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Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study., (© 2024. The Author(s).)

We report on the development of an on-site therapeutic drug monitoring (TDM) method for vancomycin (VCM) utilizing a portable spectrometer and commercially available immunoturbidimetric assay reagents designed for automated clinical chemistry analyzers. The method enables the quantification of VCM in plasma samples within 10 min, with a good correlation between the measured values and the theoretical values (r 2  = 0.995). The intra and inter-day precisions were found to be below 12.5% and 17.7%, respectively. Moreover, we established a correlation between the quantitative values using this method and those measured through HPLC-UV and automated clinical chemistry analyzers, showing good reliability (R 2  = 0.970 and 0.951, respectively). This method allows anyone to rapidly perform TDM at the bedside and is expected to be used to evaluate appropriate drug therapy., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

This study aimed to describe the real-world efficacy and safety of the combination therapy of atezolizumab and bevacizumab (Atezo/Bev) for unresectable hepatocellular carcinoma (HCC). This retrospective analysis of a multicenter registry cohort included 268 patients treated with Atezo/Bev. The incidence of adverse events (AE) and its impact on overall survival (OS) and progression-free survival (PFS) were analyzed. Of the 268 patients, 230 (85.8%) experienced AE. The median OS and PFS in the whole cohort were 462 and 239 days, respectively. The OS and PFS were not different in terms of AE, but they were significantly shorter in patients with increased bilirubin level and those with increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Regarding increased bilirubin level, the hazard ratios (HRs) were 2.61 (95% confidence interval [CI]: 1.04-6.58, P = 0.042) and 2.85 (95% CI: 1.37-5.93, P = 0.005) for OS and PFS, respectively. Regarding increased AST or ALT, the HRs were 6.68 (95% CI: 3.22-13.84, P < 0.001) and 3.54 (95% CI: 1.83-6.86, P < 0.001) for OS and PFS, respectively. Contrarily, the OS was significantly longer in patients with proteinuria (HR: 0.46 [95% CI: 0.23-0.92], P = 0.027). Multivariate analysis confirmed that proteinuria (HR: 0.53 [95% CI: 0.25-0.98], P = 0.044) and increased AST or ALT (HR: 6.679 [95% CI: 3.223-13.84], P = 0.003) were independent risk factors for a shorter OS. Furthermore, analysis limited to cases who completed at least 4 cycles confirmed that increased AST or ALT and proteinuria were negative and positive factors for OS, respectively. In the real-world setting, increased AST or ALT and bilirubin level during Atezo/Bev treatment were found to have a negative impact on PFS and OS, whereas proteinuria had a positive impact on OS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p < 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: We aimed to investigate the efficacy and safety of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (u-HCC) based on whether they had previously received systemic therapy, as well as the association of atezolizumab plus bevacizumab with early alpha-fetoprotein (AFP) response in real-world practice., Methods: A total of 52 patients with u-HCC were treated with atezolizumab plus bevacizumab between October 2020 and April 2021. The Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST were used to evaluate radiological responses., Results: The patients received atezolizumab plus bevacizumab as 1st-line (n = 23), 2nd-line (n = 16), 3rd-line (n = 6), 4th-line (n = 3), 5th-line (n = 3), or 6th-line (n = 1) therapy. According to RECIST, the objective response rate (ORR) and disease control rate (DCR) in all patients were 15.4% and 57.7%. In the 1st-line patients, ORR and DCR based on RECIST 1.1 were 27.3% and 81.8%. The median time to progression (TTP) assessed by RECIST was significantly longer among patients receiving atezolizumab plus bevacizumab as 1st-line therapy than in patients receiving atezolizumab plus bevacizumab as later-line therapy (P < 0.001). Patients with an AFP response (reduction ≥ 20% from baseline) at 6 weeks had a significantly longer TTP assessed by RECIST than those without an AFP response (P = 0.02)., Conclusion: Patients who received atezolizumab plus bevacizumab as 1st-line therapy had better clinical outcome than those who received atezolizumab plus bevacizumab in later lines. The AFP response at 6 weeks could be a predictor of disease progression., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Administration of phosphate binders can decrease serum phosphate levels and improve the prognosis of patients on dialysis. However, patients are often non-adherent to phosphate binder medication. Although community pharmacist-led education could be effective in the maintenance of adherence to phosphate binder medication, its impact has not been evaluated. Objective We aimed to evaluate the impact of community pharmacist-led intensive education focusing on phosphate binders for patients receiving haemodialysis. Setting The study comprising three phases (baseline phase, intervention phase, and follow-up phase) was conducted at the Yamauchi Pharmacy, Japan. Method Six pharmacists provided intensive education focusing on phosphate binders to patients receiving haemodialysis. As intensive education, a sheet containing checks for the remaining phosphate binders and information advising the patients on the use of the drugs was issued. Using the check sheet filled in by the patient, the pharmacists repeatedly provided education appropriate to the individual patient's medication status and level of understanding to encourage the correct use of phosphate binders for 8 weeks (intervention phase). We investigated their serum phosphate levels from their medical records from 2 months before the start of intensive education (baseline phase) to 8 months after the end of the education (follow-up phase). Main outcome measure Serum phosphate levels in patients receiving haemodialysis after intensive education by community pharmacists. Results Fifty patients were enrolled in this study. During the intervention phase, serum phosphate levels in the patients with high and the highest serum phosphate level (6-7 mg/dL and ≥ 7 mg/dL, respectively) significantly decreased by 6.9% (P = 0.007) and 10.9% (P = 0.034), respectively. The levels remained below the baseline value throughout the follow-up phase in patients with the highest serum phosphate level. Conclusion Community pharmacist-led education focusing on phosphate binders affects short- and long-term management of serum phosphate levels in patients receiving haemodialysis, especially the patients whose levels were initially high.

A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.

Background/purpose: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs., Methods: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12)., Results: Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88-100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70-91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events., Conclusion: Sofosbuvir-velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.

Purpose: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior., Methods: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d ) and absorption (R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds., Results: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased., Conclusion: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs., Competing Interests: Shinya Uchida and Tsutomu Kotegawa have received advisory fees from KUREHA CORPORATION.

The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6-7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH-IGF-1-independent manner.

Objective: The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic interactions between the oral adsorbent AST-120 and triazolam., Methods: In this randomized, cross-over study, 12 healthy volunteers received a single oral dose of triazolam 0.25 mg alone or with AST-120 2 g given 0, 30 or 60 min before triazolam administration., Results: The area under the plasma triazolam concentration-time curve (AUC(0-∞)) significantly decreased with simultaneous AST-120 + triazolam (alone vs simultaneous: 10.9 ± 6.0 vs 6.4 ± 2.6 ng·h/mL, p = 0.003). Triazolam-induced impairment in psychomotor performance assessed by the digit symbol substitution test was significantly attenuated when AST-120 was administered simultaneously. No significant changes in pharmacokinetic and pharmacodynamic parameters were observed when AST-120 was given 30 or 60 min before triazolam administration., Conclusions: Administering AST-120 simultaneously with triazolam affects the pharmacokinetics and pharmacodynamics of triazolam. Dosing AST-120 at least 30 min before triazolam administration may avoid these interactions.

Background and Aims: Protease inhibitor (PI)-resistant hepatitis C virus (HCV) variants may be present in substantial numbers in PI-untreated patients according to recent reports. However, influence of these viruses in the clinical course of chronic hepatitis C has not been well characterized., Methods: The dominant HCV nonstructural 3 (NS3) amino acid sequences were determined in 261 HCV genotype 1b-infected Japanese patients before pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, and investigated the patients' clinical characteristics as well as treatment responses including sustained virological response (SVR) rate. HCV-NS3 sequences were also determined in 39 non-SVR patients after completion of the therapy., Results: Four single mutations (T54S, Q80K, I153V, and D168E) known to confer PI resistance were found in 35 of 261 patients (13.4%), and double mutations (I153V plus T54S/D168E) were found in 6 patients (2.3%). Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations (mutation group, SVR 48%; wild-type group, SVR 40%; P = 0.38). On the other hand, two mutations appeared in two non-SVR patients after PEG-IFN/RBV therapy (I153V and E168D, 5.1%)., Conclusions: PI-resistance-associated NS3 mutations exist in a substantial proportion of untreated HCV-1b-infected patients. The impact of these mutations in the treatment of PIs is unclear, but clinicians should pay attention to avoid further development of PI resistance.

Purpose: Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudine-refractory Japanese patients treated with entecavir for 3 years., Methods: Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples., Results: After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55%(36/65) of patients had hepatitis B virus(HBV) DNA of\400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of ≤1 × upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion.A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of <400 copies/mL, 84% (27/32) had ALT of ≤1 × ULN, and 15% (4/27) achieved HBe seroconversion.Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares., Conclusions: Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.

In a country such as Japan with the average age of patients with chronic hepatitis C treated with antivirals sometimes well above 60 years, the standard combination therapy is not well tolerated. In this randomized, prospective, controlled trial, we investigated the efficacy of 24-week peginterferon α monotherapy for easy-to-treat patients. A total of 132 patients chronically infected with hepatitis C virus (HCV) genotype 2 (n = 115) or low viral load HCV genotype 1 (<100 kIU/ml, n = 17) were treated with peginterferon α-2a (180 μg/week). Patients with a rapid virological response (RVR, HCV RNA negative or <500 IU/ml at week 4) were randomized for a total treatment duration of 24 (group A) or 48 (group B) weeks. Patients who did not show RVR (group C) were treated for 48 weeks. Sustained virological response (SVR) was assessed by qualitative reverse-transcription polymerase chain reaction. One hundred eight of 132 (82%) patients with RVR were randomized. SVR rates were 60% (group A), 79% (group B), and 27% (group C), respectively. Similar SVR rates were achieved in patients infected with HCV genotype 2 with low pretreatment viral load (<1000 kIU/ml) in group A (81%) and group B (79%) (P = 0.801), whereas in those with higher viral load (≥1000 kIU/ml), a lower SVR rate was identified in group A (26%) than in group B (67%) (P = 0.041). In conclusion, in patients infected with HCV genotype 2 and pretreatment viral load below 1000 kIU/ml who achieve RVR, 24-week treatment with peginterferon α-2a alone is clinically sufficient. Those who show no RVR or have higher baseline viral load, require alternative therapies.

Lsi1 (OsNIP2;1) is the first silicon (silicic acid) transporter identified in plant, which belongs to the nodulin 26-like intrinsic membrane protein (NIP) subfamily. In this study, we characterized the function of this transporter by using the Xenopus laevis oocyte expression system. The transport activity of Lsi1 for silicic acid was significantly inhibited by HgCl2 but not by low temperature. Lsi1 also showed an efflux transport activity for silicic acid. The substrate specificity study showed that Lsi1 was able to transport urea and boric acid; however, the transport activity for silicic acid was not affected by the presence of equimolar urea and was decreased only slightly by boric acid. Furthermore, among the NIPs subgroup, OsNIP2;2 showed transport activity for silicic acid, whereas OsNIP1;1 and OsNIP3;1 did not. We propose that Lsi1 and its close homologues form a unique subgroup of NIP with a distinct ar/R selectivity filter, which is located in the narrowest region on the extra-membrane mouth and govern the substrate specificity of the pore.