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Background/aim: Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy for HCC, the concept of conversion hepatectomy has recently become widespread. The present study aimed to assess the clinical outcomes of sorafenib and lenvatinib for HCC regarding the possibility of conversion hepatectomy in clinical practice., Patients and Methods: A total of 295 patients with advanced HCC receiving sorafenib and lenvatinib, accounting for 306 treatments (sorafenib, n=157; lenvatinib, n=149, 11 patients received lenvatinib after sorafenib treatment) at five different institutions were enrolled. Patients were assessed for their clinical characteristics and therapeutic response using both Response Evaluation Criteria in Solid Tumors criteria (RECIST) and modified RECIST (mRECIST) criteria. Additionally, an indication of surgery after tyrosine kinase inhibitor administration was determined based on the tumor status of patients., Results: The median survival times of patients treated with sorafenib and lenvatinib were 12.8 and 16.4 months, respectively, without significant difference (p=0.1645). The objective response rates (ORR) of sorafenib based on mRECIST and RECIST were 10.1% and 5.9%, respectively, and those of lenvatinib were 38.1% and 19.0%, respectively. Among the 306 treatments, two cases (sorafenib and lenvatinib, one each) underwent hepatectomy after systemic chemotherapy., Conclusion: Few cases with unresectable HCC were amenable to conversion hepatectomy after sorafenib and lenvatinib treatments due to the limited ORR by RECIST. Cautious approach must be taken when administering neoadjuvant chemotherapy aimed at conversion hepatectomy., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The treatment algorithm for systemic therapies for advanced hepatocellular carcinoma (HCC) has changed dramatically; however, the therapeutic landscape for sequential second-line or later-line treatments, including ramucirumab, remains controversial. This study aimed to investigate the role of ramucirumab for treating HCC., Patients and Methods: We retrospectively analyzed data from 17 patients with advanced HCC who received ramucirumab, and 8 of them who received lenvatinib re-administration after ramucirumab treatment failure., Results: The median overall survival of 17 patients treated with ramucirumab was 11.5 months. The median ratios of the 1-month post-treatment α-fetoprotein (AFP) levels and albumin-bilirubin (ALBI) scores to the pre-treatment AFP levels and ALBI scores following ramucirumab treatment were 0.880 and 0.965, respectively. The median ratios of the 1-month post-treatment AFP and ALBI levels to the pre-treatment levels were 1.587 and 0.970 for mALBI grade 1/2a, and 1.313 and 0.936 for mALBI grade 2b/3, respectively. Six of the eight patients who received lenvatinib rechallenge treatment exhibited a decrease in AFP levels one month post-lenvatinib treatment. Deterioration of liver function 3 months post-lenvatinib treatment was noted in five of the eight patients who received lenvatinib rechallenge treatment after ramucirumab., Conclusion: Ramucirumab may be equally useful in patients with unresectable HCC who have poor liver function or whose liver function is aggravated by other therapies. Rechallenge treatment with lenvatinib after ramucirumab may be a valid treatment option for HCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recently, vessels encapsulating tumor clusters (VETC) pattern and macrotrabecular massive (MTM) pattern of hepatocellular carcinoma (HCC) have been reported as aggressive histological types. These histological patterns showed an immunosuppressive tumor immune microenvironment (TIME). Since there have been no reports on the differences of these two subtypes simultaneously, this study examined the immunophenotypes and TIME of MTM-HCC and VETC-HCC immunohistochemically., Patients and Methods: Seventy-four cases of previously diagnosed HCC, including 32 MTM-HCCs, 21 VETC-HCCs, and 21 conventional HCCs, were enrolled in immunohistochemical analysis. We conducted immunohistochemical analysis., Results: We found that MTM-HCC showed less frequent expression of HepPar-1, which is one of the most common hepatocytic markers. In MTM-HCC, the frequency of high expression levels of Keratin19, carbonic anhydrase (CA) IX, and PD-L1 was higher compared to VETC-HCC and conventional HCC. PD-L1 expression was found in 34.4% of MTM-HCC, 0% of VETC-HCC, and 19.0% of conventional HCC. The rate of PD-L1 expression in MTM-HCC was significantly higher than the others (p=0.0015). PD-L1 expression was significantly associated with epithelial cell adhesion molecules and CA IX expression, which are representative markers of tumor stemness and hypoxic conditions, respectively. The CD8 infiltration in VETC-HCC was significantly lower than that in conventional HCC., Conclusion: MTM-HCC had different immunophenotypes and TIMEs compared to HCC with the VETC pattern. Although both had immunosuppressive TIME, the elements forming TIME were quite different. To enhance the immune checkpoint inhibitor efficacy, changing TIME from a suppressive to an active form is essential., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Children with trisomy 18 tend to develop hepatoblastoma. Since the introduction of appropriate management for organ malfunction, individuals with trisomy 18 have come to have a longer life expectancy. However, the predisposition to hepatoblastoma becomes a significant issue for the quality of a case. Here, we present a rare multifocal hepatoblastoma involving predominantly Couinaud segments 5 and 7 in a 10-month-old boy with trisomy 18. Though the first-line cisplatin monotherapy resulted in unsatisfactory tumor shrinkage, the second-line neoadjuvant chemotherapy administrating irinotecan and vincristine gave rise to significant tumor reduction in volume, leading to the completion of partial resection of the liver without the microscopic residual disease. The patient has been free from recurrence for 44 months. Because anatomical right hepatectomy can cause circulatory instability, including acute onset of pulmonary hypertension in trisomy 18 patients, physicians should balance treatment benefits and potential adverse effects. Our successful experience utilizing a combination of efficacious and less cardiotoxic neoadjuvant chemotherapy followed by the partial hepatectomy encourages physicians to treat a patient with trisomy 18 and tackle hepatoblastoma with a genetic background., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

A 60-year-old woman was undergoing chemotherapy for triple-negative breast cancer and multiple liver metastases. One year and 3 months after the start of treatment, blood tests showed worsening liver function and a decrease in the platelet count. Multiple liver metastases tend to shrink on computed tomography, but pseudocirrhosis was suspected because the right lobe of the liver had atrophied and the marginal irregularities were conspicuous. The platelet count decreased because of hypersplenism, and continuing chemotherapy was difficult. Splenic artery embolization was performed by the internal medicine department, and chemotherapy was resumed once the platelet count recovered. Imaging findings consistent with cirrhosis without the typical cirrhosis histopathology are considered as pseudocirrhosis. This phenomenon has been reported for breast cancer. During chemotherapy for liver metastases, attention should be paid to its appearance. Furthermore, liver cirrhosis should be controlled, and chemotherapy should be continued in coordination with the internal medicine department.

Lymphocyte-rich hepatocellular carcinoma (LR-HCC), a newly proposed subtype of HCC, is characterized with abundant lymphocyte infiltration in the tumor. LR-HCC has a relatively good prognosis and is quite rare (<1% of all HCC). We examined LR-HCC clinicopathological and molecular characteristics by analyzing 451 surgically resected HCC cases without any prior treatment history at our hospital between 2012 and 2021. Clinicopathological features of LR-HCC and other HCCs (non-LR-HCC) were compared. Neoplastic and nonneoplastic hepatocytes from LR-HCC (n = 4) were collected with a laser microdissection system; RNA was extracted, followed by microarray analysis to examine lymphocytic infiltration-related molecular targets. Immunohistochemical staining of identified molecular target was performed in LR-HCC and non-LR-HCC. CD3, CD20, and CD8 immunostaining was also performed in LR-HCCs. There were 28 cases of LR-HCC (6%). No statistically significant differences were found in clinicopathological features, except for gross type, between LR-HCC and non-LR-HCC cases. The LR-HCC 5-year survival rate was >90%. Microarray analysis revealed high CCL20 expression in LR-HCC cases; immunohistochemical study showed significantly higher CCL20 expression in LR-HCC (P < 0.01) than in non-LR-HCC. CCR6, the only CCL20 receptor, was observed in infiltrating lymphocytes and HCC cells in LR-HCC. There were significantly more CD3-positive cells than CD20-positive cells (P < 0.0001) in tumor-infiltrating lymphocytes, most of which were CD8-positive T cells. In conclusion, there were no significant differences in clinicopathological characteristics between LR-HCC and non-LR-HCC, except for gross and LR microscopic features. CCL20 expression in LR-HCC may contribute to infiltration of large numbers of CD8-positive lymphocytes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although genome duplication, or polyploidization, is believed to drive cancer evolution and affect tumor features, its significance in hepatocellular carcinoma (HCC) is unclear. We aimed to determine the characteristics of polyploid HCCs by evaluating chromosome duplication and to discover surrogate markers to discriminate polyploid HCCs., Methods: The ploidy in human HCC was assessed by fluorescence in situ hybridization for multiple chromosomes. Clinicopathological and expression features were compared between polyploid and near-diploid HCCs. Markers indicating polyploid HCC were explored by transcriptome analysis of cultured HCC cells., Results: Polyploidy was detected in 36% (20/56) of HCCs and discriminated an aggressive subset of HCC that typically showed high serum alpha-fetoprotein, poor differentiation, and poor prognosis compared to near-diploid HCCs. Molecular subtyping revealed that polyploid HCCs highly expressed alpha-fetoprotein but did not necessarily show progenitor features. Histological examination revealed abundant polyploid giant cancer cells (PGCCs) with a distinct appearance and frequent macrotrabecular-massive architecture in polyploid HCCs. Notably, the abundance of PGCCs and overexpression of ubiquitin-conjugating enzymes 2C indicated polyploidy in HCC and efficiently predicted poor prognosis in combination., Conclusions: Histological diagnosis of polyploidy using surrogate markers discriminates an aggressive subset of HCC, apart from known HCC subgroups, and predict poor prognosis in HCC., (© 2023. The Author(s).)

Background and Aims: We aimed to validate the predictive factors for tumor response and the prognostic impact of conversion therapy aimed at cancer- and drug-free states in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing atezolizumab plus bevacizumab (Atez/Bev) therapy., Methods: This retrospective study enrolled 156 patients who were Child-Pugh class A with u-HCC treated using Atez/Beva. The profile of objective response was investigated using decision-tree analysis. Progression-free, recurrence-free, and overall survival were assessed., Results: The progression-free and overall survival were 6.1 and 18.0 months, respectively. Objective response and disease control rates were 32.0% and 84.0%, respectively. Decision-tree analysis revealed that neutrophil-to-lymphocyte ratio (NLR) <3, modified albumin-bilirubin grade (m-ALBI) 1 or 2a, and age < 75 were sequential splitting variables for the objective response, respectively. In the multivariate analysis, NLR <3 and m-ALBI grade 1 or 2a were identified as predictive factors for objective response. We successfully achieved eligibility for conversion therapy in 17 patients after Atez/Bev therapy significant response. Following conversion therapy, the curative therapy group, including surgical resection or radiofrequency ablation (RFA), had significantly higher recurrence-free survival than did the transcatheter arterial chemoembolization (TACE) and Atez/Bev discontinuation (surgical resection or RFA; not reached vs. TACE; 5.3 months, p = 0.008, Atez/Bev discontinuation; 3.9 months, p = 0.048, respectively) groups., Conclusions: NLR <3 and m-ALBI grade 1 or 2a were predictive factors for conversion therapy, leading to cancer- and drug-free states in patients with u-HCC undergoing Atez/Bev therapy. Moreover, surgery or RFA may be suitable for conversion therapy for cancer-free status., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients' lenvatinib treatment duration., Patients and Methods: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression., Results: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]., Conclusion: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child-Pugh A., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The chemotherapeutic landscape for hepatocellular carcinomas (HCCs) has changed dramatically with the availability of several treatment options. This study aimed to assess the long-term outcomes of lenvatinib treatment and analyze its feasibility in the sequential treatment of HCCs., Patients and Methods: Eighty-five consecutive patients who received lenvatinib for unresectable HCCs were investigated retrospectively. Survival was assessed based on when the patients were first radiologically diagnosed with progressive disease. Among those with radiologically diagnosed stable or progressive disease at 3 months after lenvatinib administration, the cutoff α-fetoprotein (AFP) ratio (ratio of the AFP level after lenvatinib treatment to the pretreatment AFP level) that was predictive of survival was determined using receiver operating characteristic analysis., Results: The median survival time (MST) was significantly worse among patients diagnosed with progressive disease at 1 month after treatment than among those diagnosed at 2-3 or 3-4 months after treatment [MSTs at 1, 2-3, and 3-4 months: 2.2, 10.2, and 17.3 months, respectively (p<0.001)]. An AFP ratio of 1.36 (computed using the AFP level at 3 months after lenvatinib treatment) was significantly predictive of survival in patients with stable or progressive disease (26.3 vs. 11.3 months, p=0.0024)., Conclusion: The prognosis of patients on lenvatinib who develop early progressive disease is dismal. Thus, their treatment should be ceased or switched. The 3-month AFP ratio of 1.36 may be a potentially useful cutoff for considering a switch to other treatments in patients radiologically diagnosed with stable or progressive disease., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We report a case of hepatocellular carcinoma evaluated as complete response by combined lenvatinib and radiofrequency ablation therapy. A 74-year-old man visited our hospital because medical examination abdominal ultrasonography revealed a liver tumor. Abdominal MRI and CT showed a 3.3 cm tumor on the right hepatic vein in segment 7 of the liver, and hepatocellular carcinoma was diagnosed. Lenvatinib was administrated for 6 months, and laparoscopy-assisted radiofrequency ablation was performed as additional treatment. After 1 month, dynamic CT showed the disappearance of intratumoral arterial lesion enhancement and low density lesion area. The therapeutic effect was evaluated as a complete response.

Objectives: This study aimed to analyze the global profile of the literature in non-alcoholic fatty liver disease (NAFLD) research., Background: Non-alcoholic fatty liver disease is a clinically heterogeneous condition characterized by fat accumulation in the liver and the absence of significant alcohol consumption or underlying genetic disorders. These manifestations are associated with inflammation, steatosis, and fibrosis that can develop into cirrhosis and even hepatocellular carcinoma. However, a study about the research trend in NAFLD has never been reported before., Methods: The NAFLD bibliometric analysis was performed on articles indexed in the Scopus database from 1973 to 2022., Results: The total number of articles published worldwide is 28,673 documents, with an annual average of 561 documents. The United States generated the most articles (n = 6548), followed by China (n = 6180), Italy (n = 2434), and Japan (n = 2032). Since 2013, the number of publications on NAFLD has increased dramatically worldwide. The popular topics in the field include medicine, biochemistry, genetics and molecular biology, pharmacology, toxicology and pharmaceutics, and nursing., Conclusions: This study provides a unique composite picture of NAFLD research worldwide and evaluates research productivity from 1973 to 2022. This finding suggests that the prospects for interventions in NAFLD remain promising (Tab. 5, Fig. 4, Ref. 57). Text in PDF www.elis.sk Keywords: bibliometric analysis, NAFLD, Scopus.

Background/aim: Atezolizumab plus bevacizumab and lenvatinib are the key drugs in the current systemic chemotherapeutic regimen for hepatocellular carcinoma (HCC). Studies have reported the potential effectiveness of lenvatinib introduction after an atezolizumab plus bevacizumab treatment; however, the therapeutic effectiveness of a lenvatinib rechallenge after an atezolizumab plus bevacizumab treatment remains unclear., Patients and Methods: Thirteen consecutive patients who were rechallenged with lenvatinib after clinical failure following treatments with lenvatinib and atezolizumab plus bevacizumab were included. A comparative study was conducted on the duration and treatment efficacy of the first and second lenvatinib treatments and on the pre- and post-treatment liver function., Results: The median ratios of the 1-month post-treatment alpha-fetoprotein (AFP) levels to the pretreatment AFP levels were 0.750 and 0.667 for the first and second lenvatinib treatments, respectively, without significant difference (p=0.9327). Meanwhile, the median ratios of the 1-month post-treatment albumin-bilirubin (ALBI) scores to the pretreatment ALBI scores were 1.063 and 0.827 for the first and second lenvatinib treatments, respectively, with significant difference (p=0.015). The median duration of the second lenvatinib treatment was significantly shorter than that of the first lenvatinib treatment [2.8 months (range=0.9-4.7 months) vs. 8.7 months (range=3.1-29.7 months)]., Conclusion: Lenvatinib re-administration after atezolizumab plus bevacizumab treatment can act as a double-edged sword, as it exerts an anti-tumor effect while being associated with potential liver function deterioration. However, this treatment sequence can be useful, and requires careful monitoring of the transitions in the liver function and the patient's performance status., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: Ballooned hepatocytes represent liver cell degeneration and are histological hallmarks in the diagnosis of non-alcoholic steatohepatitis, a severe form of non-alcoholic fatty liver disease. However, the identification of ballooned hepatocytes is often difficult, especially in the clinical setting of patients with other chronic liver diseases. In this study, we investigated the utility of immunostaining for positive sonic hedgehog (SHh) protein and negative Keratin 8/18 (K8/18) expression on ballooned hepatocytes., Methods and Results: Immunohistochemistry for SHh and K8/18 was evaluated independently by two experienced liver pathologists in non-tumorous liver tissue from 100 cases of resected hepatocellular carcinoma of various aetiology. The degree of hepatocyte ballooning was scored as follows: 0, none; 1, few; 2, many ballooned hepatocytes. These evaluations were performed using routine haematoxylin and eosin (H&E) staining, followed by immunostaining for SHh or K8/18. Using SHh or K8/18 immunostaining combined with H&E staining, the score of ballooned hepatocytes was upgraded in 20 and 19 cases, and downgraded in none and 2 cases, respectively. The percentage of observed agreement for ballooned hepatocytes scoring was 85% and 92%, and the weighted kappa value was 0.806 and 0.893 with SHh or K8/18 immunohistochemistry. Considering the immunohistochemistry results, background liver disease diagnosis was changed in 15 out of 100 cases (15%) evaluated., Conclusions: SHh and K8/18 immunohistochemistry are useful in detecting ballooned hepatocytes, regardless of background liver disease, and improving pathological diagnosis accuracy., (© 2022 John Wiley & Sons Ltd.)

Background/aim: Atezolizumab plus bevacizumab therapy is the new standard treatment option for advanced hepatocellular carcinoma (HCC). The clinical details and sequential course after atezolizumab plus bevacizumab therapy remain to be determined., Patients and Methods: Thirty-four consecutive patients who received atezolizumab plus bevacizumab therapy were evaluated. Their clinical outcomes were assessed according to liver function classified by modified albumin-bilirubin (ALBI) grade 1 and 2a (1/2a) versus 2b and treatment line (first-line versus second- or later-line). Furthermore, the treatment sequence after atezolizumab plus bevacizumab therapy was also assessed., Results: The objective response and disease control rates were 15.6% and 93.8%, respectively. The median proportions of ALBI scores at 1, 2, and 3 months relative to the baseline scores were 0.94, 0.97, and 0.93, respectively. The median proportions of α-fetoprotein (AFP) scores at 1, 2, and 3 months relative to the baseline scores were 0.98, 1.12, and 1.83, respectively. There were no significant differences in the changes in the proportions of AFP and ALBI scores according to both liver function and treatment line. Twelve patients were administered lenvatinib treatment after the failure of atezolizumab plus bevacizumab therapy. The proportions of AFP and ALBI scores at 1 month relative to the baseline scores were 0.55 and 0.81, respectively., Conclusion: Atezolizumab plus bevacizumab therapy can be effective for advanced HCC irrespective of the patients' liver function and treatment line. Lenvatinib administration after atezolizumab plus bevacizumab therapy can be effective, although special attention should be paid to the deterioration of liver function., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Sarcopenia has been reported to be a significant prognostic factor in patients with hepatocellular carcinoma in recent years. This study aimed to clarify the prognostic significance of sarcopenia in advanced hepatocellular carcinoma treated with reductive hepatectomy., Patients and Methods: We retrospectively analyzed 93 patients who underwent reductive hepatectomy for advanced hepatocellular carcinoma., Results: Median survival time of the sarcopenia group (16.4 months) was significantly shorter than that of the non-sarcopenia group (20.4 months). The overall survival rates at 1, 3, and 5 years of the sarcopenia group were significantly lower than those of the non-sarcopenia group (57.9%, 8.6%, and 2.9% vs. 67.3%, 29.2%, and 15.7%, respectively; p=0.035). On multivariate analysis, sarcopenia was a significant risk factor of overall survival (hazard ratio=1.60, 95% confidence interval=1.00-2.56, p=0.049)., Conclusion: Sarcopenia was a significant prognostic factor of survival after reductive hepatectomy in advanced hepatocellular carcinoma., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: While there is increasing evidence supporting the role of several first- and second-line treatment regimens for advanced hepatocellular carcinomas (HCC), the clinical relevance of rechallenge treatment with previously administered drugs, however, remains to be explored., Patients and Methods: Five consecutive patients with advanced HCC who received lenvatinib rechallenge treatment after ramucirumab were assessed., Results: All patients were clinically diagnosed with failure after ramucirumab treatment, and the frequencies of ramucirumab administration before lenvatinib re-administration ranged from 3 to 11. The alfa-fetoprotein level in four of five patients decreased 1 month after the lenvatinib rechallenge. Radiological findings via the modified Response Evaluation Criteria in Solid Tumors showed stable diseases in four patients and a partial response in one., Conclusion: Rechallenge treatment with lenvatinib after ramucirumab can be effective, and may be a treatment option for HCC in cases wherein the disease progressed after an initial response to lenvatinib treatment., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 28-year-old woman was referred to our hospital for liver dysfunction and neck pain. Blood tests revealed elevated liver enzymes and eosinophilia. Ultrasonography, computed tomography, and magnetic resonance imaging showed a mass lesion near the hepatic hilus. The tumor was considered to be an inflammatory pseudo-tumor or malignancy. A liver-mass biopsy was performed and led to a diagnosis of inflammatory pseudo-tumor. In the present case, a markedly elevated eosinophil count was a characteristic clinical feature, and the patient underwent steroid therapy. Treatment resulted in a reduced eosinophil count, improved neck symptoms, and disappearance of the inflammatory pseudo-tumor.

Beta-catenin-activated hepatocellular adenoma is potentially malignant and warrants careful follow-up and surgical resection. Here, we report a 48-year-old man in whom a 55 mm single liver tumor was incidentally detected in the S1 segment. Contrast-enhanced computed tomography scans showed no enhancement in the early phase and a slight defection in the late phase. The tumor was enhanced hyperintensity in the hepatobiliary phase on Gd-ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging. The histologic features of ultrasound-guided fine-needle aspiration biopsy indicated hepatocellular adenoma, and the tumor was immunohistochemically positive for glutamine synthetase and β-catenin. Considering the risk of malignant transformation, he underwent laparoscopic-assisted partial liver resection. The resected tumor did not contain any malignant lesions. This case indicates that aspiration needle biopsy and immunohistochemistry were useful for histological diagnosis and treatment decisions based on the molecular definition of hepatocellular adenoma.

Background: Intrahepatic cholangiocarcinoma (ICC) is primary cancer of the liver with poor prognosis because of its high potential for recurrence and metastasis. We experienced a rare case of ICC with hematogenous metastasis to the falciform ligament. We aimed to clarify the route of metastasis to the mesentery by increasing the accuracy of preoperative imaging and establish a hepatectomy to control cancer., Case Presentation: An 85-year-old woman was referred to our hospital for a detailed study of progressively increasing liver tumors. She had no subjective symptoms. Her medical history showed hypertension, aneurysm clipping for cerebral hemorrhage, and gallstones. A detailed physical examination and laboratory data evaluation included tumor markers but did not demonstrate any abnormalities. On computed tomography scan, contrast-enhanced ultrasound, and magnetic resonance imaging with gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid, the tumor appeared to be located in liver segment IV, protruding outside the liver. It appeared to contain two distinct components; we suspected ICC in the intrahepatic tumor component. Laparoscopic observation revealed that the extrahepatic lesion was an intra-falciform ligament mass; laparoscopic left hepatectomy was performed. Microscopically, the main tumor in segment IV was 15 mm in diameter and was diagnosed as moderately and poorly differentiated ICC. The tumor of the intra-falciform ligament was not continuous with the main intrahepatic nodule and was also diagnosed as ICC with extensive necrosis. There were no infiltrates in the round ligament of the liver, and several tumor thrombi were found in the small veins of the falciform ligament., Conclusions: To date, there have been a few reports of metastases of primary liver cancer to the falciform ligament. At the time of preoperative imaging and pathological diagnosis, this case was suggestive of considering that the malignant liver tumor might be suspected of metastasizing to the falciform ligament. Our case improves awareness of this pathology, which can be useful in the future when encountered by hepatic specialists and surgeons.

A 72-year-old man underwent transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) located on the S6 segment. He had a history of anti-viral therapy for hepatitis C virus and was being treated for diabetes mellitus with inadequate control. On day 28 after TACE, he visited our hospital again, with complaints of fever and abdominal pain in the right upper quadrant. Blood examination showed elevated levels of white blood cells and C-reactive protein. Computed tomography showed a poorly marginated, low-density lesion measuring 9.5 × 8.0 × 4.0 cm, forming multiple small gas bubbles, located superiorly, and in contact with HCC treated by TACE. Ultrasound-guided puncture revealed whiffy and muddy pus. Gram staining of the pus showed the presence of numerous gram-positive rods, which were identified as Cutibacterium namnetense. He underwent percutaneous trans-hepatic abscess drainage and received antibiotics treatment. The abscess was successfully treated, and he was discharged on day 19. The incidence of liver abscess after TACE is rare, and intestinal microbiota have been reported to be the common pathogens. To the best of our knowledge, this is the first case of liver abscess caused by Cutibacterium namnetense.

Background: The present study aimed to assess the clinical features of patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC)., Methods: The clinical characteristics, adverse events, and radiological responses were evaluated for 51 consecutive patients., Results: Of the study subjects, 37 patients had Child-Pugh class A (CPA) liver function, and 14 patients had Child-Pugh class B (CPB) liver function. The overall response rates in the CPA and CPB groups were 42.9% and 25.0%, respectively, and disease control rates were 82.9% and 83.3%, respectively, without significant difference (p = 0.2621 and 0.9697). There was no significant difference between CPA and CPB groups regarding the incidence of adverse events, except for hepatic coma. No significant difference was observed in the relative dose intensity between the CPA and CPB groups, for the first month, 1-2 months, or 2-3 months (p = 0.2368, 0.9368, and 0.9293)., Conclusion: The comparable outcomes between the CPA and CPB groups suggest the acceptability of lenvatinib treatment in patients with impaired liver function, at least in the acute phase. With careful follow-up, the dose can be relatively intensified, even in patients with impaired liver function and this may contribute to offering comparable treatment., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: Sorafenib have been shown to be effective in the treatment of advanced HCC and has been standard therapy since its release in Japan in 2009 (Llovet et al., 2008; Cheng et al., 2009). However, due to a low response rate, more aggressive combination treatment has been utilized as a multimodal strategy. The present study aimed to determine the efficacy of sorafenib alone and in combination with transarterial chemoembolization (TACE) for the treatment of advanced HCC., Methods: All patients with unresectable advanced HCC who were prescribed sorafenib at Kanto Rosai Hospital were included in the study. Five-year overall survival (OS) rates were estimated for patients treated with sorafenib alone or in combination with TACE. Multivariate and univariate regression analyses were performed to identify factors affecting OS. Analysis using propensity score matching and inverse-probability weights were also performed., Results: A total of 46 patients were treated with sorafenib up to June 2018. The total sorafenib dose administered was higher in the TACE combination group (70900 mg vs. 24000 mg vs. with sorafenib alone), although the relative dose intensity was lower (11.7% vs. 17.6%, respectively). The 5-year survival prognosis estimated using the Kaplan-Meier method was longer in patients treated with sorafenib in combination with TACE versus sorafenib alone (36.3% vs. 7.7%). Combination with TACE was the only factor associated with improved OS in both univariate and multivariate analysis. Among cases matched by propensity scores the hazard rate for combination with TACE was 0.067 (95% CI 0.091-1.128)., Conclusion: With an array of therapeutic options currently available, it is important to determine the efficacy of different multimodal strategies, such as sorafenib combined TACE, for patients with unresectable HCC.

Background: A large-scale Japanese study showed that low skeletal muscle index (SMI) and intramuscular fat (IMF) deposition are associated with hepatocellular carcinoma (HCC) survival. Here, we evaluated the effects of SMI and IMF on the survival of Indonesian HCC patients, whose characteristics differ from those of Japanese patients., Methods: SMI and mean muscle attenuation (MA) were evaluated using computed tomography images of the third lumbar vertebra (L3) in a prospective cohort of 100 Indonesian HCC patients. Clinical, laboratory and body composition data were analysed using the Kaplan-Meier method and Cox regression model to investigate which factors are associated with prognosis., Results: Of 100 patients, 31 were diagnosed with sarcopenia (L3 SMI value ≤36.2 cm 2 /m 2 for men and ≤ 29.6 cm 2 /m 2 for women), and 65 had IMF deposition (MA value ≤44.4 HU for men and ≤ 39.3 HU for women). These groups had shorter median survival than the reference groups (both P < 0.0001). In multivariable analysis, sarcopenia (hazard ratio [HR], 1.921; P = 0.016), IMF deposition (HR, 3.580; P < 0.001), Barcelona Clinic Liver Cancer (BCLC) stages C and D (HR: 2.396, P < 0.01 and HR: 6.131, P < 0.01, respectively), Japan Integrated Staging (JIS) score 4 (HR: 2.067, P = 0.020), and male gender (HR: 3.211, P < 0.001) were independently associated with mortality., Conclusion: Sarcopenia and IMF deposition showed superior value in combination with BCLC stage and JIS score for predicting the survival of Indonesian HCC patients. Increased awareness and strategies to prevent or reverse these factors might improve patient outcomes. (Electric word counts: 249).

Multi-site mutations in the hepatitis B virus (HBV) X gene are often found in patients with advanced liver diseases such as liver cirrhosis and hepatocellular carcinoma. It has been reported that modifications in the X protein play crucial roles in the development of HBV-related severe liver disease. However, the prevalence of genetic variations in Indonesian strains has not been systematically assessed. In this study, we sought to investigate the profile of nonsynonymous mutations in the X gene. Overall, 114 Indonesian HBV strains, including 12 in-house samples, were retrieved from GenBank. The mutation frequency in the X gene was compared among strains obtained from patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The mutation frequencies of the domain and basal core promoter regions were significantly greater in advanced liver diseases compared with chronic hepatitis. In addition, the double mutation K130M/V131I and the triple mutation N88V/K130M/V131I were associated with a 2.5 times higher risk of advanced liver disease. However, the roles of two novel X gene mutations (A12S/T and L16F/P) on hepatocarcinogenesis are unclear relative to wild-type X gene. In conclusion, the development of multi-site mutations in the X gene may represent a strategy by which HBV can escape immune surveillance and thus contribute to hepatocarcinogenesis, even though the biological roles of some variants remain unclear.

Background: Previously, we aimed to predict the effect of bevacizumab in liver metastasis using the ratio of the computed tomography (CT) value for hepatic metastatic lesions in the arterial phase in contrast-enhanced (CE) CT to that on plain CT. However, there is no report on the relation between the CT contrast effect and microvessel density (MVD) in liver metastasis., Patients and Methods: Thirty-two patients who underwent liver resection for metastasis from colorectal cancer (excluding neoadjuvant chemotherapy cases) between April 2006 and October 2011 at our Department were analyzed retrospectively. The relation between the CE ratios obtained from the whole tumor or tumor margin and the MVD using the liver metastatic lesion of colorectal cancer were analyzed. It was also examined whether the CE ratios and MVD were related to the clinicopathological factors of the primary tumor., Results: There was a significant correlation between the CE ratios obtained from assessment using the entire tumor and the tumor margin as regions of interest (ROI). Furthermore, there was a significant correlation between the MVD and CE ratios. Cases with lymphatic invasion, N2, N3 nodal status and grade B and C were significantly more often observed in the group with high MVD. In contrast, in the group with high CE using the whole tumor as ROI, cases with grade B or C were significantly fewer. However, the number of hepatic metastasis was significantly higher and the diameter was significantly larger in the group with high CE using the tumor margin as ROI. Moreover, cases with grade B or C were recognized significantly more often., Conclusion: The CE ratio correlated with the MVD. The CE ratio using the tumor margin was similar to the MVD in relation to the clinicopathological factors. Taken together, these findings suggest that the CE ratio using the tumor margin as ROI may reflect MVD., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The aim of this study was to clarify prognosis for curative resection performed for cases of colorectal cancer with synchronous liver metastasis and to use the findings as future treatment indices. Subjects comprised 61 patients who underwent curative resection at our hospital for colorectal cancer accompanied by synchronous liver metastasis between 1996 and 2014. The degree of liver metastasis was H1 for 47 cases and H2 for 14 cases. The Grade of liver metastasis was A for 29 cases, B for 18 cases, and C for 14 cases. Liver resection was performed simultaneously with that of the primary lesion for 33 cases, and after that of the primary lesion for 28 cases. The post-curative resection survival period was 58.0 months, and the 5-year survival rate was 49.9%. In terms of the relationship between prognosis and clinicopathological factors, prognosis was found to be poor when the wall depth of the primary lesion was pT4 and when the liver metastasis Grade was B or C. Meanwhile, prognosis did not differ depending on the timing of liver metastasis resection, whether chemotherapy was performed after liver resection, and whether curative resection was performed for initial occurrence only or recurrence resection was performed. The results indicated that for cases of colorectal cancer with synchronous liver metastasis, primary lesion wall depth and liver metastasis Grade were prognostic factors, and that the treatment strategy did not necessarily have to consider resection timing.

We report a case of ascending colon cancer with hepatic metastases that was treated by CapeOX plus bevacizumab with remarkable efficacy. A 40-year-old female patient presented with a medical history of surgery for resection of right breast cancer4 years ago, left-sided transverse colon 2 years ago, and right ovarian cancer 6 months ago. Follow-up computed tomography(CT)found wall thickening from the ascending colon to cecum. She was diagnosed with an ascending colon cancer by colonoscopy, and underwent right hemicolectomy. One month after the surgery, her serum marker carcinoembryonic antigen(CEA)and carbohydrate antigen 19-9(CA19-9)levels were high. She was diagnosed with unresectable multiple hepatic metastases by CT 2 months after the surgery. Her tumor was epidermal growth factor receptor(EGFR)- positive and wild-type for RAS; she received 4 courses of CapeOX plus bevacizumab. Thereafter, liver metastases were remarkably decreased in size, and she could undergo central bisegmentectomy. Pathology examination revealed no tumor and that the center of the tumor was changed to necrotic tissue and the surrounding area was changed to fibrous tissue and lymphocyte infiltration. The patient is disease-free since the last operation.

Background: Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases., Objective: The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis., Design: This was a retrospective study from a prospectively collected database., Settings: The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan., Patients: Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer., Main Outcome Measures: The primary outcome measure was overall survival., Results: The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0-46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0-9.0 mo), and the 1-year survival rate was 30.0% (95% CI, 21.1%-39.4%). Multivariate analysis revealed that ≥2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p < 0.001, 0.001, and 0.033). The number of extra-bone metastatic organs correlated with prognosis., Limitations: This study was limited by its retrospective, nonrandomized design, as well as selection bias and performance at a single institute., Conclusions: The location of colorectal cancer correlates significantly with the site of bone metastasis; the prognosis of patients with bone metastasis from colorectal cancer is very poor, and the significant prognostic factors are number of extra-bone metastatic organs, hypercalcemia, and pathologic fractures. See Video Abstract at http://links.lww.com/DCR/A589.

A 78-year-old man visited our hospital with a prolapsed hemorrhoid. He was referred to the dermatology unit due to the thickness and redness of the perianal skin. He was diagnosed as having extra mammary Paget's disease by skin biopsy. After a biopsy of the anal polyp was performed to investigate the primary site, he was diagnosed with early anal canal cancer with Pagetoid spread and underwent a radical operation. Abdominoperineal resection with skin(D2 prx D3 lymphadenectomy) was performed with perineal reconstruction using a gracilis muscle graft. Postoperative surveillance without adjuvant therapy was performed because the pathological stage was stage I. Two years and 2 months after surgery, multiple liver metastases were found, and the patient was diagnosed with multiple liver, bone, and lymph node metastases(K-ras and UGT1A1 wild type)on PET. XELOX plus bevacizumab was used as first-line treatment and the liver metastases showed remarkable shrinkage; however, disease progression occurred in the bone. IRIS plus bevacizumab was started as second-line therapy but grade 3 hematotoxicity was observed during the first course. After 4 courses, it was difficult to maintain the therapy due to toxicity and cancer-related pain. The liver metastases had almost disappeared but the patient died 11 months after the initiation of chemotherapy.

Angiogenesis is generally induced in the process of necro-inflammation and regeneration in chronic liver diseases (CLD). Whereas VEGF is a major humoral factor in relation to neo-vascularization, the receptor, VEGFR-2, is located in hepatocytes and sinusoid endothelial cells. The aim in this study is to investigate the significance of soluble form of VEGFR-2 (sVEGFR-2) in various CLDs. A cross sectional study was conducted from 2010 to 2013 at Dr. Sardjito Hospital Yogyakarta, Indonesia. 149 patients with chronic hepatitis (CH), liver cirrhosis (LC) or hepatocellular carcinoma (HCC) were enrolled in this study. sVEGFR-2 serum was examined using Quantikine®HS kit human immunoassay. Data were analyses by STATA (P value <0.05). The median of sVEGFR-2 was decreased according to the disease progression (LC: 7014.95 pg/mL; CH: 8805.15 pg/mL; healthy subject: 9785.2 pg/mL). However, sVEGFR-2 in HCC (8043.73 pg/mL) was significantly higher than that in LC (P= 0.0059). Based on AUROC analyses, the clinical cut-off point of sVEGFR-2 with >80% sensitivity was used (CH-LC ≤7236.7, LC-HCC ≥7215). The odds ratio (OR) LC to HCC was 5.87 and CH to LC was 4.63. The significant correlations were showed significantly between sVEGFR-2 with MELD and ALT in LC, and with APRI and FIB-4 in CH. In conclusion, the serum sVEGFR-2 could be used as a predictive factor progressing CH to LC, but not HCC.

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), 75% of whom reside in Asia. Approximately 600000 of infected patients die each year due to HBV-related diseases or hepatocellular carcinoma (HCC). The endemicity of hepatitis surface antigen in Indonesia is intermediate to high with a geographical difference. The risk of HBV infection is high in hemodialysis (HD) patients, men having sex with men, and health care workers. Occult HBV infection has been detected in various groups such as blood donors, HD patients, and HIV-infected individuals and children. The most common HBV subgenotype in Indonesia is B3 followed by C1. Various novel subgenotypes of HBV have been identified throughout Indonesia, with the novel HBV subgenotypes C6-C16 and D6 being successfully isolated. Although a number of HBV subgenotypes have been discovered in Indonesia, genotype-related pathogenicity has not yet been elucidated in detail. Therefore, genotype-related differences in the prognosis of liver disease and their effects on treatments need to be determined. A previous study conducted in Indonesia revealed that hepatic steatosis was associated with disease progression. Pre-S2 mutations and mutations at C1638T and T1753V in HBV/B3 have been associated with advanced liver diseases including HCC. However, drug resistance to lamivudine, which is prominent in Indonesia, remains obscure. Although the number of studies on HBV in Indonesia has been increasing, adequate databases on HBV infection are limited. We herein provided an overview of the epidemiology and clinical characteristics of HBV infection in Indonesia.

Objectives: The characteristics of hypovascular and hypervascular well-differentiated hepatocellular carcinomas (HCCs) were compared in terms of tumor size, tumor markers and detectability by imaging modalities., Methods: Well-differentiated HCC nodules that are smaller than 2 cm (n = 27) were evaluated in 27 patients using histopathology and divided into 2 groups: hypovascular (n = 10) and hypervascular (n = 17). The diagnostic sensitivity of imaging modalities was then evaluated for efficiency in disclosing tumor size and tumor markers in the 2 types., Results: No difference was observed in tumor size and tumor markers between the 2 types; however, the sensitivity of contrast-enhanced CT, contrast-enhanced ultrasonography and arterioportal angiography was significantly different between the 2 types, whereas that by Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging (Gd-EOB-DTPA MRI) demonstrated no difference., Conclusion: Hypovascular HCC could be diagnosed by Gd-EOB-DTPA MRI in the hepatobiliary phase., (© 2015 S. Karger AG, Basel.)

Background/aims: This retrospective report evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) for life threatening patients with unresectable hepatic metastases., Methodology: Seven life threatening patients with hepatic metastases who were treated with HAIC up to September 2011 were retrospectively analyzed. As HAIC regimen, 5-FU (1000mg/m2) was administered weekly via continuous 5-hour infusion using a continuous-infusion device. After improvement of liver dysfunction, cetuximab was administered simultaneously by the same dose of single administration. Treatment was repeated weekly until progression of hepatic lesion or discontinuity by unacceptable toxicity or patients' proposal., Results: In 5 patients with hepatic metastasis related complaints, 3 patients improved after the initiation of HAIC. Three out of 4 patients with PS 2 or 3 were improved by the initiation of HAIC. The median OS was 9.5 months. No severe adverse toxicities and no treatment death related to HAIC were observed. The most severe non-hematologic adverse events were ALP in 3 patients, transaminase and bilirubin in 1 patient with grade 3., Conclusion: HAIC may be considered to perform when the hepatic metastases progress as life threatening status even though those are refractory to standard systemic chemotherapy.

Objectives: The efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and α-fetoprotein (AFP) as suppressive markers of HCC were also measured., Methods: Patients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups., Results: No difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEG-IFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups., Conclusion: The preventive effect of the IFN-free, all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV., (© 2015 S. Karger AG, Basel.)

Objective: The supplementation of oral branched-chain amino acid (BCAA) granules is known to improve energy metabolism in cirrhotic patients, but not those with hepatocellular carcinoma (HCC). We aimed to clarify whether BCAA granules improve energy metabolism in HCC patients after radiofrequency ablation (RFA)., Methods: We performed a prospective cohort study (UMIN000004624) involving 40 HCC patients who underwent RFA at Kobe University Hospital. Indirect calorimetry and urinary/blood biochemical examinations were performed before and seven days after RFA. Blood biochemical examinations were also conducted three months after RFA. The patients treated with and without BCAA supplementation were compared, and univariate factors were statistically examined., Results: The non-protein respiratory quotient (npRQ) and albumin levels before RFA were significantly lower in the BCAA group than in the control group (p=0.024 and 0.005). The npRQ ratio (seven days after/before RFA) was significantly higher in the BCAA group than in the control group (p=0.019). In addition, the albumin ratio (three months after/before RFA) was significantly higher in the BCAA group than in the control group (p=0.018)., Conclusion: Supplementation with BCAA granules improves energy metabolism in addition to the liver function after RFA. Improvements in the liver function may result in consistently adequate treatment for HCC recurrence after RFA.

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC.

Background/aims: The cytotoxic regimens and bevacizumab (Bev) or anti-EGFR antibody are used for metastatic colorectal cancer (mCRC) that can expect conversion therapy. In this paper, we would present our practical data including the response, survival and toxicity of the capecitabine plus oxaliplatin (CAPEOX) with Bev for mCRC that cannot expect conversion therapy., Methodology: Nineteen patients with mCRC who were treated with CAPEOX with Bev were enrolled. All the patients had the disseminated hepatic, lung, peritoneal metastases or distant lymph node metastasis assessed as no possibility of R0 resection., Results: The median age was 66 (45-85) years old. Target lesion was liver and lung in 9 patients, peritoneum in 5 patients and distant lymph node in 3 patients. CAPEOX with Bev therapy was administered for a median of 8.0 cycles (range, 4-21 cycles). In the 16 evaluable cases, there were no patient with complete response (CR), 9 patients with partial response (PR), 6 with stable disease (SD), and 1 with progressive disease. The objective response rate (CR plus PR) was 56.3%, and disease control rate (CR, PR plus SD) was 93.8%. The median TTP was 9.3 months and the median OS was 21.1 months. No patients treated with surgery even though the good responses were obtained. No severe hematologic adverse toxicities were observed except only one case with grade 3 platelet decrease. Nonhematologic grade 3 events were observed totally 8 patients including 3 for peripheral neuropathy, 2 for bilirubin, and 1 for nausea/vomiting, amylase and stomatitis., Conclusions: We obtained the quite good results of CAPEOX plus Bev as the first-line treatment practically. This regimen might be useful for mCRC that cannot expect conversion therapy.

Background: Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC) that can occasionally lead to the shortening of life expectancy. We aimed to make a new and more accurate prognostic model taking into account the course of disease after TACE., Methodology/principal Findings: We performed a prospective cohort study involving 100 HCC patients who underwent TACE at Kobe University Hospital. Indirect calorimetry and blood biochemical examinations were performed before and 7 days after TACE. Time-dependent and time-fixed factors associated with 1-year mortality after TACE were assessed by multivariate analyses. A predictive model of 1-year mortality was established by the combination of odds ratios of these factors. Multivariate analyses showed that the ratio of non-protein respiratory quotient (npRQ) (7 days after/before TACE) and Cancer of Liver Italian Program (CLIP) score were independent factors of 1-year mortality after TACE (p = 0.014 and 0.013, respectively). Patient-specific 1-year mortality risk scores can be calculated by summarizing the individual risk scores and looking up the patient-specific risk on the graph., Conclusions: The short-term reduction of npRQ was a time-dependent prognostic factor associated with overall survival in HCC patients undergoing TACE. CLIP score was a time-fixed prognostic factor associated with overall survival. Using the prediction model, which consists of the combination of time-dependent (npRQ ratio) and time-fixed (CLIP score) prognostic factors, 1-year mortality risk after TACE would be better estimated by taking into account changes during the course of disease.

Background: Sorafenib, an oral multikinase inhibitor, was approved for the treatment of advanced hepatocellular carcinoma (HCC), but has not been adequately evaluated for safety and effectiveness in Japanese patients with advanced HCC., Aims: The purpose of this study was to prospectively assess the efficacy, safety, and risk factors for survival in patients with advanced HCC treated with sorafenib., Methods: Between May 2009 and December 2010, 96 Japanese patients with advanced HCC (76 male, 20 female, mean age: 70.4 years) were treated with sorafenib. Eighty-eight patients had Child-Pugh class A, and 8 patients had Child-Pugh class B liver cirrhosis. Barcelona Clinic Liver Cancer stage B and C were found in 64 and 32 patients, respectively., Results: Twelve patients demonstrated partial response to sorafenib therapy, 43 patients had stable disease, and 33 patients had progressive disease at the first radiologic assessment. The most frequent adverse events leading to discontinuation of sorafenib treatment were liver dysfunction (n = 8), hand-foot skin reaction (n = 7), and diarrhea (n = 4). The median survival time and time to progression were 11.6 and 3.2 months, respectively. By multivariate analysis, des-γ-carboxy prothrombin serum levels and duration of treatment were identified as independent risk factors for survival., Conclusions: This study showed that sorafenib was safe and useful in Japanese patients with advanced HCC. In addition, this study demonstrated that sorafenib should be administered as a long-term treatment for advanced HCC regardless of therapeutic effect and dosage., (Copyright © 2012 S. Karger AG, Basel.)

Background: Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC), but it sometimes makes liver function worse. The pre-TACE prediction of liver dysfunction after TACE would be helpful to avoid long-term liver dysfunction., Methods: We performed a case-control study in 100 HCC patients who underwent TACE at Kobe University Hospital. Urinary/blood biochemical examinations were performed before TACE. As an indicator of liver function, Child's score was also evaluated before and 3 months after TACE. Cases with and without an increase of 2 points or more in the Child's score were compared, and independent risk factors were statistically examined. A pre-TACE predictive model of an increase of 2 points or more in the Child's score after TACE was developed using logistic regression., Results: Univariate analyses showed that des-γ-carboxy prothrombin (DCP) and lactate dehydrogenase (LDH) before TACE were significantly higher in the Child's score-deteriorated group than in the group with no deterioration (p = 0.036 and 0.003, respectively). All possible multivariate regressions showed that DCP (p = 0.003) and LDH (p = 0.002) were independent factors determining the deterioration of Child's class. A predictive model was developed, as follows: exp(0.014 × LDH + 0.572 × ln(DCP) - 8.655)/(1 + exp(0.014 × LDH + 0.572 × ln(DCP) - 8.655)). The model discriminated well, with AUC being 0.837 (95 % confidence interval [CI] 0.662-1.000). The optimal cut-off point was 0.073, and the sensitivity and specificity were 90.9 and 69.7 %, respectively., Conclusions: High values of DCP and LDH before TACE were associated with the long-term deterioration of liver function. Our pre-therapeutic prediction model could be useful to identify high-risk cases.

Background: Transcatheter arterial chemoembolization (TACE) is an effective treatment for hepatocellular carcinoma (HCC) that can cause deterioration of liver function. We aimed to make an early predictive model of long-term liver dysfunction after TACE., Methods: We performed a prospective cohort study involving 109 HCC patients who underwent TACE at Kobe University Hospital. Indirect calorimetry and blood biochemical examinations were performed before and 7 days after TACE. As an indicator of liver function, the Child's score was evaluated before and 3 months after TACE. Patients with and without Child's score deterioration were compared, and the independent risk factors for Child's score deterioration were statistically examined. An early predictive model of Child's score deterioration after TACE was developed using multivariate logistic regression., Results: Multivariate analyses showed that the non-protein respiratory quotient (npRQ) and prealbumin (preAlb) ratios (7 days after/before TACE) were independent determinants of Child's score deterioration (p = 0.039 and 0.020, respectively). Decreases of the npRQ and preAlb ratios were significantly related to increases of Child's score 3 months after TACE (p = 0.007 and 0.002, respectively). The following predictive model of Child's score deterioration was developed: exp(-6.383 × npRQ ratio - 3.038 × preAlb ratio + 7.755)/(1 + exp(-6.383 × npRQ ratio - 3.038 × preAlb ratio + 7.755)). The model discriminated well between patients with and without Child's score deterioration (area under the receiver operating curve [ROC]; AUC 0.713; 95% confidence interval [CI] 0.613-0.812). The optimal cut-off point for the Child's score was 0.449, and the sensitivity and specificity of the model were 57.1 and 79.1%, respectively., Conclusions: Reductions in npRQ and preAlb 7 days after TACE were associated with the long-term deterioration of liver function. With our model, we were able to identify high-risk patients.

We reported two cases of colorectal cancer patients with EGFR-positive unresectable synchronous liver metastasis effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A 49-year-old female with unresectable synchronous liver metastasis from colon cancer received cetuximab monotherapy as fifth-line therapy. Then, abdominal CT showed shrinkage of the liver metastasis (PR) and the performance status was improved from 3 to 0 as upper abdominal pain reduced. Case 2: A 67-year-old female with unresectable liver metastasis from colon cancer received cetuximab with CPT-11 combined therapy as fourth-line therapy. After that, liver metastasis also decreased (PR), and upper abdominal pain and PS were improved from 2 to 0. These two cases of KRAS status on cancer tissue also showed wild-type, and in these cases cetuximab proved effective.

We report a case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after a standard chemotherapy was failed. A 61-year-old female who had sigmoid colon cancer with unresectable multiple lung and liver metastases underwent sigmoidectomy. Bevacizumab plus mFOLFOX6 was performed as first-line therapy. Partial response was obtained temporarily. After the first-line therapy failed, bevacizumab plus FOLFIRI as second-line, and cetuximab plus CPT-11 as third-line therapy were performed. Since these regimens did not work, her performance status got worse by cholangitis due to progressive liver metastases and anemia. Hepatic arterial infusion chemotherapy for liver metastases and cetuximab for lung metastases as fourth therapy were chosen because we thought her liver metastases should be critical for the maintenance of her QOL and diagnosis. After that, serum CEA was reduced from 14,715 to 6,940 ng/mL during the 3 month period. And her performance status got better as cholongitis and anemia were improved. Additionally, lung metastases were controlled by cetuximab.

Small cell change of dysplasia (SCD) is characterized as an initial step in hepatocarcinogenesis. Histopathological diagnosis is an important diagnostic procedure for nodular lesions in the liver. However, the biopsied specimen is so small that it is sometimes difficult to differentiate between regenerative nodules, dysplastic nodules, and hepatocellular carcinoma even histologically. To examine the usefulness of cytology in the differential diagnosis of hepatic nodular lesions, the cellular characteristics of SCD were evaluated using Papanicolaou staining and a micrometer. Sixty-four histologically diagnosed small nodular lesions in the liver were analyzed retrospectively. All cases were histologically classified according to the Terminology of Nodular Hepatocellular Lesions by the International Working party: hepatocellular carcinoma (HCC) (n=17); low-grade dysplastic nodule (LGDN) (n=26); high-grade dysplastic nodule (HGDN) (n=6); large regenerative nodule: (n=15). SCD was noted in all of the histological categories, and the proportion of SCD tended to be higher in W-HCC than in dysplastic nodules. Although the cellular size was the smallest in HGDN, the nuclear size was the largest in well-differentiated HCC (W-HCC). The nuclear/cytoplasmic ratio was higher in HGDN and W-HCC than in other nodular lesions. Hyperchromasia in W-HCC was obviously stronger than that in other nodules. SCD was frequently found in HGDN and W-HCC. The present study showed that detailed cytological findings of SCD are useful for differentiating HGDN from LGDN, and HGDN from W-HCC.

A 64-year-old man was admitted for further examinations of a liver tumor. The patient was diagnosed as chronic hepatitis C complicated with advanced hepatocelluar carcinoma (HCC) with left portal vein tumor thrombosis. As he refused surgical treatment, hepatic arterial infusion chemotherapy (HAIC) using cisplatin and 5-fluorouracil was performed initially. Administration of ursodesoxycholic acid (UDCA) was also started. Following HAIC, microwave coagulation therapy for residual tumor was added. Consequently, viable lesions of HCC disappeared completely. At present, after more than 8 years, neither signs of tumor recurrence, nor elevation of hepatic enzymes has been observed. Although the precise reason for long survival of this patient is not known, we speculate that suppression of levels of hepatic enzymes, as well as HAIC for subclinical intrahepatic metastasis, contributed to the good outcome. Therapeutic strategy for hepatic inflammation seems to be important for long-term prevention of hepatocarcinogenesis.