patients with complete imaging response [median NR (none recurred or died) vs. 21.5 months (95% CI: 10.1 months-NR), P<0.001] and in those with complete pathological response [median NR vs. 22.5 months (95% CI: 10.1 months-NR), P<0.001]. Conclusions: Y90 TARE using personalized dosimetry can provide high rates of imaging and pathological response in patients with PVTT, large or multifocal HCC. Subsequent surgery is safe and leads to outcomes far exceeding expectations in an otherwise poor prognosis population with no chance for cure. Trial Registration: Clinical trial number: NCT05045573.

Life expectancy of patients with hepatocellular carcinoma according to the upfront treatment: A nationwide analysis.

PURPOSE: The purpose of this study was to update the life expectancy of patients with hepatocellular carcinoma (HCC) in an exhaustive nationwide population according to the upfront treatment performed. MATERIALS AND METHODS: From the French Program for the Medicalization of Information System database, all patients older than 18 years diagnosed with a de novo HCC from January 2011 to December 2018 were retrospectively selected. Five-year survival rates (95% confidence intervals [CI]) were computed according to the first surgical or interventional radiology procedures performed. RESULTS: A total of 63,996 patients (80% men) with a median age of 68 years (Q1, Q3: 61, 77) were selected, including 24,007 patients who underwent at least one procedure (5-year survival of 45.5%; (95% CI: 44.8-46.2), and 39,989 with none (5-year survival, 9.6%; (95% CI: 9.3-10.0). Only 20.5% (13,101/63,996) of patients could undergo an upfront curative procedure. Liver transplantation achieved the best outcome, whether performed upfront (n = 791; 5-year survival, 79.0% [95% CI: 76.1-82.1]) or during subsequent steps (n = 2217; 5-year survival 80.9% [95% CI: 79.2-82.7]). Tumor ablation (n = 5306), open resection (n = 5171), and minimally-invasive resection (n = 1833) achieved 5-year survival rates of 53.8% (95% CI: 52.3-55.4), 54.1% (95% CI: 52.6-55.6), and 66.2% (95% CI: 63.7-68.7), respectively, with more patients with cirrhosis and subsequent procedures in the tumor ablation group. Patients with upfront transarterial (chemo)embolization (n = 10,247) and selective internal radiation therapy (n = 659) had 5-year survival rates of 31.3% (95% CI: 30.3-32.4) and 18.5% (95% CI: 15.2-22.5). CONCLUSION: While HCC remains mostly diagnosed at an advanced stage associated with a poor prognosis, all the curative options provide 5-year survival rates above 50%.

Liver Venous Deprivation Versus Portal Vein Embolization Before Major Hepatectomy for Colorectal Liver Metastases: A Retrospective Comparison of Short- and Medium-Term Outcomes.

BACKGROUND: Liver venous deprivation (LVD) is a recent radiological technique performed to induce hypertrophy of the future liver remnant. Medium-term results of major hepatectomy after LVD have never been compared with the actual standard of care, portal vein embolization (PVE). METHODS: We retrospectively compared data from 33 consecutive patients who had undergone LVD (n = 17) or PVE (n = 16) prior to a right hemi-hepatectomy or right extended hepatectomy indicated for colorectal liver metastases (CRLM) between May 2015 and December 2019. RESULTS: The 1-year and 3-year overall survival (OS) rates in the LVD group were 81.3% (95% confidence interval [CI]: 72-90) and 54.7% (95% CI: 46-63), respectively, against 85% (95% CI: 69-101) and 77.4% (95% CI: 54-100) in the PVE group; the differences were not statistically significant (p = 0.64). The median disease-free survival (DFS) rate was also comparable: 6 months (95% CI: 4-7) in the LVD group and 12 months (95% CI: 1.5-13) in the PVE group (p = 0.29). The overall intra-operative and post-operative complication rates were similar between the two groups. The mean daily kinetic growth rate (KGR) was found to be higher after LVD than after PVE (0.2% vs. 0.1%, p = 0.05; 10 cc/day vs. 4.8 cc/day, p = 0.03), as was the mean increase in future liver remnant volume (FLR-V) (49% vs. 27%, p = 0.01). CONCLUSIONS: The LVD technique is well tolerated in patients undergoing right hemi-hepatectomy or right extended hepatectomy for CRLM. When compared with the PVE technique, the LVD technique has similar peri-operative and medium-term outcomes, but higher KGR and FLR-V increase.

Gastrointestinal perforation in liver transplantation recipients: risk factors analysis from a 10-year retrospective study with an international multicenter survey about management strategies.

Risk factors for gastrointestinal (GI) perforations in adult liver transplantation (LT) recipients have never been deeply investigated, as well as their management. The aim of this study is to report a single-center 10 years' experience about GI perforations after LT, focusing on risk factors and management strategies according to an international survey involving expert transplant surgeons. Data regarding all consecutive patients undergoing liver transplantations from January 2009 until December 2019 in a single institution were retrospectively collected. Risk factors for GI perforation were investigated. A web survey about the management of gastrointestinal perforations was conducted among worldwide transplantation centers. On 699 adult liver transplantations performed in our center, 20 cases of GI perforations were found, with an incidence of 2.8%. A previous abdominal surgery was found to be the only risk factor (p = 0.01). Ninety-day mortality was 75%. According to the survey, a more conservative treatment was suggested in case of gastric and duodenal perforations (consisting in a direct suture or an external drain), while a more aggressive treatment was adopted for ileal or colic perforation (stoma with or without resection). The W value for inter-personal agreement was 0.41. Despite rare, GI perforations in LT recipients can represent a life-threatening complication. Surgical management can be challenging and depends on both the site of perforation and the clinical conditions of the patient.

Minimally invasive biliary anastomosis after iatrogenic bile duct injury: a systematic review.

Major bile duct injuries (BDIs) may require complex surgical repairs that are usually performed with a conventional open approach. This study aims to analyze current evidence concerning the safety and the outcomes of the minimally invasive (MI) approach for biliary anastomosis in post-cholecystectomy BDIs. A systematic search of MEDLINE, Embase, and Web-Of-Science indexed studies involving MI (laparoscopic or robotic) biliary anastomosis in patients with iatrogenic BDIs was performed. The quality of the studies was assessed using the MINORS criteria. A total of 13 studies involving 198 patients were included. One hundred and twenty-five patients (63.1%) underwent a laparoscopic biliary anastomosis, while 73 (36.1%) received an analogue robotic procedure. All the included BDIs were types D and E (E1-E5). The mean OT varied between 190 and 330 (mean = 227) minutes. Ten studies reported the mean intraoperative blood loss that ranged between 50 and 252 (mean = 135.9) mL. No conversions occurred in the robotic series, while four patients required conversion to open surgery among the laparoscopic ones. The mean length of postoperative hospital stay was 6.3 days. The reported overall morbidity was similar among the robotic and laparoscopic series. During the follow-up period, no surgery-related mortality occurred. A growing number of referral centers are showing the safety and feasibility of the MI approach for biliary anastomosis in patients with major BDIs. Further prospective comparative studies are needed to draw more definitive conclusions.

A systematic review and meta-analysis of liver venous deprivation versus portal vein embolization before hepatectomy: future liver volume, postoperative outcomes, and oncological safety.

Introduction: This systematic review aimed to compare liver venous deprivation (LVD) with portal vein embolization (PVE) in terms of future liver volume, postoperative outcomes, and oncological safety before major hepatectomy. Methods: We conducted this systematic review and meta-analysis following the PRISMA guidelines 2020 and AMSTAR 2 guidelines. Comparative articles published before November 2022 were retained. Results: The literature search identified nine eligible comparative studies. They included 557 patients, 207 in the LVD group and 350 in the PVE group. This systematic review and meta-analysis concluded that LVD was associated with higher future liver remnant (FLR) volume after embolization, percentage of FLR hypertrophy, lower failure of resection due to low FLR, faster kinetic growth, higher day 5 prothrombin time, and higher 3 years' disease-free survival. This study did not find any difference between the LVD and PVE groups in terms of complications related to embolization, FLR percentage of hypertrophy after embolization, failure of resection, 3-month mortality, overall morbidity, major complications, operative time, blood loss, bile leak, ascites, post hepatectomy liver failure, day 5 bilirubin level, hospital stay, and three years' overall survival. Conclusion: LVD is as feasible and safe as PVE with encouraging results making some selected patients more suitable for surgery, even with a small FLR. Systematic review registration: The review protocol was registered in PROSPERO before conducting the study (CRD42021287628).

Portal vein embolization failure: Current strategies and future perspectives to improve liver hypertrophy before major oncological liver resection.

Portal vein embolization (PVE) is currently considered the standard of care to improve the volume of an inadequate future remnant liver (FRL) and decrease the risk of post-hepatectomy liver failure (PHLF). PHLF remains a significant limitation in performing major liver surgery and is the main cause of mortality after resection. The degree of hypertrophy obtained after PVE is variable and depends on multiple factors. Up to 20% of patients fail to undergo the planned surgery because of either an inadequate FRL growth or tumor progression after the PVE procedure (usually 6-8 wk are needed before surgery). The management of PVE failure is still debated, with a lack of consensus regarding the best clinical strategy. Different additional techniques have been proposed, such as sequential transarterial chemoembolization followed by PVE, segment 4 PVE, intra-portal administration of stem cells, dietary supplementation, and hepatic vein embolization. The aim of this review is to summarize the up-to-date strategies to overcome such difficult situations and discuss future perspectives on improving FRL hypertrophy.

Immunotherapy for hepatocellular carcinoma: A promising therapeutic option for advanced disease.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and its incidence continues to increase. Despite improvements in both medical and surgical therapies, HCC remains associated with poor outcomes due to its high rates of recurrence and mortality. Approximately 50% of patients require systemic therapies that traditionally consist of tyrosine kinase inhibitors. Recently, however, immune checkpoint inhibitors have revolutionized HCC management, providing new therapeutic options. Despite these major advances, the different factors involved in poor clinical responses and molecular pathways leading to resistance following use of these therapies remain unclear. Alternative strategies, such as adoptive T cell transfer, vaccination, and virotherapy, are currently under evaluation. Combinations of immunotherapies with other systemic or local treatments are also being investigated and may be the most promising opportunities for HCC treatment. The aim of this review is to provide updated information on currently available immunotherapies for HCC as well as future perspectives.