Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.

OBJECTIVE: The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC. DESIGN: RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9. RESULTS: MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of ß-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC. CONCLUSIONS: CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.

Propensity Score-Matching Analysis Comparing Robotic Versus Laparoscopic Limited Liver Resections of the Posterosuperior Segments: An International Multicenter Study.

OBJECTIVE: The purpose of this study was to compare the outcomes of robotic limited liver resections (RLLR) versus laparoscopic limited liver resections (LLLR) of the posterosuperior segments. BACKGROUND: Both laparoscopic and robotic liver resections have been used for tumors in the posterosuperior liver segments. However, the comparative performance and safety of both approaches have not been well examined in the existing literature. METHODS: This is a post hoc analysis of a multicenter database of 5446 patients who underwent RLLR or LLLR of the posterosuperior segments (I, IVa, VII, and VIII) at 60 international centers between 2008 and 2021. Data on baseline demographics, center experience and volume, tumor features, and perioperative characteristics were collected and analyzed. Propensity score-matching (PSM) analysis (in both 1:1 and 1:2 ratios) was performed to minimize selection bias. RESULTS: A total of 3510 cases met the study criteria, of whom 3049 underwent LLLR (87%), and 461 underwent RLLR (13%). After PSM (1:1: and 1:2), RLLR was associated with a lower open conversion rate [10 of 449 (2.2%) vs 54 of 898 (6.0%); P =0.002], less blood loss [100 mL [IQR: 50-200) days vs 150 mL (IQR: 50-350); P <0.001] and a shorter operative time (188 min (IQR: 140-270) vs 222 min (IQR: 158-300); P <0.001]. These improved perioperative outcomes associated with RLLR were similarly seen in a subset analysis of patients with cirrhosis-lower open conversion rate [1 of 136 (0.7%) vs 17 of 272 (6.2%); P =0.009], less blood loss [100 mL (IQR: 48-200) vs 160 mL (IQR: 50-400); P <0.001], and shorter operative time [190 min (IQR: 141-258) vs 230 min (IQR: 160-312); P =0.003]. Postoperative outcomes in terms of readmission, morbidity and mortality were similar between RLLR and LLLR in both the overall PSM cohort and cirrhosis patient subset. CONCLUSIONS: RLLR for the posterosuperior segments was associated with superior perioperative outcomes in terms of decreased operative time, blood loss, and open conversion rate when compared with LLLR.

Defining Global Benchmarks for Laparoscopic Right Posterior Sectionectomy/H67: An International Multicenter Study.

OBJECTIVE: We aimed to establish global benchmark outcomes indicators for L-RPS/H67. BACKGROUND: Minimally invasive liver resections has seen an increase in uptake in recent years. Over time, challenging procedures as laparoscopic right posterior sectionectomies (L-RPS)/H67 are also increasingly adopted. METHODS: This is a post hoc analysis of a multicenter database of 854 patients undergoing minimally invasive RPS (MI-RPS) in 57 international centers in 4 continents between 2015 and 2021. There were 651 pure L-RPS and 160 robotic RPS (R-RPS). Sixteen outcome indicators of low-risk L-RPS cases were selected to establish benchmark cutoffs. The 75th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff. RESULTS: There were 573 L-RPS/H67 performed in 43 expert centers, of which 254 L-RPS/H67 (44.3%) cases qualified as low risk benchmark cases. The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, 90-day mortality and textbook outcome after L-RPS were 350.8 minutes, 12.5%, 53.8%, 22.9%, 23.8%, 2.8%, 0% and 4% respectively. CONCLUSIONS: The present study established the first global benchmark values for L-RPS/H6/7. The benchmark provided an up-to-date reference of best achievable outcomes for surgical auditing and benchmarking.

Impact of Liver Cirrhosis, Severity of Cirrhosis, and Portal Hypertension on the Difficulty and Outcomes of Laparoscopic and Robotic Major Liver Resections for Primary Liver Malignancies.

BACKGROUND: Minimally invasive liver resections (MILR) offer potential benefits such as reduced blood loss and morbidity compared with open liver resections. Several studies have suggested that the impact of cirrhosis differs according to the extent and complexity of resection. Our aim was to investigate the impact of cirrhosis on the difficulty and outcomes of MILR, focusing on major hepatectomies. METHODS: A total of 2534 patients undergoing minimally invasive major hepatectomies (MIMH) for primary malignancies across 58 centers worldwide were retrospectively reviewed. Propensity score (PSM) and coarsened exact matching (CEM) were used to compare patients with and without cirrhosis. RESULTS: A total of 1353 patients (53%) had no cirrhosis, 1065 (42%) had Child-Pugh A and 116 (4%) had Child-Pugh B cirrhosis. Matched comparison between non-cirrhotics vs Child-Pugh A cirrhosis demonstrated comparable blood loss. However, after PSM, postoperative morbidity and length of hospitalization was significantly greater in Child-Pugh A cirrhosis, but these were not statistically significant with CEM. Comparison between Child-Pugh A and Child-Pugh B cirrhosis demonstrated the latter had significantly higher transfusion rates and longer hospitalization after PSM, but not after CEM. Comparison of patients with cirrhosis of all grades with and without portal hypertension demonstrated no significant difference in all major perioperative outcomes after PSM and CEM. CONCLUSIONS: The presence and severity of cirrhosis affected the difficulty and impacted the outcomes of MIMH, resulting in higher blood transfusion rates, increased postoperative morbidity, and longer hospitalization in patients with more advanced cirrhosis. As such, future difficulty scoring systems for MIMH should incorporate liver cirrhosis and its severity as variables.

Tubular cell transcriptional intermediary factor 1γ deficiency exacerbates kidney injury-induced tubular cell polyploidy and fibrosis.

Tubulointerstitial fibrosis is considered the final convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms underlying kidney injury-induced fibrosis largely remain unknown. Recent studies have indicated that transcriptional intermediary factor 1γ (TIF1γ) inhibits the progression of fibrosis in other organs. Here, we found that TIF1γ was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1γ expression was decreased in patients with CKD, including those with diabetes, hypertension, and IgA nephropathy, and in mouse models with experimental kidney fibrosis (unilateral ureteral obstruction [UUO], folic acid nephropathy [FAN], and aristolochic acid-induced nephrotoxicity). Tubule-specific knock out of TIF1γ in mice exacerbated UUO- and FAN-induced tubular cell polyploidy and subsequent fibrosis, whereas overexpression of kidney TIF1γ protected mice against kidney fibrosis. Mechanistically, in tubular epithelial cells, TIF1γ exerted an antifibrotic role via transforming growth factor-ß (TGF-ß)-dependent and -independent signaling. TIF1γ hindered TGF-ß signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular cells, and we discovered that TIF1γ suppressed epidermal growth factor receptor (EGFR) signaling upstream of TGF-ß signaling in tubular cells by ubiquitylating EGFR at its lysine 851/905 sites thereby promoting EGFR internalization and lysosomal degradation. Pharmacological inhibition of EGFR signaling attenuated exacerbated polyploidization and the fibrotic phenotype in mice with tubule deletion of TIF1γ. Thus, tubular TIF1γ plays an important role in kidney fibrosis by suppressing profibrotic EGFR and TGF-ß signaling. Hence, our findings suggest that maintaining homeostasis of tubular TIF1γ may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD.

Association of habitual sleep duration and its trajectory with the risk of cancer according to sex and body mass index in a population-based cohort.

BACKGROUND: The relationship between sleep duration and cancer in China remains inconclusive. The authors investigated the association between sleep duration and cancer from both static and dynamic perspectives. METHODS: This study was based on the China Health and Retirement Longitudinal Study. We first tested the hazard ratios (HRs) with 95% confidence intervals (CIs) between baseline sleep duration and incident cancer using Cox proportional hazards regression analysis. Sleep duration trajectories from 2011 to 2015 were identified using group-based trajectory modeling to examine the subsequent risk of incident cancer from 2015 to 2018 using Cox proportional hazards regression model. RESULTS: The risk of incident cancer increased by 69% (HR, 1.69; 95% CI, 1.19-2.39) in individuals who slept for <7 h per day (vs. 7 to ≤8 h), 41% (HR, 1.41; 95% CI, 1.01-1.95) in those who slept for <6 h per night (vs. 6 to ≤8 h), and 60% (HR, 1.60; 95% CI, 1.01-2.55) in those who did not take any naps during the day (vs. >60 min). Stratified by sex and body mass index, the risk of cancer was evident among women with night sleep of <6 h (vs. 6-8 h). However, the duration of <7 h of total sleep among men and overweight individuals was associated with cancer risk. Moreover, individuals with a short night sleep duration but no napping had a higher risk of cancer. Furthermore, cancer risk was only observed in individuals with short stable trajectory of night sleep (HR, 2.01; 95% CI, 1.07-3.80) and among women with short stable trajectory of total sleep (HR, 2.26; 95% CI, 1.13-4.52). CONCLUSIONS: Cancer incidence risk was observed in participants with sleep duration of <7 h and among women with short stable sleep trajectory. Short nights and total sleep duration were both associated with a high risk of incident cancer, but varied by sex. Interestingly, cancer risk was restricted to women with short stable sleep trajectory. PLAIN LANGUAGE SUMMARY: This study showed that short nights and total sleep duration were associated with a high risk of cancer incidence in middle-aged and elderly Chinese population, with implications for early effective cancer prevention. Habitual sleep is a modifiable and dynamic lifestyle behavior, and long-term short sleep trajectories among women can predict cancer outcomes. Future studies should examine the association between the trajectory of sleep parameters based on objective measures and specific cancer types.

A Prospective Study Using Propensity Score Matching to Compare Long-term Survival Outcomes After Robotic-assisted, Laparoscopic, or Open Liver Resection for Patients With BCLC Stage 0-A Hepatocellular Carcinoma.

OBJECTIVE: To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Following the Balliol IDEAL classification, long-term oncological outcomes can be used to evaluate the value of minimally invasive techniques in the treatment of HCC, and to assess whether they should become a standard practice. METHODS: Data from prospective cohorts of patients with BCLC stage 0-A HCC who underwent curative liver resection using OLR, LLR, or RALR at Tongji Hospital were reviewed. The short-term and long-term oncological outcomes of these 3 different surgical approaches after adequate follow-up were compared using propensity score matching to reduce selection bias. RESULTS: Of 369 patients included in this study (71, RALR; 141, LLR; and 157, OLR), 56 patients in each of the 3 groups were chosen for further comparison, after propensity score matching. In the minimally invasive group (RALR+LLR), both the operative time and duration of Pringle's maneuver were significantly longer than those in the OLR group; however, the length of hospital stay was significantly shorter. There were no significant differences in the other intraoperative parameters and the incidence of postoperative complications among the 3 groups. HCC recurrence in the minimally invasive group when compared with the OLR group was characterized by a significantly higher proportion of single lesion or early-stage HCC. However, there were no significant differences in the 5-year disease-free survival (63.8%, 54.4%, and 50.6%) or overall survival rates (80.8%, 78.6%, and 75.7%, respectively) among the 3 groups. Clinically significant portal hypertension was the only risk factor that negatively affected the 5-year disease-free survival rate. Multivariate Cox regression analysis showed that clinically significant portal hypertension, serum alpha-fetoprotein level (≥400 ng/mL), and Edmondson-Steiner grading (III+IV) were independent risk factors for poor long-term survival. CONCLUSION: Both robotic and laparoscopic hepatectomies were safe and effective for patients with BCLC stage 0-A HCC when compared with open hepatectomy.

Propensity-score Matched and Coarsened-exact Matched Analysis Comparing Robotic and Laparoscopic Major Hepatectomies: An International Multicenter Study of 4822 Cases.

OBJECTIVE: To compare the outcomes between robotic major hepatectomy (R-MH) and laparoscopic major hepatectomy (L-MH). BACKGROUND: Robotic techniques may overcome the limitations of laparoscopic liver resection. However, it is unknown whether R-MH is superior to L-MH. METHODS: This is a post hoc analysis of a multicenter database of patients undergoing R-MH or L-MH at 59 international centers from 2008 to 2021. Data on patient demographics, center experience volume, perioperative outcomes, and tumor characteristics were collected and analyzed. Both 1:1 propensity-score matched (PSM) and coarsened-exact matched (CEM) analyses were performed to minimize selection bias between both groups. RESULTS: A total of 4822 cases met the study criteria, of which 892 underwent R-MH and 3930 underwent L-MH. Both 1:1 PSM (841 R-MH vs. 841 L-MH) and CEM (237 R-MH vs. 356 L-MH) were performed. R-MH was associated with significantly less blood loss {PSM:200.0 [interquartile range (IQR):100.0, 450.0] vs 300.0 (IQR:150.0, 500.0) mL; P = 0.012; CEM:170.0 (IQR: 90.0, 400.0) vs 200.0 (IQR:100.0, 400.0) mL; P = 0.006}, lower rates of Pringle maneuver application (PSM: 47.1% vs 63.0%; P < 0.001; CEM: 54.0% vs 65.0%; P = 0.007) and open conversion (PSM: 5.1% vs 11.9%; P < 0.001; CEM: 5.5% vs 10.4%, P = 0.04) compared with L-MH. On subset analysis of 1273 patients with cirrhosis, R-MH was associated with a lower postoperative morbidity rate (PSM: 19.5% vs 29.9%; P = 0.02; CEM 10.4% vs 25.5%; P = 0.02) and shorter postoperative stay [PSM: 6.9 (IQR: 5.0, 9.0) days vs 8.0 (IQR: 6.0 11.3) days; P < 0.001; CEM 7.0 (IQR: 5.0, 9.0) days vs 7.0 (IQR: 6.0, 10.0) days; P = 0.047]. CONCLUSIONS: This international multicenter study demonstrated that R-MH was comparable to L-MH in safety and was associated with reduced blood loss, lower rates of Pringle maneuver application, and conversion to open surgery.

Perioperative outcomes of robot-assisted versus laparoscopic liver resection for cavernous hemangioma: a propensity score matching study.

BACKGROUND: Minimally invasive techniques have increasingly been adopted for liver resection. This study aimed to compare the perioperative outcomes of robot-assisted liver resection (RALR) with laparoscopic liver resection (LLR) for liver cavernous hemangioma and to evaluate the treatment feasibility and safety. METHODS: A retrospective study of prospectively collected data was conducted on consecutive patients who underwent RALR (n = 43) and LLR (n = 244) for liver cavernous hemangioma between February 2015 and June 2021 at our institution. Patient demographics, tumor characteristics, and intraoperative and postoperative outcomes were analyzed and compared using propensity score matching. RESULTS: The postoperative hospital stay was significantly shorter (P = 0.016) in the RALR group. There were no significant differences between the two groups in overall operative time, intraoperative blood loss, blood transfusion rates, conversion to open surgery or complication rates. There was no perioperative mortality. Multivariate analysis showed that hemangiomas located in posterosuperior liver segments and those in close proximity to major vascular structures were independent predictors of increased intraoperative blood loss (P = 0.013 and P = 0.001, respectively). For patients with hemangioma in close proximity to major vascular structures, there were no significant differences in perioperative outcomes between the two groups, with the exception that intraoperative blood loss in the RALR group was significantly less than that in the LLR group (350 ml vs. 450 ml, P = 0.044). CONCLUSIONS: Both RALR and LLR were safe and feasible for treating liver hemangioma in well-selected patients. For patients with liver hemangioma in close proximity to major vascular structures, RALR was better than conventional laparoscopic surgery in reducing intraoperative blood loss.

Clinical Features of Recurrence After Hepatic Resection for Early-Stage Hepatocellular Carcinoma and Long-Term Survival Outcomes of Patients with Recurrence: A Multi-institutional Analysis.

BACKGROUND: A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC), but most HCCs, even at an early stage, eventually recur after resection. This study investigates clinical features of initial recurrence and long-term prognosis of patients with recurrence after curative resection for early-stage HCC. PATIENTS AND METHODS: From a multicenter database, patients who underwent curative hepatic resection for early-stage HCC [Barcelona Clinic Liver Cancer (BCLC) stage 0/A] were extracted. Time to initial recurrence, patterns of initial recurrence, and treatment modalities for recurrent tumors were investigated. Univariate and multivariate analysis were used to identify independent risks associated with postoperative recurrence, as well as post-recurrence survival (PRS) for patients with recurrence. RESULTS: Among 1424 patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) early recurrence (≤ 2 years after surgery) and 271 (39.9%) late recurrence (> 2 years). Independent risks of postoperative recurrence included cirrhosis, preoperative alpha-fetoprotein level > 400 ug/L, tumor size > 5 cm, multiple tumors, satellites, microvascular invasion, and intraoperative blood transfusion. Multivariate analysis revealed that receiving irregular recurrence surveillance, initial tumor beyond Milan criteria, early recurrence, BCLC stage B/C of the recurrent tumor, and noncurative treatments were independently associated with poorer PRS. CONCLUSIONS: Nearly half of patients with early-stage HCC experienced recurrence after resection. Understanding recurrence risks may help identify patients at high risk of recurrence who may benefit from future adjuvant therapies. Meaningful survival even after recurrence can still be achieved by postoperative regular surveillance and curative treatment.

Association of liver abnormalities with in-hospital mortality in patients with COVID-19.

BACKGROUND & AIMS: The evolution and clinical significance of abnormal liver chemistries and the impact of hepatitis B infection on outcome in patients with COVID-19 is not well characterized. This study aimed to explore these issues. METHODS: This large retrospective cohort study included 2,073 patients with coronavirus disease 2019 (COVID-19) and definite outcomes in Wuhan, China. Longitudinal liver function tests were conducted, with associated factors and risk of death determined by multivariate regression analyses. A prognostic nomogram was formulated to predict the survival of patients with COVID-19. The characteristics of liver abnormalities and outcomes of patients with COVID-19, with and without hepatitis B, were compared after 1:3 propensity score matching. RESULTS: Of the 2,073 patients, 1,282 (61.8%) had abnormal liver chemistries during hospitalization, and 297 (14.3%) had a liver injury. The mean levels of aspartate aminotransferase (AST) and direct bilirubin (D-Bil) increased early after symptom onset in deceased patients and showed disparity compared to levels in discharged patients throughout the clinical course of the disease. Abnormal AST (adjusted hazard ratio [HR] 1.39; 95% CI 1.04-1.86, p = 0.027) and D-Bil (adjusted HR 1.66; 95% CI 1.22-2.26; p = 0.001) levels at admission were independent risk factors for mortality due to COVID-19. A nomogram was established based on the results of multivariate analysis and showed sufficient discriminatory power and good consistency between the prediction and the observation. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes. CONCLUSIONS: Abnormal AST and D-Bil levels at admission were independent predictors of COVID-19-related mortality. Therefore, monitoring liver chemistries, especially AST and D-Bil levels, is necessary in hospitalized patients with COVID-19. LAY SUMMARY: Liver test abnormalities (in particular elevations in the levels of aspartate aminotransferase [AST] and direct bilirubin [D-Bil]) were observed after symptom onset in patients who went on to die of coronavirus disease 2019 (COVID-19). Abnormal levels of AST and D-Bil at admission were independent predictors of COVID-19-related mortality. HBV infection in patients did not increase the risk of poor COVID-19-associated outcomes.

Preoperative risk grade predicts the long-term prognosis of intrahepatic cholangiocarcinoma: a retrospective cohort analysis.

BACKGROUND: Cumulating evidence indicates that the systemic inflammatory response (SIR) plays a crucial role in the prognosis of various cancers. We aimed to generate a preoperative risk grade (PRG) by integrating SIR markers to preoperatively predict the long-term prognosis of intrahepatic cholangiocarcinoma (ICC). METHODS: 468 consecutive ICC patients who underwent hepatectomy between 2010 and 2017 were enrolled. The PRG and a nomogram were generated and their predictive accuracy was evaluated. RESULTS: The PRG consisted of two non-tumor-specific SIR markers platelet-to-lymphocyte ratio (PLR) and albumin (ALB), which were both the independent predictors of overall survival (OS). Multivariate analysis showed that the PRG was significantly associated with OS (PRG = 1: hazard ratio (HR) = 3.800, p < 0.001; PRG = 2: HR = 7.585, p < 0.001). The C-index of the PRG for predicting survival was 0.685 (95% CI 0.655 to 0.716), which was statistically higher than that of the following systems: American Joint Committee on Cancer (AJCC) 8th edition (C-index 0.645), Liver Cancer Study Group of Japan (LCSGJ) (C-index 0.644) and Okabayashi (C-index 0.633) (p < 0.05). Besides, the C-index of the nomogram only consisting of the tumor-specific factors (serum carcinoembryonic antigen, carbohydrate antigen 19-9, tumor number) could be improved to 0.737 (95% CI 0.062-0.768) from 0.625 (95% CI 0.585-0.665) when the PRG was incorporated (p < 0.001). CONCLUSIONS: The PRG integrating two non-tumor-specific SIR markers PLR and ALB was a novel method to preoperative predicting the prognosis of ICC.

ACE2 Expression in Pancreas May Cause Pancreatic Damage After SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus that causes coronavirus disease 2019 (COVID-19) in human beings, has caused a serious public health issue.1 Attention to pancreatic injury is lacking, which may impact patients' prognosis. In this study, we explored the expression and distribution of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2, in the pancreas. Combined with clinical data, we showed that pancreatic injury can occur in some COVID-19 patients.

Long-term survival and recurrence after curative resection for hepatocellular carcinoma in patients with chronic hepatitis C virus infection: a multicenter observational study from China.

BACKGROUND: Hepatocellular carcinoma (HCC) is a recognized sequalae of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. This study aimed to identify long-term survival and prognostic factors after curative resection for HCC among patients with chronic HCV infection. METHODS: From a Chinese multicenter database, the data of consecutive patients with HCV infection undergoing curative liver resection for initial HCC between 2006 and 2015 were retrospectively reviewed. Postoperative 30-day mortality and morbidity, long-term overall survival (OS) and recurrence-free survival (RFS) were evaluated. RESULTS: Among 382 HCC patients with HCV infection, 68 (18%) had concurrent HBV infection and 110 (29%) had portal hypertension. Postoperative 30-day morbidity and mortality rates were 45% and 2.9%, respectively. The 5-year OS and RFS rates were 45% and 34%, respectively. Multivariable Cox-regression analyses identified that concurrent HBV infection, presence of portal hypertension, largest tumor size > 5 cm, and macrovascular and microvascular invasion were independently associated with worse OS and RFS, while postoperative regular anti-HCV therapy was independently associated with better OS. CONCLUSION: Long-term prognosis after HCC resection among patients with HCV infection was worse in those with concurrent HBV infection and concomitant portal hypertension. Postoperative regular anti-HCV therapy was associated with better OS.

A novel online calculator to predict perioperative blood transfusion in patients undergoing liver resection for hepatocellular carcinoma: an international multicenter study.

BACKGROUND: To develop an easy-to-use model to predict the probability of perioperative blood transfusion (PBT) in patients undergoing liver resection for hepatocellular carcinoma (HCC). METHOD: 878 patients from Eastern Hepatobiliary Surgery Hospital of Shanghai were enrolled in the training cohort, while 691 patients from Tongji Hospital of Wuhan and 364 patients from two hospitals from Europe and America served as the Eastern and Western external validation cohorts, respectively. Independent predictors of PBT were identified and used for the nomogram construction. The predictive performance of the model was assessed using the concordance index (C-index) and calibration plot, and externally validated using the two independent cohorts. This model was compared with four currently available prediction risk scores. RESULTS: Eight preoperative variables were identified as independent predictors of PBT, which were incorporated into the new nomogram model, with a C-index of 0.833 and a well-fitted calibration plot. The nomogram performed well on the externally Eastern and Western validation cohorts (C-indexes: 0.786 and 0.777). The discriminatory ability of the nomogram was superior to the four currently available prediction scores (C-indexes: 0.833 vs. 0.671-0.770). The nomogram was programmed into an online calculator, which is available at http://www.asapcalculate.top/Cal3_en.html. CONCLUSION: A nomogram model, using an easy-to-access website, can be used to calculate the PBT risk and identify which patients undergoing HCC resection are at high risks of PBT and can benefit most by using blood conservation techniques.

Multicenter analysis of long-term oncologic outcomes of hepatectomy for elderly patients with hepatocellular carcinoma.

BACKGROUND: Aging of the population and prolonged life expectancy have significantly increased the number of elderly patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, potential benefits, especially long-term oncologic outcomes of hepatectomy for elderly patients with HCC remain unclear. METHOD: Patients treated with curative-intent hepatectomy for HCC in 8 Chinese hospitals were enrolled. Patients were divided into the elderly (≥70 years old) and younger (<70 years old) groups. Overall survival (OS), cancer-specific survival (CSS), and time-to-recurrence (TTR) were compared. Risk factors of CSS and TTR were evaluated by univariable and multivariable competing-risk regression analyses. RESULTS: Of 2134 patients, 259 (12.1%) and 1875 (87.9%) were elderly and younger aged, respectively. Postoperative 30-day and 90-day mortality was comparable among elderly and younger patients. Compared with younger patients, the elderly had a worse 5-year OS (49.4% vs. 55.3%, P = 0.032), yet a better 5-year CCS (74.5% vs. 61.0%, P = 0.005) and a lower 5-year TTR (33.7% vs. 44.9%, P < 0.001), respectively. Multivariable analyses identified that elder age was independently associated with more favorable CSS (HR 0.74, 95%CI 0.58-0.90, P = 0.011) and TTR (0.69, 0.53-0.88, P < 0.001) but was not associated with OS (P = 0.136). CONCLUSIONS: Age by itself is not a contraindication to surgery, and selected elderly patients with HCC can benefit from hepatectomy. Compared with younger patients, elderly patients have noninferior oncologic outcomes following hepatectomy for HCC.

Association between body mass index and postoperative morbidity after liver resection of hepatocellular carcinoma: A multicenter study of 1,324 patients.

BACKGROUND: Morbidity remains a common problem following hepatic resection. The aim of this study was to investigate the association between preoperative body mass index (BMI) and morbidity in patients undergoing liver resection for hepatocellular carcinoma (HCC). METHODS: Patients were divided into three groups according to preoperative BMI: low-BMI (≤18.4 kg/m2), normal-BMI (18.5-24.9 kg/m2) and high-BMI (≥25.0 kg/m2). Baseline characteristics, operative variables, postoperative 30-day mortality and morbidity were compared. Univariable and multivariable analyses were performed to identify independent risk factors associated with postoperative morbidity. RESULTS: Among 1324 patients, 108 (8.2%), 733 (55.4%), and 483 (36.5%) were low-BMI, normal-BMI, and high-BMI, respectively. There were no differences in postoperative 30-day mortality among patients based on BMI (P = 0.199). Postoperative 30-day morbidity was, however, higher in low-BMI and high-BMI patients versus patients with a normal-BMI (33.3% and 32.1% vs. 22.9%, P = 0.018 and P < 0.001, respectively). Following multivariable analysis low-BMI and high-BMI remained independently associated with an increased risk of postoperative morbidity (OR: 1.701, 95%CI: 1.060-2.729, P = 0.028, and OR: 1.491, 95%CI: 1.131-1.966, P = 0.005, respectively). Similar results were noted in the incidence of postoperative 30-day surgical site infection (SSI). CONCLUSION: Compared with normal-BMI patients, low-BMI and high-BMI patients had higher postoperative morbidity, including a higher incidence of SSI after liver resection for HCC.

Defining and predicting early recurrence after liver resection of hepatocellular carcinoma: a multi-institutional study.

BACKGROUND: A clear definition of "early recurrence" after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence. METHODS: Patients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort. RESULTS: Among 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction). CONCLUSIONS: An interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC.

Long-Term Survival Outcomes After Liver Resection for Binodular Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND: The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated. SUBJECTS, MATERIALS, AND METHODS: From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection. RESULTS: Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 µg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS. CONCLUSION: Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients. IMPLICATIONS FOR PRACTICE: Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients.

Improved survival following splenectomy combined with curative treatments for hepatocellular carcinoma in Child B patients: A propensity score matching study.

AIMS: To explore the benefits of curative treatments (liver resection or local ablation) combined with splenectomy for patients with hepatocellular carcinoma (HCC) and Child grade B liver function. METHODS: We reviewed 245 patients with Child grade B liver function who underwent treatment with curative intent for HCC. Among these patients, 116 patients underwent curative treatment combined with splenectomy (the splenectomy group); the other 129 patients only underwent curative treatment (the non-splenectomy group). A one-to-one matching produced 95 paired patients, perioperative and oncological outcomes were compared, and liver function changes were reassessed 1 year later. RESULTS: The perioperative liver failure rates were 7.4% and 6.3% (P = 1.000) and the 90-day mortality was 4.2% and 6.3% (P = 0.747) in the splenectomy group and non-splenectomy group, respectively. The 1-, 3-, and 5-year overall survival rates were remarkably greater in the splenectomy group than in the non-splenectomy group (92.6% vs. 79.8%, 53.4% vs. 34.7%, and 19.9% vs. 11.0%, respectively; P = 0.004). In the univariate and multivariate analyses, splenectomy was identified as a protective factor for long-term survival. The proportion of patients whose liver function improved to Child A 1 year after surgery was also higher in the splenectomy group than in the non-splenectomy group (95.4% vs. 83.3%; P = 0.048). CONCLUSIONS: Compared with non-splenectomy, curative treatments combined with splenectomy for patients with HCC and Child B grade liver function showed no different perioperative outcomes but achieved significant survival benefit. Splenectomy is a beneficial factor for patients with HCC and Child B liver function; liver function improved significantly 1 year after splenectomy.