CD271 promotes proliferation and migration in bladder cancer.

Bladder cancer is a urothelial cancer and effective therapeutic strategies for its advanced stages are limited. Here, we report that CD271, a neurotrophin receptor, promotes the proliferation and migration of bladder cancer cells. CD271 knockdown decreased proliferation in both adherent and spheroid cultures, and vice versa when CD271 was overexpressed in bladder cancer cell lines. CD271 depletion impaired tumorigenicity in vivo. Migration activity was reduced by CD271 knockdown and TAT-Pep5, a known CD271-Rho GDI-binding inhibitor. Apoptosis was induced by CD271 knockdown. Comprehensive gene expression analysis revealed alterations in E2F- and Myc-related pathways upon CD271 expression. In clinical cases, patients with high CD271 expression showed significantly shortened overall survival. In surgically resected specimens, pERK, a known player in proliferation signaling, colocalizes with CD271. These data indicate that CD271 is involved in bladder cancer malignancy by promoting cell proliferation and migration, resulting in poor prognosis.

The efficacy of molecular targeted therapy and nivolumab therapy for metastatic non-clear cell renal cell carcinoma: A retrospective analysis using the Michinoku Japan urological cancer study group database.

OBJECTIVES: To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population. METHODS: In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database. RESULTS: In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups. CONCLUSIONS: The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population.

Improving compliance with guidelines may lead to favorable clinical outcomes for patients with non-muscle-invasive bladder cancer: A retrospective multicenter study.

OBJECTIVES: Clinical guidelines recommend that patients with non-muscle-invasive bladder cancer (NMIBC) should be treated with appropriate adjuvant therapy. However, compliance with guideline recommendations is insufficient, and this may lead to unfavorable outcomes. We aimed to investigate the level of adherence to guideline recommendations in patients with NMIBC and evaluate the outcomes of those who did and did not receive guideline-recommended therapies. METHODS: We performed a retrospective analysis of patients with histologically diagnosed NMIBC. The percentage of patients with intermediate- and high-risk tumors who received adjuvant intravesical therapy or second transurethral resection (TUR) was calculated. Recurrence-free survival was assessed in patients who did and did not receive the therapies. We conducted a propensity score-matched analysis to compare outcomes between patients with intermediate-risk and T1 NMIBC who did and did not undergo guideline-recommended therapies. RESULTS: Overall, 1204 patients from the Tohoku Urological Evidence-Based Medicine Study Group and Kyoto University Hospital were included. Of patients with intermediate- and high-risk tumors, 91.0% and 74.0% did not receive maintenance bacillus Calmette-Guérin (BCG), respectively. In both groups, significantly better recurrence-free survival was found for patients treated with maintenance BCG. Among patients with T1 NMIBC, only 16.7% underwent guideline-recommended therapies, that is, a second TUR and maintenance BCG. Significantly greater recurrence-free survival was observed in patients who received guideline-recommended therapies compared with propensity-matched patients who did not. CONCLUSIONS: Guideline-recommended therapies may contribute to improvements in outcomes for patients with NMIBC, suggesting that improvements in adherence to clinical guidelines may lead to favorable outcomes.

Trends in the use of local intervention for metastatic hormone-naïve prostate cancer: A multicenter retrospective study.

OBJECTIVE: To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone-naïve prostate cancer (mHNPC) in real-world practice. METHODS: This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC-free survival in the intervention group. RESULTS: The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis-targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate-specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC-free survival. CONCLUSIONS: The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.

Clinical impact of early response to first-line VEGFR-TKI in patients with metastatic renal cell carcinoma on survival: A multi-institutional retrospective study.

It remains unknown whether the early response to vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) management in malignancies links to long-term survival. The objective of this study was to investigate the survival rates and predictive factors of early response in patients with metastatic renal cell carcinoma (mRCC) managed by VEGFR-TKIs. From Jan. 2008 to Oct. 2018, 496 patients were treated with VEGFR-TKIs as first-line treatment at the eight Japanese hospitals (Michinoku RCC). Early cessation was defined as VEGFR-TKIs being given up within 3 months after their initiation. The number of patients in early cessation VEGFR-TKIs (Cohort I) was 173 (34.9%), and in long-term use (Cohort II) was 323 (65.1%). The cancer-specific survival (CSS) and overall survival (OS) were better in Cohort II. IMDC Poor-risk was at risk of early cessation of a first-line VEGFR-TKI. Axitinib was the most preferred drug for long-term treatment. On closer examination, both Cohort I and II were divided into two groups, the patients ceased VEGFR-TKI due to adverse events (Group A [67 from Cohort I] and Group C [51 from Cohort II]) and disease progression (Group B [106 from Cohort I] and Group D [272 from Cohort II]). Despite that the cessation was adverse events, CSS and OS in Group A were worse than both Group C and D. Axitinib was administered with the safer profile. IMDC Poor risk was the risk factor for the early disease progression. Managing early adverse events may contribute to a better prognosis in mRCC patients treated VEGFR-TKIs.

Effect of upfront intensive therapy on oncological outcomes in older patients with high tumor burden metastatic castration-sensitive prostate cancer: A multicenter retrospective study.

BACKGROUND: The effect of upfront intensive therapy on the prognosis of older patients with metastatic castration-sensitive prostate cancer (mCSPC) remains unclear. Thus, we assessed the impact of older age (≥75 years) on oncological outcomes in mCSPC patients with a high tumor burden. METHODS: This multicenter retrospective study included 252 patients aged ≥75 years treated with either upfront or conventional therapy between 2014 and 2021. We compared castration-resistant prostate cancer (CRPC)-free survival (FS) and overall survival (OS) between patients with androgen deprivation therapy (ADT) plus upfront intensive therapy (docetaxel [DTX] or abiraterone acetate [ABI] plus prednisolone) and conventional therapy (ADT monotherapy or ADT combined with bicalutamide). We evaluated the effect of upfront intensive therapy on prognosis by multivariable Cox regression analysis. RESULTS: The 231 patients enrolled in our study were classified in the conventional group (n = 148) or the upfront group (n = 104; DTX = 27 and ABI = 77). The upfront group had significantly prolonged CRPC-FS and OS compared with the conventional group, and this was also the case in the background-adjusted multivariable Cox regression analysis. CONCLUSION: Patients aged ≥75 years who received upfront intensive therapy had significantly longer CRPC-FS and OS compared with similar age patients treated with conventional therapy in real-world practice. The oncological benefit may not diminish in this older population.

Machine learning diagnosis by immunoglobulin N-glycan signatures for precision diagnosis of urological diseases.

Early diagnosis of urological diseases is often difficult due to the lack of specific biomarkers. More powerful and less invasive biomarkers that can be used simultaneously to identify urological diseases could improve patient outcomes. The aim of this study was to evaluate a urological disease-specific scoring system established with a machine learning (ML) approach using Ig N-glycan signatures. Immunoglobulin N-glycan signatures were analyzed by capillary electrophoresis from 1312 serum subjects with hormone-sensitive prostate cancer (n = 234), castration-resistant prostate cancer (n = 94), renal cell carcinoma (n = 100), upper urinary tract urothelial cancer (n = 105), bladder cancer (n = 176), germ cell tumors (n = 73), benign prostatic hyperplasia (n = 95), urosepsis (n = 145), and urinary tract infection (n = 21) as well as healthy volunteers (n = 269). Immunoglobulin N-glycan signature data were used in a supervised-ML model to establish a scoring system that gave the probability of the presence of a urological disease. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). The supervised-ML urologic disease-specific scores clearly discriminated the urological diseases (AUC 0.78-1.00) and found a distinct N-glycan pattern that contributed to detect each disease. Limitations included the retrospective and limited pathological information regarding urological diseases. The supervised-ML urological disease-specific scoring system based on Ig N-glycan signatures showed excellent diagnostic ability for nine urological diseases using a one-time serum collection and could be a promising approach for the diagnosis of urological diseases.

A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex.

Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. Chromosome 2p16 and PRKAR1A on chromosome 17 are known susceptibility loci for CNC. Here we report a mother and son with CNC caused by an 8.57-kb deletion involving the transcription start site and non-coding exon 1 of PRKAR1A. The proband is a 28-year-old male with bilateral large-cell calcified Sertoli cell testicular tumors and pituitary adenoma. Comprehensive genomic profiling for cancer mutations using Foundation One CDx failed to detect any mutations in PRKAR1A in DNA from the testicular tumor. Single-nucleotide polymorphism array analysis of the proband's genomic DNA revealed a large deletion in the 5' region of PRKAR1A. Genomic walking further delineated the region an 8.57-kb deletion. A 1.68-kb DNA fragment encompassed by the deleted region showed strong promoter activity in a NanoLuc luciferase reporter assay. The patient's mother, who is suffering from recurrent cardiac myxoma, a critical sign for CNC, carried an identical deletion. The 8.57-kb deleted region is a novel lesion for CNC and will facilitate molecular diagnosis of the disease.

Impact of Gleason pattern 5 on prognosis for newly diagnosed metastatic hormone-sensitive prostate cancer with Gleason score ≥8.

OBJECTIVE: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone-sensitive prostate cancer patients with a Gleason score ≥8. METHODS: The data of 559 patients diagnosed as metastatic hormone-sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. RESULTS: The median overall survival of the 559 metastatic hormone-sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow-up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low-volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low-volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88-8.67; P = 0.0026). CONCLUSION: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone-sensitive prostate cancer with a Gleason score ≥8. In low-metastatic volume metastatic hormone-sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group.

Significance of upfront cytoreductive nephrectomy stratified by IMDC risk for metastatic renal cell carcinoma in targeted therapy era - a multi-institutional retrospective study.

BACKGROUND: This retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria. METHODS: We reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method. RESULTS: Of 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29-0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11-0.59, p < 0.01). CONCLUSIONS: Upfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.

Identification and Functional Characterization of a Novel Androgen Receptor Coregulator, EAP1.

The androgen receptor (AR) plays an essential role in the development of prostate cancer, and androgen-deprivation therapy is used as a first-line treatment for prostate cancer. However, under androgen-deprivation therapy, castration-resistant prostate cancer inevitably arises, suggesting that the interacting transcriptional coregulators of AR are promising targets for developing novel therapeutics. In this study, we used novel proteomic techniques to evaluate the AR interactome, including biochemically labile binding proteins, which might go undetected by conventional purification methods. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, we identified enhanced at puberty 1 (EAP1) as a novel AR coregulator, whereas its interaction with AR could not be detected under standard biochemical conditions. EAP1 enhanced the transcriptional activity of AR via the E3 ubiquitin ligase activity, and its ubiquitination substrate proteins included AR and HDAC1. Furthermore, in prostate cancer specimens, EAP1 expression was significantly correlated with AR expression as well as a poor prognosis of prostate cancer. Together, these results suggest that EAP1 is a novel AR coregulator that promotes AR activity and potentially plays a role in prostate cancer progression.

External validation of the REMARCC model for the selection of cytoreductive nephrectomy in patients with primary metastatic renal cell carcinoma: A multicenter retrospective study.

OBJECTIVES: This study aims to evaluate the utility of the scoring system of the Registry for Metastatic Renal Cell Carcinoma (REMARCC) model on the overall survival (OS) of patients undergoing cytoreductive nephrectomy (CN). METHODS: A total of 278 patients with primary metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019 were identified. The c-index and net benefit between the REMARCC score were compared with the International mRCC Database Consortium (IMDC) score in patients with CN (CN group, n = 146). The effect of the REMARCC score on OS was compared between the CN group and patients without CN (non-CN group, n = 132) using Cox regression analysis under the propensity score-based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. RESULTS: Of the 146 patients with CN, the c-index of the REMARCC model (0.60) was higher than the IMDC model (0.54). The decision curve analysis showed the advantage of REMARCC model predicting OS compared with the IMDC model. OS was significantly longer in the REMARCC low-score (0-2) than that in the high-score (3-6) among the patients with CN. IPTW-adjusted Cox regression analyses showed that OS was significantly longer in the CN group than that in the non-CN group among the patients with REMARCC low-score but was not significantly different between the groups among the patients with REMARCC high-score. CONCLUSIONS: The REMARCC score may be active for selecting the CN candidate in patients treated with TKIs.

Outcomes of axitinib versus sunitinib as first-line therapy to patients with metastatic renal cell carcinoma in the immune-oncology era.

Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences.

Novel metastatic burden-stratified risk model in de novo metastatic hormone-sensitive prostate cancer.

The metastatic burden is a critical factor for decision-making in the treatment of metastatic hormone-sensitive prostate cancer (HSPC). This study aimed to develop and validate a novel risk model for survival in patients with de novo low- and high-burden metastatic HSPC. The retrospective observational study included men with de novo metastatic prostate cancer who were treated with primary androgen-deprivation therapy at 30 institutions across Japan between 2008 and 2017. We created a risk model for overall survival (OS) in the discovery cohort (n = 1449) stratified by the metastatic burden (low vs high) and validated its predictive ability in a separate cohort (n = 951). Based on multivariate analyses, lower hemoglobin levels, higher Gleason grades, and higher clinical T-stage were associated with poor OS in low-burden disease. Meanwhile, lower hemoglobin levels, higher Gleason grade group, liver metastasis, and higher extent of disease scores in bone were associated with poor OS in patients with high-burden disease. In the discovery and validation cohorts, the risk model using the aforementioned parameters exhibited excellent discriminatory ability for progression-free survival and OS. The predictive ability of this risk model was superior to that of previous risk models. Our novel metastatic burden-stratified risk model exhibited excellent predictive ability for OS, and it is expected to have several clinical uses, such as precise prognostic estimation.

Impact of Nerve-Sparing Status on Positive Surgical Margin Location and Biochemical Recurrence in Patients with Prostate Cancer Post Radical Prostatectomy.

PURPOSE: This study was designed to assess the relationship between nerve-sparing (NS) status, positive surgical margin (PSM) location, and biochemical recurrence (BCR) based on a multicenter, radical prostatectomy (RP) database. METHODS: We retrospectively reviewed data from 726 patients who underwent RP without any neoadjuvant or adjuvant treatment between 2010 and 2014. We statistically assessed the impact of NS sides on PSM location and BCR. RESULTS: PSM rates were 21.9% in the 726 patients studied, 13.2% in patients with ≤pT2, and 46.8% in patients with ≥pT3. Regarding PSM locations, the anterior-apex (AA) was the most common site for PSM (43.3%). After adjusting for confounding factors, bilateral nerve sparing (BNS) had a significantly higher odds ratio of PSM than the absence of NS did (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.85-4.99). In the UNS RP in patients with ≤pT2, non-AA PSM on the non-NS side was significantly higher than that on the NS side (92.9% vs. 45.5%, p = 0.009). In all patients, 5.8% experienced BCR during a median follow-up of 43.5 months. PSM was significantly associated with BCR-free survival in patients with ≤pT2 (p = 0.013), but not in patients with ≥pT3 (p = 0.185). Non-AA PSM at the non-NS side was an independent risk factor for BCR (hazard ratio [HR] 2.56, 95% confidence interval [CI] 1.12-5.85), whereas AA PSMs, including NS/non-NS sides and non-AA PSM at the NS side, were not associated with BCR-free survival. CONCLUSIONS: Avoidance of non-AA PSM on the non-NS side may be rather important for maintaining BCR-free survival after RP.

Prognosis of Japanese metastatic renal cell carcinoma patients in the targeted therapy era.

BACKGROUND: The aims of this study were to investigate prognosis and validate prognostic models [Memorial Sloan-Kettering Cancer Center (MSKCC), International Metastatic Renal Cell Carcinoma Data Consortium (IMDC), and Japanese metastatic renal cancer (JMRC) models] in the targeted therapy era in Japanese patients with metastatic renal cell carcinoma. METHODS: We retrospectively analyzed 692 patients who were diagnosed with mRCC from January 2008 to August 2018 in the Michinoku Japan Urological Cancer Study Group database. Nivolumab as sequential therapy was widely used. Other immune checkpoint inhibitors were excluded from this study. RESULTS: The median overall survival (95% confident interval) in all, MSKCC favorable, intermediate, and poor risk patients was 41.0 months (33.9-46.8), not reached (63.5 to not estimable), 46.8 months (37.1-52.9), and 10.4 months (8.9-14.4), respectively. The median overall survival (95% confident interval) in IMDC favorable, intermediate, and poor risk patients was not reached (61.6 to not estimable), 47.4 months (41.4-56.5), and 11.5 (9.9-16.3), respectively. The c-index of the MSKCC, IMDC, and JMRC models calculated at mRCC diagnosis was 0.680, 0.689, and 0.700, respectively. No statistical differences were found in the c-index among the models. CONCLUSION: While the real-world overall survival in Japanese patients with mRCC in the targeted therapy era improved compared to that previously reported in the cytokine era, there was no clear difference in the survival of poor risk patients between these eras. There were no differences in the superiority among the models.

Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study.

BACKGROUND: Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC. METHODS: We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019). RESULTS: We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia. CONCLUSION: Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis.

BACKGROUND: The clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC. METHODS: We retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients' data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes. RESULTS: The median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% vs. 52.5%, P=0.277), CSS (61.1% vs. 56.4%, P=0.400), and CRPC-FS (33.1% vs. 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups. CONCLUSIONS: No significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.

Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein.

Cancer stem cells (CSCs) are believed to cause cancer metastasis and recurrence. BEX2 (brain expressed X-linked gene 2) is a CSC-related gene that is expressed in dormant CSCs in cholangiocarcinoma and induces resistance against chemotherapy. The aim of the present study was to identify small compounds that have activity to inhibit BEX2 expression and result in the attenuation of CSC-related phenotypes. We screened 9600 small chemical compounds in high-throughput screening using cholangiocarcinoma cell line HuCCT1 expressing BEX2 protein fused with NanoLuc, and identified a compound, BMPP (1, 3-Benzenediol, [4-(4-methoxyphenyl)-1H-pyrazol-3-yl]). BMPP was found to exert decreasing effects on BEX2 protein expression and G0 phase population of the tumor cells, and increasing effects on ATP levels and chemotherapeutic sensitivity of the cells. These findings indicate that BMPP is a valuable chemical compound for reducing dormant CSC-related phenotypes. Thus, the identification of BMPP as a potential CSC suppressor provides scope for the development of novel therapeutic modalities for the treatment of cancers with BEX2 overexpressing CSCs.