Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Phase 3 Roxadustat Trials in Japan.

INTRODUCTION: Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan. METHODS: Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters. RESULTS: Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07-33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2 fL; adjusted OR 5.55; 95% CI 1.73-17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events. CONCLUSION: In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article. TRIAL REGISTRATION: NCT02780726, NCT02952092, NCT02780141, NCT02779764.

Roxadustat is an oral medicine that treats anemia in patients with chronic kidney disease (CKD). Thromboembolic events, or blood vessels blocked by a blood clot, have occurred in clinical trials of roxadustat. This study explored potential factors that may be related to thromboembolic events in roxadustat-treated patients with anemia of CKD on dialysis before and after week 12. This study found that hemodialysis (vs peritoneal dialysis), advanced age (older than 65 years), short amount of time on dialysis (less than 4 months), previous history of thromboembolic events, and not receiving iron therapy were risk factors for thromboembolic events before week 12. Iron deficiency and high roxadustat dose were risk factors for thromboembolic events after week 12. When iron status was also considered, we did not find that roxadustat dose was related to thromboembolic events. A different model found that increased levels of transferrin, a protein that transports iron, from baseline and decreased mean corpuscular volume, or smaller red blood cells, increased the risk of thromboembolic events. Patients with anemia of CKD on dialysis may benefit from more intentional monitoring and management of iron while receiving roxadustat.

Proton pump inhibitors and risk of bloodstream infection without an identifiable source: a hospital-based case-control study.

The association between proton-pump inhibitor (PPI) use and systemic infections caused by bacterial translocation is unclear. This study aims to investigate whether patients receiving PPI therapy have a higher risk for bloodstream infections (BSI) without an identifiable source of infection, as an alternative indicator of BSI secondary to bacterial translocation. We conducted a hospital-based case-control study which enrolled all patients aged 20 years and older who developed BSI confirmed by two sets of positive blood culture and had inpatient care in Ichinomiya-Nishi Hospital in 2019. Patients' data were collected from medical records, and bacterial translocation type (BT-type) BSI group were defined as those who had BSI without an identifiable source of infection, whereas the others were classified control group based on the diagnostic criteria for each infectious disease. We analyzed data from 309 patients, including 66 cases and 243 controls. PPI users had a 2.4-fold higher risk of developing BT-type BSI compared to non-PPI-users after controlling for potential confounders (OR: 2.41, 95% CI: 1.29-4.51, p=0.006). In conclusion, PPI use is associated with higher risk of BSI without an identifiable source and therefore, PPI use may increase the risk of septic morbidity secondary to bacterial translocation.

Safety and effectiveness of pembrolizumab monotherapy in Japanese patients with unresectable urothelial carcinoma: a nation-wide post-marketing surveillance.

BACKGROUND: This study was conducted to identify factors associated with the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma and to confirm the real-world safety and effectiveness of pembrolizumab in Japanese patients. METHODS: This multicenter, observational, post-marketing surveillance was conducted over a 1-year observation period starting at pembrolizumab initiation (200-mg pembrolizumab every 3 weeks); data were collected from case report forms (3 months and 1 year). Safety measures included treatment-related adverse events and adverse events of special interest (AEOSI). Effectiveness assessments included tumor response, objective response rate (ORR), and disease control rate (DCR). RESULTS: Overall, 1293 patients were evaluated for safety and 1136 for effectiveness. At 12 months, the treatment-related adverse event incidence was 53.8% (n = 696) and that of AEOSI was 25.0% (n = 323). The most frequent AEOSI of any grade were endocrinological disorder (10.4%, n = 134), interstitial lung disease (ILD) (7.2%, n = 93), and hepatic function disorder (4.9%, n = 64). Multivariate analysis demonstrated that the risk of developing ILD was almost seven times greater (odds ratio 6.60) in patients with a comorbidity of ILD, and approximately twice as high in patients aged ≥ 65 years (odds ratio 2.24) and with smoking history (odds ratio 1.79). The ORR was 26.1% and the DCR was 50.7%. The ORR was 46.4% in patients with a Bellmunt risk score of 0 and decreased as the Bellmunt risk score increased. CONCLUSIONS: This post-marketing surveillance confirmed the safety and effectiveness of pembrolizumab in Japanese patients with unresectable urothelial carcinoma in the real-world setting.

A retrospective database analysis of erythropoiesis-stimulating agent treatment patterns and associated healthcare resource use in patients with non-dialysis-dependent chronic kidney disease-related anaemia in Japan.

AIM: This study was conducted to evaluate clinical characteristics, treatment patterns, and healthcare resource use (HCRU) for patients in Japan with non-dialysis-dependent chronic kidney disease (CKD) and anaemia. METHODS: This retrospective, longitudinal, epidemiological database extraction study used the JMDC Claims Database, comprising ~9.4 million unique beneficiaries. The observation period for anaemia and erythropoiesis-stimulating agent (ESA)/iron treatment was 1 January 2015 to 31 December 2018, and for HCRU and costs was 1 April 2016 to 31 March 2018. The non-dialysis-dependent CKD anaemia population, and the ESA treatment, iron treatment, and no-treatment cohorts were evaluated. Patient characteristics, treatment patterns, and outcomes were summarised descriptively. RESULTS: The non-dialysis-dependent CKD anaemia population included 5908 patients (7.9%), with 464 patients in the ESA treatment cohort, 809 patients (13.7%) in the iron treatment cohort (13.7%), and 4405 (74.6%) patients in the no-treatment cohort. The prevalence of patients prescribed an antihypertensive, antidiabetic, and/or antihyperlipidaemic medication generally increased with increasing baseline CKD stage. Proportions of no treatment for anaemia decreased while ESA treatment increased with increasing CKD stage; ESA treatment increased with decreasing baseline haemoglobin levels. Patients in the ESA treatment cohort generally had more frequent events associated with HCRU and higher costs from HCRU-associated activities (e.g., inpatient and outpatient care, pharmacy). CONCLUSION: As CKD severity increased, anaemia management changed from iron use or no treatment to ESA use; however, anaemia may be undertreated across all CKD stages. ESA-treated patients incurred greater HCRU-associated costs relative to other patients with non-dialysis-dependent CKD anaemia in Japan.

Real-world safety and effectiveness of pembrolizumab in Japanese patients with radically unresectable melanoma: An all-case postmarketing surveillance in Japan.

This all-case postmarketing surveillance (PMS) survey (101 centers; February 15, 2017, to March 3, 2020) captured factors that impact the safety and effectiveness of newly initiated pembrolizumab monotherapy for the treatment of radically unresectable melanoma in Japan. Eligible patients were enrolled both retrospectively and prospectively, and followed up at 1, 3, 6, and 12 months. Safety assessments included treatment-related adverse events (TRAEs), adverse events of special interest (AEOSIs) from the Japanese Risk Management Plan (J-AEOSIs), and J-AEOSIs related to pembrolizumab. Effectiveness assessments included objective response rate (ORR; complete response/partial response) and disease control rate (DCR) according to the RECIST criteria. Overall, 294 and 236 patients comprised the safety and effectiveness (RECIST) assessment sets, respectively. Median (range) age of the patients was 70 (22-94) years, and the majority (60.4%) received pembrolizumab as first-line therapy. The most common type of melanoma was cutaneous (41.5%), followed by mucosal (29.3%), acral (24.8%), and unknown (4.4%). Overall, 45.2% and 24.8% of patients experienced TRAEs and AEOSIs, respectively. In total, 24.8% and 9.2% of patients experienced any-grade and grade ≥3 pembrolizumab-related AEOSIs, respectively. The most common grade ≥3 pembrolizumab-related AEOSIs were endocrine disorders and liver dysfunction (2.4% each), followed by colitis/severe diarrhea (2.0%), interstitial lung disease (1%), and type 1 diabetes (0.7%). No grade 5 J-AEOSIs were observed. ORR was 16.5% at the 1-year follow-up: mucosal melanoma (20%), acral melanoma (10%), and cutaneous melanoma (17.5%). ORR was higher among patients who did not receive versus those who did receive previous systemic therapy across all three melanoma types. DCR was 52.1% at the 1-year follow-up: cutaneous melanoma (57.3%), acral melanoma (51.7%), and mucosal melanoma (43.1%). This all-case PMS survey confirmed the real-world safety and effectiveness of pembrolizumab monotherapy for the treatment of radically unresectable melanoma in Japan.

Real-world outcomes of pembrolizumab monotherapy in non-small cell lung cancer in Japan: A post-marketing surveillance.

This post-marketing surveillance (PMS) was initiated in Japan to identify factors affecting the safety and effectiveness of pembrolizumab monotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death ligand-1 (PD-L1) expression. This PMS was conducted from December 2016 to June 2019 at 717 centers across Japan. Patients with unresectable advanced/recurrent NSCLC who received pembrolizumab monotherapy as first-line (1L) treatment for PD-L1-expressing tumors (Tumor Proportion Score [TPS] ≥ 50%) or second-line or later (2L+) treatment for tumors with PD-L1 TPS ≥ 1% were enrolled and followed up for 1 year. Of 2805 registered patients, 2740 and 2400 comprised the safety and effectiveness analysis sets, respectively. The median age (range) was 69 (27-92) years; 55.7% and 29.2% of patients experienced treatment-related adverse events and adverse events of special interest (AEOSIs), respectively. More common AEOSIs included interstitial lung disease, endocrine disorders, liver dysfunction, colitis/severe diarrhea, infusion reactions, and severe skin disorders. The frequency of experiencing ≥2 AEOSIs was low (1L, 6.5%; 2L+, 2.8%). Most AEOSIs occurred within 150 days after initiation of pembrolizumab monotherapy. At 1-year follow-up, the objective response rate was 39.2% (1L, 51.5%; 2L+, 30.0%). In conclusion, the 1-year safety and effectiveness of pembrolizumab monotherapy in patients with unresectable advanced/recurrent NSCLC as 1L treatment for tumors with PD-L1 TPS ≥ 50% and 2L+ treatment for tumors with PD-L1 TPS ≥ 1% were similar to those reported in phase 2/3 trials.

Reduction in cardiovascular disease events in patients with type 2 diabetes mellitus treated with a sodium-glucose cotransporter 2 inhibitor versus a dipeptidyl peptidase-4 inhibitor: A real-world retrospective administrative database analysis in Japan.

AIMS/INTRODUCTION: To evaluate the benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) in reducing cardiovascular disease (CVD) events in patients with type 2 diabetes mellitus with and without a CVD history. MATERIALS AND METHODS: This retrospective cohort study used Japanese hospital administrative data from the Medical Data Vision database (January 2015 to April 2020). Patients with type 2 diabetes mellitus (n = 625,739) who were new users of an SGLT2i (n = 57,070; 9.1%) or DPP4i (n = 568,669; 90.9%) were included. Outcomes included hospitalization for heart failure (hHF), all-cause death (ACD) and the composite of hHF or ACD. Hazard ratios (HR) were calculated using the inverse probability weighting Cox proportional hazards model to compare CVD event risks between treatment groups. RESULTS: Compared with DPP4i, SGLT2i was associated with a significant reduction in hHF risk among patients without a CVD history (HR 0.507, 95% confidence interval 0.283-0.907), but not in the full cohort or those with a CVD history. SGLT2i was associated with a significant risk reduction of ACD (HR 0.592, 95% confidence interval 0.481-0.729) and the composite of hHF or ACD (HR 0.712, 95% confidence interval 0.613-0.826), compared with DPP4i in the full cohort; similar results were observed among patients with and without a CVD history. CONCLUSIONS: In this real-world study, SGLT2i versus DPP4i was associated with a significant reduction in hHF, ACD and hHF or ACD events in patients with type 2 diabetes mellitus without a CVD history.

Estimating the causal effect of transient anemia status on renal and cardiovascular outcomes in community-dwelling patients in Japan at the beginning of impaired renal function using marginal structural modeling.

BACKGROUND: Anemia status may be transient. Causal associations between changes in anemia status over time and adverse outcome development are not well characterized in community-dwelling subjects at the beginning of impaired kidney function. METHODS: This retrospective cohort study used annual health checkup and medical and pharmacy claims data from the JMDC between January 2005 and June 2019. Community-dwelling subjects in Japan with a pre-index estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 followed by a subsequent eGFR < 60 mL/min/1.73 m2 (index) were included. The composite renal outcome was ≥ 30% eGFR reduction over 3 years from baseline, serum creatinine doubling, progression to chronic dialysis, kidney transplantation, or eGFR < 15 mL/min/1.73 m2. The composite cardiovascular outcome was fatal and non-fatal unstable angina, myocardial infarction, heart failure, or cerebrovascular event. Time-dependent anemia risk was evaluated using Breslow's estimator and marginal structural Cox models (MSM). RESULTS: In 32,870 included subjects, 1,396 had anemia at baseline. Adverse outcome incidence was higher in the baseline anemic group, but absolute differences in renal and cardiovascular outcomes between groups were diminished after adjusting for baseline characteristics. In MSM, time-dependent anemia status was associated with higher risk of renal (hazard ratio [95% confidence interval]; 2.6 [1.7-3.8]) and cardiovascular (1.6 [1.2-2.2]) outcomes and mortality (2.8 [1.8-4.3]). Absolute differences in survival probabilities were retained over time but were clinically marginal (1.1-2.7% over 6 years). CONCLUSIONS: Even in subjects at the very early stage of impaired kidney function, early detection and treatment of anemia may help reduce the development of negative sequelae.

Real-World Effectiveness of Sodium Glucose Co-Transporter-2 Inhibitors in Japanese Patients with Diabetes Mellitus.

INTRODUCTION: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been on the market for 5 years in Japan. We explored the real-world effectiveness of SGLT2i in Japan. METHODS: We retrospectively analyzed two large Japanese administrative databases from JMDC Inc.: insurance-dataset (I-dataset) and Medical Data Vision Co. Ltd. [hospital-dataset (H-dataset)]. Patients who newly started SGLT2i or other oral antidiabetic drugs (OADs) between 1 April 2014 and 31 March 2016 were selected for this analysis and followed for 1 year from the index date. Changes in glycated hemoglobin (HbA1c), body mass index (BMI), and estimated glomerular filtration rate (eGFR) were evaluated during the 1-year period. RESULTS: A total of 127,961 patients in the H-dataset and 26,436 in the I-dataset were included in this analysis. Baseline HbA1c, BMI, and eGFR levels tended to be higher in SGLT2i users than in other OAD cohorts. After 1 year, 44.3% (I-dataset) and 53.3% (H-dataset) of SGLT2i users and 33.0-44.2% (I-dataset) and 47.0-58.1% (H-dataset) of other users were still on their medications. The mean HbA1c level decreased by - 0.7 to - 0.9% in SGLT2i users versus - 0.4 to - 1.5% in the other cohorts. The mean BMI decreased by - 0.8 kg/m2 in SGLT2i users whereas the change in other cohorts was - 0.5 to 0.4 kg/m2. No clinically relevant changes in eGFR were observed over the period. CONCLUSION: This study showed that around half of the SGLT2i users were still on medication after 1 year from treatment initiation. Initiation of SGLT2i was associated with improvement in HbA1c and BMI, with no abnormal changes in renal function observed in the first year following treatment. These findings support the results from clinical trials and will expand the existing evidence of SGLT2i use in real-life practice in Japan. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Safety of Ipragliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Phase II/III/IV Clinical Trials.

INTRODUCTION: Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials. METHODS: Safety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements. RESULTS: The overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies. CONCLUSION: In randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed. TRIAL REGISTRATION NUMBERS: NCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094. FUNDING: Astellas Pharma Inc.

Drug Utilization Patterns in Patients with Diabetes Initiating Sodium Glucose Co-Transporter-2 Inhibitors (SGLT2i) in Japan: A Multi-Database Study (2014-2017).

INTRODUCTION: This study aimed to identify drug utilization patterns in patients initiating sodium glucose co-transporter-2 inhibitors (SGLT2i) in the first 3 years of their launch in Japan. METHODS: This was a retrospective study using three administrative databases in Japan: a pharmacy claims database, a hospital-based database, and an insurance claims database. Prescription data were extracted from adult outpatients with diabetes who started SGLT2i between April 2014 and March 2017 to evaluate pre-index and concomitant medications. For glimepiride and insulin co-users, dose at SGLT2i add-on was also assessed. RESULTS: Data from a total of 14,861 patients in the pharmacy dataset (P-dataset), 27,039 in the hospital dataset (H-dataset), and 12,408 in the insurance dataset (I-dataset) were analyzed. The majority of SGLT2i new users (ca. 70%) were taking one to three concomitant antidiabetic medications. Around half of SGLT2i initiators used dipeptidyl peptidase 4 inhibitors and/or biguanides before using SGLT2i or concomitantly with SGLT2i. The average daily glimepiride dose decreased from 2.1 mg/day during the pre-index period to 1.8 mg/day at SGLT2i add-on in the P-dataset and from 1.9 to 1.7 mg/day in the both H- and I-datasets, respectively, with a decreasing trend observed during the first 3 years of launch. The average daily insulin dose at SGLT2i add-on was higher during the first 15 months of launch and then decreased thereafter. Nearly 40% or more SGLT2i new users were taking at least five concomitant medications: cardiovascular agents were predominantly co-prescribed. CONCLUSION: SGLT2i were frequently used as second- or later-line treatment and as part of a dual, triple, or quadruple regimen, as well as co-prescribed with many other medications in the first 3 years of their launch. For SGLT2i users taking concomitant SU or insulin medications, the average daily doses of SU and insulin at SGLT2i add-on decreased slightly over the study period. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Characteristics of Patients with Diabetes Initiating Sodium Glucose Co-transporter-2 Inhibitors (SGLT2i): Real-World Results from Three Administrative Databases in Japan.

INTRODUCTION: The aim of this study was to evaluate the characteristics of new users of sodium glucose co-transporter-2 inhibitors (SGLT2i) in comparison with those of new users of other oral antidiabetic drugs (OADs) using data retrieved from three administrative databases in Japan. METHODS: This study included adult patients from each database who started an OAD between 2014 and 2017. Outpatients who started SGLT2i therapy were included in the SGLT2i cohort. The remaining outpatients were grouped according to the OAD class of their earliest initial prescription after no use of the index OAD during the 6-month pre-index period. Diabetes-related complications were evaluated using the Diabetes Complication Severity Index. RESULTS: In total, 176,355 patients in the hospital-based administrative database (H-dataset), 98,361 in the pharmacy claims database (P-dataset) and 37,786 in the insurance claims database (I-dataset) were analyzed. In the H-dataset, SGLT2i users, compared with users of other OADs, tended to be younger (mean age at index: 57.7 vs. 60.3-69.2 years) and to have a higher prevalence of hypercholesterolemia (73.5 vs. 55.2-71.4%), a higher mean body weight (74.4 vs. 60.5-70.8 kg), a higher body mass index (27.6 vs. 23.5-26.4 kg/m2) and a higher glycated hemoglobin level (8.4 vs. 7.4-8.1%). There were no distinct differences in the prevalence of complications between SGLT2i users and users of other OADs in the H-dataset. Similar trends were noted in the other datasets. CONCLUSION: Patients initiating SGLT2i therapy differed in several characteristics from new users of other OADs. SGLT2i were prescribed more frequently to younger patients, those at increased cardiovascular risk or those with poorer glycemic control. FUNDING: Astellas Pharma Inc., Tokyo, Japan.

Little Impact on Renal Function in Advanced Renal Cell Carcinoma Patients Treated with Sorafenib--Analyses of Postmarketing Surveillance in Japan in over 3,200 Consecutive Cases.

BACKGROUND: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance. METHODS: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR): G1 (eGFR≥90), G2 (eGFR≥60-<90), G3a (eGFR≥45-<60), G3b (eGFR≥30-<45), G4 (eGFR≥15-<30), and G5 (eGFR<15). A total of 3,255 and 3,171 patients were included in this analysis for safety and efficacy, respectively. RESULTS: The mean eGFRs (mL/min/1.73 m2) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726 mg (G1), 522 mg (G2), 524 mg (G3a), 517 mg (G3b), 483 mg (G4), and 400 mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4 and G5 groups (9%and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. One-year survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%). CONCLUSIONS: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON.

BACKGROUND: GIDEON was a prospective, global, non-interventional study evaluating the safety of sorafenib in patients with unresectable hepatocellular carcinoma in real-world practice. The aim of this subgroup analysis was to assess the safety and efficacy of sorafenib as used by Japanese patients. METHODS: In Japan, 508 patients were valid for safety analysis. Efficacy and safety were evaluated by the Child-Pugh score. RESULTS: The number of patients with Child-Pugh A and B was 432 (85.0 %) and 58 (11.4 %), respectively. The median overall survival time and time to progression in patients with Child-Pugh A and Child-Pugh B were 17.4 and 4.9 months, 3.7 and 2.3 months, respectively. The most common drug-related adverse events (AEs) included hand-foot skin reaction (47.8 %), diarrhea (35.8 %) and hypertension (24.2 %). The incidences of all or drug-related AEs were similar between patients with Child-Pugh A and B. However, all or drug-related serious AEs, AEs resulting in permanent discontinuation of sorafenib and deaths were observed more frequently in patients with Child-Pugh B compared with Child-Pugh A. Duration of treatment tended to be shorter as the Child-Pugh score worsened. CONCLUSIONS: Sorafenib was well tolerated by Japanese HCC patients in clinical settings. Patients with Child-Pugh B had shorter duration of treatment and higher incidence of SAEs. It is important to carefully evaluate patients' conditions and assess the benefit and risk before making a decision to treat patients with sorafenib.

Safety and effectiveness of sorafenib in Japanese patients with hepatocellular carcinoma in daily medical practice: interim analysis of a prospective postmarketing all-patient surveillance study.

BACKGROUND: Sorafenib was approved for treatment of unresectable hepatocellular carcinoma (HCC) in Japan in 2009. A prospective postmarketing all-patient surveillance (PMS) study was requested by Japanese authorities to confirm safety and effectiveness of sorafenib in Japanese HCC population. METHODS: Patients with unresectable HCC treated with sorafenib were followed up for 12 months. Data on patient demographic characteristics, treatment status, clinical outcome, and adverse events (AEs) were collected. RESULTS: This interim analysis included 1109 and 1065 patients evaluable for safety and effectiveness, respectively. Most patients (83.4 %) received the recommended initial dose of 400 mg twice daily. After a follow-up of 12-months, 89.8 % had discontinued treatment, most because of AEs (44.5 %) or progression (33.8 %). The most common drug-related adverse events (DRAE) were hand-foot skin reaction (51.4 %), liver dysfunction (26.4 %), diarrhea (25.1 %), and hypertension (21.6 %). The median overall survival (OS) was 348 days [95 % confidence interval (CI) 299-389 days], and the median duration of treatment was 87 days (95 % CI 78-98 days). Multivariate analyses identified baseline prognostic factors for longer OS, including female sex, low Child-Pugh score, Eastern Cooperative Oncology Group performance status 0, tumor stage I/II/III, low aspartate aminotransferase level, high hemoglobin level, hepatitis C and history of surgical resection. CONCLUSIONS: In general, the safety and effectiveness findings in this PMS were consistent with findings from previous clinical studies. Sorafenib was well tolerated and clinically useful for Japanese patients. CLINICAL TRIAL REGISTRATION NUMBER: NCT01411436.

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer.

BACKGROUND: Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP. METHODS: Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m(2) bid, days 1-21), and CDDP (60 mg/m(2), day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1. RESULTS: Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP. CONCLUSIONS: The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.

Regorafenib in Japanese patients with solid tumors: phase I study of safety, efficacy, and pharmacokinetics.

The safety, pharmacokinetics, and antitumor activity of the multikinase inhibitor regorafenib in Japanese patients was assessed in this multicenter, single-arm, phase I trial. Fifteen patients with treatment-refractory advanced solid tumors received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle until disease progression, unacceptable toxicity, or investigator or patient decision to stop. The median duration of treatment was 2.1 months (range, 0.9-20.1 months). At data cutoff, one patient was still receiving regorafenib in cycle 21. Reasons for treatment discontinuation were disease progression (n = 12) and adverse events (liver enzyme elevation n = 1; anemia n = 1). Adverse events necessitated dose reduction in six patients, interruption of daily treatment in seven patients, and cycle delay in four patients. All patients experienced at least one drug-related adverse event, particularly gastrointestinal (87 %), dermatologic (73 %), or hematologic (67 %) events. There was no significant change in time to maximum concentration or terminal half-life of regorafenib and its active metabolites M2 and M5 between single dosing and 21-day continuous dosing. The area under the concentration-time curve was 2.1-fold higher for regorafenib, 5.2-fold higher for M2, and 37.3-fold higher for M5, and the maximum concentration was 2.0-fold, 4.8-fold, and 36.0-fold higher, respectively, after continuous dosing than after single dosing. One patient had a partial response (duration 10.5 months) and seven patients had stable disease. This study indicates that regorafenib 160 mg orally once daily (21 days on/7 days off treatment) can be given to Japanese patients who have solid tumors, without undue toxicity.

MRI can determine the adequate area for debridement in the case of Fournier's gangrene.

A 57-year-old man was transferred to our hospital because of gluteal pain. His right buttock had flare and swelling. Complete blood count showed leukocytosis, and renal failure was evident. Pelvic computed tomography (CT) revealed that the abscess, including gas, was widespread into the hypodermal tissue of the right buttock. Fournier's gangrene had been suspected, and immediate drainage was performed on the right buttock. The symptom and the condition improved rapidly, but on the day after the operation, the patient became drowsy and fell into endotoxic shock. Magnetic resonance imaging (MRI) revealed strong inflammation along the entire fascia of the right femur and necrotizing fasciitis. MRI was very useful for identification of the necrotic range. Immediately, an emergency operation was performed; 3 wide incisions were made on the right thigh and crus for drainage. The patient was cared for intensively under a sedated condition, and irrigation and debridement were repeated every day. Culture of the pus revealed mixed infection of Escherichia coli and anaerobic bacteria, and a large quantity of antimicrobial drug was used. The inflammatory reaction decreased, and the patient's general condition tentatively improved. With Fournier's gangrene, initiating adequate surgical and medical treatment is essential. Therefore, MRI should be used in the early exact diagnosis of this disease to obtain knowledge of the extent of necrosis and to determine the adequate area for debridement.

Efficacy and limitation of bone marrow transplantation in the treatment of acute and subacute liver failure in rats.

AIM: Recent reports have shown that bone marrow cells (BMC) retain the potential to differentiate into hepatocytes. Thus, the BMC have been recognized as an attractive source for liver regenerative medicine. However, it has not been clarified whether BMC transplantation can be used to treat liver damage in vivo. In the present study, we explored whether BMC possess therapeutic potential to treat acute and/or subacute liver failure. METHODS: Fulminant hepatic failure (FHF) was induced by 70% hepatectomy with ligation of the right lobe pedicle (24% liver mass), followed by transplantation of BMC into the spleen. Dipeptidyl peptidase IV-positive (DPPIV(+)) BMC were then transplanted into DPPIV-negative (DPPIV(-)) recipients following hepatic irradiation (HIR) in which 70% of the liver was resected and the remnant liver irradiated. RESULTS: There was no benefit of BMC transplantation towards survival in the FHF model. DPPIV(+) hepatocytes appeared in the liver tissues of the DPPIV(-) HIR model rats, but DPPIV(+) hepatocytes replaced less than 13% of the recipient liver. CONCLUSION: BMC transplantation may have limitations in the treatment of fulminant or acute liver failure because they do not have sufficient time to develop into functional hepatocytes. Preparative HIR may be beneficial in help to convert the transplanted BMC into host hepatocytes, and provide a survival benefit. Although, However, the precise mechanism warrants further studies.