Analysis of treatment benefits and prognostic factors for Post-Transplant hepatocellular carcinoma recurrence in a large Euro-American-Asian cohort.

BACKGROUND: Post-transplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent disease is needed. METHODS: In this retrospective study across six centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. Efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. RESULTS: In our study, 431 of 3349 (14%) transplanted HCC patients developed recurrence within a median interval of 18 (IQR:9-32) months. 147 (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with median survival of 45 (95%CI:36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving non-curative treatments (median: 11 (95%CI:10-13) months, 1/3/5-year survival of 46%/10%/7%, log-rank p<0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over previous era (HR 0.64 (95%CI:0.47-0.86)). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR 3.5 (95%CI:2.7-4.6)), recurrence within 1-year (HR 1.7 (95%CI:1.3-2.1)), poor tumor differentiation (HR 1.5 (95%CI:1.1-1.9)), RETREAT score ≥3 (HR 1.4 (95%CI:1.1-1.8)) and AFP at recurrence ≥400 ng/mL (HR 1.4 (95%CI:1.1-1.9)). These factors contributed to a prognostic scoring system (0-9) that stratified patients into three prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. CONCLUSION: Curative-intent treatments should be advocated for patients with post-transplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past five years.

Current management of hepatobiliary malignancies between centers with or without a liver transplant program: A multi-society national survey.

BACKGROUND: Availability of liver transplantation (LT) as a treatment for hepatocellular carcinoma (HCC) and other liver malignancies may determine heterogeneity of therapeutic strategies across different centers. AIMS: To investigate the practice between hepato-biliary centers without (HB centers) and with a LT program (LT centers), we launched a 38-item web-based national survey, with directors of centers as a target. METHODS: The survey, including 4 clinical vignettes, collected data on their approach to HCC and transplant oncology. RESULTS: After duplicates removal, 75 respondents were considered. Respondents from LT centers (n = 22, 29.3 %) were more in favor of LT in the case of HCC outside Milan criteria (90.9 % vs. 67.9 %, p = 0.037), recurrent HCC (95.5 % vs. 50.9 %, p = 0.002) and other malignancies such as cholangiocarcinoma or neuroendocrine tumors. No significant difference was observed concerning the proportion of centers favorable to LT for unresectable colorectal liver metastases (100 % vs. 88.7 %, p = 0.100). CONCLUSION: This national survey showed how management of HCC and awareness of transplant oncology may differ between HB and LT centers. Effective networking between HB and LT centers is crucial to provide optimal treatment and access to LT.

Primary hyperparathyroidism-induced acute pancreatitis in pregnancy: A systematic review with a diagnostic-treatment algorithm.

BACKGROUND: Primary hyperparathyroidism (PHPT)-induced acute pancreatitis (AP) during pregnancy has rarely been described. Due to this rarity, there are no diagnostic or treatment algorithms for pregnant patients. AIM: To determine appropriate diagnostic methods, therapeutic options, and factors related to maternal and fetal outcomes for PHPT-induced AP in pregnancy. METHODS: A literature search of articles in English, Japanese, German, Spanish, and Italian was performed using PubMed (1946-2023), PubMed Central (1900-2023), and Google Scholar. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol was followed. The search terms included "pancreatite acuta," "iperparatiroidismo primario," "gravidanza," "travaglio," "puerperio," "postpartum," "akute pankreatitis," "primärer hyperparathyreoidismus," "Schwangerschaft," "Wehen," "Wochenbett," "pancreatitis aguda," "hiperparatiroidismo primario," "embarazo," "parto," "puerperio," "posparto," "acute pancreatitis," "primary hyperparathyroidism," "pregnancy," "labor," "puerperium," and "postpartum." Additional studies were identified by reviewing the reference lists of retrieved studies. Demographic, imaging, surgical, obstetric, and outcome data were obtained. RESULTS: Fifty-four cases were collected from the 51 studies. The median maternal age was 29 years. PHPT-induced AP starts at the 20th gestational week; higher gestational weeks were seen in mothers who died (mean gestational week 28). Median values of amylase (1399, Q1-Q3 = 519-2072), lipase (2072, Q1-Q3 = 893-2804), serum calcium (3.5, Q1-Q3 = 3.1-3.9), and parathormone (PTH) (384, Q1-Q3 = 123-910) were reported. In 46 cases, adenoma was the cause of PHPT, followed by 2 cases of carcinoma and 1 case of hyperplasia. In the remaining 5 cases, the diagnosis was not reported. Neck ultrasound was positive in 34 cases, whereas sestamibi was performed in 3 cases, and neck computed tomography or magnetic resonance imaging was performed in 9 cases (the enlarged parathyroid gland was not localized in 3 cases). Surgery was the preferred treatment during pregnancy in 33 cases (median week of gestation 25, Q1-Q3 = 20-30) and postpartum in 12 cases. The timing was not reported in the remaining 9 cases, or surgery was not performed. AP was managed surgically in 11 cases and conservatively in 43 (79.6%) cases. Maternal and fetal mortality was 9.3% (5 cases). Surgery was more common in deceased mothers (60.0% vs 16.3%; P = 0.052), and PTH values tended to be higher in this group (910 pg/mL vs 302 pg/mL; P = 0.059). Maternal mortality was higher with higher serum lipase levels and earlier delivery week. Higher calcium (4.1 mmol/L vs 3.3 mmol/L; P = 0.009) and PTH (1914 pg/mL vs 302 pg/mL; P = 0.003) values increased fetal/child mortality, as well as abortions (40.0% vs 0.0%; P = 0.007) and complex deliveries (60.0% vs 8.2%; P = 0.01). CONCLUSION: If serum calcium is not tested during admission, definitive diagnosis of PHPT-induced AP in pregnancy is delayed, while early diagnosis and immediate intervention lead to excellent maternal and fetal outcomes.

Percutaneous thermal segmentectomy for liver malignancies over 3 cm: mid-term oncological performance and predictors of sustained complete response from a multicentric Italian retrospective study.

INTRODUCTION: Percutaneous thermal segmentectomy is a single-step combination of microwave ablation, performed during arterial occlusion obtained with a balloon micro catheter, followed in the same session by balloon-occluded TACE. The aim of this multicenter retrospective study is to report the mid-term oncological performance of this technique for liver malignancies > 3.0 cm and to identify risk factors for the loss of sustained complete response. METHODS: Oncological results were evaluated with CT or MRI according to m-RECIST (HCC) and RECISTv1.1 (metastasis/intra-hepatic cholangiocarcinoma, iCC) at 1-month, 3-6-month and then at regular-6-month intervals. To identify predictive variables associated with not achieving or losing complete response two mixed-effects multivariable logistic regression models were constructed. RESULTS: Sixty-three patients (40/23, male/female) with primary liver malignancies (HCC = 49; iCC = 4) and metastasis (n = 10) were treated. Median diameter of target lesion was 4.5 cm (range 3.0-7.0 cm). The median follow-up time was 9.2 months. At one-month follow-up, 79.4% of patients presented with a complete response and the remaining 20.6% were partial responders. At the 3-6-month follow-up, reached by 59 of the initial 63 patients, 83.3% showed a sustained complete response, while 10.2% had a partial response and 8.5% a local recurrence. At the last follow-up, 69.8% of the lesions showed a complete response. The initial diameter of the target lesion ≥ 5.0 cm was the only independent variable associated with the risk of failure in maintaining a complete response at 6 months (OR = 8.58, 95% CI 1.38-53.43; P = 0.02). CONCLUSION: Percutaneous thermal segmentectomy achieves promising oncological results in patients with tumors > 3.0 cm, with tumor dimension ≥ 5.0 cm being the only risk factor associated with the failure of a sustained complete response.

Validation of the R3-AFP model for risk prediction of HCC recurrence after liver transplantation in the SiLVER randomized clinical trial.

Explant-based models for assessing hepatocellular carcinoma (HCC) recurrence post-liver transplantation (LT) serve as the gold standard, guiding post-LT screening and immunosuppression adjustment. Incorporating alpha-fetoprotein (AFP) levels into these models, such as the novel R3-AFP score, has notably enhanced risk stratification. However, validation of these models in high-evidence data is mandatory. Therefore, the aim of the present research was to validate the R3-AFP score in a randomized clinical trial. We analyzed the intention-to-treat (ITT) population from the 2-arm SiLVER trial (NCT00355862), comparing calcineurin-based (CNI-Group A) versus mammalian target of rapamycin inhibitors (mTOR)-based (Sirolimus-Group B) immunosuppression for post-LT HCC recurrence. Competing risk analysis estimated sub-hazard ratios (SHR), with testing of discriminant function and calibration. Overall, 508 patients from the ITT analysis were included (Group A, n=256; Group B, n=252). The R3-AFP score distribution was as follows: 42.6% low risk (n=216), 35.7% intermediate risk (n=181), 19.5% high risk (n=99), and 2.2% very high risk (n=11) groups. The R3-AFP score effectively stratified HCC recurrence risk, with increasing risk for each stratum. Calibration of the R3-AFP model significantly outperformed other explant-based models (Milan, Up-to-7, and RETREAT), while discrimination power [0.75 (95% CI 0.69;0.81)] surpassed these models, except for the RETREAT model (p=0.49). Sub-group analysis showed lower discrimination power in the mTOR group versus the CNI group (p=0.048). In conclusion, the R3-AFP score accurately predicted HCC recurrence using high-quality evidence-based data, exhibiting reduced performance under mTOR immunosuppression. This highlights the need for further research to evaluate surveillance schedules and adjuvant regimens.

Single large hepatocellular carcinoma > 5 cm with surgical indication: is it mandatory a major hepatectomy? a propensity-score weighted analysis.

PURPOSE: Single large hepatocellular carcinoma >5cm (SLHCC) traditionally requires a major liver resection. Minor resections are often performed with the goal to reduce morbidity and mortality. Aim of the study was to establish if a major resection should be considered the best treatment for SLHCC or a more limited resection should be preferred. METHODS: A multicenter retrospective analysis of the HE.RC.O.LE.S. Group register was performed. All collected patients with surgically treated SLHCC were divided in 5 groups of treatment (major hepatectomy, sectorectomy, left lateral sectionectomy, segmentectomy, non-anatomical resection) and compared for baseline characteristics, short and long-term results. A propensity-score weighted analysis was performed. RESULTS: 535 patients were enrolled in the study. Major resection was associated with significantly increased major complications compared to left lateral sectionanectomy, segmentectomy and non-anatomical resection (all p<0.05) and borderline significant increased major complications compared to sectorectomy (p=0.08). Left lateral sectionectomy showed better overall survival compared to major resection (p=0.02), while other groups of treatment resulted similar to major hepatectomy group for the same item. Absence of oncological benefit after major resection and similar outcomes among the 5 groups of treatment was confirmed even in the sub-population excluding patients with macrovascular invasion. CONCLUSION: Major resection was associated to increased major post-operative morbidity without long-term survival benefit; when technically feasible and oncologically adequate, minor resections should be preferred for the surgical treatment of SLHCC.

Cornerstones and divergencies in the implementation and use of liver hypertrophy techniques: results from a nationwide survey for the set-up of the prospective registry.

BACKGROUND: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers. METHODS: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions. RESULTS: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized. CONCLUSIONS: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols.

TTV and CMV viral load dynamics: Which emerges first during immunosuppression?

Novel biomarkers reflecting the degree of immunosuppression in transplant patients are required to ensure eventual personalized equilibrium between rejection and infection risks. With the above aim, Torque Teno Virus (TTV) viremia was precisely examined in a large cohort of transplanted immunocompromised patients (192 hematological and 60 solid organ transplant recipients) being monitored for Cytomegalovirus reactivation. TTV load was measured in 2612 plasma samples from 448 patients. The results revealed a significant increase in TTV viral load approximately 14 days following CMV reactivation/infection in solid organ transplant (SOT) patients. No recognizable difference in TTV load was noted among hematological patients during the entire timeframe analyzed. Furthermore, a temporal gap of approximately 30 days was noted between the viral load peaks reached by the two viruses, with Cytomegalovirus (CMV) preceding TTV. It was not possible to establish a correlation between CMV reactivation/infection and TTV viremia in hematological patients. On the other hand, the SOT patient cohort allowed us to analyze viral kinetics and draw intriguing conclusions. Taken together, the data suggest, to our knowledge for the first time, that CMV infection itself could potentially cause an increase in TTV load in the peripheral blood of patients undergoing immunosuppressive therapy.

Efficacy of surgical treatments for the management of solitary rectal ulcer syndrome: a network meta-analysis.

AIM: Solitary rectal ulcer syndrome (SRUS) is a benign and poorly understood disorder with complex management. Typical symptoms include straining during defaecation, rectal bleeding, tenesmus, mucoid secretion, anal pain and a sense of incomplete evacuation. Diagnosis is based on characteristic clinical symptoms and endoscopic/histological findings. Several treatments have been reported in the literature with variable ulcer healing rates. This study aimed to evaluate the efficacy of different treatments for SRUS. MATERIALS AND METHODS: A systematic review and network meta-analysis were performed according to the PRISMA guidelines. Studies in English, French and Spanish languages were included. Papers written in other languages were excluded. Other exclusion criteria were reviews, case reports or clinical series enrolling less than five patients, study duplications, no clinical data of interest and no article available. A systematic literature search was conducted from January 2000 to March 2024 using the following databases: PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus. The biases of the studies were assessed using the Newcastle-Ottawa scale or the Jadad scale when appropriate. Types of treatment and their efficacy for the cure of SRUS were collected and critically assessed. The study's primary outcome was to estimate the rate of patients with ulcer healing. RESULTS: A total of 22 studies with 911 patients (men 361, women 550) diagnosed with SRUS were analysed in the final meta-analysis. The pooled effect estimates of treatment efficacy revealed that surgery showed the highest ulcer healing rate (70.5%; 95% CI 0.57-0.83). Surgery was superior in the cure of ulcers with respect to medical therapies and biofeedback (OR 0.09 and OR 0.14). CONCLUSION: Solitary rectal ulcer syndrome is a challenging clinical entity to manage. Proficient results have been reported with the surgical approach, suggesting its positive role in cases refractory to medical and biofeedback therapy. Further studies in homogeneous populations are required to evaluate the efficacy of surgery in this setting. (PROSPERO registration number CRD42022331422).

Protective Effect of Minimally Invasive Approach on Postoperative Peak Transaminase Following Liver Resection: A Single-Center Propensity Score-Based Analysis.

BACKGROUND: Postoperative serum ALT levels are one of the most frequently used marker to detect liver tissue damage following liver resection. The aim of this study was to evaluate if minimally invasive liver surgery (MILS) may result in less hepatic injury than open hepatectomy by assessing the differences of postoperative ALT levels. METHODS: Patients who underwent MILS between 2009 and 2019 at our unit were included and compared with open liver resections. Median ALT levels was measured on postoperative day (POD) 1, 3 and 5. Postoperative peak transaminase (PPT) of ALT was determined on POD 1. The stabilized inverse probability treatment weighing (SIPTW) process was used to balance the two groups. A multivariable logistic regression analysis was used to analyze factors associated with high PPT. RESULTS: After SIPTW, 292 MILS were compared with 159 open resections. Median ALT levels on POD 1, 3 and 5 were significantly higher in the open group than in the MILS group (301 vs. 187, p = 0.002; 180 vs. 121, p < 0.0001; 104 vs. 60, p < 0.0001; respectively). At the multivariable logistic regression analysis, MILS showed a protective effect for high PPT. CONCLUSIONS: MILS was associated with significantly lower postoperative ALT levels compared with open liver resections. MILS showed a protective effect for high PPT.

The impact of socioeconomic deprivation on liver transplantation.

Despite global expansion, social disparities impact all phases of liver transplantation, from patient referral to post-transplant care. In pediatric populations, socioeconomic deprivation is associated with delayed referral, higher waitlist mortality, and reduced access to living donor transplantation. Children from socially deprived communities are twice as much less adherent to immunosuppression and have up to a 32% increased incidence of graft failure. Similarly, adult patients from deprived areas and racial minorities have a higher risk of not initiating the transplant evaluation, lower rates of waitlisting, and a 6% higher risk of not being transplanted. Social deprivation is racially segregated, and Black recipients have an increased risk of post-transplant mortality by up to 21%. The mechanisms linking social deprivation to inferior outcomes are not entirely elucidated, and powered studies are still lacking. We offer a review of the most recent evidence linking social deprivation and post-liver transplant outcomes in pediatric and adult populations, as well as a literature-derived theoretical background model for future research on this topic.

Liver Resection vs Nonsurgical Treatments for Patients With Early Multinodular Hepatocellular Carcinoma.

Importance: The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller. Objective: To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC. Design, Setting, and Participants: This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023. Interventions: LR, PRFA, or TACE. Main Outcomes and Measures: Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes. Results: A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE. Conclusions and Relevance: For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.

REDISCOVER guidelines for borderline-resectable and locally advanced pancreatic cancer: management algorithm, unanswered questions, and future perspectives.

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC.

Evolution of transplant oncology indications: a single-institution experience over 40 years.

Liver transplantation (LT) for uncommon tumoral indications has changed across the decades, with impaired results reported in the first historical series mainly for non-tumoral-related causes. Recently, renewed interest in liver transplant oncology has been reported. The study aims to analyze a mono-center experience exploring the evolution and the impact on patient survival of LT in uncommon tumoral indications. A retrospective analysis of 851 LT performed during 1982-2023 was investigated. 33/851 (3.9%) uncommon tumoral indications were reported: hepatocellular carcinoma (HCC) on non-cirrhotic liver (n = 14), peri-hilar (phCCA) (n = 8) and intrahepatic cholangiocarcinoma (i-CCA) (n = 3), metastatic disease (n = 4), hepatic hemangioendothelioma (n = 2), and benign tumor (n = 2). Uncommon tumoral indications were mainly transplanted during the period 1982-1989, with a complete disappearance after the year 2000 and a slight rise in the last years. Poor outcomes were reported: 5-year survival rates were 28.6%, 25.0%, 0%, and 0% in the case of HCC on non-cirrhotic liver, phCCA, i-CCA, and metastases, respectively. However, the cause of patient death was often related to non-tumoral conditions. LT for uncommon oncological diseases has increased worldwide in recent decades. Historical series report poor survival outcomes despite more recent data showing promising results. Hence, the decision to transplant these patients should be under the risk and overall benefit of the patient. The results of the ongoing protocol studies are expected to confirm the validity of the unconventional tumor indications.

Transjugular Intrahepatic Portosystemic Shunt as a Bridge to Abdominal Surgery in Cirrhosis.

Abdominal surgery is associated with high postoperative mortality and morbidity in cirrhotic patients. Despite improvements in surgical techniques, clinical management, and intensive care, the outcome could be influenced by the degree of portal hypertension, the severity of hepatopathy, or the type of surgery. Preoperative transjugular intrahepatic portosystemic shunt (TIPS) placement, in addition to medical therapy, plays an important role in managing the complications of portal hypertension such as ascites, hepatic encephalopathy, variceal bleeding or portal vein thrombosis. To date, the improvement of post-surgery outcomes in cirrhotic patients after TIPS placement remains unclear. Only observational data existing in the literature and prospective studies are urgently needed to evaluate the efficacy and safety of TIPS in this setting. This review aims to outline the role of TIPS as a tool in postoperative complications reduction in cirrhotic patients, both in the setting of emergency and elective surgery.

Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

Recipient hepatectomy technique may affect oncological outcomes of liver transplantation for hepatocellular carcinoma.

To date, caval sparing (CS) and total caval replacement (TCR) for recipient hepatectomy in liver transplantation (LT) have been compared only in terms of surgical morbidity. Nonetheless, the CS technique is inherently associated with an increased manipulation of the native liver and later exclusion of the venous outflow, which may increase the risk of intraoperative shedding of tumor cells when LT is performed for HCC. A multicenter, retrospective study was performed to assess the impact of recipient hepatectomy (CS vs. TCR) on the risk of posttransplant HCC recurrence among 16 European transplant centers that used either TCR or CS recipient hepatectomy as an elective protocol technique. Exclusion criteria comprised cases of non-center-protocol recipient hepatectomy technique, living-donor LT, HCC diagnosis suspected on preoperative imaging but not confirmed at the pathological examination of the explanted liver, HCC in close contact with the IVC, and previous liver resection for HCC. In 2420 patients, CS and TCR approaches were used in 1452 (60%) and 968 (40%) cases, respectively. Group adjustment with inverse probability weighting was performed for high-volume center, recipient age, alcohol abuse, viral hepatitis, Child-Pugh class C, Model for End-Stage Liver Disease score, cold ischemia time, clinical HCC stage within Milan criteria, pre-LT downstaging/bridging therapies, pre-LT alphafetoprotein serum levels, number and size of tumor nodules, microvascular invasion, and complete necrosis of all tumor nodules (matched cohort, TCR, n = 938; CS, n = 935). In a multivariate cause-specific hazard model, CS was associated with a higher risk of HCC recurrence (HR: 1.536, p = 0.007). In conclusion, TCR recipient hepatectomy, compared to the CS approach, may be associated with some protective effect against post-LT tumor recurrence.

What Is the Role of Minimally Invasive Liver Surgery in Treating Patients with Hepatocellular Carcinoma on Cirrhosis?

Minimally invasive liver surgery (MILS) has been slowly introduced in the past two decades and today represents a major weapon in the fight against HCC, for several reasons. This narrative review conveys the major emerging concepts in the field. The rise in metabolic-associated steatotic liver disease (MASLD)-related HCC means that patients with significant cardiovascular risk will benefit more profoundly from MILS. The advent of efficacious therapy is leading to conversion from non-resectable to resectable cases, and therefore more patients will be able to undergo MILS. In fact, resection outcomes with MILS are superior compared to open surgery both in the short and long term. Furthermore, indications to surgery may be further expanded by its use in Child B7 patients and by the use of laparoscopic ablation, a curative technique, instead of trans-arterial approaches in cases not amenable to radiofrequency. Therefore, in a promising new approach, multi-parametric treatment hierarchy, MILS is hierarchically superior to open surgery and comes second only to liver transplantation.

Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis.

BACKGROUND: Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET. AIM: To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET. METHODS: A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival. RESULTS: A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET. CONCLUSION: T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.