Long-term outcomes of radical prostatectomy versus low-dose-rate brachytherapy in patients with intermediate-risk prostate cancer: Propensity score matched comparison.

PURPOSE: To compare long-term outcomes of radical prostatectomy (RP) and low-dose-rate brachytherapy (LDR-BT) using propensity score-matched analysis in patients with clinically localized, intermediate-risk prostate cancer (PCa). METHODS: Between October 2003 and March 2014, our institution treated 1241 patients with intermediate-risk PCa (RP: n = 531; LDR-BT: n = 710). Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) levels of 0.2 ng/ml or greater for RP, and as PSA nadir plus 2 ng/ml or higher (Phoenix definition) for LDR-BT. We calculated propensity scores by multivariate logistic regression based on covariates that included age, pretreatment PSA, biopsy Gleason grade, the percentage of positive biopsy cores (PPBC), and clinical T stage. RESULTS: Median follow-up was 108 months for RP and 99 months for LDR-BT. After propensity score adjustment, a total of 642 (321 each) patients remained for further analysis. Kaplan-Meier curves showed no statistically significant difference in overall survival (OS) (p = 0.99). LDR-BT was associated with improved BCR-free survival and salvage therapy-free survival  compared to RP (p < 0.001), and RP was associated with improved metastasis-free survival (MFS, p < 0.001). CONCLUSION: BCR cannot be a surrogate for survival comparison, primarily due to differences between treatment modalities in how this term was defined post-therapy. Long-term follow-up showed that RP was associated with lower MFS in intermediate-risk PCa. However, this has not yet translated into superior OS.

Comparison of outcomes in high-risk prostate cancer patients treated with low-/high-dose-rate brachytherapy plus external beam radiotherapy.

BACKGROUND: Although brachytherapy is a standard treatment option for patients with high-risk prostate cancer, only a few studies have compared low-dose-rate brachytherapy (LDR-BT) and high-dose-rate brachytherapy (HDR-BT). We applied propensity score-based inverse probability treatment weighting (IPTW) to compare oncological outcomes for LDR-BT and HDR-BT. METHODS: We retrospectively assessed prognosis in 392 patients with high-risk localized prostate cancer who had undergone brachytherapy plus external beam radiation. IPTW was applied to adjust the Kaplan-Meier survival analyses and Cox proportional hazards regression analyses, with the goal of minimizing bias from patient background. RESULTS: The IPTW-adjusted Kaplan-Meier survival analyses showed no statistically significant differences for time to biochemical recurrence, clinical progression, castration-resistant prostate cancer, or death from any cause. The IPTW-adjusted Cox regression analyses also showed that the modality of brachytherapy was not an independent factor in these oncological outcomes. Notably, the two groups differed regarding complications; LDR-BT was associated with a higher rate of acute grade ≥ 2 GU toxicity, and late grade 3 toxicity was noted only in HDR-BT. CONCLUSION: Our analysis of long-term outcomes in patients with high-risk localized prostate cancer shows no significant differences in oncological outcomes between LDR-BT and HDR-BT, but some differences in toxicity, and offers patients and clinicians useful information in deciding management strategies for high-risk localized prostate cancer.

The prognostic significance of the clinical T stage and Grade Group in patients with locally advanced prostate cancer treated via high-dose-rate brachytherapy and external beam radiation.

BACKGROUND: Although the optimal management of locally advanced prostate cancer (PCa) remains unclear, local definitive therapy, thus combined radiotherapy and androgen deprivation, is one option. We evaluated the long-term outcomes of patients with locally advanced PCa who underwent high-dose-rate brachytherapy (HDR-BT) and external beam radiation therapy (EBRT). METHODS: We retrospectively analyzed 173 patients with locally advanced PCa (cT3a-4N0-1M0) who underwent HDR-BT and EBRT. We employed Cox's proportional hazards models to identify pre-treatment predictors of oncological outcomes. Treatment outcomes (biochemical recurrence-free survival [BCRFS], clinical progression-free survival [CPFS], and castration-resistant prostate cancer-free survival [CRPCFS] were compared according to the combination of the pre-treatment predictors. RESULTS: The 5-year BCRFS, CPFS, and CRPCFS rates were 78.5, 91.7, and 94.4% respectively; there were two PCa deaths. Multivariate analysis revealed that the clinical T stage (cT3b and cT4) and Grade Group (GG) 5 status were independent risk factors for poor BCRFS, CPFS, and CRPCFS. In the GG ≤ 4 group, the Kaplan-Meier curves for BCRFS, CPFS, and CRPCFS revealed excellent outcomes. However, in the GG5 group, patients with cT3b and cT4 PCa evidenced significantly poorer oncological outcomes than those with cT3a PCa. CONCLUSION: The clinical T stage and GG status were significantly prognostic of oncological outcomes in patients with locally advanced PCa. In patients of GG ≤ 4 PCa, HDR-BT was effective even in patients with cT3b or cT4 PCa. However, in patients with GG5 PCa, careful monitoring is essential, particularly of patients with cT3b or cT4 PCa.

Clinical characteristics of secondary bladder cancer developing after low-/high-dose-rate brachytherapy to treat localized prostate cancer.

BACKGROUND: To explore correlations between the clinical attributes of secondary bladder cancer and brachytherapy, we retrospectively reviewed our institutional database on patients with localized prostate cancer who underwent low-dose-rate brachytherapy (LDR-BT) or high-dose-rate brachytherapy (HDR-BT) with or without external beam radiation therapy (EBRT) or radical prostatectomy (RP). METHODS: From October 2003 to December 2014, 2551 patients with localized prostate cancer were treated at our institution. Of these, data on 2163 were available (LDR-BT alone: n = 953; LDR-TB with EBRT: n = 181; HDR-BT with EBRT: n = 283; RP without EBRT: n = 746). The times of secondary bladder cancer development subsequent to radical treatment, and their clinical characteristics, were studied. RESULTS: Age-adjusted Cox's regression analyses indicated that brachytherapy did not significantly impact the incidence of secondary bladder cancer. However, the pathological characteristics of such cancer differed between patients treated via brachytherapy and RP without EBRT; invasive bladder cancer was more common in such patients. CONCLUSION: The risk for secondary bladder cancer was not significantly increased after brachytherapy compared to non-irradiation therapy. However, brachytherapy patients exhibited a higher incidence of invasive bladder cancer. Therefore, meticulous follow-up is crucial for early detection and treatment of bladder cancer in such patients.

Patients with PSA below 0.2 ng/mL at 8 years post high-dose-rate brachytherapy have an extremely low risk of subsequent recurrence.

OBJECTIVES: We have analyzed the long-term follow-up data of patients with prostate cancer (PCa) who underwent high-dose-rate brachytherapy (HDR-BT) and external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT). The objective was to determine the optimal time for cessation of PSA monitoring after HDR-BT. METHODS: We included 309 patients with clinical stage T1c-T4 N0-1 M0 PCa who received HDR-BT and EBRT combined with long-term ADT between 2005 and 2018. We stratified the patients based on their prostate-specific antigen (PSA) levels and identified the factors associated with biochemical recurrence (BCR) and clinical progression (CP). RESULTS: The median follow-up duration was 98 months (range: 31-207 months). Among the 306 patients, 76 developed BCR and 47 developed CP subsequently. We found that the PSA levels at 3, 5, and 8 years significantly correlated with the oncological outcomes of brachytherapy. No patient with a PSA level ≤ 0.2 ng/mL at 8 years later developed BCR or CP. CONCLUSION: Our long-term data suggest that in the presence of a PSA level ≤ 0.2 ng/mL at 8 years later, PSA monitoring may be safely discontinued due to the extremely low risk of subsequent oncological events. The data presented in this study will assist clinicians in determining the optimal management strategy for patients with PCa following HDR-BT and EBRT combined with long-term ADT.

Clinical significance of unfavorable findings in intermediate-risk prostate cancer patients for predicting treatment outcomes after contemporary, dose-escalated multimodal radiotherapy.

PURPOSE: Few studies have documented the long-term oncological outcomes of favorable and unfavorable intermediate-risk (IR) prostate cancer patients treated via contemporary high-dose irradiation. We analyzed the ultimate clinical outcomes of such patients using the current risk sub-stratification schema. PATIENTS AND METHODS: We included 693 patients with localized IR prostate cancer treated via low-dose-rate brachytherapy (LDR-BT) with or without external beam radiation (EBRT) and with or without androgen-deprivation therapy (ADT) in a single institution. Treatment outcomes (biochemical recurrence-free survival [BCRFS] and clinical progression-free survival [CPFS]) were compared according to the numbers of unfavorable findings. RESULTS: Out of the 693 IR patients, 292 (42.1%) exhibited favorable disease; the remaining 401 (57.9%) exhibited unfavorable disease. Compared with favorable IR status, unfavorable IR status was associated with shorter BCRFS and CPFS (p < 0.001 and p < 0.001, respectively). Patients with two to three unfavorable factors experienced the worst oncological outcomes (p < 0.001 and p < 0.001). Although patients with one or no unfavorable factors responded similarly to LDR-BT monotherapy, this treatment modality was insufficient for preventing biochemical and clinical progression in patients with multiple unfavorable findings. CONCLUSION: Long-term treatment outcomes indicate that patients with IR disease scheduled for LDR-BT should undergo multimodal irradiation if they exhibit two or more unfavorable factors at diagnosis.

How long is long enough to secure disease control after low-dose-rate brachytherapy in combination with other modalities in intermediate-risk, localized prostate cancer?

PURPOSE: Previous studies have demonstrated excellent overall outcomes in patients who underwent low-dose-rate brachytherapy (LDR-BT) in intermediate-risk, localized prostate cancer (PCa). We thus investigated the appropriate length of time before completing prostate-specific antigen (PSA) monitoring after treatment. PATIENTS AND METHODS: Between 2003 and 2014, 710 localized, intermediate-risk PCa patients underwent LDR-BT with or without supplemental external beam radiotherapy (EBRT). Data from 567 of those patients was analyzed in this study. Neoadjuvant hormonal therapy (NHT) was administered to 315 patients (55.6 %) and NHT with adjuvant hormonal therapy (AHT) to 59 patients (10.4 %), as per the protocol of a prospective randomized controlled trial (SHIP0804). We stratified patients by posttreatment PSA levels at specific times and assessed the factors for association with biochemical recurrence (BCR) and for clinical progression (CP). RESULTS: The median follow-up was 109 months (range, 60-205 months). Of 529 patients who were BCR-free at 3 years after treatment, 56 subsequently developed BCR, and 47 developed CP. PSA at 3 and 5 years after treatment were significantly correlated with long-term oncological outcomes. No patients with 5-year PSA levels ≤0.1 ng/mL subsequently developed BCR or CP. CONCLUSION: Discontinuation of PSA monitoring could be discussed with patients with intermediate-risk PCa as a reasonable option if PSA levels remain ≤0.1 ng/mL at 5 years after LDR-BT, either alone or with other combined modalities, as subsequent recurrences are quite rare.

Prognostic value of PSA bounce after definitive radiotherapy revisited.

BACKGROUND: Prostate-specific antigen (PSA) bounce after definitive radiotherapy has been reported as a predictor of improved biochemical recurrence-free survival (BCRFS). We revisited this phenomenon to confirm its clinical impact on oncological outcomes in patients with long-term follow-up who were free of biochemical recurrence (BCR) at least 3 years after treatment. MATERIALS AND METHODS: A total of 541 patients with localized, intermediate-risk prostate cancer underwent low-dose rate brachytherapy with iodine-125 seeds with or without supplemental external beam radiotherapy in combination. Neoadjuvant hormonal therapy was administered to 273 patients (50.5%) with a median duration of 3 months (range 1-108 months). PSA bounce was defined as ≥ 0.2 ng/ml increase above the interval PSA nadir, followed by a decrease below that value. RESULTS: The median age was 69 years (range 49-90 years). The median follow-up duration was 102 months (range 36-205 months). One-hundred and fifty patients (27.7%) had PSA bounce with a median magnitude of 0.47 ng/ml (range 0.2-3.19 ng/ml). Age was significantly associated with the occurrence of PSA bounce [age: hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.93-0.98]. It was found to be independently associated with a decreased risk for BCR (HR 0.29; 95% CI 0.12-0.69) and clinical progression (HR 0.44; 95% CI 0.95-0.98). CONCLUSION: PSA bounce indicated a favorable BCRFS and clinical progression-free survival in patients who had been free of BCR for at least 3 years after definitive radiotherapy.

Trimodal therapy with high-dose-rate brachytherapy and hypofractionated external beam radiation combined with long-term androgen deprivation for unfavorable-risk prostate cancer.

PURPOSE: To assess the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiation therapy (EBRT) combined with long-term androgen deprivation therapy (ADT) in very-high-risk (VHR) versus high-risk (HR) prostate cancer (PCa), as defined in the National Comprehensive Cancer Network (NCCN) criteria. METHODS: Data from 338 consecutive HR or VHR PCa patients who had undergone this tri-modal therapy between 2005 and 2018 were retrospectively analyzed. Biochemical recurrence (BCR)-free, progression-free, overall, and cancer-specific survival (BCRFS/PFS/OS/CSS) rates were analyzed using the Kaplan-Meier method and Wilcoxon test. Cox regression models were used to evaluate candidate prognostic factors for survival. C­indexes were used to assess model discrimination. RESULTS: Within a median follow-up of 84 months, 68 patients experienced BCR, 58 had disease progression including only 3 with local progression, 27 died of any cause, and 2 died from PCa. The 5­year BCRFS, PFS, OS, and CSS rates were 82.2% (HR 86.5%; VHR 70.0%), 90.0% (HR 94.3%; VHR 77.6%), 95.7% (HR, 97.1%; VHR, 91.8%), and 99.6% (HR, 100%; VHR, 98.0%), respectively. In multivariable analyses that adjusted for standard clinicopathologic features, the risk subclassification was associated both PFS and OS (p = 0.0003 and 0.001, respectively). Adding the risk subclassification improved the accuracy of models in predicting BCRFS, PFS, and OS. CONCLUSION: While the outcome of this trimodal approach appears favorable, VHR PCa patients had significantly worse oncological outcomes than those with HR PCa. The NCCN risk subclassification should be integrated into prognostic tools to guide risk stratification, treatment, and follow-up for unfavorable PCa patients receiving this trimodal therapy.

National survey of radiation oncologists' practice patterns regarding hormone-naïve prostate cancer with bone metastases.

OBJECTIVE: To explore radiation oncologists' attitudes and practice patterns of radiotherapy for hormone-naïve prostate cancer with bone metastases in Japan. METHODS: An internet-based survey was distributed to board-certified radiation oncologists of the Japanese Society of Radiation Oncology. Three hypothetical cases were assumed: hormone-naïve prostate cancer with single, three or multiple non-symptomatic bone metastases. The respondents described their attitude regarding such cases, treatment methods and the radiotherapy dose fractionation that they would recommend. RESULTS: Among the 1013 board-certified radiation oncologists in Japan, 373 (36.8%) responded to the questionnaire. Most of the respondents (85.0%) believed that radiotherapy may be applicable as a primary treatment for hormone-naïve prostate cancer with bone metastases in some circumstances. For Case 1 (single bone metastasis), 55.0% of the respondents recommended radiotherapy for the prostate and bone metastasis. For Case 2 (three bone metastases), only 24.4% recommended radiotherapy for all lesions, and 31.4% recommended radiotherapy for the prostate only. For Case 3 (multiple bone metastases), 49.1% of the respondents stated that there was no indication for radiotherapy. However, 34% of the respondents still preferred to administer radiotherapy for the prostate. The radiotherapy techniques and dose fractionations varied widely among the respondents. CONCLUSION: Most of the respondent radiation oncologists believed that radiotherapy may be beneficial for hormone-naïve prostate cancer with bone metastases.

Novel Protease Inhibitors Containing C-5-Modified bis-Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2' Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance.

Combination antiretroviral therapy has achieved dramatic reductions in the mortality and morbidity in people with HIV-1 infection. Darunavir (DRV) represents a most efficacious and well-tolerated protease inhibitor (PI) with a high genetic barrier to the emergence of drug-resistant HIV-1. However, highly DRV-resistant variants have been reported in patients receiving long-term DRV-containing regimens. Here, we report three novel HIV-1 PIs (GRL-057-14, GRL-058-14, and GRL-059-14), all of which contain a P2-amino-substituted-bis-tetrahydrofuranylurethane (bis-THF) and a P2'-cyclopropyl-amino-benzothiazole (Cp-Abt). These PIs not only potently inhibit the replication of wild-type HIV-1 (50% effective concentration [EC50], 0.22 nM to 10.4 nM) but also inhibit multi-PI-resistant HIV-1 variants, including highly DRV-resistant HIVDRVRP51 (EC50, 1.6 nM to 30.7 nM). The emergence of HIV-1 variants resistant to the three compounds was much delayed in selection experiments compared to resistance to DRV, using a mixture of 11 highly multi-PI-resistant HIV-1 isolates as a starting HIV-1 population. GRL-057-14 showed the most potent anti-HIV-1 activity and greatest thermal stability with wild-type protease, and potently inhibited HIV-1 protease's proteolytic activity (Ki value, 0.10 nM) among the three PIs. Structural models indicate that the C-5-isopropylamino-bis-THF moiety of GRL-057-14 forms additional polar interactions with the active site of HIV-1 protease. Moreover, GRL-057-14's P1-bis-fluoro-methylbenzene forms strong hydrogen bonding and effective van der Waals interactions. The present data suggest that the combination of C-5-aminoalkyl-bis-THF, P1-bis-fluoro-methylbenzene, and P2'-Cp-Abt confers highly potent activity against wild-type and multi-PI-resistant HIV strains and warrant further development of the three PIs, in particular, that of GRL-057-14, as potential therapeutic for HIV-1 infection and AIDS.

Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants.

We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2'-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2' ligands, respectively. GRL-001-15 and GRL-003-15 have meta-monofluorophenyl and para-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 µM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50 of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1DRVRP30), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC50 of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PRWT) complexed with the novel PIs revealed that GRL-001-15's meta-fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81' (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81', Ile82', and Arg8'. In contrast, GRL-003-15 forms halogen bond interactions with Pro81' alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation.

We describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing a squaramide-derived scaffold as the P2 ligand in combination with a (R)-hydroxyethylamine sulfonamide isostere. Inhibitor 3h with an N-methyl-3-(R)-aminotetrahydrofuranyl squaramide P2-ligand displayed an HIV-1 protease inhibitory Ki value of 0.51 nM. An energy minimized model of 3h revealed the major molecular interactions between HIV-1 protease active site and the tetrahydrofuranyl squaramide scaffold that may be responsible for its potent activity.

Efficacy of intensity-modulated radiation therapy for optic nerve sheath meningioma.

PURPOSE: The present study examined the efficacy and complications associated with intensity-modulated radiation therapy (IMRT) for optic nerve sheath meningioma (ONSM) in 15 cases and compared visual function before and after treatment. METHODS: Consecutively diagnosed patients with ONSM treated with IMRT were evaluated from 2012 to 2017. We categorized ONSM with three growth patterns (diffuse, fusiform, or globular). Visual acuity, visual fields, and optic disc findings were assessed before and after IMRT. Ocular and systemic complications were evaluated during and after treatment. RESULTS: The 15 patients selected for analysis ranged in age from 33 to 77 years. Post-treatment observation periods were 8 to 57 months. After IMRT, tumor enlargement was not detected in any eyes, and tumor reduction was seen in 2 eyes. At final post-treatment follow-up, eyes with fusiform and globular growth maintained better visual acuity compared with pre-treatment, whereas 2 of 5 eyes with diffuse growth showed reduced vision. Five eyes with no apparent optic disc abnormality maintained better visual acuity compared with pre-treatment, whereas 8 of 10 eyes with disc edema and atrophy remained stable or showed reduced vision. Improvements were seen in all 5 eyes with optic discs negative for pre-treatment abnormalities. Final post-treatment visual field abnormalities improved in 11 eyes. All adverse events identified during IMRT improved rapidly during the treatment period. CONCLUSION: IMRT for the treatment of ONSM achieved improvement and preserved visual function. In particular, early treatment with IMRT before the appearance of optic disc abnormalities can be more effective for improving visual function.

GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants.

We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C-5 position of P2 tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2' cyclopropyl (Cp) (or isopropyl)-aminobenzothiazole (Abt) moiety. Their 50% effective concentrations (EC50s) were 2.5 to 30 nM against wild-type HIV-1NL4-3, 0.3 to 6.7 nM against HIV-2EHO, and 0.9 to 90 nM against laboratory-selected PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIVMDR). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV) (HIVDRVrp51), with EC50s of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined (amprenavir, atazanavir, lopinavir [LPV], and DRV) had virtually no activity (EC50s of >1,000 nM) against HIVDRVrp51 Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between Tp-THF modified at C-5 and Asp29/Asp30/Gly48 of wild-type protease, while the P2' Cp-Abt group forms strong hydrogen bonds with Asp30'. The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. For selection with LPV and DRV by use of a mixture of 11 HIVMDR strains (HIV11MIX), HIV11MIX became highly resistant to LPV and DRV over 13 to 32 and 32 to 41 weeks, respectively. However, for selection with GRL-079 and GRL-058, HIV11MIX failed to replicate at >0.08 µM and >0.2 µM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the P2 Tp-THF group modified at C-5 and the P2' Abt group contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1NL4-3 and a wide spectrum of HIVMDR strains.

Nationwide Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS): first analysis on survival.

BACKGROUND: Investigating oncological outcomes in patients registered in the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS) in terms of biochemical relapse-free survival (bRFS) by the Phoenix and the newly developed J-POPS definitions, exploration of predictive factors for bRFS, and preliminary verification of pitfalls of prostate-specific antigen (PSA) failure definitions. METHODS: Between July 2005 and June 2007, 2316 clinically localized patients underwent permanent seed implantation. The primary endpoint was bRFS. One of the secondary endpoints was overall survival (OS). RESULTS: The median age was 69 and performance status was 0 in 99.1% of participants. The median biologically effective dose (BED) was about 180 Gy2. During a median follow-up of 60.0 months, 8.4 and 5.9% had PSA failure by the Phoenix and the J-POPS definitions, respectively. The 5-year bRFSs based on the Phoenix and the J-POPS definitions were 89.1 and 91.6%, respectively. The 5-year OS was 97.3%. According to multivariate analyses, only age affected bRFS based on the Phoenix definition, whereas the risk group and BED independently affected bRFS based on the J-POPS definition. A spontaneous PSA decrease was seen in 91.1% of participants after PSA failure based on the Phoenix definition alone, but in only 22.2% after PSA failure based on the J-POPS definition alone. CONCLUSION: The world's largest registration study, J-POPS, consisted of patients with longevity, and a highly quality-controlled BED resulted in excellent bRFS and OS. The high likelihood of PSA bounce by the Phoenix definition should be taken into account, especially in younger patients. CLINICAL TRIAL INFORMATION: NCT00534196.

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Ki of 0.025nM and antiviral IC50 of 69nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27Å resolution. These structures revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.

Dimerization of HIV-1 protease (PR) subunits is an essential process for PR's acquisition of proteolytic activity, which plays a critical role in the maturation of HIV-1. Recombinant wild-type PR (PR(WT)) proved to dimerize, as examined with electrospray ionization mass spectrometry; however, two active site interface PR mutants (PR(T26A) and PR(R87K)) remained monomeric. On the other hand, two termini interface PR mutants (PR(1-C95A) and PR(97/99)) took both monomeric and dimeric forms. Differential scanning fluorimetry indicated that PR(1-C95A) and PR(97/99) dimers were substantially less stable than PR(WT) dimers. These data indicate that intermolecular interactions of two monomers occur first at the active site interface, generating unstable or transient dimers, and interactions at the termini interface subsequently occur, generating stable dimers. Darunavir (DRV), an HIV-1 protease inhibitor, inhibits not only proteolytic activity but also PR dimerization. DRV bound to protease monomers in a one-to-one molar ratio, inhibiting the first step of PR dimerization, whereas conventional protease inhibitors (such as saquinavir) that inhibit enzymatic activity but not dimerization failed to bind to monomers. DRV also bound to mutant PRs containing the transframe region-added PR (TFR-PR(D25N) and TFR-PR(D25N-7AA)), whereas saquinavir did not bind to TFR-PR(D25N) or TFR-PR(D25N-7AA). Notably, DRV failed to bind to mutant PR containing four amino acid substitutions (V32I, L33F, I54M, and I84V) that confer resistance to DRV on HIV-1. To our knowledge, the present report represents the first demonstration of the two-step PR dimerization dynamics and the mechanism of dimerization inhibition by DRV, which should help design further, more potent novel PIs.