Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

Distinct Situational Cue Processing in Individuals with Kleptomania: A Preliminary Study.

BACKGROUND: Impulse control disorder has been suggested to meet the criteria of addiction and is often considered a behavioral addiction; however, few studies have examined whether the disorder involves altered responses to situational cues that are associated with symptoms. In this study, we examined behavioral and neural responses to situational cues among individuals with an impulse control disorder: kleptomania. METHODS: Healthy adults and kleptomania patients whose symptoms were characterized by repetitive, uncontrolled shoplifting of sales goods in stores were recruited. Images with and without situational cues (e.g., a grocery store) were presented, and gazing patterns for the images were detected with the eye-tracker. Additionally, prefrontal cortical (PFC) responses were measured using functional near-infrared spectroscopy. PFC activities were further examined while participants were watching video clips in virtual reality with and without situational cues. RESULTS: Among kleptomania patients, the gazing pattern for an image with situational cues was distinct from gazing patterns for other images; such differences were not observed in healthy individuals. Consistent with gazing patterns, PFC local network responses by hemoglobin changes to images and videos with situational cues were substantially different from other images and videos in kleptomania patients, whereas PFC responses were consistent across all image and video presentations in healthy individuals. CONCLUSIONS: These results suggest that kleptomania patients may perceive situational cues associated with their problematic behaviors differently from healthy individuals.

Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography-Photodiode array detection.

BACKGROUND: Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs. METHODS: Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system. RESULTS: The calibration ranges were 2-500 ng/ml for dasatinib, 100-5000 ng/ml for nilotinib, and 10-500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%-96.0%, 80.7%-86.1%, 91.6%-99.0%, and 86.4%-92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively. CONCLUSION: To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

Higher Risk Taking and Impaired Probability Judgment in Behavioral Addiction.

BACKGROUND: Accumulating evidence suggests that deficits in decision-making and judgment may be involved in several psychiatric disorders, including addiction. Behavioral addiction is a conceptually new psychiatric condition, raising a debate of what criteria define behavioral addiction, and several impulse control disorders are equivalently considered as types of behavioral addiction. In this preliminary study with a relatively small sample size, we investigated how decision-making and judgment were compromised in behavioral addiction to further characterize this psychiatric condition. METHOD: Healthy control subjects (n = 31) and patients with kleptomania and paraphilia as behavioral addictions (n = 16) were recruited. A battery of questionnaires for assessments of cognitive biases and economic decision-making were conducted, as was a psychological test for the assessment of the jumping-to-conclusions bias, using functional near-infrared spectroscopy recordings of prefrontal cortical (PFC) activity. RESULTS: Although behavioral addicts exhibited stronger cognitive biases than controls in the questionnaire, the difference was primarily due to lower intelligence in the patients. Behavioral addicts also exhibited higher risk taking and worse performance in economic decision-making, indicating compromised probability judgment, along with diminished PFC activity in the right hemisphere. CONCLUSION: Our study suggests that behavioral addiction may involve impairments of probability judgment associated with attenuated PFC activity, which consequently leads to higher risk taking in decision-making.

General anesthesia with a transcutaneous pacemaker for a Noonan syndrome patient with advanced atrioventricular block discovered in the remote period after open-heart surgery: a case report.

We provided general anesthesia management to a patient with advanced atrioventricular block, which was discovered in the remote period after open-heart surgery. A 21-year-old man with Noonan syndrome was scheduled to undergo excision of a median intramandibular tumor. At 2 months of age, the patient underwent endocardial repair for congenital heart disease. During our preoperative examination, an atrioventricular block was detected, which had not been previously noted. Emergency drugs were administered, and a transcutaneous pacemaker was placed. During anesthesia induction, mask ventilation was easy, and intubation was performed smoothly using a video laryngoscope. The transcutaneous pacemaker was activated in demand mode at a pacing rate of 50 cycles/min approximately throughout the anesthesia time, and the hemodynamic status remained stable. The effect of intraoperatively administered atropine was brief, lasting only a few seconds. Although body movements due to thoracoabdominal muscle spasm were observed during pacemaker activation, they did not interfere with surgery. In postoperative patients with congenital heart disease, an atrioventricular block may be identified in the remote period, and preoperative evaluation should be based on this possibility. In addition, during anesthesia management, it is important to prepare multiple measures to maintain hemodynamic status.

Risk factors for postoperative nausea and vomiting in patients of orthognathic surgery according to the initial onset time: a cross-sectional study.

Background: A high incidence (40-73%) of postoperative nausea and vomiting (PONV) has been reported following orthognathic surgery, and various risk factors have been associated with it. Identifying PONV risk factors based on initial onset time will help establish preventive measures. This study aimed to identify factors that are significantly related to PONV based on the initial onset time after orthognathic surgery. Methods: This study included 590 patients who underwent orthognathic surgery. Multivariate logistic regression analysis was performed to identify the risk factors that are significantly related to PONV. The objective variables were classified into three categories: no PONV, early PONV (initial onset time: 0-2 h after anesthesia), and late PONV (initial onset time: 2-24 h after anesthesia). The explanatory variables included relevant risk factors for PONV, as considered in previous studies. Results: Total intravenous anesthesia with propofol was a significant depressant factor for early PONV (adjusted odds ratio [aOR] = 0.340, 95% confidence interval [CI] = 0.209-0.555) and late PONV (aOR = 0.535, 95% CI = 0.352-0.814). The administration of a combination of intraoperative antiemetics (vs. no administration) significantly reduced the risk of early PONV (aOR = 0.464, 95% CI = 0.230-0.961). Female sex and young age were significant risk factors for late PONV (aOR = 1.492, 95% CI = 1.170-1.925 and unit aOR = 1.033, 95% CI = 1.010-1.057, respectively). Conclusion: We identified factors that are significantly related to PONV based on the initial onset time after orthognathic surgery. Total intravenous anesthesia with propofol significantly reduced the risk of PONV not only in the early period (0-2 h after anesthesia) but also in the late period (2-24 h after anesthesia).

[Docetaxel in combination with epirubicin as the first-line chemotherapy for advanced and recurrent breast cancer: a multicenter phase II study].

This study examined the efficacy and tolerability of docetaxel(DOC)in combination with epirubicin(EPI)as the first-line treatment for patients with advanced and recurrent breast cancer. A total of 56 female patients with metastatic breast cancer not previously treated for metastatic disease received DOC(60mg/m²)and EPI(60mg/m2)on day 1 every 3 weeks. The patient characteristics included a median age of 53 years. Advanced disease was present in 86% of patients, and recurrent disease was found in 14%; 3 or more metastatic sites had been diagnosed in 38% of patients, and 59% patients were ER+. The median number of courses administered was 6. The median dose intensity was 18. 7mg/m²week for DOC and EPI, and the relative dose intensities were 93. 5%and 93. 3%, respectively. The clinical responses included a complete response in 5%, a partial response in 54%, and stable disease in 33% of patients, with a disease control rate of 92%. The progression-free survival was 78. 3%, and the overall survival was 91. 9% at 1 year. Grade 3/4 toxicities included neutropenia in 82%, leukopenia in 71%, febrile neutropenia in 16%, anorexia in 9%, and anemia in 7%of the patients. Neither congestive heart failure nor toxic death occurred. The D and E combination with doses of 60mg/m2 is an active and generally well-tolerated regimen that can be used as first-line chemotherapy for patients with metastatic breast cancer.

A Cohen syndrome patient whose muscle-relaxant effect may have been prolonged during general anesthesia: a case report.

Cohen syndrome is a rare genetic disorder associated with mutations in the VPS13B gene. Individuals with this disorder present with diverse clinical manifestations, including muscle hypotonia, intellectual disabilities, and typical facial characteristics, such as prominent upper central incisors and micrognathia. General anesthesia was administered to a 23-year-old man with Cohen syndrome. Although we observed prominent upper central incisors, an overjet of 10 mm, micrognathia, and thyromental distance of 4 cm, hypotonia was not observed in the patient. Intubation was rendered difficult when performing a direct laryngoscopy. However, smooth intubation was achieved using a video laryngoscope. The patient's train of four (TOF) count remained zero close to 60 min after rocuronium administration, suggesting that the drug's muscle-relaxant effect may have been prolonged. A TOF ratio of 0.79 was confirmed 130 min after rocuronium administration, and a TOF ratio of 1.0 was confirmed after administration of 150 mg of sugammadex. The patient's respiration remained stable after extubation, and no recurarization of muscle relaxation was observed. As demonstrated in this case report, it is important to closely monitor recovery from muscle relaxation and prepare multiple techniques for airway management in general anesthesia management of patients with Cohen syndrome.

Cross-sectional Study of PONV Risk Factors for Oral Surgery After Intubated General Anesthesia With Total Intravenous Anesthesia.

OBJECTIVE: The incidence of postoperative nausea and vomiting (PONV) after general anesthesia with total intravenous anesthesia (TIVA) was reported to be significantly lower than with volatile inhalational agents (13.3% vs 25%). However, no investigation of PONV risk factors associated with TIVA has ever been reported. This cross-sectional retrospective study aimed to investigate whether known risk factors influenced PONV in intubated general anesthetics utilizing TIVA for dental or oral and maxillofacial surgery. METHODS: Subjects were 761 patients who underwent dental or oral and maxillofacial surgery under TIVA with propofol, fentanyl, and remifentanil. Univariate and multivariable logistic regression analyses were performed using PONV (within 24 hours) as the dependent variable and previously reported risk factors as independent variables. RESULTS: Age (odds ratio [OR]: 1.020 per year decrease; 95% confidence interval [CI]: 1.0002-1.0418; P = .047) and female sex (OR: 2.73; 95% CI: 1.60-4.84; P < .001) were positively associated with PONV. Sagittal split ramus osteotomy (SSRO) (OR: 2.28; 95% CI: 1.21-4.33; P = .011) and bimaxillary osteotomy (OR: 5.69; 95% CI: 2.09-15.99; P < .001) were more likely to be associated with PONV than operations that were neither bimaxillary osteotomy nor SSRO. Late PONV (2-24 hours) had an ∼2.7 times higher incidence than early PONV (0-2 hours). CONCLUSION: These findings suggest further PONV countermeasures, aside from TIVA with propofol and prophylactic antiemetics for orthognathic surgeries especially bimaxillary osteotomy, are needed.

Cross-sectional study of propofol dose during intravenous sedation for dental surgery in patients with long-term oral benzodiazepine therapy: A secondary publication.

OBJECTIVES: The amount of propofol required for intravenous sedation (IVS) in patients on long-term oral benzodiazepine (BZD) therapy may be affected by drug interactions and central changes in sensitivity. However, there is no research on the effect of long-term oral BZD use on the amount of propofol required for IVS. We aimed to clarify the difference between the total propofol dose required for IVS in patients with or without long-term oral BZD therapy. MATERIAL AND METHODS: Among patients treated for 4 years, the total administered dose required for IVS with propofol alone and local anesthesia for the extraction of bilateral impacted mandibular wisdom teeth, was retrospectively compared between patients with continuous oral BZD use for ≥6 months (BZD group; n = 24) and those without such use (control group; n = 307). The aimed sedation level was the Ramsay sedation scale 3-4. RESULTS: The amount of propofol required for IVS was significantly lower in the BZD group compared to the control group (4.83 ± 1.30 vs. 5.91 ± 1.25 mg/kg/h, p < .001; 95% confidence interval, -1.22 to -0.94 mg/kg/h; Cohen's d, 0.84). The required propofol dose was not influenced by preoperative oral BZD administration on the day of extraction (presence [n = 13] vs. absence [n = 11]: 4.9 ± 1.3 vs. 4.8 ± 1.7 mg/kg/h, p = .83). Long-term oral BZD therapy remained a significant factor for a lower required propofol dose after adjusting for age with multiple linear regression analysis. The underlying mechanism cannot be an additive action process but might pertain to competitive inhibition via an enzyme involved in glucuronate conjugation or competitive albumin binding. CONCLUSIONS: Clinicians should understand that patients on long-term oral BZDs therapy might require less propofol for IVS than those not on BZDs, irrespective of whether BZDs were taken preoperatively on the day of surgery.

Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum.

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 µL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5-125.0 ng/mL for afatinib, 2.5-125.0 ng/mL for dacomitinib, 4.0-800.0 ng/mL for osimertinib, 1.0-125.0 ng/mL for AZ5104, and 2.5-125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis.

BACKGROUND: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. METHODS: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≥6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. RESULTS: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216-0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336-1.017, p = 0.0575). CONCLUSIONS: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.

Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the role of des-γ-carboxyprothrombin (DCP) as a marker for the efficacy of sorafenib therapy for hepatocellular carcinoma (HCC). METHODS: Patients with advanced HCC treated with sorafenib were retrospectively evaluated, focusing on DCP levels and clinical characteristics. RESULTS: 50 patients with advanced HCC were treated with sorafenib alone. In 25 of these patients, the serum levels of DCP were evaluated twice (pretreatment and within 2 weeks after starting therapy). The time to progression was significantly longer in patients in whom the DCP level at 2 weeks after starting sorafenib was ≥2-fold higher than the pretreatment levels, as compared with patients without an increase in DCP (p = 0.0296). CONCLUSIONS: The serum level of DCP is a surrogate marker for tissue hypoxia and can be a predictive marker to assess the tumor response to sorafenib therapy.

Comparable level of aggression between patients with behavioural addiction and healthy subjects.

Heightened aggression is identified in several psychiatric disorders, including addiction. In this preliminary study with a relatively small number of samples, aggression in subjects diagnosed with behavioural addiction (BA) was implicitly assessed using the point subtraction aggression paradigm (PSAP) test along with measurements of oxy- and deoxyhaemoglobin dynamics in the prefrontal cortex (PFC) during the test using functional near-infrared spectroscopy. Aggression in BA patients was no higher than that of healthy control (CT) subjects in the PSAP test. Although no apparent increase or decrease in haemoglobin concentrations was observed in the PFC of either BA patients or CT subjects, abnormal correlations within the PFC network were present in BA patients. Consistent with comparable aggression between the groups, blood concentrations of the sex hormone testosterone, which has been shown to be associated with aggressiveness, was even lower in BA patients than in CT subjects. In contrast, when a set of questionnaire surveys for the assessment of aggression were administered, BA patients rated themselves as more aggressive than non-BA subjects. Collectively, these results suggest that aggression may not be heightened in BA, but BA patients may overestimate their aggressiveness, raising concerns about the use of questionnaire surveys for assessments of affective traits such as aggression in behavioural addiction.

Radiofrequency ablation for hepatocellular carcinoma: assistant techniques for difficult cases.

PURPOSE: To confirm the safety and effectiveness of techniques to assist radiofrequency ablation (RFA) for difficult cases, we retrospectively evaluated successful treatment rates, early complications and local tumor progressions. PATIENTS AND METHODS: Between June 1999 and April 2009, a total of 341 patients with 535 nodules were treated as difficult cases. Artificial pleural effusion assisted ablation was performed on 64 patients with 82 nodules. Artificial ascites-assisted ablation was performed on 11 patients with 13 nodules. Cooling by endoscopic nasobiliary drainage (ENBD) tube-assisted ablation was performed on 6 patients with 8 nodules. When the tumors were not well visualized with conventional B-mode ultrasonography (US), contrast-enhanced US-assisted ablation with Levovist or Sonazoid or virtual CT sonography-assisted ablation was performed. Contrast-enhanced US-assisted ablation was performed on 139 patients with 224 nodules and virtual CT sonography-assisted ablation was performed on 121 patients with 209 nodules. RESULTS: In total, complete ablation was achieved in 514 of 535 (96%) nodules in difficult cases. For RFA with artificial pleural effusion, artificial ascites and ENBD, complete response was confirmed in all cases. For contrast-enhanced US- and CT sonography-assisted ablation, complete response was 95%. Early complications were recognized in 24 cases (4.5%). All cases recovered with no invasive treatment. Local tumor recurrence was investigated in 377 nodules of 245 patients, and 69 (18%) nodules were positive. Tumor recurrences in each assisted technique were 14.7% in artificial pleural effusion cases, 7% in artificial ascites, 12.5% in ENBD tube cases, 31% in virtual CT sonography, and 8.5% in contrast-enhanced US. CONCLUSION: Although local tumor progression needs to be carefully monitored, assisted techniques of RFA for difficult cases are well tolerated and expand the indications of RFA.

Hepatic arterial infusion chemotherapy using low-dose 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma.

BACKGROUND: Although hepatic arterial infusion chemotherapy (HAIC) using low-dose 5-fluorouracil (5-FU) and cisplatin (low-dose FP) is commonly used for advanced hepatocellular carcinoma (HCC) with vascular invasion in Japan, few reports have investigated the efficacy and safety of this approach. We investigated the efficacy and toxicity of HAIC using low-dose FP for patients with advanced HCC as a phase II trial. METHODS: Low-dose FP consisted of a continuous arterial infusion of 5-FU (250-500 mg/day, 5 days/week, for the first 2 weeks) and cisplatin (10 mg/day, 5 days/week, for the first 2 weeks). Then, 5-FU (1,000 mg/body for 5 h) and cisplatin (10 mg/body) were administered once weekly. RESULTS: In these patients treated with low-dose FP, the response rate was 38.5%, the median time to progression was 4.1 months (95% CI 2.1-6.1 months) and the median survival time was 15.9 months (95% CI 9.8-22.0 months). The most frequent adverse events were myelosuppression such as neutropenia or thrombocytopenia. CONCLUSIONS: HAIC using low-dose FP is an effective treatment option for locally advanced HCC. However, it is not well tolerated hematologically because of potent pancytopenia and poor hepatic reserve. Therefore, this regimen should be performed carefully with regular monitoring of hematological function.

Usefulness of the post-vascular phase of contrast-enhanced ultrasonography with sonazoid in the evaluation of gross types of hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to assess the usefulness of post-vascular phase (PVP) images of contrast-enhanced ultrasonography (CE-US) in the evaluation of the gross types of hepatocellular carcinoma (HCC) that is closely related to the malignant potential of the tumor. METHODS: A total of 29 patients with 40 HCCs of <5 cm in diameter, who underwent hepatic resection, were enrolled. The gross type of the tumor was evaluated using real-time scanning during the PVP of CE-US with Sonazoid prior to surgery. The tumors were classified into three types based on the macroscopic classification of the Liver Cancer Study Group of Japan: single nodular (SN) type, single nodular with extranodular growth (SNEG) type, and confluent multinodular (CMN) type. The ability of CE-US to correctly depict the gross type of HCC was evaluated. RESULTS: 26 tumors were macroscopically diagnosed as the SN type, 11 tumors as the SNEG type, and 3 tumors as the CMN type. The sensitivity, specificity and accuracy of CE-US were 96, 80 and 90%, respectively. CONCLUSION: The PVP image of CE-US with Sonazoid is a useful tool in the evaluation of the gross type of HCC and is considered essential in deciding treatment strategy.

Prolonged PEG-IFN and RBV is effective in patients with HCV genotype 1 and high viral load who achieved virological response later than 24 weeks.

OBJECTIVE: The extension of treatment duration has been proposed in late virological responders with hepatitis C virus (HCV) genotype 1 and high viral load. However, the effectiveness of extended treatment in patients whose serum HCV RNA become undetectable later than 24 weeks of treatment (ultra-late virological responder; ULVR) has not yet been determined. METHODS: A total of 130 patients infected with HCV genotype 1 and who had high viral load were treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy. We retrospectively analyzed 10 ULVR who received extended combination treatment beyond 48 weeks. RESULTS: The duration of the combination treatment for ULVR ranged between 59 and 119 weeks, and the mean duration was 80 weeks. Although the majority of ULVR were older female patients (> or = 60 years) with factors related to poor therapeutic response, 8 patients (80%) achieved sustained virological response (SVR). The SVR rate correlated well with the duration of the treatment. Five ULVR achieved SVR when treatment was continued until serum HCV RNA remained undetectable for longer than 48 weeks. CONCLUSION: The extended duration of PEG-IFN and RBV combination treatment is a possible strategy to improve treatment response in HCV genotype 1 infection, even for ULVR.

PEG-IFNalpha/RBV combination therapy for chronic hepatitis C patients increases serum ferritin level while it improves sustained viral response rate.

OBJECTIVES: We investigated the significance of serum ferritin levels in pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C (CHC) and examined its correlation with serum alanine aminotransferase (ALT) levels during therapy and response to the therapy. METHODS: A total of 175 patients with CHC received the combination therapy. Correlations between serum ferritin levels and serum ALT levels at 12 and 24 weeks of therapy were examined. Differences in serum ferritin levels during therapy between patients with sustained viral response (SVR) and non-SVR were also examined. RESULTS: Only 24 (13.7%) and 20 (11.4%) patients showed elevated serum ALT levels (> or = 70 IU/l) at 12 and 24 weeks of therapy, respectively. There was no correlation between serum ferritin levels and ALT levels. Ninety-five (54.3%) of 175 patients achieved SVR. Serum ferritin levels increased dramatically in both SVR and non-SVR groups after starting the therapy and were significantly higher in the SVR group throughout the therapy. CONCLUSIONS: Serum ferritin level increases during PEG-IFN and RBV combination therapy; however, it did not correlate with either serum ALT level or the total dose of RBV. Higher serum ferritin levels during combination therapy appear to be associated with favorable therapeutic response.

Non-invasive evaluation of hepatic fibrosis for type C chronic hepatitis.

OBJECTIVE: The aim of this study was to investigate liver fibrosis using non-invasive Real-time Tissue Elastography (RTE) and transient elastography (FibroScan) methods. METHODS: RTE, FibroScan and percutaneous liver biopsy were all performed on patients with chronic liver disease, particularly hepatitis C, to investigate liver fibrosis. RESULTS: FibroScan and RTE were compared for fibrous liver staging (F stage), which was pathologically classified using liver biopsy. In FibroScan, significant differences were observed between F1/F3 and F2/F4, but no such differences were observed between F1/F2, F2/F3 and F3/F4. In RTE, significant differences were observed between F1/F2, F2/F3 and F2/F4. But for F3/F4, no significant differences were observed. CONCLUSION: FibroScan and RTE correlated well with F staging of the liver. In particular RTE was more successful than FibroScan in diagnosing the degree of liver fibrosis.