Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.

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Expression of Cancer testis Antigens in Tumor-adjacent Normal Liver Predicts Post-resection Recurrence of Hepatocellular Carcinoma

10.21203/rs.3.rs-45347/v1 ◽

2020 ◽

Author(s):

Lisanne Noordam ◽

Zhouhong Ge ◽

Hadiye Özturk ◽

Michail Doukas ◽

Shanta Mancham ◽

...

Keyword(s):

Protein Expression ◽

Mrna Level ◽

Tumor Resection ◽

Hepatocellular Cancer ◽

Recurrence Rates ◽

Curative Intent ◽

Cancer Testis Antigens ◽

Increased Risk ◽

Hcc Recurrence ◽

Cancer Testis

Abstract Background: High recurrence rates after resection of hepatocellular cancer (HCC) with curative intent and lack of effective therapy for advanced disease impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims of this study were to establish a panel of CTAs that are frequently and selectively expressed in tumors of HCC-patients, and to investigate whether CTAs might be expressed in tumor-free liver tissues of HCC-patients.Methods: Surgically-resected tumor and paired tumor-free (TFL) tissues of HCC patients (n=100), healthy livers (n=21), and other healthy tissues (n=22 different tissues) were assessed for mRNA expression of 49 carefully selected CTAs by RT-qPCR. Protein expression of 5 CTAs was determined by immunohistochemistry (n=78).Results: Twelve CTAs were expressed at mRNA level in ≥10% of HCC-tumor tissues and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein expression was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA expression in TFL was an independent negative prognostic factor for HCC-recurrence and survival after tumor resection.Conclusions: We established a novel panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients, that can be safely used for immunotherapeutic targeting of HCC. The increased risk of HCC recurrence in patients with CTA expression in TFL suggests that CTA-expressing (pre-)malignant cells may be a source of HCC recurrence. Therefore, immunotherapeutic targeting of these antigens should be considered as adjuvant therapy to prevent HCC-recurrence after tumor resection. Lay summary:Expression of multiple defined cancer testis antigens in non-cancerous liver tissue is associated with significantly increased cancer-recurrence and worse patient survival after tumor resection. We propose that immunotherapeutic targeting of these antigens may prevent HCC recurrence after tumor resection.

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Identification of the cancer/testis antigens AKAP3 and CTp11 by SEREX in hepatocellular carcinoma

Oncology Reports ◽

10.3892/or.2012.2002 ◽

2012 ◽

Vol 28 (5) ◽

pp. 1792-1798 ◽

Cited By ~ 17

Author(s):

MYUNG-HA SONG ◽

KYUNG-UN CHOI ◽

DONG-HOON SHIN ◽

CHANG-HUN LEE ◽

SANG-YULL LEE

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Testis Antigens ◽

Cancer Testis

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Role of Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation

Progress in Transplantation ◽

10.1177/1526924816664083 ◽

2016 ◽

Vol 26 (4) ◽

pp. 348-355 ◽

Cited By ~ 13

Author(s):

Nicola de’Angelis ◽

Filippo Landi ◽

Marco Nencioni ◽

Anais Palen ◽

Eylon Lahat ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Survival Rates ◽

Early Recurrence ◽

Best Supportive Care ◽

Curative Intent ◽

Sorafenib Group ◽

Hepatocellular Carcinoma Recurrence ◽

Retrospective Comparative Study ◽

Hcc Recurrence

Context: The management of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is challenging, especially if it is not treatable by surgery or embolization. Objectives: The present study aims to compare the survival rates of liver transplanted patients receiving sorafenib or best supportive care (BSC) for HCC recurrence not amenable to curative intent treatments. Design: This is a retrospective comparative study on a prospectively maintained database. Participants: Liver transplanted patients with untreatable HCC recurrence receiving BSC (n = 18) until 2007 or sorafenib (n = 15) thereafter were compared. Results: No group difference was observed for demographic characteristics at the time of transplantation and at the time of HCC recurrence. On the explant pathology of the native liver, 81.2% patients were classified within the Milan criteria, and 53.1% presented with microvascular invasion. Hepatocellular carcinoma recurrence was diagnosed 17.8 months (standard deviation: 14.5) after LT, with 17 (53.1%) patients presenting with early recurrence (≤12 months). The 1-year survival from untreatable progression of HCC recurrence was 23.9% for the BSC and 60% for the sorafenib group ( P = .002). The type of treatment (sorafenib vs BSC) was the sole independent predictor of survival (hazard ratio: 2.98; 95% confidence interval: 1.09-8.1; P = .033). In the sorafenib group, 8 (53.3%) patients required dose reduction, and 2 (13.3%) patients discontinued the treatment due to intolerable side effects. Conclusion: Sorafenib improves survival and is superior to the BSC in cases of untreatable posttransplant hepatocellular carcinoma recurrence.

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mTOR Expression in Liver Transplant Candidates with Hepatocellular Carcinoma: Impact on Histological Features and Tumour Recurrence

International Journal of Molecular Sciences ◽

10.3390/ijms20020336 ◽

2019 ◽

Vol 20 (2) ◽

pp. 336 ◽

Cited By ~ 2

Author(s):

Marta Guerrero ◽

Gustavo Ferrín ◽

Manuel Rodríguez-Perálvarez ◽

Sandra González-Rubio ◽

Marina Sánchez-Frías ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplant ◽

Cox Regression ◽

Cell Signalling ◽

Mtor Pathway ◽

Tumour Recurrence ◽

Recurrence Rates ◽

Explanted Liver ◽

Peritumoral Tissue ◽

Hcc Recurrence

(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012–2015). MTOR pathway expression was evaluated in the explanted liver by using the “PathScan Intracellular Signalling Array Kit” (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 ± 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (ΔSignal 22.2%; p < 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) ΔSignal 18.2%, p = 0.004; phospho-AMPKa (Thr172) ΔSignal 56.3%, p < 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) ΔSignal 33.3%, p < 0.001 and phospho-S6RP (Ser235/236) ΔSignal 54.6%, p < 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral p = 0.01; peritumoral p = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, p = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates.

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Follow-Up Liver Stiffness Measurements after Liver Resection Influence Oncologic Outcomes of Hepatitis-B-Associated Hepatocellular Carcinoma with Liver Cirrhosis

Cancers ◽

10.3390/cancers11030425 ◽

2019 ◽

Vol 11 (3) ◽

pp. 425 ◽

Cited By ~ 1

Author(s):

Jung Lee ◽

Hyun Lee ◽

Seung Kim ◽

Sang Ahn ◽

Kwan Lee

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Hepatitis B ◽

Antiviral Therapy ◽

Liver Stiffness ◽

Late Recurrence ◽

Oncologic Outcomes ◽

Increased Risk ◽

Hcc Recurrence

The severity of liver fibrosis can be noninvasively evaluated by measuring liver stiffness (LS) using transient elastography. This study aimed to evaluate the prognostic value of achieving low liver stiffness measurement (LSM) in patients with cirrhosis confirmed from the resected liver due to hepatocellular carcinoma (HCC). A total of 184 patients that received curative surgery for HCC related to the hepatitis B virus at Barcelona Clinic Liver Cancer stage 0–A, and had a METAVIR fibrosis score of 4 were investigated. LSM significantly decreased after antiviral therapy during follow-up (p = 0.001), and achieving LSM ≤8 kilopascal (kPa) suggested a reduced risk of late recurrence (>12 months) (hazard ratio (HR), 0.519; 95% confidence interval (CI), 0.307–0.877; p = 0.014). Older age at surgery (≥45 years) and multiple HCC nodules predicted an increased risk of late recurrence (HR, 3.270; 95% CI, 1.296–8.251; p = 0.012; and HR, 3.146; 95% CI, 1.396–7.089; p = 0.006). Decreased LSM also suggested decreased mortality (HR, 0.251; 95% CI, 0.086–0.756; p = 0.045) along with baseline low aspartate aminotransferase-to-platelet ratio index (APRI) score (<1.5) (HR, 0.251; 95% CI, 0.086–0.759; p = 0.041). Having early HCC recurrence (HR, 9.416; 95% CI, 3.566–24.861; p < 0.001) and microvascular tumor invasion (HR, 3.191; 95% CI, 1.188–8.568; p = 0.021) predicted increased mortality. Among HCC patients with liver cirrhosis under antiviral therapy, achieving low LSM (≤8 kPa) predicted reduced late HCC recurrence.

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Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study

Cancers ◽

10.3390/cancers13092257 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2257

Author(s):

Joji Tani ◽

Tomonori Senoh ◽

Akio Moriya ◽

Chikara Ogawa ◽

Akihiro Deguchi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Antiviral Treatment ◽

Survival Rates ◽

Long Term Outcomes ◽

Recurrence Rates ◽

Virus Eradication ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Hcc Recurrence

There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924–8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016–1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.

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Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients

Clinical and Molecular Hepatology ◽

10.3350/cmh.2020.0016 ◽

2020 ◽

Vol 26 (4) ◽

pp. 516-528

Author(s):

Jihye Kim ◽

Wonseok Kang ◽

Dong Hyun Sinn ◽

Geum-Youn Gwak ◽

Yong-Han Paik ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Radiofrequency Ablation ◽

Recurrence Rate ◽

Early Stage ◽

Cancer Staging ◽

High Recurrence Rate ◽

Recurrence Rates ◽

Substantial Risk ◽

Hcc Recurrence

Background/Aims: Although hepatocellular carcinoma (HCC) is notorious for its high recurrence rate, some patients do not experience recurrence for more than 5 years after resection or radiofrequency ablation for early-stage HCC. For those with five recurrence-free period, the risk of HCC recurrence within the next 5 years remains unknown.Methods: A total of 1,451 consecutive patients (median, 55 years old; males, 79.0%; hepatitis B virus-related, 79.3%) with good liver function (Child-Pugh class A) diagnosed with early-stage HCC by Barcelona Clinic Liver Cancer Staging and received radiofrequency ablation or resection as an initial treatment between 2005 and 2010 were analyzed.Results: During a median follow-up period of 8.1 years, 961 patients (66.2%) experienced HCC recurrence. The cumulative recurrence rates increased to 39.7%, 60.3%, and 71.0% at 2, 5, and 10 years, respectively, and did not reach a plateau. Five years after HCC diagnosis, 487 patients were alive without experiencing a recurrence. Among them, during a median of 3.9 additional years of follow-up (range, 0.1–9.0 years), 127 patients (26.1%) experienced recurrence. The next 5-year cumulative recurrence rate (5–10 years from initial diagnosis) was 27.0%. Male sex, higher fibrosis-4 scores, and alpha-fetoprotein levels at 5 years were associated with later HCC recurrence among patients who did not experience recurrence for more than 5 years.Conclusions: The HCC recurrence rate following 5 recurrence-free years after HCC treatment was high, indicating that HCC patients warrant continued HCC surveillance, even after 5 recurrence-free years.

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Expression of cancer-testis antigens in hepatocellular carcinoma

World Journal of Gastroenterology ◽

10.3748/wjg.v10.i14.2034 ◽

2004 ◽

Vol 10 (14) ◽

pp. 2034 ◽

Cited By ~ 21

Author(s):

Li Zhao

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Testis Antigens ◽

Cancer Testis

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Application of cancer-testis antigens in immunotherapy of hepatocellular carcinoma

Immunotherapy ◽

10.2217/imt-2017-0154 ◽

2018 ◽

Vol 10 (5) ◽

pp. 411-421 ◽

Cited By ~ 8

Author(s):

Mahnaz Seifi-Alan ◽

Roshanak Shamsi ◽

Soudeh Ghafouri-Fard

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Testis Antigens ◽

Cancer Testis

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Recurrence of hepatocellular carcinoma after liver transplantation: Comparison between superselective and non-superselective chemoembolization.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.238 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 238-238

Author(s):

Andrew Smith ◽

Michael Heckman ◽

Daniel Serie ◽

Denise M Harnois ◽

Justin H. Nguyen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Necrosis ◽

Multivariable Analysis ◽

Tumor Stage ◽

Meld Score ◽

Recurrence Rates ◽

Exact Test ◽

Risk Of Death ◽

Strong Trend ◽

Hcc Recurrence

238 Background: To compare post-transplant recurrence rates of hepatocellular carcinoma (HCC) and differences in percent tumor necrosis in patients with pre-operative superselective chemoembolization (CE) vs. non-superselective CE. Methods: Retrospective review of 147 patients with liver transplant (LT) for HCC treated with pre-operative CE. Those transplanted less than 24 hours after CE and those who had other concomitant treatments were excluded. The angiographic studies and written reports were reviewed to categorize patients into superselective and non-superselective groups. CE was done with an emulsion of lipiodol, cisplatin, doxorubicin, mitomycin C, and contrast, with or without embolization particles. Superselective CE was defined as treatment directly into the vessel(s) feeding the tumor. Treatment from more proximal vessels was considered non-superselective. Data gathered included age, gender, date of CE, date of LT, tumor size and number, tumor stage, MELD score, Child-Pugh class, alpha fetoprotein, percent tumor necrosis at explant, date of recurrence, date and cause of death, and date of last follow-up. Patient and disease characteristics and percent tumor necrosis were analyzed with a Wilcoxon rank sum test or Fisher’s exact test. The Kaplan-Meier method was used to estimate the cumulative incidences of death due to recurrent disease after LT. Results: 99 patients were included, 53 had superselective CE and 46 non-superselective. HCC recurrence rates at 1, 3, 5, and 8 years were all significantly less for superselective CE compared to non-superselective CE (p = 0.039 single, p = 0.011 multivariable). Using multivariable analysis, superselective CE had a lower risk of death due to recurrent HCC at 1, 3, 5, and 8 years (p = 0.046). There was a trend toward more percent tumor necrosis after superselective CE, but it did not reach significance (p = 0.057). Conclusions: This study provides evidence that HCC recurrence after LT and death due to recurrent HCC is lower after pre-LT superselective CE versus non-superselective CE. The strong trend for greater percent tumor necrosis with superselective CE may explain the differences in recurrence rate.

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