Most patients with hepatocellular carcinoma (HCC) have lost the opportunity for direct surgery at the time of diagnosis. Transarterial chemoembolization (TACE) combined with immune checkpoint inhibitors or tyrosine kinase inhibitors (TKI) can partially transform some unresectable HCC and improve the prognosis effectively. However, based on the promising prospects of combined targeted and immunotherapy for the effective treatment of HCC, the positive role of palliative surgery in the conversion treatment of advanced HCC urgently needs further intensive re-assessment.

In this study, we describe two successful cases of "conversion therapy for unresectable HCC" achieved mainly by palliative surgery combined with TACE plus immunotherapy and TKIs. A 48-year-old patient with newly diagnosed HCC, presenting with a 6-cm mass in the segment VII/VIII of the right liver with multiple intrahepatic metastases, could not undergo one-stage radical surgical resection. He underwent palliative surgery with radiofrequency of metastatic lesions and the palliative resection of the primary mass, and received subsequent TACE treatments twice in the early postoperative period (2 weeks and 6 weeks), in addition to targeted and immune combination therapy with sintilimab injection and oral lenvatinib. No evidence of recurrence was observed during the 11-month follow-up period after surgery. The other patient was a 47-year-old patient with massive HCC (18 cm × 15 cm × 4.5 cm) in the left liver with severe cirrhosis. The left portal branch was occluded and a tumor thrombus formed, and the tumor partly involved the middle hepatic vein. The patient underwent palliative surgery of left hemihepatectomy (including resection of the middle hepatic vein) for HCC, followed by three TACE procedures and oral TKIs 2 weeks after surgery. Six months later, the re-examination via computed tomography revealed no tumour activity in the remaining right liver, while magnetic resonance imaging revealed slight local tumor enhancement in the caudate lobe of the liver considered, TACE was performed once again, and during the next follow-up of 10 months did not reveal new intrahepatic lesions or distant metastases.

These cases demonstrate that the addition of palliative surgery to conversion therapy in a selected population with a high tumor burden could benefit patients with initially unresectable HCC.

The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC).

We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability.

We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures.

Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.

Hepatocellular carcinoma (HCC) is a malignancy associated with high morbidity and mortality rates. Conversion therapy provides patients with unresectable HCC (uHCC) the opportunity to undergo radical treatment and achieve long-term survival. Despite accumulating evidence regarding the efficacy of conversion therapy, the optimal treatment approach for such therapy remains uncertain. Lenvatinib (LEN) has shown efficacy and tolerable rates of adverse events (AEs) when applied in combination with immune checkpoint inhibitors (ICIs) or locoregional therapy (LRT) over the past decade. Therefore, the present meta-analysis was performed to systematically assess the safety and efficacy of LEN-based treatment regimens in conversion therapies for uHCC. Data on outcomes, including the conversion rate, objective response rate (ORR), disease control rate (DCR) and AE incidence in patients with uHCC, were collected. A systematic literature search was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases, up to the date of September 1, 2023. In total, 16 studies, encompassing a total of 1,650 cases of uHCC, were included in the final meta-analysis. The pooled conversion rates for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were calculated to be 0.04 (95% CI, 0.00-0.07; I2=77%), 0.23 (95% CI, 0.16-0.30; I2=66%), 0.14 (95% CI, 0.10-0.18; I2=0%) and 0.35 (95% CI, 0.23-0.47; I2=88%), respectively. The pooled ORRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were found to be 0.45 (95% CI, 0.23-0.67; I2=96%), 0.49 (95% CI, 0.39-0.60; I2=78%), 0.43 (95% CI, 0.24-0.62; I2=88%) and 0.69 (95% CI, 0.56-0.82; I2=92%), respectively. The pooled DCRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were observed to be 0.77 (95% CI, 0.73-0.81; I2=23%), 0.82 (95% CI, 0.69-0.95; I2=90%), 0.67 (95% CI, 0.39-0.94; I2=94%) and 0.87 (95% CI, 0.82-0.93; I2=67%), respectively. The pooled grade ≥3 AEs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were 0.25 (95% CI, 0.14-0.36; I2=89%), 0.43 (95% CI, 0.34-0.53; I2=23%), 0.42 (95% CI, 0.19-0.66; I2=81%) and 0.35 (95% CI, 0.17-0.54; I2=94%), respectively. These findings suggested that LEN-based combination strategies may confer efficacy and acceptable tolerability for patients with uHCC. In particular, LEN + ICI, with or without LRT, appears to represent a highly effective conversion regimen, with an acceptable conversion rate and well-characterized safety profile.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer associated with an appalling prognosis. The diagnosis and management of this entity have been challenging to physicians, radiologists, surgeons, pathologists, and oncologists alike. The diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin, a progenitor cell marker, have been explored recently. With a better understanding of biology and the clinical course of cHCC-CCA, newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare disease. In this review, we give an account of the recent developments in the pathology, diagnostic approach, and management of cHCC-CCA.

Programmed cell death protein-1 (PD-1) inhibitors have shown promising clinical efficacy in treating advanced hepatocellular carcinoma (HCC). However, little evidence exists regarding their treatment patterns and outcomes in real-world practice in China. This study aimed to investigate real-world treatment patterns and outcomes of PD-1 inhibitors as first-line therapies for patients with advanced HCC in China.

The study population included adult patients with advanced HCC who were initially treated with PD-1 inhibitors from April 2020 to November 2022 in China. Descriptive statistics were used to report first-line treatment patterns and associations between patient characteristics and the most frequently used treatment patterns. The effectiveness of first-line treatment with PD-1 inhibitors was also evaluated according to survival and tumor response.

The analyses enrolled 480 patients. The four most frequently used first-line treatment patterns of camrelizumab, tislelizumab, camrelizumab + TACE, and tislelizumab + TACE showed statistical differences in patient characteristics of gender, HBV infection, liver cirrhosis, BCLC stage, and portal vein tumor thrombus (all P < 0.05). However, there was no significant difference in median progression-free survival among the first-line treatments of tislelizumab, camrelizumab, and tislelizumab + TACE (not reached vs. 4.4 months vs. 3.6 months, P = 0.5178). The three groups had similar objective response rates (25.0 % vs. 28.6 % vs. 28.6 %, P = 0.927), and disease control rates (73.1 % vs. 78.6 % vs. 64.3 %, P = 0.573) with no statistical significance.

Our findings provided insights into potential therapeutic strategies of PD-1 inhibitors in first-line settings for advanced HCC in real-world practice in China. It was recommended to consider patient characteristics associated with therapeutic options when making clinical decisions. Prospective randomized controlled studies with larger sample sizes and longer follow-up times were warranted further to verify the potential clinical benefits of PD-1 inhibitors.

Renal cell carcinoma originates from the lining of the proximal convoluted renal tubule and represents the most common type of kidney cancer. Risk factors and comorbidities might be associated to renal cell carcinoma, while a small fraction of 2-3% emerges from patients with predisposing cancer syndromes, typically associated to hereditary mutations in VHL, folliculin, fumarate hydratase or MET genes. Here, we report a case of renal cell carcinoma in patient with concurrent germline mutations in BRCA1 and RAD51 genes. This case displays an unusual high mutational burden and chromosomal aberrations compared to the typical profile of renal cell carcinoma. Mutational analysis on whole genome sequencing revealed an enrichment of the MMR2 mutational signature, which is indicative of impaired DNA repair capacity. Overall, the tumor displayed a profile of unusual high genomic instability which suggests a possible origin from germline predisposing mutations in the DNA repair genes BRCA1 and RAD51. While BRCA1 and RAD51 germline mutations are well-characterised in breast and ovarian cancer, their role in renal cell carcinoma is still largely unexplored. The genomic instability detected in this case of renal cell carcinoma, along with the presence of unusual mutations, might offer support to clinicians for the development of patient-tailored therapies.

To establish and verify a prognostic nomogram model for selecting in unresectable hepatocellular carcinoma (uHCC) treated by transarterial chemoembolization plus lenvatinib (TACE-L) with or without PD-1 inhibitor.

Data of 241 uHCC patients who underwent TACE-L (n = 128) and TACE-L plus PD-1 inhibitor (TACE-L-P, n = 113) were retrospectively reviewed. The differences in tumour responses, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) between two groups were compared, and a prognostic nomogram model was established based on independent clinical-radiologic factors and confirmed by Cox regression analysis for predicting PFS and OS. The treatment selection for uHCC patients was stratified by the nomogram score.

Compared to TACE-L, TACE-L-P presented prolonged PFS (14.0 vs. 9.0 months, P < .001), longer OS (24.0 vs. 15.0 months, P < .001), and a better overall objective response rate (54.0% vs. 32.8%, P = .001). There was no significant difference between the rate of AEs in the TACE-L-P and the TACE-L (56.64% vs. 46.09%, P = .102) and the rate of grade ≥ 3 AEs (11.50% vs. 9.38%, P = .588), respectively. The nomogram model presented good discrimination, with a C-index of 0.790 for predicting PFS and 0.749 for predicting OS. Patients who underwent TACE-L and obtained a nomogram score >9 demonstrated improved 2-year PFS when transferred to TACE-L-P, and those with a nomogram ≤25 had better 2-year OS when transferred to TACE-L-P.

TACE-L-P showed significant improvements in efficiency and safety for uHCC patients compared with TACE-L. The nomogram was useful for stratifying treatment decisions and selecting a suitable population for uHCC patients.

Prognostic nomogram model is of great value in predicting individualized survival benefits for uHCC patients after TACE-L or/and TACE-L-P. And the nomogram was helpful for selection between TACE-L-P and TACE-L among uHCC patients.

The objective of this study was to systematically analyse methodological and structural assumptions utilised in model-based health economic evaluations of systemic advanced hepatocellular carcinoma (HCC) therapies, discuss the existing challenges, and develop methodological recommendations for future models in advanced HCC.

We performed literature searches using five databases (Embase, PubMed, Web of Science, Econlit, and CNKI) up to December 4, 2022. Technology appraisals from Canada, England, Australia, and the United States were also considered. Model-based full economic evaluations of systemic advanced HCC therapies in English or Chinese met the eligibility criteria. The reporting quality was assessed by using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist.

Of 12,863 records retrieved, 55 were eligible for inclusion. Markov model (n = 29, 53%) and partitioned survival model (n = 27, 49%) were the most commonly used modelling techniques. Most studies were based on health-state-driven structure (n = 51, 93%), followed by treatment-line-driven structure (n = 2, 4%) and combination structure (n = 1, 2%). Only three studies (5%) adopted external real-world data to extrapolate the overall survival or calibrate the extrapolation. Few studies reported the assumptions of transition probabilities. Utility modelling approaches were state-based (n = 51, 93%) and time-to-death (n = 1, 2%). Only 13 studies (24%) reported five types of model validation. Economic evaluation results of specific treatment strategies varied among studies.

Disease modelling for health economic evaluations of systemic therapies in advanced HCC has adopted various modelling approaches and assumptions, leading to marked uncertainties in results. By proposing methodological recommendations, we suggest that future model-based studies for health economic evaluation of HCC therapies should follow good modelling practice guidelines and improve modelling methods to generate reliable health and economic evidence.

Hepatocellular carcinoma (HCC) is one of the most common leading causes of cancer death worldwide. As most patients are diagnosed with advanced disease, systemic therapy remains the backbone of treatment. In recent years, we have witnessed the transformation of advanced HCC treatment landscapes from single-agent targeted therapies to immunotherapy combinations, with atezolizumab plus bevacizumab becoming the new first-line standard of care with an increase in overall survival, progression-free survival, and objective response rate compared to sorafenib, and a positive impact on quality of life. Although the efficacy and safety of this combination have been confirmed regardless of ethnicity, age, and etiology, only a subgroup of patients seems to benefit the most from this treatment. Currently, predictive serum and tissue biomarkers to select patients who are most likely to respond to atezolizumab plus bevacizumab are lacking. Moreover, the optimal subsequent therapy for patients who progress on first-line atezolizumab plus bevacizumab remains unknown, clinical trials are ongoing, and real-world data are needed to determine the most effective treatment sequence. Importantly, careful evaluation of bleeding risk and preservation of adequate liver function are fundamental to improve patients' prognosis, especially when subsequent treatments are administered.

Immune checkpoint inhibitors (ICIs) have improved the management of patients with intermediate- and advanced-stage HCC, even making some of them potential candidates for liver transplantation. However, acute rejection has been observed after ICI therapy, challenging its safety in transplant settings. We summarize the key basic impact of immune checkpoints on HCC and liver transplantation. We analyze the available case reports and case series on the use of ICI therapy prior to and after liver transplantation. A three-month washout period is desirable between ICI therapy and liver transplantation to reduce the risk of acute rejection. Whenever possible, ICIs should be avoided after liver transplantation, and especially so early after a transplant. Globally, more robust prospective data in the field are required.

Immune checkpoint inhibitors (ICIs)-based therapy has recently been demonstrated to greatly ameliorate survival outcomes in advanced hepatocellular carcinoma (HCC). We aimed to evaluate clinical outcomes of ICIs-based monotherapy and combination therapy as first-line treatment of adults with advanced HCC in real-world practice by conducting a systematic literature review and meta-analysis.

PubMed, Web of Science, and Embase were searched up to 25 April 2022. Retrospective or prospective real-world studies evaluating progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) of patients with advanced HCC receiving first-line ICIs-based therapy were included.

Of 7805 studies retrieved, 38 were deemed eligible for inclusion. For patients receiving first-line ICIs-based therapy in real-world practice, the pooled median PFS and OS were 7.03 (95% CI: 5.55-8.51) and 14.39 (95% CI: 10.91-17.86) months. The ORR and DCR were 0.432 (95% CI: 0.327-0.538) and 0.756 (95% CI: 0.677-0.836), according to mRECIST 1.1, 0.317 (95% CI: 0.218-0.416) and 0.740 (95% CI: 0.644-0.835), judged by RECIST 1.1. The best outcomes of survival and response rate were observed in ICIs-based combination therapy of ICIs, TKIs, plus LRTs. Furthermore, ORR, DCR judged by mRECIST 1.1, and PFS could be potential prognostic factors for OS.

This research revealed diversified first-line ICIs-based therapies for advanced HCC in real-world practice. Future studies are needed to adopt prospective, multicentric and comparative designs to test the ICIs-based combination therapies, especially triple therapies of ICIs, TKIs, plus LRTs.