A study on prevention of bleeding complications using lusutrombopag for safe RFA in patients with hepatocellular carcinoma with low platelet counts: prospective observational study.

BACKGROUND: Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available. METHODS: Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL- 1). We collected demographic data concerning the patients' liver function and PLT counts. RESULTS: Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 104 ± 1.4 × 104 to 8.6 × 104 ± 2.5 × 104 PLT µL- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL- 1 but > 50,000 µL- 1. CONCLUSIONS: Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts. TRIAL REGISTRATION: This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

[A Case of Pancreatic Tail Cancer Causing Gastrointestinal Hemorrhage Due to Transverse Colon Invasion].

An 81-year-old woman was admitted to our hospital due to frequent bleeding and hemorrhagic shock. Blood tests revealed anemia and contrast-enhanced abdominal CT revealed a pancreatic tail tumor with a diameter of 60 mm. The boundary between pancreatic tumor and the transverse colon, stomach and spleen was unclear, and invasion of the transverse colon as well as the stomach and spleen was suspected. Hemorrhage due to colon invasion of the pancreatic tail cancer and intra-tumoral hemorrhage were suspected. Due to persistent bleeding, the patient had emergency surgery to control bleeding. The pancreatic tail tumor invaded not only the colon but also stomach and spleen, distal pancreatectomy, partial gastrectomy and splenectomy was performed in combination with resection of the transverse colon, and transverse colon colostomy. We report a case of gastrointestinal bleeding caused by transverse colon invasion of pancreatic tail cancer, which resulted in emergency surgery.

Effectiveness of direct acting antiviral agents for hepatitis C virus related recurrent hepatocellular carcinoma patients who had multiple courses of recurrence.

Eradication of hepatitis C virus (HCV) using direct acting antiviral agents (DAAs) has been reported to alter liver function and reduce the recurrence rate after curative treatment in naïve hepatocellular carcinoma (HCC) patients. However, it is not well known whether administration of DAAs had favourable effect on HCC patients with multiple courses of recurrence. We retrospectively extracted 146 HCV-related HCC (C-HCC) patients who received curative treatment using radiofrequency ablation (RFA) followed by eradication treatment with DAA between 1 January 2015 and 31 December 2017. We also extracted 184 C-HCC patients who were curatively treated using RFA without HCV eradication treatment between 1 January 2009 and 31 July 2014 as controls. We used propensity score matching method and adjusted following factors between the 2 groups: age, sex, liver function, number of recurrence times, tumour diameter and tumour numbers. We finally enrolled 47 C-HCC patients with eradication of HCV, and 47 C-HCC patients without HCV eradication as controls. Primary end point was time to curative treatment failure. We defined time to curative treatment failure as the interval from curative treatment initiation to premature discontinuation of this type of therapy. Their clinical data, time to curative treatment failure and overall survival were compared. We also assessed the prognostic values of time to curative treatment failure and overall survival using multivariate Cox proportional hazard models. The median age was 74.8 years, 60 patients (63.8%) were male, and 81 patients (86.2%) were Child-Pugh class A. The median tumour number was 1, tumour diameter was 20 mm, and frequency of recurrence was 3 times. There were no significant differences about patients' backgrounds between the 2 groups. The cumulative time to curative treatment failure rates of patients who received DAA were 93.6% and 73.2% at 1 and 3 years, respectively; those of controls were 72.5%, and 37.1% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.23, 95% CI; 0.12-0.43, p < .01) and DCP >50 mAU/ml (HR 2.62, 95% CI; 1.45-4.74, p < .01) as independent factors contributed to time to curative treatment failure. The cumulative overall survival rates of patients who received DAAs were 93.6% and 72.6% at 1 and 3 years, respectively; those of controls were 72.8% and 37.4% (p < .01). Multivariate analysis indicated that eradication with DAAs (HR 0.32, 95% CI; 0.17-0.60, p < .01) and frequency of recurrence times (HR 1.20 per 1 time, 95% CI; 1.01-1.42, p = .038) as independent factors related to overall survival. Eradication of HCV using DAAs prolonged not only time to curative treatment failure but also overall survival even in C-HCC patients with multiple courses of recurrence.

Emergency endoscopic variceal ligation following variceal rupture in patients with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a retrospective study.

BACKGROUND: The outcomes of treatment of ruptured varices in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) are unclear. We therefore evaluated the long- (rebleeding and death) and short-term (immediate death within 24 h of variceal bleeding diagnosis) outcomes of patients with PVTT who underwent emergency variceal band ligation. METHODS: Data on 62 patients with PVTT and endoscopically proven esophageal or gastric variceal bleeding from 2007 to 2012 were studied. In most cases, the varices were treated using endoscopic variceal band ligation (EVL). We assessed the patients' rebleeding-free and overall survival using the Kaplan-Meier method, and a Cox proportional hazard model was used to analyze effect of independent factors on rebleeding-free and overall survival times. RESULTS: Most patients had decompensated cirrhosis and were classified as Child-Pugh class B (56%) or C (36%). A total of 35 patients (56%) had PVTT in the main portal trunk. Among all patients, 58 (94%) and 4 (6%) had esophageal and gastric variceal bleeding, respectively. Bleeding was managed using EVL in all, but one patient (98%) who was treated with a Sengstaken-Blakemore tube. A total of 24 patients (39.3%) experienced rebleeding, and these patients had a median overall survival time of 36 days. A PVTT in the main portal trunk was predictive of rebleeding (hazard ratio 3.706, p = .0223), and α-fetoprotein-L3 levels <37.4% (hazard ratio 0.464, p = 0.015) and Child-Pugh class A/B (hazard ratio 0.398, p = 0.007) were associated with overall survival. We observed 95 bleeding events in 62 patients. EVL achieved hemostasis in 92 of the 95 bleeding events, whereas seven immediate deaths occurred due to variceal bleeding (7/92, 7.6%). All three bleeding events treated with modalities other than EVL resulted in immediate deaths. CONCLUSIONS: EVL is a safe and effective treatment of variceal ruptures in patients with HCC and PVTT. After successful hemostasis, alleviation of the underlying liver function impairment and tumor control are equally important for a good prognosis.

Tumor markers are more useful in patients undergoing surveillance for hepatocellular carcinoma with unreliable results by ultrasonography.

AIM: The objectives of this study was to evaluate the utility of tumor markers in hepatocellular carcinoma (HCC) surveillance based on the reliability of ultrasonography. METHODS: We analyzed 313 patients with HCC detected through a surveillance program using ultrasonography combined with three tumor markers from February 2000 to December 2010. The patients were categorized into two groups based on the triggering event: the US group (n = 281) in which a tumor was first detected using ultrasonography and the TM group (n = 32) in which elevated tumor markers led to the diagnosis of a tumor that was undetected using ultrasonography. The reliability of ultrasonography was scored on a 4-point scale based on three items (coarseness of liver parenchyma, patient obesity and liver atrophy). Additionally, patient survival was assessed using the Kaplan-Meier method and log-rank test. RESULTS: The median tumor size was 20 mm (interquartile range, 15-24). The reliability of ultrasonography was evaluated as good in 208 (66.5%), satisfactory in 80 (8.0%), poor in 21 (6.7%) and unsatisfactory in four (1.2%) patients. The proportion of patients in the TM group increased significantly according to the score, from 7.2% to 25.0% (P = 0.01). The survival rates of patients at 3 and 5 years were 83.7% and 57.2% in the US group, and 79.3% and 59.4% in the TM group, respectively (P = 0.98). CONCLUSION: Tumor markers may play a diagnostic role in patients with unreliable ultrasonography results. The survival of patients diagnosed by elevated tumor markers was not significantly different from those diagnosed by ultrasonography.

Increased activity of serum mitochondrial isoenzyme of creatine kinase in hepatocellular carcinoma patients predominantly with recurrence.

BACKGROUND & AIMS: Mitochondrial isoenzyme of creatine kinase (MtCK) is reportedly highly expressed in hepatocellular carcinoma (HCC). Clinical relevance of serum MtCK activity in patients with HCC was assessed using a novel immuno-inhibition method. METHODS: Among patients with cirrhosis caused by hepatitis B or C virus, 147 patients with HCC (12 with the first occurrence and 135 with recurrence) and 92 patients without HCC were enrolled. RESULTS: Serum MtCK activity was higher in cirrhotic patients with HCC than in those without HCC or healthy subjects. Elevated serum MtCK activity in HCC patients decreased after radiofrequency ablation. In case of prediction of HCC, MtCK had a sensitivity of 62.6% and a specificity of 70.7% at a cut-off point of 8.0 U/L, with an area under the receiver operating curve of 0.722 vs. 0.713 for alpha-fetoprotein (AFP) and 0.764 for des-gamma-carboxy prothrombin (DCP). Among the HCC patients, serum MtCK activity was elevated in 52.9% individuals with serum AFP level < 20 ng/ml and 63.2% individuals with serum DCP level < 40 mAu/ml. Even in patients with a single HCC ≤ 2 cm, the sensitivity of serum MtCK activity for the prediction of HCC was 64.4%, which was comparable to the overall sensitivity. This increased activity was due to an increase in ubiquitous MtCK, not sarcomeric MtCK, and the enhanced mRNA expression of ubiquitous MtCK was observed in cell lines originating from HCCs in contrast to healthy liver tissues. CONCLUSIONS: Serum MtCK activity merits consideration as a novel marker for HCC to be further tested as for its diagnostic and prognostic power.

Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors.

OBJECTIVES: Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center. METHODS: We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database. RESULTS: Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7-63.9%) and 27.3% (95% CI: 21.5-34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1-4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8-77.8%) and 80.8% (95% CI: 77.4-84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%). CONCLUSIONS: RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.

Possible Duration of WISH-type Hip Brace Use: Prognostic Value of Timed Up and Go Test.

Objectives: The WISH-type S-form hip brace (WISH brace) has significantly improved hip function and functional mobility in patients with hip osteoarthritis (OA). However, most patients later undergo surgery. The main purpose of this study was to evaluate how long the orthosis can be effectively used by patients with hip OA, and to reveal the associated prognostic factors. Methods: This prospective study examined the survival curve of the equipment by using surgery as an endpoint and investigated how the duration of use affects patients. Harris Hip Score, muscle strength, and the Timed Up and Go test (TUG) were evaluated as prognostic factors. Results: By drawing the survival curves of 26 patients, approximately one third were expected to be still using the brace after 7 years. A rapid decrease in use was observed at around 1 year. A significant difference between patients with and without bracing at 1 year was found for the TUG result with the unaffected leg inside (ULI) at the start of bracing. A cut-off value of 9.5 s for the TUG with ULI significantly differentiated patients with and without bracing at 1 year, suggesting a possible predictor of brace survivorship in the early phase. Conclusions: The TUG with ULI with a cut-off value of 9.5 s, or at most 10 s, may be a possible predictor of persistence of brace use in the early phase.

Intra-abdominal ectopic bronchogenic cyst with a mucinous neoplasm harboring a GNAS mutation: A case report.

BACKGROUND: Bronchogenic cysts are congenital cysts caused by abnormal sprouting from the ventral foregut during fetal life. They usually occur in the mediastinum or lung, but there are very rare cases of ectopic bronchogenic cysts that develop in the abdominal cavity. A unique intra-abdominal ectopic bronchogenic cyst with a mucinous neoplasm that was producing carcinoembryonic antigen (CEA), harboring a GNAS mutation, is reported. The present case may contribute to clarifying the mechanism of tumorigenesis and malignant transformation of ectopic bronchogenic cysts. CASE SUMMARY: In 2007, a man in his 50s was incidentally found to have an intra-abdominal cystic mass, 8 cm in diameter. Surgical resection was recommended, but he preferred to remain under observation. In 2020, his serum CEA level increased to 26.7 ng/mL, and abdominal computed tomography showed a 15 cm × 12 cm, multifocal, cystic mass located predominantly on the lesser curvature of the stomach. Since malignancy could not be ruled out, he finally underwent surgical resection. Histologically, the cystic wall was lined by ciliated columnar epithelium, accompanied by bronchial gland-like tissue, bronchial cartilage, and smooth muscle. Part of the cyst consisted of atypical columnar epithelium with an MIB-1 index of 5% and positive for CEA. Moreover, a GNAS mutation (p.R201C) was detected in the atypical epithelium, leading to a diagnosis of an ectopic bronchogenic cyst with a low-grade mucinous neoplasm. The patient is currently undergoing outpatient follow-up without recurrence. CONCLUSION: An extremely rare case of an abdominal bronchogenic cyst with a low-grade mucinous neoplasm harboring a GNAS mutation was reported.

Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.

UNLABELLED: Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV-RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow-up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person-year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM < or =10 kPa, of 16.7 (95% confidence interval [CI], 3.71-75.2; P < 0.001) when LSM 10.1-15 kPa, 20.9 (95% CI, 4.43-98.8; P < 0.001) when LSM 15.1-20 kPa, 25.6 (95%CI, 5.21-126.1; P < 0.001) when LSM 20.1-25 kPa, and 45.5 (95% CI, 9.75-212.3; P < 0.001) when LSM >25 kPa. CONCLUSIONS: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development.

Hemorrhagic complications of percutaneous radiofrequency ablation for liver tumors.

BACKGROUND: Although radiofrequency ablation (RFA) is widely accepted as a percutaneous treatment for liver tumors; serious complications may occur resulting in 0.1% to 0.5% mortality. This study analyzed the risk factors and management of hemorrhagic complications, such as hemoperitoneum, hemothorax, and hemobilia. METHODS: We performed 4133 RFA treatments in 2154 patients with primary and metastatic liver tumors from February 1999 to December 2007. Of these, we enrolled patients with hemorrhagic complications and reviewed their medical records thoroughly. The risk factors for each hemorrhagic complication were analyzed using unconditional logistic regression. RESULTS: Hemorrhagic complications occurred in 63 out of 4133 treatments (1.5%), including hemoperitoneum in 29 (0.7%), hemothorax in 14 (0.3%), and hemobilia in 20 (0.5%). Eleven, 8, and 4 of these patients, respectively, were categorized as major complications requiring blood transfusion or drainage. Two patients died after hemoperitoneum. Logistic regression analysis revealed large tumor size [odds ratio (OR) 1.06 per 1 mm increase in diameter] and low platelet count (OR 0.88 per 10,000/microL increase) were significant risk factors for hemoperitoneum. The location of tumor nodules was a significant risk factor for hemothorax (segment 7, OR 2.31) and hemobilia (segment 1, OR 3.30). Other factors, including the number of needle insertions or the duration of ablation, were not significant. CONCLUSIONS: Although hemorrhagic complications were relatively rare with percutaneous RFA, specific treatments, such as blood transfusion and drainage, were required in some cases. Care must be taken, especially in high-risk patients.

Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: A Multicenter Retrospective Study.

BACKGROUND AND OBJECTIVE: Experience of the use of lenvatinib (LEN) in the clinical setting remains limited. We conducted this study to elucidate the factors associated with progression-free survival (PFS) in patients with advanced HCC treated with LEN. METHODS: In this multicenter retrospective study, we analyzed data on patient characteristics, treatment outcomes, and adverse events (AEs) for 77 patients with advanced hepatocellular carcinoma (HCC). We also analyzed PFS and factors that influence PFS. RESULTS: The response rate to LEN was 29.9% and the disease control rate was 77.9%. Patients who achieved relative dose intensities of more than 70% had better outcomes (response rate 45.2% vs. 11.4%, P < 0.01). Appetite loss, fatigue, diarrhea, hypertension, and thyroid dysfunction were the most frequent AEs. Twenty-three patients (29.9%) had grade 3 or 4 AEs. Fifty-two patients (67.5%) required a dose reduction and 47 (61.0%) stopped taking the drug due to AEs. The PFS rates at 3, 6, and 12 months were 81.2%, 49.8%, and 34.8%, respectively. The median PFS was 5.6 months. Multivariate analysis showed that thyroid dysfunction of grade ≥ 2 (hazard ratio [HR] 4.57, 95% confidence interval [CI] 2.05-10.2, P < 0.01), appetite loss (HR 3.58, 95% CI 1.72-7.52, P < 0.01), and tumor diameter ≥ 40 mm (HR: 2.27, 95% CI 1.17-4.40, P = 0.015) were independent factors associated with poor PFS. On the other hand, Child-Pugh class 5A (HR 0.41, 95% CI 0.19-0.90, P = 0.027) and complete or partial response (HR 0.40, 95% CI 0.17-0.95, P = 0.039) were independent factors associated with better PFS. CONCLUSIONS: Thyroid dysfunction and appetite loss after the administration of LEN were independent factors associated with shorter PFS, so these AEs should be carefully managed after administering LEN.

Oxoammonium salt/NaClO2: an expedient, catalytic system for one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability.

A facile, green, one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability has been developed by employing an expedient catalytic system consisting of 1-Me-AZADO+X-/NaClO2.

Treatment strategy for hepatocellular carcinoma: expanding the indications for radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is ordinarily indicated for those with three or fewer nodules, none of which exceeds 3 cm in diameter. This study investigated whether an apparent threshold exists in the diameter and number of nodules in terms of the prognosis of patients with HCC. METHODS: We enrolled 663 naïve patients with HCC who were treated with RFA at our hospital between 1999 and 2005. We analyzed the patients' prognosis using multivariate Cox proportional regression with the diameter and number of nodules as covariates and Child-Pugh class as a stratification factor. The diameter and number were categorized as 5 cm and 1, 2-3, 4-5, and >5, respectively. RESULTS: The adjusted hazard ratio of patients whose largest nodule was 5 cm was 1, 1.51, 2.56, 2.25, and 2.71, respectively. The adjusted hazard ratio of patients with one, two or three, four or five, and more than five nodules was 1, 1.35, 1.70, and 2.12, respectively. Therefore, patients with three or fewer nodules, none of which exceeds 5 cm in diameter, have a 5-year survival of 40%. CONCLUSIONS: The prognosis of the patients worsened gradually as the diameter and number of nodules increased. No apparent threshold in the diameter or number of HCC nodules was detected. RFA can be applied beyond the conventional indications.

Biomechanical analysis of gait in patients with painful osteoarthritis of the hip treated with WISH-type hip brace.

BACKGROUND: A hip brace, the WISH-type S-form brace, improved hip function scores markedly in patients with painful hip osteoarthritis (OA). To evaluate the biomechanical effects of the brace, gait analysis using a force plate was performed. METHODS: For the gait of seven patients with this hip brace, characteristic parameters calculated from three-dimensional (i.e., vertical, forward, and medial) components of the floor reaction force were analyzed using a flat force plate. RESULTS: Gait analyses revealed several tendencies: a shorter time for one step, a stronger step, and a shift of the center of gravity of the body to the contralateral side. In particular, stronger vertical reaction force at the first peak in the early stance and earlier switch from backward to forward reaction force vectors were observed as effects of the hip brace, with statistically significant difference. CONCLUSIONS: These biomechanical assessments suggest that abnormal gait in hip OA may be closer to normal gait in patients using this brace, although the deceleration and weighing-off effects, which are indicators useful for observing gait recovery, did not reach significance.

The efficacy and safety of lenvatinib for advanced hepatocellular carcinoma in a real-world setting.

BACKGROUND/PURPOSE: Lenvatinib (an inhibitor of vascular endothelial growth factor (GF) receptors 1-3, fibroblast GF receptors 1-4, platelet-derived GF receptor α, rearranged during transfection, and stem cell factor receptor) was non-inferior to sorafenib in a phase 3 (REFLECT) trial of advanced hepatocellular carcinoma. This study examined the efficacy and safety of lenvatinib in a real-world setting. METHODS: This was a retrospective, multicenter, observational study. Inclusion and exclusion criteria were based on the phase 3 trial, and participants were observed for at least 12 weeks. Therapeutic effect was determined using the modified Response Evaluation Criteria In Solid Tumors (m-RECIST) at the 8th week. Patients received oral lenvatinib 12 mg/day (body weight > 60 kg) or 8 mg/day (body weight < 60 kg). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events (AEs) complied with the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: All 16 patients included in this study had prior treatment history, and a median 3.9 years had passed since the first treatment. Fatigue, hypertension, and proteinuria were the most frequent AEs, and were higher than Grade 2. AEs could be controlled by appropriate dose reduction, interruption, and symptomatic treatment according to the protocol. In the m-RECIST evaluation at the 8th week, 0, 6, 8, and 1 patients had achieved complete response, partial response, stable disease, and progressive disease, respectively. The objective response rate was 40%. CONCLUSION: Lenvatinib treatment could be accomplished with safety and good response in a real-world setting.

Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients.

BACKGROUND & AIMS: It is not fully elucidated whether obesity enhances hepatocarcinogenesis in patients with chronic hepatitis C. The aim of this study was to investigate the relationship between body weight and risk of hepatocarcinogenesis in chronic hepatitis C patients. METHODS: We enrolled 1431 patients with chronic hepatitis C who visited our liver clinic between 1994 and 2004, excluding those with hepatocellular carcinoma (HCC) at their visit or with a previous history of HCC. They were divided into 4 groups according to body mass index (BMI): underweight (< or =18.5 kg/m(2), N = 112); normal (18.5 to less than 25 kg/m(2), N = 1023); overweight (25 to less than 30 kg/m(2), N = 265); and obese (>30 kg/m(2), N = 31). We assessed the impact of obesity on the hepatocarcinogenesis adjusted by multivariate Cox proportional hazard regression with other risk factors found significant in univariate analysis. RESULTS: During the follow-up period (mean, 6.1 y), HCC developed in 340 patients, showing cumulative incidence rates of 10.5%, 19.7%, and 36.8% at 3, 5, and 10 years, respectively. The incidence differed significantly among the BMI groups (P = .007). Adjusting for other significant factors, overweight and obesity were shown to be an independent risk factor of HCC, with a hazard ratio of 1.86 (95% confidence interval, 1.09-3.16; P = .022) and 3.10 (95% confidence interval, 1.41-6.81; P = .005) as compared with the underweight patients. CONCLUSIONS: The risk of HCC in patients with chronic hepatitis C increases in proportion to BMI in a wide range of its values, from underweight to obese.

Neoplastic seeding after radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Neoplastic seeding reportedly occurs in up to 12.5% of patients treated with radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). The aim of this study is to assess the incidence, risk factors, and prognosis of neoplastic seeding after RFA among a large number of patients with a long-term follow-up. METHOD: From February 1999 to December 2004, 1,031 patients underwent a total of 1,845 treatments with RFA for a total of 3,837 HCC nodules. The following variables were assessed to elucidate the risk factors of neoplastic seeding: age, sex, positivity for viral markers, tumor size, number of tumor nodules, number of RFA sessions, tumor location, percutaneous biopsy prior to RFA, alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP) and lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) levels, and the degree of tumor differentiation. RESULTS: Neoplastic seeding was detected in 33 patients (3.2% per patient) at intervals of 4.8-63.8 (median, 15.2) months after RFA. On multivariate logistic regression analysis, only the poor differentiation degree was associated with the risk of neoplastic seeding (P= 0.012). Of tumor factors, tumor size, and AFP, DCP, and AFP-L3 levels were significantly associated with the poor differentiation degree. The cumulative survival rates 1 and 2 yr after the detection of neoplastic seeding were 86% and 47%, respectively. CONCLUSION: Poor differentiation degree was the risk factor of neoplastic seeding after RFA for HCC. The surrogate markers for poor differentiation degree were larger tumor size and elevated tumor marker levels. Indication for RFA should be carefully considered for HCC patients under these conditions.

Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors.

BACKGROUND: Extrahepatic metastasis of hepatocellular carcinoma (HCC) is of growing importance as the survival of patients has been improved owing to advances in treatments to intrahepatic lesions. METHODS: To elucidate the incidence and risk factors of extrahepatic metastasis of HCC, we enrolled 1573 (1131 treatment-naïve and 442 previously treated on referral) patients with HCC without extrahepatic tumour spread treated at the authors' department between 1990 and 2003. Patients received medical treatment including percutaneous ablation and transcatheter arterial chemoembolization, and followed by dynamic computed tomography (CT) or magnetic resonance imaging (MRI) and tumour markers every 3-4 months. Extrahepatic metastasis was diagnosed by plain X-ray, CT, MRI and scintigraphy. Clinical parameters at the time of treatment to intrahepatic lesions were evaluated as a predictor of subsequent extrahepatic metastasis among the 1131 treatment-naïve patients by Cox's proportional hazard model. RESULTS: During the average observation period of 3.9 years, extrahepatic metastasis was diagnosed in 123 in the treatment-naïve and 53 in the patients treated previously. The incidence rate of extrahepatic metastasis, as detected during the lifetime after medical treatment of HCC, was approximately 13% at 5 years. Multivariate analysis with Cox proportional hazard model revealed that positivity for viral markers, lager tumour diameter, multiple tumour nodules, presence of vascular tumour invasion and elevated tumour markers were associated with the development of extrahepatic metastasis. CONCLUSION: The incidence of extrahepatic metastasis of HCC diagnosed during clinical course was not frequent. Advanced intrahepatic lesions, presence of vascular tumour invasion, elevated tumour markers and presence of viral hepatitis were risk factors for extrahepatic metastasis.

Comparison of liver biopsy and transient elastography based on clinical relevance.

BACKGROUND: Liver stiffness measurement (LSM) by transient elastography has recently been validated for the evaluation of liver fibrosis in chronic liver diseases. The present study focused on cases in which liver biopsy and LSM were discordant. METHODS: Three hundred eighty-six patients with chronic hepatitis C who underwent a liver biopsy between December 2004 and April 2007 were studied. First, the optimal cut-off value of LSM was selected for the determination of cirrhosis based on the receiver operating characteristic curve. Then, the cases in which liver histology and evaluation by LSM were discordant were selected. Laboratory test results such as serum total bilirubin concentration, prothrombin activity, albumin concentration, platelet count and the aspartate aminotransferase to platelet ratio index, together with the presence of esophageal varices, were analyzed. RESULTS: The optimal cut-off value was chosen to be 15.9 kPa for cirrhosis (fibrosis stage [F] 4) determination to maximize the sum of sensitivity (78.9%) and specificity (81.0%). There were 78 discordant cases: 51 patients showed an LSM of 15.9 kPa or higher and a fibrosis stage of F1 to F3 (high LSM group), and 27 patients had an LSM lower than 15.9 kPa and a fibrosis stage of F4 (low LSM group). Esophageal varices were seen in 11 patients in the high LSM group (n=51) and in no patients in the low LSM group (n=27) (P=0.0012). The aspartate aminotransferase to platelet ratio index was significantly higher in the high LSM group (1.49 versus 0.89, P=0.019). Other parameters did not differ significantly. However, platelet count, prothrombin activity and albumin concentration tended to be lower in the high LSM group. CONCLUSIONS: Patients with a high LSM need proper attention for cirrhosis, even if liver biopsy does not reveal cirrhosis.