Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands.

We report here the design, synthesis and evaluation of a series of HIV-1 protease inhibitors that incorporate substituted oxaspirocyclic carbamate derivatives to serve as the P2 ligands. Various substituted ligand derivatives were synthesized in a racemic manner, using a tandem Prins/pinacol reaction as the key reaction. This reaction sets the relative stereochemistry of the oxaspirocyclic template in a highly diastereoselective manner.

An orally available P1'-5-fluorinated M inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier.

We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits the enzymatic activity of SARS-CoV-2's main protease (M) and more effectively blocks the infectivity and replication of all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2 and SARS-CoV-2 than two M inhibitors: nirmatrelvir and ensitrelvir. Notably, the administration of ritonavir-boosted nirmatrelvir and ensitrelvir causes drug-drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting their clinical utility. When orally administered, TKB272 blocked SARS-CoV-2 replication without ritonavir in B6.

Ten-Year Outcomes of a Phase 3, Multicenter, Randomized Controlled Trial (SHIP0804) With 3-Month Neoadjuvant Androgen Deprivation Prior to I-Seed Transperineal Prostate Brachytherapy Followed by Nil Versus 9-Month Adjuvant Hormonal Therapy in Patients With Intermediate-Risk Prostate Cancer.

Purpose: To analyze the effects of adjuvant hormonal therapy (AHT) on time to event after neoadjuvant androgen deprivation therapy (ADT) and I-transperineal prostate brachytherapy (TPPB), compared with neoadjuvant ADT and TPPB only, in patients with intermediate-risk prostate cancer (IRPC).

Methods And Materials: In this multicenter, open-label, phase 3 randomized controlled trial (SHIP0804), 421 patients with IRPC were randomly assigned to either 9-month AHT (AHT arm) or no AHT (non-AHT arm) after 3 months of neoadjuvant ADT and TPPB. The primary endpoint was biochemical progression-free survival, and secondary endpoints included overall survival and clinical progression-free survival.

Optimizing prostate cancer detection in transition zone: an analysis of apparent diffusion coefficient values in prostate magnetic resonance imaging evaluation with Prostate Imaging Reporting and Data System (PI-RADS) assessment.

Background: Multiparametric magnetic resonance imaging (mpMRI) is increasingly used for the early detection of clinically significant prostate cancer (csPCa). However, the achievement of accurate detection rates, particularly for transition zone (TZ) lesions, remains challenging. We investigated the relationship between apparent diffusion coefficient (ADC) values in Prostate Imaging Reporting and Data System (PI-RADS) 3-5 lesions and csPCa within the TZ.

The impact of multidisciplinary approaches on the outcomes of olfactory neuroblastoma treated with postoperative radiotherapy.

Background: We investigated the outcomes of postoperative radiation therapy for olfactory neuroblastoma (ONB) and our cross-departmental collaboration to enhance the effectiveness of cancer treatment.

Methods: We retrospectively evaluated 22 patients with ONB who underwent postoperative radiotherapy after tumor resection. En bloc resection was performed; pathology specimens were prepared in coronal sections; and irradiation fields were determined after discussion with radiation oncologists, head and neck surgeons, and pathologists.

Clinical Significance of Intraductal Carcinoma of the Prostate After High-Dose Brachytherapy With External Beam Radiation Therapy: A Single Institution Series and an Updated Meta-Analysis.

Background: We compared oncological outcomes between prostate cancer (PCa) patients with and without intraductal carcinoma of the prostate (IDC-P) after high-dose-rate brachytherapy (HDR-BT) with external beam radiation therapy (EBRT).

Methods: We performed a retrospective analysis of 138 patients with clinically high-risk, very high-risk, or locally advanced PCa who received HDR-BT with EBRT. Of these, 70 (50.

Predictive factors for disease progression after salvage radiation therapy in biochemical recurrent patients treated by radical prostatectomy.

Objective: Salvage radiation therapy (SRT) is standard treatment for patients after radical prostatectomy (RP). However, the optimal timing of SRT remains to be elucidated.

Material And Methods: We retrospectively reviewed 133 prostate cancer (PCa) patients who underwent SRT for biochemical recurrence after RP.

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.

GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants.

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIV) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIV was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC of 130 femtomolar.

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).

Treatment Results of High-dose-rate Brachytherapy and External Beam Radiation With Long-term Androgen Deprivation Therapy for Patients With Metastatic Prostate Cancer.

Background/aim: A recent clinical trial indicated the usefulness of local radiation therapy of the prostate in patients with low-volume metastatic prostate cancer. High-dose-rate brachytherapy (HDR-BT) is used mainly for high-risk, localized, and locally advanced cases. However, few studies exist on the efficacy of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer.

Effect of Adequate Local Radiation Dose on Oncological Outcomes in Localized Prostate Cancer Patients Treated With Low-dose-rate Brachytherapy.

Background/aim: We retrospectively investigated the effect of a biologically effective dose (BED) of Low-dose rate brachytherapy (LDR-BT) and its possible interaction with androgen deprivation therapy (ADT) during LDR-BT treatment for intermediate-risk prostate cancer (PCa).

Patients And Methods: A total of 693 patients with localized, intermediate-risk PCa, who underwent LDR-BT with or without supplemental external beam radiotherapy, were included in this study. We stratified patients into two groups according to BED (<180 Gy2, lower BED group; ≥180 Gy2, higher BED group) and evaluated the effect of ADT duration on the oncological outcomes of each group.

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.

Radiotherapy after radical prostatectomy for prostate cancer: clinical outcomes and factors influencing biochemical recurrence.

Background: Radiotherapy (RT) after radical prostatectomy (RP) includes adjuvant radiotherapy (ART) and salvage radiotherapy (SRT), which can prevent or cure biochemical recurrence.

Aims: To evaluate long-term outcomes of RT after RP and to examine factors affecting biochemical recurrence-free survival (bRFS).

Methods: Sixty-six received ART and 73 received SRT between 2005 and 2012 were included.

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.

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.

Design, Synthesis and X-Ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-Furofuran Derivatives as P2 Ligands.

The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity.

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.

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).

Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy.

Background: Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited.

Objectives: We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer.

Prognostic value of PSA bounce in prostate cancer following definitive radiation therapy: a systematic review and meta-analysis.

Background: The prognostic significance of PSA bounce following definitive radiation therapy remains controversial. To develop a sense of current opinion in this area, we performed a systematic search of the literature based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Methods: In January 2021, we systematically searched PubMed, the Cochrane library, and Scopus for studies that compared patients who had localized prostate cancer with or without PSA bounce after definitive radiation therapy.

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.