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A human immunodeficiency virus-1 (HIV-1) protease is a homodimeric aspartic protease essential for the replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analogues have been developed. However, serious drug-resistant mutants have emerged. For understanding the molecular mechanism of the drug resistance, an accurate examination of the impacts of the mutations on ligand binding and enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of indinavir, a potent transition state analogue inhibitor, to the wild-type protein and a V82T/I84V drug-resistant mutant of the HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free-energy optimization technique which combines a highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of the MM protein environment by long-time molecular dynamics simulations. Through the free-energy calculations of protonation states of catalytic groups at the binding pocket and of the ligand-binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug resistance through the direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

The impact of the assimilation of high spatial and temporal resolution atmospheric motion vectors (AMVs) on tropical cyclone (TC) forecasts has been investigated. The high-resolution AMVs are derived from the full disk scan of the new generation geostationary satellite Himawari-8. Forecast experiments for three TCs in 2016 in a western North Pacific basin are performed using the National Centers for Environmental Prediction (NCEP) operational Hurricane Weather Research and Forecasting Model (HWRF). Two different ensemble–variational hybrid data assimilation configurations (using background error covariance created by global ensemble forecast and HWRF ensemble forecast), based on the Gridpoint Statistical Interpolation (GSI), are used for the sensitivity experiments. The results show that the inclusion of high-resolution Himawari-8 AMVs (H8AMV) can benefit the track forecast skill, especially for long-range lead times. The diagnosis of optimal steering flow indicates that the improved track forecast seems to be attributed to the improvement of initial steering flow surrounding the TC. However, the assimilation of H8AMV increases the negative intensity bias and error, especially for short-range forecast lead times. The investigation of the structural change from the assimilation of H8AMV revealed that the following two factors are likely related to this degradation: 1) an increase of inertial stability outside the radius of maximum wind (RMW), which weakens the boundary layer inflow; and 2) a drying around and outside the RMW. Assimilating H8AMV using background error covariance created from HWRF ensemble forecast contributes to a significant reduction in negative intensity bias and error, and there is a significant benefit to TC size forecast.

Typhoon Lionrock (2016) was unusual among tropical cyclones (TCs) in that it formed east of the monsoon gyre in the western North Pacific, and moved counterclockwise. It rapidly intensified in the monsoon gyre in an environment of weak upper-tropospheric winds and vertical wind shear. This study used a 3-km mesh nonhydrostatic model to examine the warm-core intensification of Typhoon Lionrock, which was associated with cyclone-scale vigorous convection [i.e., convective bursts (CBs)]. The simulation reproduced the multiple CBs at intervals of 1 day or shorter, which were related to the diurnal cycles and other short time-scale variations in the TC convection. Each CB tended to precede peak temperature anomalies near the TC center by 0–12 h, indicating that the warm-core intensification occurred due to diabatic heating released by the vigorous eyewall convection. Notably, updrafts due to convection during the intensification phase were stronger than those occurring during the mature and decay phases, and the maximum temperature anomaly of the upper-tropospheric warm core rapidly increased during eyewall formation. In addition, this study indicated that most of the asymmetric inner-core vigorous convection associated with CBs, which was induced by the vertical wind shear, contributed to the warm-core intensification. Furthermore, the budget analysis of potential temperature within the TC inner core showed that adiabatic heating due to subsidence from near the tropopause within the eye, often following CBs, was essential in developing the eye. The lag correlation suggested the lag time between the CBs and the subsidence within the eye was 3–9 h.

This study investigates the assimilation impact of rapid-scan (RS) atmospheric motion vectors (AMVs) derived from the geostationary satellite Himawari-8 on tropical cyclone (TC) forecasts. Forecast experiments for three TCs in 2016 in the western North Pacific basin are performed using the National Centers for Environmental Prediction (NCEP) operational Hurricane Weather Research and Forecasting Model (HWRF). An ensemble&ndash, variational hybrid data assimilation system is used as an initialization. The results show that the assimilation of RS-AMVs can improve the track forecast skill, while the weak bias or slow intensification bias increases at the shorter forecast lead time. A vortex initialization in HWRF has a substantial impact on TC structure, but it has neutral impacts on the track and intensity forecasts. A thinning of AMVs mitigates the weak bias caused by RS-AMV assimilation, resulting in the reduction of intensity error. However, it degrades the track forecast skill for a longer lead time. A decomposition of the TC steering flows demonstrated that the change in TC-induced flow was a primary factor for reducing the track forecast error, and the change in environmental flow has less impact on the track forecast. The investigation of the structural change from the assimilation of RS-AMV revealed that the following two factors are likely related to the intensity forecast degradation: (1) an increase of inertial stability outside the radius of maximum wind (RMW), which weakens the boundary layer inflow, and (2) a drying around and outside the RMW.

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) is uncommon. CNS prophylaxis is not regularly included in second-line treatments for patients who develop CNS-negative relapses. We report a pediatric case of recurrent ALK-negative ALCL who developed isolated CNS progression during the treatment with brentuximab vedotin monotherapy. The patient achieved CNS remission after receiving the CNS-directed treatments including craniospinal irradiation. There is no evidence regarding whether brentuximab vedotin can cross the blood-brain barrier. CNS prophylaxis should be considered in high-risk patients with relapsed ALCL who receive second-line treatments containing agents with limited CNS penetration.

Percutaneous coronary intervention for chronic total occlusion (CTO) lesions typically requires two vascular accesses; one for the advancement of the antegrade guidewire and another for contralateral angiography or retrograde approach. The one puncture and one guiding catheter (1P1G) technique had been introduced as a special technique, in which a single guiding catheter is used both as a treatment device and a contralateral angiography device for the treatment of CTO. The chronic total occlusion angioplasty with Modified usage of a single guiding catheter for collateral angiography (Chameleon) technique was introduced as a similar yet improved technique of 1P1G technique for CTO intervention. These techniques are introduced for slender percutaneous coronary intervention using a small-size guide catheter. However, larger guide catheters may also be used with additional techniques. Moreover, we introduce a technique that reduces the amount of contrast media used in the Chameleon technique. In this chapter, these new techniques are discussed.

The temporally dense geostationary satellite observations made possible by recent technological advances enable atmospheric motion vectors (AMVs) to be derived that are suitable for capturing atmospheric flows even of mesoscale phenomena, for which in situ data are scarce. Tropical cyclone (TC) outflows around the cloud top, reflecting TC secondary circulation, were computed by using AMVs derived from successive Multifunctional Transport Satellite (MTSAT) imagery, and the relationship between TC intensification rate (defined as the change of the best-track maximum sustained wind in the previous 24 h) and the outflow was investigated for 44 TCs occurring during 2011–14. During the TC intensification phase, temporal changes in the outflow were generally synchronous with changes in the cloud-top temperature of TC inner-core convective clouds detected by MTSAT infrared band. It was noteworthy that the intensification rates of 66% of the TCs peaked 0–36 h after outflow maximization and that the intensification rate for TCs with a maximum rate of >15 m s−1 day−1 peaked after the outflow maximum. Furthermore, TCs with a large intensification rate and latent-heat release around the midlevel tended to have a large outflow during the intensification phase. A comparison of TCs with and without convective bursts (CBs) revealed that the correlation between outflow and the TC intensification rate was higher for TCs accompanied by CBs than for those without CBs, implying that a rapid deepening of inner-core convection is important for intensification of a TC’s secondary circulation. The outflow tended to be most correlated with the TC intensification rate 0–6 h earlier.

Background Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC. Methods In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1. Results All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC0–24. Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92–310.11) ng/mL at baseline to 11.70 (0.37–47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients. Conclusion Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients. Trial registration ClinicalTrials.gov identifier: NCT02162836. Electronic supplementary material The online version of this article (10.1007/s10147-019-01526-7) contains supplementary material, which is available to authorized users.

T-LGL leukemia has been rarely reported in children. We report a child with T-LGL leukemia who presented with anemia and went on to develop Crohn's disease. Although prednisolone treatment proved effective in the treatment of anemia, large granular lymphocyte counts increased as the doses were tapered. T-cell rearrangement studies revealed a clonal rearrangement of the TCR Vβ/jβ2 gene. Concurrently, the patient developed severe diarrhea. Inflammatory changes across the upper and lower intestines led to the diagnosis of Crohn's disease. This case highlights that T-LGL leukemia could be occurred in children. Flow cytometry and/or T-cell gene rearrangement studies are recommend in patients of anemia and various kind of autoimmune diseases including Crohn's disease, even in children.

A long-term global atmospheric reanalysis, named “Japanese 25-year Reanalysis (JRA-25)” was completed using the Japan Meteorological Agency (JMA) numerical assimilation and forecast system. The analysis covers the period from 1979 to 2004. This is the first long-term reanalysis undertaken in Asia. JMA's latest numerical assimilation system, and specially collected observational data, were used to generate a consistent and high-quality reanalysis dataset designed for climate research and operational monitoring and forecasts. One of the many purposes of JRA-25 is to enhance the analysis to a high quality in the Asian region.Six-hourly data assimilation cycles were performed, producing 6-hourly atmospheric analysis and forecast fields of various physical variables. The global model used in JRA-25 has a spectral resolution of T106 (equivalent to a horizontal grid size of around 120 km) and 40 vertical layers with the top level at 0.4 hPa. In addition to conventional surface and upper air observations, atmospheric motion vector (AMV) wind retrieved from geostationary satellites, brightness temperature from TIROS Operational Vertical Sounder (TOVS), precipitable water retrieved from orbital satellite microwave radiometer radiance and other satellite data are assimilated with three-dimensional variational method (3D-Var). JMA produced daily sea surface temperature (SST), sea ice and three-dimensional ozone profiles for JRA-25. A new quality control method for TOVS data was developed and applied in advance.Many advantages have been found in the JRA-25 reanalysis. Predicted 6-hour global total precipitation distribution and amount are well reproduced both in space and time. The performance of the long time series of the global precipitation is the best among the other reanalyses, with few unrealistic variations from degraded satellite data contaminated by volcanic eruptions. Secondly, JRA-25 is the first reanalysis to assimilate wind profiles around tropical cyclones reconstructed from historical best track information; tropical cyclones were analyzed properly in all the global regions. Additionally, low-level cloud along the subtropical western coast of continents is well simulated and snow depth analysis is also of a good quality. The article also covers material which requires attention when using JRA-25.

Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required.

The progress and status of a new atmospheric re-analysis, JRA-25 the Japanese 25-year Re-analysis which covers the 26 years from 1979 to 2004, are introduced. Observational data include some newly produced for JRA-25 and advantages and drawbacks of performance are briefly described. JRA-25 has many advantages such as its handling of precipitation amounts, tropical cyclone analysis, and the extent of low-level cloud along western continents that are among the best compared to other re-analyses. The snow analysis is also good and stable. JRA-25 outputs analysis products every 6 hours. Copyright © 2005 Royal Meteorological Society

In this paper, the evolution of the cloud activities for six typhoons in 1997 is examined, utilizing TBB (equivalent Black Body temperature) data of GMS (Geostationary Meteorological Satellite)-5 split window channels. As the result, periods of 24-hour and about 10-hour are found in the time variation of the cloud areas whose cloud top temperature is lower. Diurnal variation is found most distinctly in the time series of the cloud area of TBB lower than -40°C, which corresponds to the one whose cloud top gets at the upper level of the troposphere. The maximum and the minimum peaks of this variation appear around at 1500 JST (Japan Standard Time) and 0800 JST. And, the maximum appears corresponding to vigorous convections at 0600-1000 JST of all the vigorous convections. About 10-hour period time variation is found most distinctly in the time series of the cloud areas of TBB lower than -60°C, which corresponds to the one whose cloud top gets at the upper level of tropopause or over. The maximum of this variation appears corresponding to a preceding vigorous convective activity which occurs in the wide region of the typhoon a few hours before.

Abiraterone acetate(AA)has been approved in more than 80 countries for the treatment of patients with metastatic castration-resistant prostate cancer(mCRPC). In July 2013, a marketing approval application for AA was submitted to the Japanese Ministry of Health, Labour, and Welfare. AA is a selective inhibitor of CYP17A1, a crucial enzyme for androgen biosynthesis. AA exerts its anti-tumor activity by directly inhibiting androgen production at all three sources, i. e., the testes, adrenal glands, and tumor itself. Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life(QoL)of patients with mCRPC. Herein, we have summarized the development of AA and the results of important international and local clinical trials in Japan. In addition, the effect of food on AA bioavailability, concomitant steroid use, and liver function test abnormalities have been discussed regarding the appropriate use of AA.

A new extracellular quinoprotein oxidase named enacyloxin oxidase (ENX oxidase), which is involved in biosynthesis of ENX IIa, a congener of ENX, was found in the culture supernatant of Frateuria sp. W-315 and purified as a homogeneous protein on SDS-PAGE. ENX oxidase was shown to have a molecular mass of 73 kDa by SDS-PAGE and 79 kDa by gel filtration. The enzyme was inhibited by various carbonyl reagents and the activity was stimulated by addition of PQQ. This is the first report on a quinoprotein oxidase that is secreted into the culture medium in the logarithmic growth phase, and acts for biosynthesis of the antibiotic.

Various types of silylmethanols were converted into their corresponding silanols in good to excellent yield under mild oxidation conditions using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl).

Background: Hematopoietic stem cell transplantation (HSCT) recipients carry a high risk of primary varicella and varicella-zoster virus (VZV) reactivation. VZV infections can be fatal, and VZV reactivation can be complicated by postherpetic neuralgia, which worsens the recipients’ post-HSCT quality of life. VZV vaccines may prevent such infections; however, international vaccination guidelines do not recommend VZV vaccination of HSCT recipients because few data regarding safety among HSCT recipients are available. In Japan, we use a high-titer Oka stain vaccine for varicella vaccination and zoster prevention in the elderly; the plaque forming unit (PFU) value of this vaccine is as high as the zoster vaccine used in the U.S. Data regarding the safety of zoster vaccine in HSCT recipients is limited; therefore, we report our experience with this high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients. Patients and Methods: Forty-seven pediatric allogeneic HSCT recipients who underwent transplantation at the Saitama Children’s Medical Center from 2000-2011 were vaccinated with live vaccines and their antibody titers were evaluated after vaccination. Among the 47 recipients, the Japanese high-titer varicella vaccine was administered to 32 recipients. Since establishing the live vaccine initiation criteria in 2009, allogeneic HSCT recipients were considered as recipients for live vaccines, including the varicella vaccine, if 24 months had passed after HSCT without active chronic GVHD or required immunosuppression. In addition, recipients were required to have a lymphocyte count >1500/μl or CD4 cell count >700/μl if they were 1000/μl or CD4 cell count >500/μl if they were >6 years, normal phytohemagglutinin response, and serum IgG level >500 mg/dL. Before 2009, time for vaccination depended on each doctor’s judgment. Patients were given a single dose of the Biken varicella vaccine containing a minimum of 23,000 PFUs. We use EIA to measure the antibody titer and defined seropositivity as a titer >6.0. The time to evaluate the antibody titer was not fixed. We retrospectively collected the clinical data of recipients and laboratory data by reviewing the medical records. Results: The 32 recipients, who received the Japanese varicella vaccine, underwent HSCT at a median age of 5.15 years (range: 0.5-16.4 years) and were vaccinated at a median of 20.65 months (range: 4.8-112.1 months) after HSCT. Twenty and 11 patients had received myeloablative and nonmyeloablative conditioning, respectively. Nine patients received related-donor transplant, of which eight were bone marrow and one was peripheral blood. Twenty-three patients received unrelated-donor transplant, of which 14 were bone marrow and nine were cord blood. Antithymocyte globulin was administered to four patients. Eighteen of the 32 patients (56.3%) were seropositive after vaccination. Of the 26 patients, whose vaccination histories and pre-transplantation histories were available, eight were affected by natural disease, six had been immunized, and 12 had not been immunized. At vaccination, the median lymphocyte count was 3201/μl (range: 817-6630/μl) and the median IgG value was 880 mg/dL (range: 233-1461 mg/dL). There was no significant risk factor associated with vaccine failure. We experienced one case of varicella because of wild type VZV and no cases of zoster after vaccination during a median follow-up period of 4.8 years (range: 0.4-11.3 years); the single patient developed varicella 13 days after vaccination, immediately after an influenza virus infection. Whereas, two cases of varicella and one case of zoster developed before vaccination. Of the other 15 recipients, who did not receive varicella vaccine, three varicella and two zoster developed in three recipients. Conclusion: We safely vaccinated pediatric allogeneic HSCT recipients with the Japanese high-titer varicella vaccine. This finding could encourage the use in the U.S. of zoster vaccines such as Zostavax@, which contains similarly high PFUs, and low-titer varicella vaccines such as Varivax@. However, the efficacy of high-titer varicella vaccines for preventing VZV reactivation in this population remains unclear. Further studies are warranted to elucidate the efficacy and difference between low-titer and high-titer varicella and zoster vaccines. Disclosures No relevant conflicts of interest to declare.

Some properties of enacyloxin (ENX) oxidase from Frateuria sp. [Oyama et al., Biosci. Biotech. Biochem., 58, 1914-1917 (1994)] were studied. The enzyme catalyzed the oxidation of ENX IVa, ENX IIIa, and decarbamoyl ENX IVa, specifically. The optimum pH and temperature for the enzyme activity were pH 9.0 and 60°C, respectively. It is suggested that the enzyme is a quinoprotein but its redox cofactor is different from pyrroloquinoline quinone.

Various types of silylmethanols were converted into their corresponding silanols in good to excellent yield under mild oxidation conditions using TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl).

Previous studies have demonstrated an association between prostate-specific antigen (PSA) kinetics and predictive value for treatment outcomes. Abiraterone acetate (AA) is a newly approved cytochrome-P450C17 inhibitor for treatment of metastatic castration-resistant prostate cancer (mCRPC), and few studies have evaluated PSA kinetics using AA so far. Results of a study evaluating PSA kinetics in the beginning of AA and enzalutamide responded chemotherapy-treated patients suggested different trends between the drugs. PSA kinetics of AA-treated patients has been reported using large datasets; however, no studies which have fully evaluated PSA kinetics in the beginning treatment. The present study aimed to assess the PSA kinetics and relationship between the PSA kinetics and PSA progression in chemotherapy-naive and chemotherapy-treated mCRPC patients receiving AA. We used two Japanese phase II trial datasets: JPN-201, chemotherapy-naive mCRPC (n = 48) and JPN-202, chemotherapy-treated mCRPC (n = 46). PSA kinetic parameters were calculated using actual PSA values measured every 4 weeks, and a subgroup analysis was performed to evaluate the influence of early PSA response on time to PSA progression (TTPP). In addition, we used a Cox proportional hazard model to investigate the influence of variables on TTPP. PSA declined from week 4 but took more time to achieve nadir. PSA kinetic parameters were different between the datasets, mean time to PSA nadir was 5.3 ± 5.6 and 2.0 ± 3.4 months, and TTPP was 9.5 ± 7.4 and 3.8 ± 4.8 months in JPN-201 and JPN-202, respectively. In the subgroup analysis of week 4 PSA decline status, Kaplan–Meier curves for TTPP were similar between early responders and non-progression patients in JPN-201 (median, 9.2 vs. 6.5 months, respectively) but separated in JPN-202 (median, 3.7 vs. 1.9 months, respectively). According to univariate Cox regression analysis, achievement of PSA response (≥50 %) at week 12 was associated with TTPP in the both trials, but the hazard ratio of PSA decline (≥30 %) at week 4 was not significant in JPN-201. Our results suggest that PSA kinetics were not comparable and early PSA response showed different association to TTPP according to prior history of chemotherapy. The original trials are registered at ClinicalTrials.gov. The identifiers are; JNJ-212082-JPN-201 , registered 20 December 2012 and JNJ-212082-JPN-202 , registered 30January 2013.