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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 17937

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Dr. Atsushi Ono

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Guest Editor

Department of Gastroenterology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
Interests: carcinogenesis, biomarker and microenvironment of hepatocellular carcinoma

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, also associated with poor prognosis. Novel systemic treatments for intermediate to advanced HCC, including chemotherapy, molecularly targeted therapy, immune checkpoint inhibitor immunotherapy and their combinations, have been evolving rapidly. Furthermore, the efficacies of therapeutic strategies, such as conversion therapy after systemic therapy or a recurrence prevention treatment after curative treatment, have previously been discussed.

To improve patient outcomes through the use of well-timed optimal treatments, it is necessary to deepen our knowledge of each treatment and develop novel agents/regimens.

This Special Issue aims to review the current literature and provide novel findings regarding systemic therapy mechanisms, biomarkers and strategies for advanced HCC.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

The mechanism of responsiveness/resistance to therapeutic agents.
Biomarkers predicting responsiveness/resistance.
Novel therapeutic candidates overcoming resistance to current therapies.
Therapeutic strategies for treatment methods after first-line treatment.

I look forward to receiving your contributions.

Dr. Atsushi Ono
Guest Editor

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Keywords

hepatocellular carcinoma
systemic therapy
molecularly targeted therapy
immune checkpoint inhibitor
conversion therapy
prevention treatment
biomarker

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Published Papers (9 papers)

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Research

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11 pages, 1147 KiB

Open AccessArticle

Impact of KIR-HLA Genotype on Natural-Killer-Cell-Based Immunotherapy for Preventing Hepatocellular Carcinoma after Living-Donor Liver Transplantation

by Naoki Tanimine, Masahiro Ohira, Emi Kurita, Ryosuke Nakano, Hiroshi Sakai, Hiroyuki Tahara, Kentaro Ide, Tsuyoshi Kobayashi, Yuka Tanaka and Hideki Ohdan

Cancers 2024, 16(3), 533; https://doi.org/10.3390/cancers16030533 - 26 Jan 2024

Cited by 2 | Viewed by 1675

Abstract

Natural killer (NK) cells have immunosurveillance potential in hepatocellular carcinoma (HCC). We performed adaptive immunotherapy using donor-liver-derived natural killer (NK) cells after living-donor liver transplantation (LDLT) to prevent HCC recurrence. Dominant inhibitory signals tightly regulate NK cell activity via human leukocyte antigen (HLA)-specific inhibitory receptors, such as killer immunoglobulin-like receptors (KIRs). The functional recognition of HLA through KIR raises the NK cell capacity, which is a process termed “licensing.” Here, we investigated the effect of polymorphic KIR-HLA genotypes on the efficacy of NK-cell-based immunotherapy after LDLT. Seventy-seven Japanese recipients with HCC who underwent LDLT and their corresponding donors between 1996 and 2016 were enrolled in this study. The median follow-up period was 8.3 years. The HCC recurrence risk was stratified using radiological and pathological assessments according to the Milan criteria. Of the 77 recipients, 38 received immunotherapy. Immunotherapy improves early post-transplantation survival and lowers the recurrence rate in the intermediate-risk recipients. We analyzed the genotypes of five inhibitory KIRs and HLA using sequence-specific polymorphism-based typing. The polymorphic KIR-HLA genotype revealed that genetically vulnerable liver transplant recipients with a poorly licensed NK genotype have an improved prognosis by immunotherapy with donor-liver-derived NK cells. Thus, the combination of recipient and donor KIR-HLA genotypes is worthy of attention for further investigation, especially considering the clinical application of NK-cell-based immunotherapy. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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13 pages, 1184 KiB

Open AccessArticle

Survival Improvements in Advanced Hepatocellular Carcinoma with Sequential Therapy by Era

by Yoshiko Nakamura, Masashi Hirooka, Atsushi Hiraoka, Yohei Koizumi, Ryo Yano, Makoto Morita, Yuki Okazaki, Yusuke Imai, Hideko Ohama, Kana Hirooka, Takao Watanabe, Fujimasa Tada, Osamu Yoshida, Yoshio Tokumoto, Masanori Abe and Yoichi Hiasa

Cancers 2023, 15(21), 5298; https://doi.org/10.3390/cancers15215298 - 6 Nov 2023

Cited by 2 | Viewed by 1462

Abstract

Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009–2013, n = 86; period 2: 2014–2018, n = 132; period 3: 2019–2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1–3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin–bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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11 pages, 6268 KiB

Open AccessArticle

Dose Consideration of Lenvatinib’s Anti-Cancer Effect on Hepatocellular Carcinoma and the Potential Benefit of Combined Colchicine Therapy

by Zu-Yau Lin, Ming-Lun Yeh, Po-Cheng Liang, Po-Yao Hsu, Chung-Feng Huang, Jee-Fu Huang, Chia-Yen Dai, Ming-Lung Yu and Wan-Long Chuang

Cancers 2023, 15(20), 5097; https://doi.org/10.3390/cancers15205097 - 22 Oct 2023

Cited by 1 | Viewed by 1502

Abstract

Purpose: The dose-dependent anti-cancer effect of lenvatinib on hepatocellular carcinoma (HCC) cells and the potential benefit of combined colchicine therapy were investigated. Methods: Four primary cultured HCC (S103, S143, S160, S176) cell lines were investigated by differential expressions of genes (11 lenvatinib target genes and NANOG) and anti-proliferative effect using clinically achievable plasma lenvatinib (250, 350 ng/mL) and colchicine (4 ng/mL) concentrations. Results: Colchicine showed an anti-proliferative effect on all cell lines. Lenvatinib at 250 ng/mL inhibited proliferation in all cell lines, but 350 ng/mL inhibited only three cell lines. For lenvatinib target genes, colchicine down-regulated more genes and up-regulated less genes than lenvatinib did in three cell lines. Lenvatinib up-regulated NANOG in all cell lines. Colchicine down-regulated NANOG in three cell lines but up-regulated NANOG with less magnitude than lenvatinib did in S103. Overall, combined colchicine and 250 ng/mL lenvatinib had the best anti-cancer effects in S143, with similar effects with combined colchicine and 350 ng/mL lenvatinib in S176 but less effects than combined colchicine and 350 ng/mL lenvatinib in S103 and S160. Conclusions: Lenvatinib does not show a dose-dependent anti-cancer effect on HCC. Combined colchicine and lenvatinib can promote the total anti-cancer effects on HCC. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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17 pages, 3525 KiB

Open AccessArticle

Association of Hepatobiliary Phase of Gadoxetic-Acid-Enhanced MRI Imaging with Immune Microenvironment and Response to Atezolizumab Plus Bevacizumab Treatment

by Yosuke Tamura, Atsushi Ono, Hikaru Nakahara, Clair Nelson Hayes, Yasutoshi Fujii, Peiyi Zhang, Masami Yamauchi, Shinsuke Uchikawa, Yuji Teraoka, Takuro Uchida, Hatsue Fujino, Takashi Nakahara, Eisuke Murakami, Masataka Tsuge, Masahiro Serikawa, Daiki Miki, Tomokazu Kawaoka, Wataru Okamoto, Michio Imamura, Yuko Nakamura, Kazuo Awai, Tsuyoshi Kobayashi, Hideki Ohdan, Masashi Fujita, Hidewaki Nakagawa, Kazuaki Chayama, Hiroshi Aikata and Shiro Oka Show full author list Hide full author list

Cancers 2023, 15(17), 4234; https://doi.org/10.3390/cancers15174234 - 24 Aug 2023

Viewed by 1611

Abstract

It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting the immune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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13 pages, 1875 KiB

Open AccessArticle

Early Prediction of Response Focused on Tumor Markers in Atezolizumab plus Bevacizumab Therapy for Hepatocellular Carcinoma

by Norikazu Tanabe, Issei Saeki, Yuki Aibe, Takashi Matsuda, Tadasuke Hanazono, Maiko Nishi, Isao Hidaka, Shinya Kuwashiro, Shogo Shiratsuki, Keiji Matsuura, Maho Egusa, Natsuko Nishiyama, Tsuyoshi Fujioka, Daiki Kawamoto, Ryo Sasaki, Tatsuro Nishimura, Takashi Oono, Takuro Hisanaga, Toshihiko Matsumoto, Tsuyoshi Ishikawa, Takahiro Yamasaki and Taro Takami Show full author list Hide full author list

Cancers 2023, 15(11), 2927; https://doi.org/10.3390/cancers15112927 - 26 May 2023

Cited by 5 | Viewed by 1887

Abstract

Despite the promising efficacy of atezolizumab plus bevacizumab (atezo/bev), some patients with unresectable hepatocellular carcinoma (HCC) experience disease progression. This retrospective study, which included 154 patients, aimed to evaluate predictors of treatment efficacy of atezo/bev for unresectable HCC. Factors associated with treatment response were examined, focusing on tumor markers. In the high-alpha-fetoprotein (AFP) group (baseline AFP ≥ 20 ng/mL), a decrease in AFP level > 30% was an independent predictor of objective response (odds ratio, 5.517; p = 0.0032). In the low-AFP group (baseline AFP < 20 ng/mL), baseline des-gamma-carboxy prothrombin (DCP) level < 40 mAU/mL was an independent predictor of objective response (odds ratio, 3.978; p = 0.0206). The independent predictors of early progressive disease were an increase in AFP level ≥ 30% at 3 weeks (odds ratio, 4.077; p = 0.0264) and the presence of extrahepatic spread (odds ratio, 3.682; p = 0.0337) in the high-AFP group and up-to-seven criteria, OUT (odds ratio, 15.756; p = 0.0257) in the low-AFP group. In atezo/bev therapy, focusing on early AFP changes, baseline DCP, and tumor burden of up-to-seven criteria are useful in predicting response to treatment. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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13 pages, 1139 KiB

Open AccessArticle

Pretreatment Proteinuria Predicts the Prognosis of Patients Receiving Systemic Therapy for Unresectable Hepatocellular Carcinoma

by Kazuyuki Mizuno, Norihiro Imai, Takafumi Yamamoto, Shinya Yokoyama, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Takashi Honda, Teiji Kuzuya, Masatoshi Ishigami and Hiroki Kawashima

Cancers 2023, 15(10), 2853; https://doi.org/10.3390/cancers15102853 - 21 May 2023

Cited by 3 | Viewed by 1923

Abstract

Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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13 pages, 1388 KiB

Open AccessArticle

Evaluation of Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma Using the Combination of Response Evaluation Criteria in Solid Tumors and Alpha-Fetoprotein

by Takahiro Kinami, Kei Amioka, Tomokazu Kawaoka, Shinsuke Uchikawa, Shintaro Yamasaki, Masanari Kosaka, Yusuke Johira, Shigeki Yano, Kensuke Naruto, Yuwa Ando, Kenji Yamaoka, Yasutoshi Fujii, Hatsue Fujino, Takashi Nakahara, Atsushi Ono, Eisuke Murakami, Wataru Okamoto, Masami Yamauchi, Daiki Miki, Masataka Tsuge, Michio Imamura, Hiroshi Aikata and Shiro Oka Show full author list Hide full author list

Cancers 2023, 15(8), 2304; https://doi.org/10.3390/cancers15082304 - 14 Apr 2023

Cited by 7 | Viewed by 2308

Abstract

Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is currently positioned as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). It may be difficult to decide whether to continue this treatment if radiological response is assessed as stable disease (SD). Therefore, the relationship between radiological response and prognosis was analyzed. A total of 109 patients with u-HCC and Child–Pugh Score of 5–7 received this treatment. Radiological response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at the first and second evaluations. Of SD patients (n = 71) at the first RECIST evaluation, partial response, SD, and progressive disease (PD) were seen in 10, 55, and 6 patients, respectively, at the second evaluation. On multivariate analysis, in patients with SD at the first RECIST evaluation, a 25% or greater increase in the alpha-fetoprotein (AFP) value from initiation of treatment (odds ratio, 7.38; p = 0.037) was the independent factor for PD at the second evaluation. In patients with SD (n = 59) at the second RECIST evaluation, decreased AFP from initiation of treatment (hazard ratio, 0.46; p = 0.022) was the independent factor related to progression-free survival on multivariate analysis. AFP trends could help decide the Atezo + Beva treatment strategy. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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14 pages, 1435 KiB

Open AccessArticle

Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma

by Zijian Yang, Goki Suda, Osamu Maehara, Masatsugu Ohara, Tomoka Yoda, Takashi Sasaki, Risako Kohya, Sonoe Yoshida, Shunichi Hosoda, Yoshimasa Tokuchi, Takashi Kitagataya, Kazuharu Suzuki, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi and Naoya Sakamoto

Cancers 2023, 15(3), 593; https://doi.org/10.3390/cancers15030593 - 18 Jan 2023

Cited by 6 | Viewed by 2297

Abstract

The possible mechanisms of resistance to atezolizumab/bevacizumab for unresectable HCC, and the subsequent response to these therapies, remain underexplored. The sequential changes in serum growth factors, including VEGF-A, VEGF-C, VEGF-D, ANG-2, FGF-19, HGF, and EGF during atezolizumab/bevacizumab for unresectable HCC were evaluated in 46 patients. Patients who experienced PD after CR, PR, or SD to atezolizumab/bevacizumab were evaluated. A total of 4, 9, 19, and 14 patients showed CR, PR, SD, and PD, respectively. Of 32 patients with disease control, 28 experienced PD after CR, PR, or SD with atezolizumab/bevacizumab. Baseline growth factor levels were similar between patients with or without disease control and those with or without an objective response. Growth factor changes between the baseline and the best overall response points (BOR) for patients with disease control showed that FGF-19 significantly increased and ANG2 significantly decreased at the BOR. Growth factor changes between the BOR and the PD point in 28 patients who experienced PD after disease control showed that VEGF-D and ANG2 significantly increased at the PD point compared with that at the BOR. Summarily, increased serum VEGF-D and ANG-2 levels might contribute to developing resistance to atezolizumab/bevacizumab for unresectable HCC and might be target molecules in subsequent salvage therapies. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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Review

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18 pages, 1081 KiB

Open AccessReview

Combination Therapy of Immune Checkpoint Inhibitors with Locoregional Therapy for Hepatocellular Carcinoma

by Yasuyuki Tamai, Naoto Fujiwara, Takamitsu Tanaka, Shugo Mizuno and Hayato Nakagawa

Cancers 2023, 15(20), 5072; https://doi.org/10.3390/cancers15205072 - 20 Oct 2023

Cited by 5 | Viewed by 2398

Abstract

Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer–immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC. Full article

(This article belongs to the Special Issue Systemic Therapy for Hepatocellular Carcinoma)

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