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Background: To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC)., Methods: In total, 188 patients with HCC, who received atezolizumab plus bevacizumab combination therapy as the first-line chemotherapy, were studied. Patients who achieved complete response (CR) with systemic chemotherapy alone were excluded. Clinical factors possibly linked to successful transition to conversion therapy and the achievement of cancer-free status were identified., Results: Fifteen (8.0%) patients underwent conversion therapy. In the conversion group, there was a significantly higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B (73.3% versus [vs.] 45.1%; p = .03) and tended to have lower Child-Pugh scores and alpha-fetoprotein levels. Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04). Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01), and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01). In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03)., Conclusion: BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC. Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Purpose: To elucidate how precisely microvascular invasion (MVI) in hepatocellular carcinoma (HCC) can be predicted using multiparametric assessment of gadoxetic acid-enhanced MRI., Methods: In this retrospective single-center study, patients who underwent liver resection or transplantation of HCC were evaluated. Data obtained in patients who underwent liver resection were used as the training set. Nine kinds of MR findings for predicting MVI were compared between HCCs with and without MVI by univariate analysis, followed by multiple logistic regression analysis. Using significant findings, a predictive formula for diagnosing MVI was obtained. The diagnostic performance of the formula was investigated in patients who underwent liver resection (validation set 1) and in patients who underwent liver transplantation (validation set 2) using a receiver operating characteristic curve analysis. The area under the curves (AUCs) of these three groups were compared., Results: A total of 345 patients with 356 HCCs were selected for analysis. Tumor diameter (D) (P = 0.021), tumor washout (TW) (P < 0.01), and peritumoral hypointensity in the hepatobiliary phase (PHH) (P < 0.01) were significantly associated with MVI after multivariate analysis. The AUCs for predicting MVI of the predictive formula were as follows: training set, 0.88 (95% confidence interval (CI) 0.82,0.93); validation set 1, 0.81 (95% CI 0.73,0.87); validation set 2, 0.67 (95% CI 0.51,0.80). The AUCs were not significantly different among three groups (training set vs validation set 1; P = 0.15, training set vs validation set 2; P = 0.09, validation set 1 vs validation set 2; P = 0.29, respectively)., Conclusion: Our multiparametric assessment of gadoxetic acid-enhanced MRI performed quite precisely and with good reproducibility for predicting MVI., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary hepatic lymphoma (PHL) is a lymphoproliferative disorder confined to the liver, with no evidence of lymphomatous involvement in other organs. Here, we report a case of diffuse large B-cell lymphoma (DLBCL)-type PHL in a patient with a long history of primary biliary cholangitis (PBC) and Sjögren's syndrome (SS). A 78-year-old woman presented with epigastralgia and was found to have a solitary liver tumor by contrast-enhanced computed tomography (CT). A CT scan performed 8 months earlier was unremarkable, with no extrahepatic lesions observed. The patient underwent laparoscopic left lateral segmentectomy, and the resected specimen showed histological features of DLBCL in the background of PBC-affected liver parenchyma. The patient received postoperative R-CHOP chemotherapy and has remained in complete remission for 4 years. PBC-associated PHL is extremely rare, and five of six reported cases of PBC-associated PHL cases showed a histological subtype of MALT lymphoma. In this case, immune dysregulation caused by PBC and secondary SS may have contributed to the development of DLBCL-type PHL.

Background and Aims: The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice., Methods: A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD., Results: There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001)., Conclusions: The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Hepatoid adenocarcinoma (HAC) is an adenocarcinoma with components similar to those of hepatocellular carcinoma. Primary HAC of the gallbladder is extremely rare; to our knowledge, there is no consensus on the treatment after diagnosis. We reported an 82-year-old Japanese female of primary HAC of the gallbladder with postoperative recurrence that responded to lenvatinib. A total of 9 months has passed since the start of chemotherapy with lenvatinib, and the patient is in good general condition. To establish an effective treatment for primary HAC of the gallbladder, further accumulation and investigation of cases are recommended., (© 2022. Japanese Society of Gastroenterology.)

This study sought to identify factors that are predictive of a therapeutic response to hepatic arterial infusion chemotherapy (HAIC) by focusing on the number of prior transcatheter arterial chemoembolization (TACE) sessions. To determine the parameters predicting a good response to HAIC, we retrospectively analyzed 170 patients with hepatocellular carcinoma (HCC) who received HAIC regimens comprising low-dose cisplatin combined with 5-fluorouracil (LFP) or cisplatin (CDDP) for the first time. In both the LFP and CDDP regimens, the response rates were significantly lower in patients with three or more prior TACE sessions than in those with two or fewer prior TACE sessions (LFP 57% versus 28%; p=0.01, CDDP 27% versus 6%; p=0.01). Multivariable logistic regression analysis revealed that the number of prior TACE sessions (≥ 3) was significantly associated with non-responder status (odds ratio 4.17, 95% Confidence Interval (CI) 1.76-9.86) in addition to the HAIC regimen. Multivariable analysis using the Cox proportional hazards model revealed that a larger number of prior TACE sessions (≥ 3) was a significant risk factor for survival (hazard ratio 1.60, 95% CI 1.12-2.29) in addition to Child-Pugh class, serum alpha-fetoprotein concentration, and maximum diameter of HCC. HCC patients who receive fewer prior TACE sessions (≤ 2) were found to be better responders to HAIC., Competing Interests: No potential conflict of interest relevant to this article was reported.

Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure., (© 2021. Japanese Society of Gastroenterology.)

A 75-year-old man was admitted to our hospital for breathing difficulty. CT showed a 20 cm mass with clear boundaries and internal non-uniformity, which we suspected to be a gastrointestinal stromal tumor(GIST). Surgical resection was been considered to be risky because the mass was close to surrounding organs, such as the stomach, liver and diaphragm. Thus, we chose imatinib therapy. After 2 months, he was admitted to our hospital for anemia. CT showed the size of mass to be smaller, but the area of low density with internal non-uniformity had increased. We diagnosed intratumoral bleeding, and chose surgical resection. The mass was under the omentum, and had infiltrated the extrahepatic area and lesser curvature of the stomach. We diagnosed the mass derived from the stomach, and performed partial gastrectomy with partial liver resection. Pathological diagnosis was extrahepatically growing hepatocellular carcinoma(HCC, pT3N0M0, pStage Ⅲ).

In November 2020, atezolizumab plus bevacizumab became available for the treatment of hepatocellular carcinoma (HCC), and its efficacy is expected as a new treatment option for HCC. However, the occurrence of immune-related adverse events (irAEs) associated with the administration of immune checkpoint inhibitors is a major concern in clinical practice. We reported a case of irAE-induced myocarditis after the treatment for HCC. Based on the symptoms and echocardiographic findings, we suspected irAE-induced myocarditis and acute heart failure, and the patient was admitted to the hospital for further investigation and treatment. From starting the patient on therapy with methylprednisolone succinate sodium, the laboratory data and symptoms tended to improve. The patient was discharged to home on the 25th day of treatment. Because the number of patients with irAE myocarditis is expected to increase in clinical practice in the near future, further accumulation and investigation of cases are necessary., (© 2021. Japanese Society of Gastroenterology.)

Background Andaim: Human telomerase reverse transcriptase (TERT) promoter mutations were the most prevalent mutations in patients with hepatocellular carcinoma (HCC). We tried to detect the mutations with plasma circulating tumor DNA (ctDNA) in patients with advanced HCC and elucidated their clinical utility., Methods: Circulating tumor DNA in plasma was extracted from 130 patients with advanced HCC who were treated with systemic chemotherapy (n = 86) or transcatheter arterial chemoembolization (n = 44), and TERT promoter mutations were examined with digital droplet polymerase chain reaction. The correlations between these mutations and the clinical outcome of patients were analyzed., Results: Of the 130 patients examined, 71 patients (54.6%) were positive for TERT promoter mutations in ctDNA, of which 64 patients were -124bp G > A and 10 were -146bp G > A. The presence of TERT promoter mutations was correlated with large intrahepatic tumor size (P = 0.05) and high des-gamma carboxyprothrombin (P = 0.005). Overall survival of the patients with the mutations was significantly shorter than those without them (P < 0.001), and the patients with high (≥ 1%) fractional abundance of the mutant alleles showed shorter survival than those with low (< 1%) fractional abundance. Multivariate analysis revealed that TERT promoter mutation (hazard ratio [HR]: 1.94; 95% confidence interval [CI], 1.18-3.24; P < 0.01), systemic chemotherapy (HR: 2.38; 95% CI, 1.29-4.57; P < 0.01), and vascular invasion (HR: 2.16; 95% CI, 1.22-3.76; P < 0.01) were significant factors for poor overall survival., Conclusions: TERT promoter mutations in ctDNA were associated with short survival and could be a valuable biomarker for predicting the prognosis of patients with advanced HCC., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

This is the case of a 77-year-old man with hepatitis C. AFP was increased by 95.9 ng/mL, and abdominal computed tomography(CT)revealed a 20 mm mass in the S6 segment of the liver. Therefore, the patient was referred to our hospital for further examination. Abdominal echo at our hospital showed a 10 mm, low echoic lesion in S6, which tended to shrink. Similarly, CT showed a low-concentration nodule of 10 mm in S6, but the contrast effect in the arterial phase was not clear. EOB-MRI showed a 10 mm nodule of DWI hyperintensity and hepatocyte phase hypointensity in S6. Based on these, a diagnosis of hepatocellular carcinoma(T1N0M0, StageⅠ)was made, and we decided to perform surgery. Intraoperative findings showed no tumor on the liver surface, and echo did not reveal a reproducible nodule. The tumor site was estimated using a 3-dimensional image analysis system created preoperatively. Laparoscopic partial resection of the liver S6 segment was performed at a position distant from the estimated tumor site. Rapid pathological examination showed no malignant findings, but no significant lesion was found in the residual liver, and the surgery was completed. The postoperative pathological diagnosis revealed no clear tumor. EOB-MRI was performed again postoperatively, but no tumor was found in the residual liver. The tumor site that had been indicated preoperatively was resected, and we hypothesized that the hepatocellular carcinoma had spontaneously regressed. Although several mechanisms have been reported for the spontaneous regression of hepatocellular carcinoma, few cases of spontaneous regression during surgery have been reported. We do not have a definite opinion on the treatment protocol for hepatocellular carcinoma that regresses spontaneously; therefore, we will report on past cases.

A 70-year-old man visited our hospital because of a body weight loss. Upper gastrointestinal fiberscope revealed a type 3 tumor and an enhanced MRI showed 30 or more liver metastases. He received docetaxel plus cisplatin plus S-1(DCS)therapy. Although main tumor had shrinked only partially, multiple liver metastases could not be detected. Thus, he was performed distal gastrectomy. After gastrectomy, he received S-1 plus oxaliplatin(SOX)therapy followed by S-1 therapy. Two years and 2 months after surgery, chemotherapy was finished because of no signs of tumor progression. He is alive without recurrence for 2 years and 11 months after gastrectomy.

Abdominal ultrasound in a 50-year-old Japanese man revealed a cystic lesion on the caudate lobe of the liver. Four-month follow-up imaging showed a rapid increase in the size of the cystic lesion. The patient underwent laparoscopic partial hepatectomy because of a suspicion and perceived risk that the lesion might be malignant. The initial histological diagnosis was a hepatic cyst. Eleven months later, computed tomography showed a giant cystic lesion in the abdominal cavity and multiple liver metastases. The patient underwent excision of the giant cystic lesion and a partial hepatectomy. Immunohistochemistry for the recurring lesion revealed undifferentiated embryonal sarcoma of the liver.

Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is a promising method for controlling tumors, although it does not entirely eliminate recurrence. Oxidative stress is associated with the progression of hepatocarcinogenesis, while also acting as an anticancer response. The objective of the present study was to investigate the factors influencing post-RFA outcomes. We recruited 235 newly diagnosed HCC patients who received RFA for single tumors. The patients with recurrence were sub-grouped into early and segmental recurrence groups. The characteristics of the sub-grouped patients were evaluated, including by measuring oxidative stress marker reactive oxygen metabolites and antioxidant marker OXY-adsorbent tests. The factors associated with poor survival were a high Child-Pugh score and early recurrence within 2 years in the same segment. The patients who experienced recurrence within 2 years in the same segment showed a larger tumor diameter than did others. According to a multivariate analysis, the OXY values were also significantly low in these patients. In conclusion, maintaining the antioxidant reservoir function with a high OXY value might be necessary to prevent early recurrence within the RFA-treated segment., Competing Interests: No potential conflict of interest relevant to this article was reported.

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients' disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis., Competing Interests: The authors declare no conflict of interest.

Background: Mutations in the human telomerase reverse transcriptase (hTERT) gene promoter have been reported in hepatocellular carcinoma (HCC); however, analyses of these mutations in liquid biopsies have been technically difficult because of the high GC content of the regions of interest within this promoter. We evaluated the feasibility and prognostic value of hTERT promoter mutations identified in circulating cell-free DNA (cfDNA) from the serum of patients with HCC., Objective: A cohort of HCC patients (n = 36) who were curatively treated by surgical resection between June 2003 and September 2014 were enrolled in this study., Methods: The presence of hTERT promoter mutations in cfDNA from the patients' serum was analyzed via modified droplet digital polymerase chain reaction, and associations were sought between specific promoter mutations and patients' disease-free survival (DFS)., Results: The G>A hTERT mutation at -124 bp was detected in the serum of 25 patients (69%). Although no marked differences were observed between the characteristics of the serum mutation-positive and serum mutation-negative patient groups, the DFS of patients with the mutation was significantly shorter than that of the serum mutation-negative patients (p = 0.02). Among 18 clinicopathologic and background liver factors examined, the presence of the -124 bp G>A mutation was an independent and significant predictor of patients' DFS (hazard ratio = 3.01, 95% confidence interval 1.11-10.5, p = 0.03) in multivariate analyses., Conclusions: The -124 bp G>A hTERT promoter mutation was observed in the serum of 69% of HCC patients who underwent surgical resection and was an independent predictor of disease progression in HCC., (© 2020 S. Karger AG, Basel.)

Gastroscopy ofa 79-year-old man complaining ofanemia showed a type 3 tumor at the lesser curvature ofthe gastric body. A biopsy revealed poorly differentiated HER2-negative adenocarcinoma. Abdominal CT showed the tumor at the lesser curvature ofthe gastric body, multiple lymph nodes with a maximum diameter of 25mm at the lesser curvature, and a mass measuring 50mm with ring enhancement on S6 ofthe liver. The clinical diagnosis was cT4aN2M1(Hep), cStage Ⅳ. He was treated with chemotherapy comprising 4 courses ofS -1 plus oxaliplatin. Although the tumor had shrunk remarkably, chemotherapy was discontinued because of anorexia. Therefore, we performed total gastrectomy and hepatic partial resection(S6). The final staging was ypT3N0M0, ypStage ⅡA. We achieved R0 resection, and he has shown no recurrence without adjuvant chemotherapy for 3 years.

We report 2 cases with long-term survival following stereotactic body radiotherapy(SBRT)for liver metastasis from gastric cancer. Case 1 was a 65-year-old man. We performed distal gastrectomy for gastric cancer with liver metastasis prior to chemotherapy due to pyloric stenosis. Postoperative S-1 chemotherapy was administered. Two liver metastases observed before the operation were temporarily reduced in size but subsequently enlarged; therefore, SBRT was performed 13 months postoperatively. The liver metastases showed a complete response(CR)and the patient is alive 4 years and 11 months after SBRT(6 years postoperatively). Case 2 was a 71-year-old woman. After performing distal gastrectomy, liver metastasis emerged during postoperative S-1 adjuvant chemotherapy; therefore, SBRT was performed 11 months postoperatively. She was then administered weekly paclitaxel. However, she underwent a right hepatic lobectomy 13 months after SBRT for suspected remnant or marginal recurrence by abdominal enhanced CT. Histopathological examination showed that the tumors contained fibrotic connective tissue with no viable cancer cell remnants; therefore, the therapeutic effect was determined to be of Grade 3. The patient is alive without recurrence in the remnant liver 4 years and 7 months after SBRT(5 years and 6 months after the operation of gastric cancer). Thus, SBRT for liver metastasis from gastric cancer may be considered an effective local treatment.

This study will assess the safety and efficacy of the administration of adenoviral vector expressing the human-reduced expression in immortalized cells (Ad-REIC) to a liver tumor in patients with hepatocellular carcinoma (HCC) or liver metastasis of pancreatic cancer. A Phase I clinical study of Ad-REIC administration to a liver tumor in a patient with HCC or liver metastasis of pancreatic cancer will be conducted. The study is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed in Okayama University Hospital, Okayama, Japan. Ad-REIC will be injected into the liver tumor under ultrasound guidance. Ad-REIC administration will be repeated a total of three-times every 2 weeks. The primary end point is the dose-limiting toxicity and incidence of adverse events. The secondary end points are the objective response rate and disease control rate. This study aims to expand the indication of Ad-REIC by assessing its safety and efficacy in patients with HCC or liver metastasis of pancreatic cancer.

Steroids are often administered at the time of transcatheter arterial chemoembolization (TACE), a standard treatment of hepatocellular carcinoma (HCC), with the expectation of preventing postembolization syndrome. Here we investigated the precise effects of steroids on TACE. We prospectively enrolled 144 HCC patients from 10 hospitals who underwent TACE. Three hospitals used steroids (steroid group, n=77) and the rest did not routinely use steroids (control group, n=67). The occurrence of adverse events and the algetic degree at 1-5 days post-treatment were compared between the groups. Fever (grades 0-2) after TACE was significantly less in the steroid group (56/21/0) compared to the control group (35/29/3, p=0.005, Cochran-Armitage test for trend). The suppressive effect of steroids against fever was prominent in females (p=0.001). Vomiting (G0/G1/ G2-) was also less frequent in the steroid group (70/5/2) versus the control group (53/10/3), but not significantly (p=0.106). The algetic degree and the grade of hematological adverse events, including hyperglycemia, did not differ between the groups. We conclude that the administration of steroids was useful for the prevention of adverse events after TACE in patients with HCC., Competing Interests: No potential conflict of interest relevant to this article was reported.

Background and Aim: Several factors, including proangiogenic cytokines, have been reported as predictive markers for the treatment effect of sorafenib in patients with hepatocellular carcinoma (HCC); however, most of them were determined based on one-time measurements before treatment., Methods: We consecutively recruited 80 advanced HCC patients who were treated with sorafenib prospectively. Serum levels of eight proangiogenic cytokines and the appearance of adverse events were monitored periodically, and their correlations with the prognoses of the patients were evaluated., Results: Among six significant risk factors for overall survival in univariate analyses, high angiopoietin-2 (hazard ratio, 2.06), high hepatocyte growth factor (hazard ratio, 2.08), and poor performance status before the treatment (hazard ratio, 2.48) were determined as independent risk factors. In addition, high angiopoietin-2 at the time of progressive disease was a marker of short post-progression survival (hazard ratio, 4.27). However, there was no significant variable that predicted short progression-free survival except the presence of hepatitis B virus surface antigen., Conclusions: Predictions of overall survival and post-progression survival were possible by periodically measuring serum proangiogenic cytokines, especially angiopoietin-2, in patients with HCC treated with sorafenib., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Introduction: Sepsis due to Clostridium perfringens, one of several clostridial species, is an important cause of massive intravascular hemolysis in patients with underlying malignancies. Chronic liver diseases, immunosuppression, and presence of malignancies were risk factors for Clostridium perfringens sepsis. Therefore, Clostridium perfringens sepsis should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. This case report focuses on findings characteristic of an intravascular hemolysis due to Clostridium perfringens after transhepatic arterial chemoembolization., Case Presentation: An 83-year-old Japanese man presented to our hospital because of a third recurrence of hepatocellular carcinoma. He had nonalcoholic steatohepatitis-related cirrhosis, and underwent radiofrequency ablation and transhepatic arterial chemoembolization therapy for hepatocellular carcinoma of S4/S8 and S2. He had a medical history of pancreatic carcinoma and underwent pylorus-preserving pancreaticoduodenectomy approximately 5 years ago. Because follow-up computed tomography showed a recurrence of the hepatocellular carcinoma, he underwent transhepatic arterial chemoembolization with a hepatic arterial infusion of 20 mg epirubicin, followed by 4 mL Lipiodol (ethiodized oil). On the sixth day after the procedure, he complained of fever and hematuria with jaundice. Laboratory findings indicated hemolysis and increased inflammatory response. Although we initiated antibiotic therapy combined with surgical debridement for infection after transhepatic arterial chemoembolization, he died within 6 hours. The autopsy showed a 4-cm local necrotic hepatic tumor. The cut surface revealed a tumor with an internal spongiform appearance, which was a pseudocystic and partially necrotic lesion. In addition, a diffuse spread of Gram-positive rods in multiple organs including the heart was histologically confirmed. The culture obtained by fluid aspiration from the hepatic abscess revealed Clostridium perfringens. Although the role of Clostridium perfringens was never established during the life of this patient, based on the clinical course and the culture from the hepatic abscess at postmortem, intravascular hemolysis secondary to Clostridium perfringens sepsis was suspected., Conclusion: Intravascular hemolysis secondary to Clostridium perfringens should always be considered in patients presenting with liver damage after chemo-embolic therapy for hepatocellular carcinoma. Biliary reconstruction is an especially important risk factor for infection.

A 69-year-old man was found to have a hepatocellular carcinoma of 2.3 cm in diameter, with extrahepatic growth in liver S4 during follow-up for chronic hepatitis C and liver cirrhosis. We performed a laparoscopic partial liver resection, but the tumor capsule was injured by the retractor used to keep the working space at the bleeding site. The pathological diagnosis was moderately differentiated hepatocellular carcinoma(pT2N0M0, pStage Ⅱ). 7 months after the surgery, intrahepatic reoccurrence appeared. Thus, transcatheter arterial chemoembolization(TACE)and radiofrequency ablation were performed. However, a single recurrence ofperitoneal dissemination appeared 8 months after the reoperation. We selected laparoscopic operation this time. Intraperitoneally, we found 4 peritoneal disseminated lesions and resected all the lesions macroscopically. However, even after the resection, peritoneal dissemination recurred and increased. Therefore, we continued treatment with sorafenib and S-1 as systemic therapy, TACE and transcatheter arterial infusion(TAI)for the multiple recurrences in the liver, and radiotherapy for the peritoneal dissemination focuses. However, his general condition worsened, and liver failure occurred. Thus, he was shifted to complete palliative treatment and died 2 years 6 months after the initial operation. The recurrent form ofhepatocellular carcinoma is mainly an intrahepatic recurrence, and recurrence ofperitoneal dissemination is rare. In this case, the intraoperative operation was considered to be the possible cause ofthe recurrence.

Transcatheter arterial chemoembolization (TACE) is often performed before radiofrequency ablation (RFA) for the treatment of early-stage hepatocellular carcinoma (HCC). TACE prior to RFA can expand the ablated area and reduce the tumor size, facilitating complete ablation. However, the factors correlated with size reduction remain uncertain. The aim of this study was to identify the factors associated with size reduction by TACE and develop a formula to predict the reduction rate. A total of 100 HCC patients treated with TACE followed by RFA at least 20 days later were enrolled. The tumor size was measured at the time of TACE and RFA, and correlations between the reduction rate and 13 clinical factors were examined. A formula to predict the reduction rate was built using the factors obtained by the analysis. Reduction in the tumor size was observed in 69 nodules, and the median reduction rate was 16.2%. A multivariate regression analysis revealed that a large tumor size (p< 0.01) and a long interval between the therapies (p= 0.01) were factors for a high tumor reduction rate, with tumor size more strongly related to the degree of reduction. A size reduction of more than 10% can be expected by waiting 20 days after TACE when the size of the tumor at TACE is over 25 mm in diameter. The tumor size., Competing Interests: No potential conflict of interest relevant to this article was reported.

a-fetoprotein(AFP)-producing gastric cancer is relatively rare and tends to show a poor prognosis because of hepatic and lymph node metastasis. We experienced a case of AFP-producing gastric cancer with synchronous liver metastasis wherein the patient survived for 5 years without recurrence after undergoing surgery and adjuvant chemotherapy. A 39-year-old woman was admitted to our hospital complaining of tarry stool. Upper gastrointestinal endoscopy revealed a 40mm type 2 tumor in the greater curvature of the lower gastric body, and abdominal CT indicated a 50mm liver metastasis at the S2 segment. The AFP serum level had risen to 71,000 ng/mL. We performed distal gastrectomy and hepatic left lateral segmentectomy. The primary gastric tumor and the hepatic metastasis were both positive for AFP by immunohistochemistry. After conducting 3 courses of S-1/CDDP(SP)therapy as adjuvant chemotherapy, the serum level of AFP had decreased to normal levels. Be- cause the level had risen to 116 ng/mL after a change to S-1 oral administration alone, we decided to re-start SP therapy and carried out 16 courses through the third postoperative year. The patient is still alive without recurrence 5 years after surgery.

Background and Aim: Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed., Methods: Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice., Results: REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6)., Conclusions: Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Transcatheter arterial chemoembolization (TACE) is a standard therapy for the treatment of intermediate-stage hepatocellular carcinoma (HCC). In this study, we tried to elucidate the possibility of using radiofrequency ablation (RFA) as an alternative treatment of intermediate-stage HCC., Methods: Among 246 patients who were initially diagnosed with intermediate-stage HCC, 76 who were treated with TACE (TACE group) and 91 who were treated with RFA (RFA group) were enrolled in this study. The risk for survival was analyzed with the Cox Proportional Hazard Model, and the survival rates were compared using propensity score matching., Results: About half (50.6%) of the intermediate-stage HCC patients in the RFA group were diagnosed with Barcelona Clinic Liver Cancer substage-B1 (BCLC-B1) compared with only 19.7% of the patients in the TACE group. Survival of the RFA group was longer than that of TACE group in patients with BCLC-B1 and BCLC-B2. In contrast, no difference between groups was observed in patients with BCLC-B3/4. Multivariate analysis revealed that large tumor size (>30 mm, hazard ratio = 1.685, P = 0.043), high des-γ-carboxyprothrombin (>100 mAU/mL, hazard ratio = 1.920, P = 0.012), and TACE group (hazard ratio = 1.896, P = 0.016) were significant risk factors for survival. Overall 3-year survival of the patients in the RFA group (69.5%) was significantly longer than that of patients in the TACE group (51.5%) after propensity score matching (P = 0.032). No significant adverse events were observed in either group., Conclusions: RFA was useful for the treatment of less advanced intermediate-stage HCC and could be an alternative to TACE in selected cases., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma. Therefore, sorafenib was administered;however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged > 35 years, HBV DNA > 4 log copies/mL and positive HBeAg at diagnosis (n＝184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p＝0.013). Among the patients aged >35 years with HBV DNA > 4 log copies/mL and negative HBeAg (n＝237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p＞0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged > 35 years with HBV DNA > 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

The anti-Hu antibody is one of the most famous onco-neural antibodies related to paraneoplastic neurological syndrome, and is associated with small cell lung carcinoma in most cases. Here, we report a case of poorly differentiated hepatocellular carcinoma accompanied by paraneoplastic peripheral neuropathy positive for the anti-Hu antibody. Image inspection before operation revealed that no tumors were found in organs other than the liver, including lung, and that the liver tumor had no metastatic lesion. The liver tumor showed histological appearance of poorly differentiated carcinoma with cartilaginous metaplasia and partial blastoid cell appearance. Most tumor cells presented trabecular-like structure lined by sinusoidal vessels. Immunohistochemically, the tumor cells were positive for low molecular weight cytokeratin and vimentin, partially positive for cytokeratin 19 and CD56, but negative for synaptophysin, chromogranin A and alpha-fetoprotein. Based on the trabecular-like morphology and the results of immunohistochemical staining, we concluded that the tumor was diagnosed as poorly differentiated hepatocellular carcinoma. Anti-Hu antibody-positive paraneoplastic peripheral neuropathy accompanied with liver tumor is extremely rare as far as is known. The presented case indicates that poorly differentiated carcinoma has the potential to be the responsible lesion of anti-Hu antibody-positive paraneoplastic neurological syndrome and systemic work-up is important for the management of this neurological disorder., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients., Methods: We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT)., Results: Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p < 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18%, p < 0.01) and PVTT (45 vs. 18%, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively)., Conclusions: CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT.

We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n＝397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2%, 7.4% and 9.5%, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (＞2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (＜3mm) were independent predisposing factors for local recurrence after RFA (HR＝1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications;therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.

Recurrent esophagus cancer has an extremely poor prognosis in spite of systemic chemotherapy. Herein, we report cases of long survival after recurrence owing to topical treatment. The first patient was a 75-year-old man. He was diagnosed with clinical stage IIA esophagus cancer and underwent subtotal esophagectomy. The pathological stage was IIIB. Liver metastases appeared in S8 and S5, 8 months after surgery. Systemic chemotherapy and transcatheter arterial chemoembolization were performed. He had kept CR but died due to brain metastasis 1 year and 4 months after the recurrence. The second patient was a 68-year-old man. He underwent esophagectomy for clinical stage IIIB esophagus cancer. The pathological stage was also IIIB. Five metastases were seen in the bilateral lobes of the liver 8 months after surgery. Transcatheter arterial chemoembolization and stereotactic irradiation were performed and he has been in complete remission for a year. Topical treatment may represent an important strategy for treating liver metastasis from esophagus cancer.

The artificial ascites technique is often used during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) treatment because it prevents visceral damage and improves visualization by minimizing interference of the lungs and mesentery. This study determined the efficacy and safety of RFA using the artificial ascites technique in HCC patients. We examined 188 HCC patients who were treated by RFA and fulfilled the Milan criteria. Treatment outcomes (complete ablation rate, local recurrence rate, complication rate, liver function including total bilirubin level, alanine aminotransferase level, albumin level, and prothrombin time) were compared among patients divided into 3 groups based on the volume of artificial ascites injected:Group I (n = 86), no artificial ascites injected;Group II (n = 35), < 1,000 ml artificial ascites injected;and Group III (n = 67), > 1,000 ml artificial ascites injected. No significant difference was observed in complete ablation or local recurrence rates among the 3 groups, or in the extent of liver function damage after RFA. Artificial ascites disappeared within 7 days; additional diuretics were needed only in 5 (all from Group III) of 102 patients. No serious complications such as intestinal perforation or intraperitoneal bleeding were observed. Thus, we found that artificial ascites injection during RFA is effective and safe, and can be used to prevent major procedural complications.

Objective: This study aimed to evaluate the efficacy and safety of percutaneous radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC) in the caudate lobe, where RFA is considered to be difficult., Materials and Methods: Of a total of 810 patients treated by ultrasound-guided radiotherapy between July 2002 and May 2010, medical records of 50 consecutive patients with HCC in the caudate lobe were reviewed in this retrospective study. Twenty-two tumors were found to be in the paracaval portion and 28 in the Spiegel lobe. We retrospectively reviewed the procedures, treatment effect, and complications., Results: For all paracaval tumors and eight Spiegel lobe tumors, we used the intercostal approach, and for the remaining Spiegel tumors (n = 20) we used the pass-the-left approach. We found that all tumors were successfully treated, and the local recurrence rate after 2 years was 12%. Cases of mortality or major complications after RFA were absent., Conclusion: RFA appears to be an effective treatment modality for HCC in the caudate lobe.

Background: Radiofrequency ablation (RFA) is used to treat early-stage hepatocellular carcinoma (HCC), but is sometimes avoided in patients with decompensated liver cirrhosis because of the possible side effect of deterioration of liver function., Aims: In this study, we report the safety and effects of RFA for treating HCC patients with Child-Pugh B/C liver cirrhosis., Methods: Sixty-six consecutive HCC patients with Child-Pugh B/C cirrhosis, who were treated by RFA, were enrolled in this study. We analyzed patient outcomes, the complications of RFA, and changes in liver function and tumor markers., Results: Fifty-six patients were classified as Child-Pugh class B, and 10 were classified as class C. The overall survival rates in patients with Child-Pugh B and C cirrhosis were 82 and 83% at 1 year and 47 and 31% at 3 years, respectively. Serum total bilirubin (T.Bil), albumin, prothrombin time, ascites, and encephalopathy were unchanged at 1, 3, and 6 months after RFA in patients with Child-Pugh B cirrhosis; however, serum T.Bil levels increased significantly at 6 months after RFA in 6/10 (60%) patients with Child-Pugh C cirrhosis. Hemothorax and rupture of esophageal varices were observed in 2 patients; however, there were no complications related to poor liver function., Conclusion: RFA is a useful modality for treating HCC in patients with poor liver function such as Child-Pugh B and C, but careful monitoring after RFA must be needed., (Copyright © 2011 S. Karger AG, Basel.)

The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biological functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relationship of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relationship between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that overexpression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Overexpression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.

Matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and membrane-type matrix metalloproteinase 1 (MT1-MMP) are involved in colorectal cancer invasion and metastasis. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) inhibits MMP-2, MMP-9 and MT1-MMP. We examined the clinicopathological significance of the relative expression of these genes in patients with colorectal cancer, especially with regard to metastasis. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal carcinoma. MMP-2, MMP-9, MT1-MMP, RECK and beta-actin mRNA of cancer tissue and adjacent normal mucosa were measured by quantitative real-time reverse-transcriptase polymerase chain reaction. MT1-MMP gene expression was higher in cancer tissue than in adjacent normal mucosa. In contrast, MMP-2, MMP-9 and RECK gene expression levels were lower in cancer tissue than in adjacent normal mucosa. As for the relationship between the gene expression and clinicopathological factors, MMP-2 expression correlated with the depth of invasion, venous invasion and liver metastasis; MMP-9 and RECK expression correlated with venous invasion. There were positive correlations among the gene expression levels of MMP-2, MMP-9 and RECK. MMP-2 gene expression was considered a useful predictor of liver metastasis from colorectal cancer.

Claudins, members of a large family of adherent junction proteins, regulate the integrity and function of tight junctions and influence tumorigenesis. Studies have suggested that altered levels of different claudins are related to carcinoma-cell invasion and disease progression. This study examined the relationship between the relative expression of claudin genes and clinicopathological factors, especially invasion and metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa from 205 patients with untreated colorectal carcinoma. The relative expression levels of claudin-1, -3, -4 and -7 mRNA in cancer and in normal adjacent mucosa were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression levels of the claudin-1, -3 and -4 genes were higher in cancer than in normal adjacent mucosa, whereas the relative expression of the claudin-7 gene was similar. An analysis of the relationship between the clinicopathological features and gene expression showed that reduced expression of claudin-7 correlated with venous invasion and liver metastasis. There was also a correlation between claudin-3 and -4 gene expression. Our results suggested that a reduced expression of the claudin-7 gene might lead to venous invasion and liver metastasis in colorectal cancer. Reduced expression of the claudin-7 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.

Arsenic trioxide, As(2)O(3) (ATO), has been established to be an effective agent for treating acute promyelocytic leukemia, but its effect on solid tumors has not been fully explored. In the present study in a murine xenograft system, we found that ATO significantly inhibited tumor growth of the inoculated human hepatocellular carcinoma cell line HuH7 when administered either intravenously or intratumorally. Pathological examination revealed that ATO induced extensive cell death in the tumor. Some of the dead cells in intratumorally ATO-treated mice showed characteristic features of apoptosis, such as nuclear condensation and fragmentation, and were TUNEL-positive. The measurement of arsenic by using particle induced X-ray emission revealed that arsenic was accumulated more in the tumor than in brain, kidney or liver after the intravenous injection of ATO, which is consistent with the hemorrhagic cell death observed in ATO-treated tumor tissues. Thus, ATO appears to have potential for the treatment of solid tumors, as well as hematopoietic malignancies.

A 68-year-old man who had Borrmann type 4 gastric cancer with multiple liver metastases was admitted to our hospital on October 20, 1998. He was considered nonresectable and placed on neoadjuvant chemotherapy consisting of low-dose CDDP and 5-FU. After 9 weeks of administration, the liver metastases had disappeared on abdominal computed tomography, but the primary lesion had progressed. On May 12, 1999, a total gastrectomy with a partial resection of the transverse colon and resectional biopsy of a white nodule of the liver were performed. This was a non-curative operation because of the peritoneal dissemination. A histopathological examination of the liver nodule revealed that the cancer cells had disappeared. The patient had an uneventful postoperative course and 4 weeks of chemotherapy were added. He remains alive with no symptoms or re-growth of the liver metastatic tumor 4 months after the surgery.

A case of invasive thymoma associated with pure red cell aplasia and liver metastasis was reported. A 57-year-old male was admitted to our hospital because of hepatic abnormal shadow on computed tomography. Malignant tumor was suspected by imaging procedures. Left lateral segmental resection of liver was performed and histo-pathological examination proved the tumor to be liver metastasis of thymoma. He was received 50 Gy irradiation after incomplete resection of thymoma. In the course of time he contracted pure red cell aplasia. But he is well controlled medically and alive 7 years after the surgery.

The histological observation that well-differentiated cancer cells in early hepatocellular carcinoma (HCC) invade portal tracts and/or fibrous bands and that these fibrous tissues then disappear suggests the participation of matrix metalloproteinase-1 (MMP-1) in the degradation of fibrous tissue. To confirm this hypothesis, the authors investigated the localization of both the MMP-1 protein and its messenger RNA (mRNA) in early HCC immunohistochemically and by in situ hybridization using complementary DNA (cDNA) and synthetic antisense probe of MMP-1; they then compared the results with those in advanced HCC. MMP-1 gene transcripts and protein were observed in well-differentiated cancer cells of early HCC but not in moderately or poorly differentiated cancer cells. Thus, cancer cells producing MMP-1 in early HCC may destroy the portal tract tissue adjacent to the cancer lesion and/or the fibrous band of cirrhosis. These results seem to have demonstrated a difference in the mechanism of cancer growth and invasion between early and advanced HCCs.