Platelet-to-lymphocyte ratio predicts tumor response and survival of patients with hepatocellular carcinoma undergoing immunotherapies.

BACKGROUND: Lymphocyte-related factors were associated with survival outcome of different types of cancers. Nevertheless, the association between lymphocytes-related factors and tumor response of immunotherapy remains unclear. METHODS: This is a retrospective study. Eligible participants included patients with unresectable or advanced hepatocellular carcinoma (HCC) who underwent immunotherapy as their first-line treatment. Radiological assessment of tumor response adhered to RECIST 1.1 and HCC-specific modified RECIST (mRECIST) criteria. Univariate and multivariate logistic analyses were employed to analyze clinical factors associated with tumor response. Kaplan-Meier survivial analysis were employed to compare progression-free survival (PFS) and overall survival (OS) across different clinical factors. Furthermore, patients who received treatment with either a combination of bevacizumab and anti-PD-1(L1) antibody (Beva group) or tyrosine-kinase inhibitor (TKI) and anti-PD-1 antibody (TKI group) were examined to explore the relation between clinical factors and tumor response. RESULTS: A total of 208 patients were enrolled in this study. The median PFS and OS were 9.84 months and 24.44 months,respectively. An independent factor associated with a more favorable tumor response to immunotherapy was identified when PLR<100. Patients with PLR<100 had longer PFS than other patients, while OS showed no significant difference. Further analysis revealed that PLR exhibited superior prognostic value in patients of the Beva group as compared to those in the TKI group. CONCLUSIONS: There exisits an association between PLR and tumor response as well as survival outcomes in patients receiving immunotherapy, particularly those treated with the combination of bevacizumab and anti-PD-1.

Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Tumor Radiomic Features on Pretreatment MRI to Predict Response to Lenvatinib plus an Anti-PD-1 Antibody in Advanced Hepatocellular Carcinoma: A Multicenter Study.

Introduction: Lenvatinib plus an anti-PD-1 antibody has shown promising antitumor effects in patients with advanced hepatocellular carcinoma (HCC), but with clinical benefit limited to a subset of patients. We developed and validated a radiomic-based model to predict objective response to this combination therapy in advanced HCC patients. Methods: Patients (N = 170) who received first-line combination therapy with lenvatinib plus an anti-PD-1 antibody were retrospectively enrolled from 9 Chinese centers; 124 and 46 into the training and validation cohorts, respectively. Radiomic features were extracted from pretreatment contrast-enhanced MRI. After feature selection, clinicopathologic, radiomic, and clinicopathologic-radiomic models were built using a neural network. The performance of models, incremental predictive value of radiomic features compared with clinicopathologic features and relationship between radiomic features and survivals were assessed. Results: The clinicopathologic model modestly predicted objective response with an AUC of 0.748 (95% CI: 0.656-0.840) and 0.702 (95% CI: 0.547-0.884) in the training and validation cohorts, respectively. The radiomic model predicted response with an AUC of 0.886 (95% CI: 0.815-0.957) and 0.820 (95% CI: 0.648-0.984), respectively, with good calibration and clinical utility. The incremental predictive value of radiomic features to clinicopathologic features was confirmed with a net reclassification index of 47.9% (p < 0.001) and 41.5% (p = 0.025) in the training and validation cohorts, respectively. Furthermore, radiomic features were associated with overall survival and progression-free survival both in the training and validation cohorts, but modified albumin-bilirubin grade and neutrophil-to-lymphocyte ratio were not. Conclusion: Radiomic features extracted from pretreatment MRI can predict individualized objective response to combination therapy with lenvatinib plus an anti-PD-1 antibody in patients with unresectable or advanced HCC, provide incremental predictive value over clinicopathologic features, and are associated with overall survival and progression-free survival after initiation of this combination regimen.

Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study.

BACKGROUND: HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. METHODS: HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. FINDINGS: Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer. FUNDING: Zymeworks, Jazz, and BeiGene.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study.

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.

Effectiveness and safety of lenvatinib plus anti-programmed death-1 antibodies in patients with hepatocellular carcinoma: A real-world cohort study.

OBJECTIVE: Lenvatinib plus anti-programmed death-1 (anti-PD-1) antibody combinations have shown potent anti-tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma (HCC), but real-world data are limited. METHODS: To investigate the effectiveness and safety of lenvatinib plus anti-PD-1 antibodies in a real-world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022. RESULTS: The objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression-free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first-line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child-Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin-bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment-related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%). CONCLUSION: Lenvatinib combined with anti-PD-1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child-Pugh class B or ALBI grade 2/3.

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported. METHODS: A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors' hospital between August 2018 and September 2020 was eligible for this study. Patients who were responding to systemic therapy and met the criteria for hepatectomy underwent liver resection with curative intention. The study also investigated the association of clinical factors with successful conversion resection and postoperative recurrence. RESULTS: The study enrolled 101 patients including 24 patients (23.8 %) who underwent R0 resection a median of 3.9 months (interquartile range: 2.5-5.9 months) after initiation of systemic therapy. Patients with an Eastern cooperative oncology group performance status of 0, fewer intrahepatic tumors, or a radiographic response to systemic therapy were more likely to be able to receive curative resection. After a median follow-up period of 21.5 months, hepatectomy was independently associated with a favorable overall survival (hazard ratio [HR], 0.050; 95 % confidence interval [CI], 0.007-0.365; P = 0.003). For the 24 patients who underwent surgery, the 12-month recurrence-free survival and overall survival rates were respectively 75% and 95.8%. Achieving a pathologic complete response (n = 10) to systemic therapy was associated with a favorable recurrence-free survival after resection, with a trend toward significance (HR, 0.345; 95% CI, 0.067-1.785; P = 0.187). CONCLUSIONS: Selected patients with initially unresectable HCC can undergo hepatectomy after systemic therapy with combined TKI/anti-PD-1 antibodies. In this study, conversion resection was associated with a favorable prognosis.

Perioperative and oncologic outcomes of laparoscopic versus open liver resection for combined hepatocellular-cholangiocarcinoma: a propensity score matching analysis.

BACKGROUND: Laparoscopic liver resection (LLR) has now been established as a safe and minimally invasive technique that is deemed feasible for treating hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). However, the role of LLR in treating combined hepatocellular-cholangiocarcinoma (cHCC-CC) patients has been rarely reported. This study aimed to assess the efficacy of LLR when compared with open liver resection (OLR) procedure for patients with cHCC-CC. METHODS: A total of 229 cHCC-CC patients who underwent hepatic resection (34 LLR and 195 OLR patients) from January 2014 to December 2018 in Zhongshan Hospital, Fudan University were enrolled and underwent a 1:2 propensity score matching (PSM) analysis between the LLR and OLR groups to compare perioperative and oncologic outcomes. Overall survival (OS) and recurrence-free survival (RFS) parameters were assessed by the log-rank test and the sensitivity analysis. RESULTS: A total of 34 LLR and 68 OLR patients were included after PSM analysis. The LLR group displayed a shorter postoperative hospital stay (6.61 vs. 8.26 days; p value < 0.001) when compared with the OLR group. No significant differences were observed in the postoperative complications' incidence or a negative surgical margin rate between the two groups (p value = 0.409 and p value = 1.000, respectively). The aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory indicators in the LLR group were significantly lower than those in the OLR group on the first and third postoperative days. Additionally, OS and RFS were comparable in both the LLR and OLR groups (p value = 0.700 and p value = 0.780, respectively), and similar results were obtained by conducting a sensitivity analysis. CONCLUSION: LLR can impart less liver function damage, better inflammatory response attenuation contributing to a faster recovery, and parallel oncologic outcomes when compared with OLR. Therefore, LLR can be recommended as a safe and effective therapeutic modality for treating selected cHCC-CC patients, especially for those with small tumors in favorable location.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Criteria for identifying potentially resectable patients with initially oncologically unresectable hepatocellular carcinoma before treatment with lenvatinib plus an anti-PD-1 antibody.

Background: Conversion therapy is feasible in patients with oncologically unresectable hepatocellular carcinoma (HCC). However, it is challenging to prospectively identify patients who are more likely to achieve successful conversion before initiating systemic therapy, either alone or combined with locoregional therapy. Methods: Criteria for identifying potentially resectable patients with initially oncologically unresectable HCC before treatment with lenvatinib plus an anti-PD-1 antibody were proposed based on real-world evidence. Multivariate Firth logistic regression was used to validate the proposed criteria in a retrospective cohort of consecutive patients with advanced HCC, who received combination therapy with lenvatinib plus an anti-PD-1 antibody between September 2018 and September 2021. Results: The proposed criteria were as follows: (1) Eastern Cooperative Oncology Group performance status of 0 or 1; (2) Child-Pugh class A; (3) intrahepatic tumors confined to one lobe (left, right, or middle lobe), or present in one lobe alongside a single tumor with diameter ≤5 cm or up to three tumors each with diameter ≤3 cm in the remaining lobes, with R0 resection achievable by hemihepatectomy, alone or combined with locoregional therapy to the remaining lobes during surgery; and (4) no portal vein tumor thrombus involving the contralateral liver lobe or reaching the superior mesenteric vein, no hepatic vein tumor thrombus involving more than two major hepatic vein branches on the tumor side, and no tumor thrombus of the inferior vena cava reaching the atrium. Firth logistic regression confirmed the criteria were an independent predictor of surgery following conversion therapy with lenvatinib plus an anti-PD-1 antibody. Conclusions: This study proposed and validated criteria for identifying patients with initially oncologically unresectable HCC who are potentially resectable when treated with combination therapy with lenvatinib plus an anti-PD-1 antibody. The proposed criteria could help standardize conversion therapy studies in advanced HCC.

Effectiveness and Safety of Avatrombopag in Liver Cancer Patients with Severe Thrombocytopenia: Real-World Data and Challenges.

Background: Avatrombopag has been approved in patients who have severe thrombocytopenia (<50 × 109/L) and chronic liver disease (CLD) while receiving invasive procedures. The real-world application and effectiveness of avatrombopag in the subgroup patients with liver cancer remain unknown. Methods: Liver cancer patients (including primary liver cancer and colorectal cancer liver metastasis) who had severe thrombocytopenia and received avatrombopag were retrospectively enrolled. Avatrombopag dose, peak and absolute platelet count increase, combination treatment with other thrombopoietic agents, responder (peak count ≥50 × 109/L with absolute increase ≥20 × 109/L) rate, and anticancer treatment effect were analyzed. Thrombosis and bleeding events were assessed. Results: In total, 93 patients were enrolled, with 72 and 21 in the CLD and non-CLD groups, respectively. Patients with CLD had hepatitis B or C, larger spleen volume, and a higher cirrhosis degree. Baseline platelet counts were similar between two groups (median, 37.0 × 109/L vs. 39.0 × 109/L; P=0.594), while patients without CLD had higher peak platelet (median, 134.0 × 109/L vs. 74.0 × 109/L; P=0.015) and absolute increase (median, 101.0 × 109/L vs. 41.0 × 109/L; P=0.020) after avatrombopag treatment. The responder rate was higher in patients without CLD (100% vs. 76.4%; P=0.010). Combined avatrombopag with other thrombopoietic agents significantly increased platelet count; repeated use of avatrombopag produced similar effects with that of initial treatment. Concerning anticancer treatment effect, patients who responded to avatrombopag had a higher disease control rate. No thrombosis or hemorrhagic events were observed, even in patients with portal vein tumor thrombosis. Conclusion: Avatrombopag was safe and effective and ensured successful implementation of anticancer treatment in liver cancer patients with severe thrombocytopenia, accompanied with or without CLD.

Hazard rate for postoperative recurrence in patients with hepatocellular carcinoma at Barcelona Clinic Liver Cancer stage 0 or A1: A multicenter observational study.

AIM: Surgical treatment is the first-line treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A1 hepatocellular carcinoma (HCC), and postoperative monitoring improves long-term survival. We aimed to establish a reasonable short-interval follow-up duration for patients with HCC. METHODS: The cohort for this retrospective study included 1396 HCC patients with BCLC stage 0 or A1 disease who underwent curative resection from 2013 to 2016 at five centers in China. Hazard rates for recurrence were calculated using the hazard function. RESULTS: The recurrence rates in patients with BCLC stage 0 and A1 HCC were 46.4% and 58.0%, respectively. The hazard curve for stage 0 patients was relatively flat, and the hazard rate was consistently low (peak hazard rate 0.0163). The hazard rate curve for recurrence was initially high (peak hazard rate 0.0441) in patients with BCLC stage A1 disease and showed a rapid decreasing trend within 1 year, followed by a slow decreasing trend, reaching a low level (<0.0163) at approximately 36 months. The time to low risk was 47, 41, and 51 months in patients with cirrhosis, hepatitis B virus (HBV) infection, and satellite lesions, respectively. CONCLUSIONS: A short-interval follow-up of 1 year is sufficient for HCC patients with BCLC stage 0 disease, whereas a short-interval follow-up time of 3 years should be considered for patients with stage A1 disease. The follow-up period should be appropriately prolonged for patients with cirrhosis, HBV infection, and satellite lesions.

An mALBI-Child-Pugh-based nomogram for predicting post-hepatectomy liver failure grade B-C in patients with huge hepatocellular carcinoma: a multi-institutional study.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is a severe complication in patients with hepatocellular carcinoma (HCC) who underwent hepatectomy. This study aims to develop a nomogram of PHLF grade B-C in patients with huge HCC (diameter ≥ 10 cm). METHODS: We retrospectively collected clinical information of 514 and 97 patients who underwent hepatectomy for huge HCC at two medical centers between 2016 and 2021. Univariate and multivariate analysis were carried out to screen the independent risk factors of PHLF grade B-C, which were visualized as a nomogram. RESULTS: Three Hundred Forty Three Thousand One Hundred Seventy One  and 97 HCC patients were included in the training cohort, internal validation cohort, and external validation cohort, with probabilities of PHLF grade B-C of 15.1%, 12.9%, and 22.7%, respectively. Pre-operative modified albumin-bilirubin (mALBI) grade (p < 0.001), Child-Pugh classification (p = 0.044), international normalized ratio (INR) (p = 0.005), cirrhosis (p = 0.019), and intraoperative blood loss (p = 0.004) were found to be independently associated with PHLF grade B-C in the training cohort. All the five independent factors were considered in the establishment of the nomogram model. In the internal validation cohort and external validation cohort, the area under receiver operating characteristic curve for the nomogram in PHLF grade B-C prediction reached 0.823 and 0.740, respectively. Divided into different risk groups according to the optimal cut-off value, patients in the high-risk group reported significantly higher frequency of PHLF grade B-C than those in the low-risk group, both in the training cohort and the validation cohort (p < 0.001). CONCLUSIONS: The proposed noninvasive nomogram based on mALBI-Child-Pugh and three other indicators achieved optimal prediction performance of PHLF grade B-C in patients with huge HCC.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition).

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma (HCC) have resulted in improved response rates. This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection, a 'conversion therapy' strategy. However, conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed. Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice. Evidence review: Many research centers in China have accumulated significant experience implementing HCC conversion therapy. Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC; however, there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields. In order to summarize and learn from past experience and review current challenges, the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma (2021 Edition) was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice. Sixteen consensus statements on the implementation of conversion therapy for HCC were developed. The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Physical activity improves outcomes of combined lenvatinib plus anti-PD-1 therapy in unresectable hepatocellular carcinoma: a retrospective study and mouse model.

BACKGROUND: Physical activity is known to have anti-cancer effects, including immunomodulatory actions. This study investigated the hypothesis that physical activity synergizes with combined lenvatinib plus anti-PD-1 therapy to enhance efficacy in patients with unresectable HCC. METHODS: The physical activity levels of patients with unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy were recorded by questionnaire. Patients were categorized according to physical activity levels (active vs. sedentary). The primary outcome was overall survival (OS). Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). A subcutaneous syngeneic HCC model was generated in C57BL/6 mice. Mice were randomized to receive placebo, combined lenvatinib plus anti-PD-1 antibodies or combination therapy plus physical activity. Tumors were measured every 3 days and harvested for immunohistochemistry analysis at 20 mm maximum diameter. RESULTS: Fifty-nine patients with unresectable HCC were categorized to active (n = 28) or sedentary (n = 31) groups. The active group had higher albumin and des-γ-carboxy prothrombin levels and lower hepatitis B virus load at baseline; other clinical and oncologic characteristics were comparable between the two groups. Patients in the active group had significantly longer OS (HR = 0.220, 95% CI 0.060-0.799) and PFS (HR = 0.158, 95% CI 0.044-0.562) and higher ORR (OR = 4.571, 95% CI 1.482-14.102) than patients in the sedentary group. Regular physical activity was independently associated with OS, PFS and ORR. The mouse model showed that physical activity significantly suppressed tumor growth and prolonged survival of tumor-bearing mice. Furthermore, physical activity inhibited Treg cell infiltration and immune checkpoint expression (including CTLA4, TIGIT and TIM3) induced by long-term combined lenvatinib plus anti-PD-1 therapy, improving efficacy. CONCLUSIONS: Regular physical activity was associated with improved outcomes in unresectable HCC receiving combined lenvatinib plus anti-PD-1 therapy. Physical activity may improve therapeutic efficacy by reprograming the tumor microenvironment from an immunosuppressive to immunostimulatory phenotype.

Future liver volume combined with platelet count predicts liver failure after major hepatectomy.

BACKGROUND: Major hepatectomy is associated with high incidence of post-hepatectomy liver failure (PHLF). This study aimed to evaluate the effect of future remnant liver volume combined with liver function tests on predicting PHLF. METHODS: Patients who underwent major hepatectomy from April 2009 to May 2017 were enrolled in the training cohort. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of PHLF and generate a logistic regression model for the prediction of PHLF. A conditional inference tree was generated based on the optimal cutoff value of independent predictive factors of PHLF. The precedent results were validated in an independent cohort from June 2017 to March 2018. RESULTS: One hundred and eighteen patients were included in the training cohort, while another 34 in the validation cohort. Future remnant liver volume/estimated standard total liver volume (FLV/eTV) and preoperative platelet count were independent predictive factors of PHLF (P = 0.0021 and P = 0.012, respectively). The conditional inference tree showed that patients with FLV/eTV ≤0.56 and PLT count ≤145 × 109/L were at high risk of developing PHLF. CONCLUSION: FLV/eTV combined with preoperative PLT count is effective in predicting PHLF after major hepatectomy.

The Safety Profile of Hepatectomy Following Preoperative Systemic Therapy with Lenvatinib Plus Anti-PD-1 Antibodies Versus Hepatectomy Alone in Patients With Hepatocellular Carcinoma.

Objective: To determine the safety of hepatectomy after combined lenvatinib and anti-PD-1 preoperative systemic therapy (PST) in patients with marginally resectable hepatocellular carcinoma (HCC). Background: PST followed by hepatectomy (PSTH) is an emerging treatment for HCC. However, the impact of PST with lenvatinib plus anti-PD-1 antibodies on surgical safety is unknown. Methods: Medical records from consecutive patients with marginally resectable advanced HCC who underwent hepatectomy after PST with lenvatinib and anti-PD-1 antibodies between January 2018 and August 2021 were retrieved from a prospectively designed database. Propensity score matching (1:2) was performed with a further 2318 HCC patients who underwent upfront hepatectomy (UH) without initial antitumor treatment during the same period. Results: In total, 49 and 98 matched patients were included in the PSTH and UH groups, respectively. Compared to the UH group, individuals in the PSTH group experienced more intraoperative blood loss, blood transfusions, and longer postoperative hospital stays. Moreover, posthepatectomy liver failure was more common in the PSTH group, who also had worse albumin-bilirubin (ALBI) scores on postoperative days 1-7. A significantly greater amount of drainage was also required in the PSTH group. However, the 30-day morbidity and 90-day mortality were similar among the two groups. Additionally, the duration of surgery, use of hepatic inflow occlusion during surgery, and the levels of postoperative inflammation-based markers were not statistically different between the two groups. Conclusions: Despite more intraoperative and postoperative adverse events, PSTH had comparable 30-day morbidity and 90-day mortality as UH. Thus, PSTH appears to be a viable treatment option for marginally resectable HCC patients with careful preoperative evaluation.