The activated complement pathway in the fibrous process of benign prostatic hyperplasia.

BACKGROUND: To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. METHODS: Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. RESULTS: Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). CONCLUSIONS: In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.

Regulation of the innate immune response and gut microbiome by p53.

p53 is a key tumor suppressor mutated in half of human cancers. In recent years, p53 was shown to regulate a wide variety of functions. From the transcriptome analysis of 24 tissues of irradiated mice, we identified 553 genes markedly induced by p53. Gene Ontology (GO) enrichment analysis found that the most associated biological process was innate immunity. 16S rRNA-seq analysis revealed that Akkermansia, which has anti-inflammatory properties and is involved in the regulation of intestinal barrier integrity, was decreased in p53-knockout (p53-/- ) mice after radiation. p53-/- mice were susceptible to radiation-induced GI toxicity and had a significantly shorter survival time than p53-wild-type (p53+/+ ) mice following radiation. However, administration of antibiotics resulted in a significant improvement in survival and protection against GI toxicity. Mbl2 and Lcn2, which have antimicrobial activity, were identified to be directly transactivated by p53 and secreted by liver into the circulatory system. We also found the expression of MBL2 and LCN2 was decreased in liver cancer tissues with p53 mutations compared with those without p53 mutations. These results indicate that p53 is involved in shaping the gut microbiome through its downstream targets related to the innate immune system, thus protecting the intestinal barrier.

Coincidental occurrence of bilateral neonatal testicular torsion, with an extravaginal and a contralateral intravaginal testicular torsion.

Introduction: We report a case of bilateral neonatal testicular torsion, with an extravaginal and a contralateral intravaginal testicular torsion. Case presentation: A 5-day-old boy with bilateral scrotal swelling and palpable induration was diagnosed with bilateral neonatal testicular torsion by color Doppler ultrasonography. The right testis was black with 360-degree extravaginal torsion of the spermatic cord, and the left testis was brown with 90-degree intravaginal torsion. We repaired the torsion and incised the tunica albuginea to reduce intratesticular pressure. The left testis became pink in color, but the right testis remained unchanged. Based on the pathological findings of the intraoperative biopsy of tissue specimens from both testes, we performed a right orchiectomy and preserved the left testis. Conclusions: Our experience suggests that testicular color improvement after fasciotomy and pathological findings of intraoperative testicular biopsy may indicate testicular preservation.

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.

Preoperative prognostic model for localized and locally advanced renal cell carcinoma: Michinoku Japan Urological Cancer Study Group.

BACKGROUND: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). METHODS: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. RESULTS: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. CONCLUSION: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials.

SMARCB1-deficient basal cell carcinoma of the prostate controlled using radiation therapy.

Introduction: Basal cell carcinoma of the prostate is rare, with no established treatment for its recurrence or metastasis. We report a case involving basal cell carcinoma of the prostate controlled using radiotherapy. Case presentation: A 57-year-old man complained of perineal pain. Although his prostate-specific antigen was 0.657 ng/mL, a digital rectal examination revealed his prostate was stone hard. Prostate needle biopsy showed basal cell carcinoma of the prostate. The patient then underwent radical prostatectomy. Local recurrence and sacral bone metastasis appeared 2 months after surgery. OncoGuide™ NCC Oncopanel System showed deletion of SMARCB1; however no recommended treatment was identified. Thus, we decided to perform radiotherapy, which reduced all lesions. Conclusion: Basal cell carcinoma of the prostate may have a poor prognosis with recurrence or metastasis, hence evaluation of prognostic factors is important. In this case, the genomic profiling test suggested that SMARCB1 deletion may be a prognostic factor associated with disease progression.

Efficacy and Safety of First-Line Cytokines versus Sunitinib and Second-Line Axitinib for Patients with Metastatic Renal Cell Carcinoma (ESCAPE Study): A Phase III, Randomized, Sequential Open-Label Study.

BACKGROUND: The sequence of first-line cytokine and second-line molecular targeted therapies may be suitable for some patients with metastatic renal cell carcinoma (mRCC) because of the expectation of complete remission and durable response achieved with cytokine therapy. METHODS: This was a phase III randomized controlled trial investigating the outcomes of low-dose interleukin-2 (IL-2) plus interferon alfa (IFNα) versus sunitinib as the first line and axitinib as the second line in patients with low- and intermediate-risk mRCC. RESULTS: Thirty-five patients were randomly assigned. The total progression-free survival (PFS) to the end of the second line was 29.0 months (95% CI, 11.7-46.3) in the IL-2 + IFNα group and 16.3 months (95% CI, 6.3-26.4) in the sunitinib group. The PFS hazard ratio for the IL-2 + IFNα group relative to the sunitinib group was 0.401 (95% CI, 0.121-1.328; p = 0.135). The hazard ratio for overall survival (OS) was 1.675 (95% CI, 0.418-6.705; p = 0.466), which was better in the sunitinib group than in the IL-2 + IFNα group but not statistically significant. The types of adverse events (AEs) differed significantly, although there was no significant difference in the incidence of AEs. CONCLUSIONS: There was a trend toward better total PFS for IL-2 + IFNα, but it was not significant. There was also no advantage of IL-2 + IFNα in terms of OS. The study was underpowered to draw any definitive conclusions. The results showed no clear advantage of IL-2 + IFNα over sunitinib in the first-line setting; however, it may be an option in some relatively low-risk mRCC cases due to the difference in the AE profile. This trial was registered with the University Hospital Medical Information Network (UMIN), center identifier UMIN 000012522.

Involvement of Mast-Cell-Tryptase- and Protease-Activated Receptor 2-Mediated Signaling and Urothelial Barrier Dysfunction with Reduced Uroplakin II Expression in Bladder Hyperactivity Induced by Chronic Bladder Ischemia in the Rat.

We aimed to investigate the relationship between mast cell (MC) infiltration into the bladder with urothelial barrier dysfunction and bladder hyperactivity in a chronic bladder ischemia (CBI) rat model. We compared CBI rats (CBI group; n = 10) with normal rats (control group; n = 10). We measured the expression of mast cell tryptase (MCT) and protease-activated receptor 2 (PAR2), which are correlated with C fiber activation via MCT, and Uroplakins (UP Ia, Ib, II and III), which are critical to urothelial barrier function, via Western blotting. The effects of FSLLRY-NH2, a PAR2 antagonist, administered intravenously, on the bladder function of CBI rats were evaluated with a cystometrogram. In the CBI group, the MC number in the bladder was significantly greater (p = 0.03), and the expression of MCT (p = 0.02) and PAR2 (p = 0.02) was significantly increased compared to that of the control group. The 10 µg/kg FSLLRY-NH2 injection significantly increased the micturition interval of CBI rats (p = 0.03). The percentage of UP-II-positive cells on the urothelium with immunohistochemical staining was significantly lower in the CBI group than in the control group (p < 0.01). Chronic ischemia induces urothelial barrier dysfunction via impairing UP II, consequently inducing MC infiltration into the bladder wall and increased PAR2 expression. PAR2 activation by MCT may contribute to bladder hyperactivity.

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.

Concurrent Reduced Expression of Contiguous PKD1, TSC2 and NTHL1 Leading to Kidney Diseases and Multiple Diverse Renal Cancers.

BACKGROUND/AIM: Several cases of concurrent reduction of expression of polycystin 1 (PKD1) and Tuberous Sclerosis Complex 2 (TSC2) that are contiguous in chromosome 16p13 have been previously reported. This study newly addresses the concurrent reduction of expression of PKD1, TSC2 and NTHL1, which is adjacent to TSC2 and is a tumor suppressor gene. MATERIALS AND METHODS: We investigated the mRNA expression levels of PKD1, TSC2, PKD2, TSC1 and NTHL1 in blood and renal cell carcinoma (RCC) tissues in a proband with autosomal dominant polycystic kidney disease (ADPKD), tuberous sclerosis complex (TSC) and multiple pathologically diverse RCCs, including clear cell, papillary and chromophobe types. Additionally, we investigated germline variants in blood using whole exome sequencing (WES) in the proband and her four siblings. RESULTS: mRNA expression levels of PKD1, TSC2 and NTHL1 were reduced in the proband's blood and RCCs, compared with control groups. WES identified one novel variant with amino acid changes in the PKD1 exon in the three subjects with ADPKD, including the proband. Moreover, two variants in the TSC2 intron specific to the proband were also identified. CONCLUSION: In this study, we report a novel pathogenic variant in the PKD1 exon which likely led to ADPKD, and two variants in the TSC2 intron, which might have led to reduction in the expression of both TSC2 and NTHL1, consequently leading to TSC and multiple pathologically diverse RCCs.

Association between the presence of bacteria in prostate tissue and histopathology in biopsies from men not complaining of lower urinary tract symptoms.

OBJECTIVE: To investigate the presence of bacteria in prostate tissue, and relationships between the bacteria and histopathological findings. METHODS: Samples were collected from prostate biopsy patients with no obvious lower urinary tract symptoms (LUTS). Detection and identification of bacterial species in the prostate tissues were performed with PCR for 16SrDNA and DNA sequencing. Histopathology was also evaluated. LUTS and lower urinary tract function were assessed by questionnaires, uroflowmetry, and ultrasonography. RESULTS: DNA was extracted from 97 prostate biopsies, with 5 bacterial species detected among samples from 7 patients (7.2%). The stroma-to-gland ratio in the prostate tissues from patients with bacteria was lower than in those without bacteria (p < 0.01). Glandular epithelial hyperplasia was also identified in the prostates harboring bacteria. International Prostate Symptom Score (IPSS), IPSS-quality of life (IPSS-QOL), Overactive Bladder Symptom Score (OABSS), maximum flow rate, urine volume by uroflowmetry, and post-voided residual urine were not significantly different when comparing patients with and without bacteria in their prostate samples. CONCLUSIONS: The present study demonstrated that 7.2% of men without obvious LUTS had bacteria in their prostate tissues. The presence of such bacteria might induce glandular hyperplasia and contribute to pathological changes in the early stages of benign prostate enlargement before affecting LUTS.

Impacts of Neoadjuvant Hormonal Therapy Prior to Robot-Assisted Radical Prostatectomy on Postoperative Hormonal- and Sexual-Related Quality of Life - Assessment by Patient-Reported Questionnaire.

PURPOSE: Neoadjuvant hormonal therapy (HT) before radical prostatectomy (RP) is not recommended by current guidelines in terms of oncological outcomes. Despite this, neoadjuvant HT is sometimes conducted before RP for a small proportion of patients in clinical practice. This study evaluated the impacts of neoadjuvant HT on hormonal- and sexual-related quality of life (QOL) among patients who underwent robot-assisted RP (RARP). MATERIALS AND METHODS: Participants comprised 470 patients divided into a non-neoadjuvant HT group (n = 408) and a neoadjuvant HT group (n = 62). Hormonal- and sexual-related QOL were measured using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. RESULTS: Hormonal summary scores at 6 and 9 months, function scores before and 3, 6, and 9 months and bother score at 6 months after RARP were significantly lower in the neoadjuvant HT group than in the non-neoadjuvant HT group. Sexual function scores were decreased in the neoadjuvant HT group compared to the non-neoadjuvant HT group before and 6 months after RARP. In the neoadjuvant HT group, sexual function at 3 months after RARP was significantly worse in patients with >5 months of neoadjuvant HT than in patients with ≤5 months of neoadjuvant HT. Conversely, sexual bother at 3 months after RARP was significantly worse in patients with ≤5 months of neoadjuvant HT than in patients with >5 months of neoadjuvant HT. CONCLUSION: Vintage neoadjuvant HT prior to RARP should not be recommended due to not only oncological outcomes, but also the impacts on postoperative hormonal- and sexual-related QOL.

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.

Insights into the development of a new index, vesical adaptation response to diuresis, for understanding lower urinary tract dysfunction.

OBJECTIVES: To clarify how vesical adaptation response, the homeostatic system that constantly changes voided volume to adapt to diuresis, is involved in male lower urinary tract symptoms and bladder storage function. METHODS: We included male patients older than 65 years with lower urinary tract symptoms. Vesical adaptation response to diuresis was defined as a positive correlation between urine output rate and voided volume on 3-day sensory-related frequency volume charts. Patients were divided into two groups according to the presence or absence of vesical adaptation response to diuresis, and characteristics were compared between groups. RESULTS: Ninety-four male patients were finally analyzed. Vesical adaptation response to diuresis was found in 48 patients (51%) and was lacking in 46 patients (49%). Patients without vesical adaptation response to diuresis were significantly more often diagnosed with overactive bladder (P = 0.04). After adjusting for confounders, absence of vesical adaptation response to diuresis was significantly associated with overactive bladder (adjusted odds ratio 3.76, 95% confidence interval 1.34-10.55; P = 0.01) and benign prostatic enlargement (adjusted odds ratio 1.04, 95% confidence interval 1.01-1.07; P = 0.02). CONCLUSIONS: The absence of vesical adaptation response to diuresis, characterized by decreased voided volume during a diuretic phase, can be interpreted as a form of bladder storage dysfunction. Assessment of vesical adaptation response to diuresis may provide a new index of bladder storage function and contribute to a better understanding of the pathophysiology underlying bladder storage dysfunction in patients with lower urinary tract symptoms.

l-Theanine Protects Bladder Function by Suppressing Chronic Sympathetic Hyperactivity in Spontaneously Hypertensive Rat.

Chronic sympathetic hyperactivity is known to affect metabolism and cause various organ damage including bladder dysfunction. In this study, we evaluated whether l-theanine, a major amino acid found in green tea, ameliorates bladder dysfunction induced by chronic sympathetic hyperactivity as a dietary component for daily consumption. Spontaneously hypertensive rats (SHRs), as an animal model of bladder dysfunction, were divided into SHR-water and SHR-theanine groups. After 6 weeks of oral administration, the sympathetic nervous system, bladder function, and oxidative stress of bladder tissue were evaluated. The mean blood pressure, serum noradrenaline level, and media-to-lumen ratio of small arteries in the suburothelium were significantly lower in the SHR-theanine than in the SHR-water group. Micturition interval was significantly longer, and bladder capacity was significantly higher in the SHR-theanine than in the SHR-water group. Bladder strip contractility was also higher in the SHR-theanine than in the SHR-water group. Western blotting of bladder showed that expression of malondialdehyde was significantly lower in the SHR-theanine than in the SHR-water group. These results suggested that orally administered l-theanine may contribute at least partly to the prevention of bladder dysfunctions by inhibiting chronic sympathetic hyperactivity and protecting bladder contractility.

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.

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.

Upregulation of glucocorticoid receptor-mediated glucose transporter 4 in enzalutamide-resistant prostate cancer.

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.