Association Between Frailty and Pelvic Organ Prolapse in Elderly Women: A Retrospective Study.

INTRODUCTION AND HYPOTHESIS: This study evaluated the association between pelvic organ prolapse (POP), frailty, and sarcopenia to explore how POP treatment can extend healthy life expectancy in elderly women. METHODS: We conducted a retrospective study of prospectively collected data, comparing women with mild POP (stages 0-II) with those with advanced POP (stages III and IV). The inclusion criteria for this study were women who visited the clinic with at least one symptom of pelvic floor dysfunction and underwent imaging studies between April 2020 and November 2022. Initially, 119 patients met these inclusion criteria. Patients were excluded if they had a history of previous POP treatment, did not respond to the study survey, or were lost to follow-up. After applying these exclusion criteria, 82 patients were included in the final analysis, of whom 65 underwent surgery (laparoscopic sacrocolpopexy, colpocleisis, tension-free vaginal tape, and native tissue repair). Assessments included POP Quantification, Kihon Checklist, Pelvic Organ Prolapse Quality of Life (P-QOL) questionnaire, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and Incontinence Symptom Questionnaire (ICIQ-SF). Pelvic muscles were measured using MRI or CT. Immunohistochemical analysis of estrogen receptor alpha (ERα), estrogen receptor beta , and androgen receptor was performed on surgical specimens from 43 patients. RESULTS: The median age of participants was 75 years. Of the 82 patients, 48 (58.5%) were classified as frail or pre-frail, and 22 (26.8%) exhibited motor impairment. Advanced POP (stages 3 and 4) was seen in 41 patients. These patients had more motor function impairments (advanced, 16; mild, 6; p = 0.01). Patients with advanced POP had poorer P-QOL, ICIQ-SF (median: 9.5 vs 4, p = 0.006) and OABSS (7 vs 4, p = 0.008) scores, and smaller pubococcygeus muscle diameter (2.5 vs 3 cm, p = 0.017). Postoperatively, significant improvements were seen in P-QOL (all domains except personal relationships: p < 0.001), total IPSS (11 vs 4, p < 0.001), OABSS (6 vs 5, p = 0.033), and ICIQ-SF scores (6 vs 2, p < 0.001). ERα expression was associated with preoperative frailty (r = -0.37, p = 0.014). CONCLUSIONS: Advanced POP correlates with poorer QOL, worse urinary symptoms, and reduced pubococcygeus muscle diameter, consistent with sarcopenia, compared with mild POP.

Oncologic and Functional Outcomes of Salvage Robot-Assisted Radical Prostatectomy: Report of the First 10 Cases.

BACKGROUND: Salvage robot-assisted radical prostatectomy (sRARP) after PSA failure in patients who underwent initial radiotherapy or focal therapy has rarely been reported in Japan. We aimed to report the oncologic and functional outcomes of the first 10 cases of sRARP. METHODS: Ten patients underwent sRARP after failing to respond to initial radiotherapy or focal therapy. Initial definitive treatment included volumetric modulated arc therapy, intensity-modulated radio therapy, stereotactic body radiotherapy, heavy-ion radiotherapy, low-dose-rate brachytherapy, and high-intensity focused ultrasound. We retrospectively investigated 10 cases on oncologic and functional outcomes of sRARP. RESULTS: The median PSA level at sRARP, amount of blood loss, and console time were 2.17 ng/mL, 100 mL, and 136 min, respectively. Positive surgical margins were found in half of the cases. Median follow-up was 1.1 years. There were no 30-day major complications. No patients had erections after sRARP. Urinary continence and biochemical recurrence (BCR) rate were 40% and 30% at 1 year after sRARP, respectively. CONCLUSIONS: Salvage RARP may be a feasible option after PSA failure in patients who underwent radiotherapy or focal therapy as initial treatment, showing acceptable BCR rate.

Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor.

BACKGROUND: Prostate cancer is dependent on androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) has proven effective in targeting prostate cancer. However, castration-resistant prostate cancer (CRPC) eventually emerges. AR signaling inhibitors (ARSI) have been also used, but resistance to these agents develops due to genetic AR alterations and epigenetic dysregulation. METHODS: In this study, we investigated the role of OCT1, a member of the OCT family, in an AR-positive CRPC patient-derived xenograft established from a patient with resistance to ARSI and chemotherapy. We conducted a genome-wide analysis chromatin immunoprecipitation followed by sequencing and bioinformatic analyses using public database. RESULTS: Genome-wide analysis of OCT1 target genes in PDX 201.1 A revealed distinct OCT1 binding sites compared to treatment-naïve cells. Bioinformatic analyses revealed that OCT1-regulated genes were associated with cell migration and immune system regulation. In particular, C-terminal Binding Protein 2 (CTBP2), an OCT1/AR target gene, was correlated with poor prognosis and immunosuppressive effects in the tumor microenvironment. Metascape revealed that CTBP2 knockdown affects genes related to the immune response to bacteria. Furthermore, TISIDB analysis suggested the relationship between CTBP2 expression and immune cell infiltration in prostate cancer, suggesting that it may contribute to immune evasion in CRPC. CONCLUSIONS: Our findings shed light on the genome-wide network of OCT1 and AR in AR-positive CRPC and highlight the potential role of CTBP2 in immune response and tumor progression. Targeting CTBP2 may represent a promising therapeutic approach for aggressive AR-positive CRPC. Further validation will be required to explore novel therapeutic strategies for CRPC management.

AKR1C3-negative high-risk metastatic castration-sensitive prostate cancer has long-term response to first-line treatment with abiraterone: Four case reports.

We experienced four cases of high-risk metastatic castration-sensitive prostate cancer (mCSPC) in which first-line treatment with abiraterone showed a sustained long-term response of over 5 years. We conducted immunohistochemical staining of aldo-keto reductase family 1 member C3 (AKR1C3) expression, which associate with poor prognosis of metastatic castration-resistant prostate cancer (mCRPC), and all prostate cancer tissue from four cases showed negative. These results suggested that AKR1C3-negative high-risk mCSPC cases may respond well to first-line treatment with abiraterone. This is the first report describing association of high-risk mCSPC and negative AKR1C3.

Brain metastasis in a patient with BRCA2-mutated treatment-related neuroendocrine prostate carcinoma and long-term response to radiotherapy and Olaparib: A case report and literature review.

BACKGROUND: A new subtype of prostate cancer called treatment-related neuroendocrine prostate carcinoma (t-NEPC) was added to the revised World Health Organization classification of prostate cancer in 2022. t-NEPC cases are increasing, and there is no established standard treatment. METHODS: A 49-year-old male patient was referred to our department for dysuria. A rectal examination and a prostate biopsy revealed stony hardness and prostate adenocarcinoma, respectively. Imaging studies confirmed the presence of multiple bone and lymph node metastases. The patient was started on upfront treatment with androgen deprivation therapy and an androgen receptor signaling inhibitor, which resulted in a significant (>90%) decrease in prostate-specific antigen (PSA) levels. The patient experienced postrenal failure 6 months later, attributable to local disease progression. Concurrently, there was an elevation in neuron-specific enolase (NSE) levels and an enlargement of pelvic lymph node metastases, without PSA progression. RESULTS: Biopsy specimen for cancer genome profiling revealed deletion of BRCA 2 and PTEN, AR amplification, and the presence of the TMPRSS2-ERG fusion gene. Based on increased NSE and BRCA2 mutations, a diagnosis of t-NEPC with BRCA2 mutation was eventually made. The patient received docetaxel chemotherapy and pelvic radiotherapy. Subsequently, he was treated with olaparib. His NSE levels decreased, and he achieved a complete response (CR). However, 18 months following the olaparib administration, brain metastases appeared despite the absence of pelvic tumor relapse, and the patient's PSA levels remained low. Consequently, the patient underwent resection of the brain metastases using gamma knife and whole-brain radiotherapy but died approximately 3 months later. CONCLUSION SUBSECTIONS: Platinum-based chemotherapy is often administered for the treatment of t-NEPC, but there are few reports on the effectiveness of olaparib in patients with BRCA2 mutations. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

Exploring androgen receptor signaling pathway in prostate cancer: A path to new discoveries.

Androgen deprivation therapy has achieved significant success in treating prostate cancer through strategies centered on the androgen receptor. However, the emergence of castration-resistant prostate cancer highlights this therapy limitation, underscoring the need to elucidate the mechanisms of treatment resistance. This review aimed to focus on multifaceted resistance mechanisms, including androgen receptor overexpression, splice variants, missense mutations, the involvement of the glucocorticoid receptor, and alterations in coregulators and transcription factors, revealing their roles in castration-resistant prostate cancer progression. These mechanisms promote cell survival and proliferation, depending on the androgen receptor signaling pathway, leading to resistance to conventional therapies. Amplification and mutations in the androgen receptor gene facilitate selective adaptation in treatment-resistant cells, consequently diminishing therapeutic efficacy. Furthermore, the activation of glucocorticoid receptors and aberrant regulation of specific coregulators and transcription factors contribute to the activation of androgen receptor-independent signaling pathways, promoting cell survival and proliferation. These findings hold promise for identifying new targets for treating castration-resistant prostate cancer and developing personalized treatment strategies. The development of future therapies will hinge on precisely targeting the androgen receptor signaling pathway, necessitating a deeper understanding of the molecular targets unique to castration-resistant prostate cancer.

Rezum water vapor thermal therapy in patients with benign prostatic hyperplasia: Initial real-world data from Japan.

Benign prostatic hyperplasia (BPH) is prevalent in older men. As surgery can be high risk in this group, minimally invasive procedures are preferrable. This study aimed to assess the initial results of minimally invasive Rezum water vapor thermal therapy (WVTT) in patients with BPH. This single-center retrospective study included 25 consecutive patients with BPH who underwent WVTT between September 2022 and July 2023. Parameters including age, Charlson Comorbidity Index and Geriatric 8 (G8) scores, operative time, and number of vapor injections were evaluated. The International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score, and Core Lower Urinary Tract Symptom Score (CLSS) were used to assess symptoms before the procedure, and at 1 and 3 months after it. Urinary function indicators such as single voiding volume, maximum flow rate (MFR), and post-void residual volume were assessed at the same time points. The mean patient age was 76.0 years and the mean prostate volume was 54.8 mL. The mean G8 score was 14.4 and the Charlson Comorbidity Index score averaged 1.2. The mean operative time was 6.84 min, and included a mean of 4.8 vapor injections. Three months after WVTT, significant improvements were observed in the maximum flow rate (P = .02), post-void residual volume (P = .001), and urine volume (P < .001), as well as in the IPSS incomplete emptying (P = .01) and weak stream (P = .01) domains. No significant changes were observed in the remaining IPSS domains or in the Overactive Bladder Symptom Score or CLSS. This study provides the first report on Rezum WVTT outcomes in Japan using the CLSS assessment tool. The initial results indicate a promising experience with this new treatment method. With a rapidly aging population, the incidence of BPH is expected to increase, making the minimally invasive Rezum system a valuable addition to BPH treatment options.

Initial experience with prostatic urethral lift versus enucleation of the prostate: a retrospective comparative study.

BACKGROUND: This study aimed to assess initial results and patient characteristics of prostatic urethral lift (PUL) compared with those of bipolar transurethral enucleation of the prostate (TUEB) in the treatment of benign prostatic hyperplasia (BPH) in older patients. METHODS: This retrospective study was conducted at a single institution and involved 25 consecutive patients with BPH who underwent PUL between April 2022 and May 2023. Patient characteristics, operative details, and pre- and postoperative symptom scores were evaluated. The results were compared with those of a previously reported TUEB group (n = 55). RESULTS: The mean age of the patients in the PUL group was 74.6 years, and the mean prostate volume was 47.5 ml. The PUL procedure significantly improved urinary symptoms, particularly incomplete emptying (p = 0.041), intermittency (p = 0.005), and weak stream (p = 0.001). The PUL group had higher comorbidity scores (p = 0.048) and included older patients (p = 0.002) than the TUEB group. TUEB showed better improvements in some symptoms and maximum flow rate (p = 0.01) than PUL; however, PUL had a shorter operative time and fewer complications than TUEB (p < 0.001). CONCLUSION: The initial results demonstrate the efficacy and safety of PUL in older patients with BPH. Despite TUEB showing better outcomes in certain aspects than PUL, PUL offers advantages such as shorter operative time and fewer complications. Therefore, PUL can be considered a viable option for high-risk older patients with BPH.

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study.

OBJECTIVE: Enfortumab vedotin (EV) was approved for advanced urothelial carcinoma (UC) in 2021 after the EV-301 trial showed its superiority to non-platinum-based chemotherapy as later-line treatment after platinum-based chemotherapy and immune checkpoint inhibitors including pembrolizumab. However, no study has compared EV with rechallenging platinum-based chemotherapy (i.e., "platinum rechallenge") in that setting. METHODS: In total, 283 patients received pembrolizumab for advanced UC after platinum-based chemotherapy between 2018 and 2023. Of them, 41 and 25 patients received EV and platinum rechallenge, respectively, as later-line treatment after pembrolizumab. After excluding two patients with EV without imaging evaluation, we compared oncological outcomes, including progression-free survival (PFS) and overall survival (OS), between the EV (n = 39) and platinum rechallenge groups (n = 25) using propensity score matching (PSM). RESULTS: Analyses on crude data (n = 64) showed no significant differences between the two groups regarding patients' baseline characteristics. PFS (5 months) and OS (11 months) in the EV group were comparable to those (8 and 12 months, respectively) in the platinum rechallenge group. After PSM (n = 36), the baseline characteristics between the two groups became more balanced, and PFS (not reached) and OS (not reached) in the EV group were comparable to those (8 and 11 months, respectively) in the platinum rechallenge group. CONCLUSIONS: EV and platinum rechallenge showed equivalent oncological outcomes, even after PSM, and both treatments should therefore be effective treatment options for post-platinum, post-pembrolizumab advanced UC.

Validation of a drug-based score in advanced urothelial carcinoma treated with pembrolizumab.

Aim: To validate a 'drug score' that stratifies patients receiving immunotherapy based on concomitant medications (antibiotics/proton pump inhibitors/corticosteroids) in urothelial carcinoma (UC). Materials & methods: We assessed oncological outcomes according to the drug score in 242 patients with advanced UC treated with pembrolizumab. Results: The drug score classified patients into three risk groups with significantly different survivals. Heterogeneous treatment effect analyses showed that the primary cancer site (bladder UC [BUC] or upper-tract UC [UTUC]) significantly affected the prognostic capability of the drug score; it significantly correlated with survivals in BUC, while there were no such correlations in UTUC. Conclusion: A drug score was examined in advanced UC treated with pembrolizumab and was validated in BUC but not in UTUC.

Drug treatment for cancer may be weakened by other drugs. We checked whether some kinds of drugs really weakened the effect of drug treatment for cancer. We found that it was true for some kinds of cancer but not for other kinds.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer.

OBJECTIVE: To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. METHODS: For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. RESULTS: Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. CONCLUSION: Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

Clinical characteristics of patients with metastatic castration-resistant prostate cancer after treatment with combined androgen blockade.

BACKGROUND: Although the second-generation androgen receptor inhibitors and taxanes have recently been recommended for the initial treatment of metastatic prostate cancer, bicalutamide and flutamide are still used in a large number of cases. Therefore, it is important to elucidate the clinical characteristics of these treated CRPC cases and their sensitivity to the currently used therapeutic agents. We aimed to examine the outcomes of metastatic castration-resistant prostate cancer following combined androgen blockade as initial therapy at our institution. METHODS: Ninety-four patients who developed metastatic castration-resistant prostate cancer after hormonal treatment with combined nonsteroidal androgen receptor antagonists and continuous androgen deprivation therapy between January 2015 and December 2020 were included. The presence of visceral metastases, duration of efficacy of each treatment, and overall survival after castration-resistant prostate cancer were evaluated. RESULTS: Patients with a longer duration of castration-resistant prostate cancer tended to have a longer response duration to subsequent enzalutamide administration (p = 0.003). Patients who achieved a 90% reduction in prostate-specific antigen levels with enzalutamide had a significantly better castration-resistant prostate cancer prognosis (p = 0.002). Meanwhile, those with visceral metastases at the time of castration-resistant prostate cancer diagnosis had a significantly poorer prognosis (p < 0.001). A positive correlation was observed between the treatment efficacy of abiraterone and taxanes for castration-resistant prostate cancer. CONCLUSION: The study provides scientific evidence to support that patients with longer time to castration-resistant prostate cancer are more sensitive to enzalutamide, and the use of abiraterone between docetaxel and cabazitaxel has favorable prognostic impact. These findings provide instrumental evidence that can enable better treatment selection for prostate cancer patients.

Characteristics of prostate biopsy in patients under the dutasteride treatment.

We performed a retrospective study to clarify the characteristics of prostate biopsies in patients treated with dutasteride, a benign prostate hyperplasia treatment drug that inhibits 5α-reductase. We studied the digital clinical data of 677 patients, including 96 cases treated with dutasteride, with suspected localized prostate cancer. All patients underwent transrectal ultrasonography-guided prostate biopsy between 2014 and 2017 in our department. A propensity score matching analysis was performed based on prostate-specific antigen (PSA) (calculated as double the PSA value for the dutasteride group) and age. Ninety-six patients in each of the dutasteride and control groups were assessed and their characteristics were compared. The characteristics of the patients in the dutasteride and control groups were well balanced by matching. There were fewer prostate cancer-positive patients in the dutasteride group. When comparing only the prostate cancer-positive patients in each group, there were significantly more cases of high-grade cancers and abnormal magnetic resonance imaging (MRI) findings in the dutasteride group. In the dutasteride group, abnormal MRI findings and advanced age were significant predictors of high grade cancer. This study shows the characteristics of prostate biopsies in patients treated with dutasteride and indicates that patients on dutasteride with advanced age and abnormal MRI findings should undergo prostate biopsy.

Real-world efficacy of sequential nivolumab for metastatic renal cancer after first-line molecular targeting therapy.

This study aimed to clarify the real-world efficacy of sequential nivolumab for treating metastatic renal cancer after first-line molecular targeting therapy. Patients were divided into two groups (2014-2016 and 2017-2020) according to the year when they started primary treatment with molecular targeted drugs (MTDs). We compared the overall survival of patients and investigated a contributing factor for survival. The mean duration of overall survival was significantly longer in the 2017-2020 group (44.0 months) than in the 2014-2016 group (8.5 months). Univariate analysis showed that nivolumab treatment was a significant prognostic factor (P = .0021). Patients treated with nivolumab as second-line therapy had a significantly higher 5-year survival rate compared to that of other patients (70% vs 32%). In addition, the time from commencement of MTDs to switch to nivolumab was significantly shorter in the 2017-2020 group compared to the 2014-2016 group (8.94 vs 34.12 months, P = .03). In our study, cases with first-line MTDs had markedly prolonged outcomes after the 2017 guideline update, and sequential nivolumab with prompt switching to nivolumab was an important factor.

Improved survival in real-world patients with advanced urothelial carcinoma: A multicenter propensity score-matched cohort study comparing a period before the introduction of pembrolizumab (2003-2011) and a more recent period (2016-2020).

OBJECTIVES: Although the treatment strategy for advanced urothelial carcinoma (aUC) has drastically changed since pembrolizumab was introduced in 2017, studies revealing current survival rates in aUC are lacking. This study aimed to assess (1) the improvement in survival among real-world patients with aUC after the introduction of pembrolizumab and (2) the direct survival-prolonging effect of pembrolizumab. METHODS: This multicenter retrospective study included 531 patients with aUC undergoing salvage chemotherapy, including 200 patients treated in the pre-pembrolizumab era (2003-2011; earlier era) and 331 patients treated in a recent 5-year period (2016-2020; recent era). Using propensity score matching (PSM), cancer-specific survival (CSS) and overall survival (OS) were compared between the earlier and recent eras, in addition to between the recent era, both with and without pembrolizumab use, and the earlier era. RESULTS: After PSM, the recent era cohort had significantly longer CSS (21 months) and OS (19 months) than the earlier era cohort (CSS and OS: 12 months). In secondary analyses using PSM, patients treated with pembrolizumab had significantly longer CSS (25 months) and OS (24 months) than those in the earlier era cohort (CSS and OS: 11 months), whereas patients who did not receive pembrolizumab in the recent era had similar outcomes (CSS and OS: 14 months) as the earlier era cohort (CSS and OS: 12 months). CONCLUSIONS: Patients with aUC treated in the recent era exhibited significantly longer survival than those treated before the introduction of pembrolizumab. The improved survival was primarily attributable to the use of pembrolizumab.

Antitumor effects of pyrrole-imidazole polyamide modified with alkylating agent on prostate cancer cells.

Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.

Tension-free vaginal mesh for patients with pelvic organ prolapse: mid-term functional outcomes.

OBJECTIVE: We aimed to evaluate the mid-term efficacy of tension-free vaginal mesh (TVM) for pelvic organ prolapse (POP), and observe the time course of lower urinary tract symptoms and sexual function. METHODS: In this retrospective study, we included 112 female patients who underwent TVM at a single center for stage 2 or higher POP, and replied to questionnaires before, and 2 and 4 years after TVM. We evaluated the anatomical cure rate, prolapse quality of life questionnaire scores, international prostate symptom scores, International Consultation on Incontinence Questionnaire-Short Form scores, and Female Sexual Function Index scores. RESULTS: The anatomical cure rate at 4 years was 89%. Voiding and storage symptoms improved in patients after TVM. We found that 25/112 patients had sexual intercourse before TVM, and among them, 15/25 (60%) continued sexual intercourse after TVM. Additionally, of the 87 patients who had no sexual intercourse before TVM, 13 resumed sexual intercourse after TVM. CONCLUSION: Cases of TVM have decreased because of the Food and Drug Administration statements concerning mesh problems. However, this study showed relatively favorable mid-term results for lower urinary tract symptoms. Furthermore, sexual activity was restored in some patients, indicating the efficacy of TVM for sexual function.

OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer.

Androgen and androgen receptor (AR) targeted therapies are the main treatment for most prostate cancer (PC) patients. Although AR signaling inhibitors are effective, tumors can evade this treatment by transforming to an AR-negative PC via lineage plasticity. OCT1 is a transcription factor interacting with the AR to enhance signaling pathways involved in PC progression, but its role in the emergence of the AR-negative PC is unknown. We performed chromatin immunoprecipitation sequencing (ChIP-seq) in patient-derived castration-resistant AR-negative PC cells to identify genes that are regulated by OCT1. Interestingly, a group of genes associated with neural precursor cell proliferation was significantly enriched. Then, we focused on neural genes STNB1 and PFN2 as OCT1-targets among them. Immunohistochemistry revealed that both STNB1 and PFN2 are highly expressed in human AR-negative PC tissues. Knockdown of SNTB1 and PFN2 by siRNAs significantly inhibited migration of AR-negative PC cells. Notably, knockdown of PFN2 showed a marked inhibitory effect on tumor growth in vivo. Thus, we identified OCT1-target genes in AR-negative PC using a patient-derived model, clinicopathologial analysis and an animal model.

Urethral injection of dedifferentiated fat cells ameliorates sphincter damage and voiding dysfunction in a rat model of persistence stress urinary incontinence.

PURPOSE: Dedifferentiated fat (DFAT) cells are mature adipocyte-derived multipotent cells that can be applicable to cell-based therapy for stress urinary incontinence (SUI). This study developed a persistence SUI model that allows long-term evaluation using a combination of vaginal distention (VD) and bilateral ovariectomy (OVX) in rats. Then, the therapeutic effects of DFAT cell transplantation in the persistence SUI model was examined. METHODS: In total, 48 Sprague-Dawley rats were divided into four groups and underwent VD (VD group), bilateral OVX (OVX group), VD and bilateral OVX (VD + OVX group), or sham operation (Control group). At 2, 4, and 6 weeks after injury, leak point pressure (LPP) and histological changes of the urethral sphincter were evaluated. Next, 14 rats undergoing VD and bilateral OVX were divided into two groups and administered urethral injection of DFAT cells (DFAT group) or fibroblasts (Fibroblast group). At 6 weeks after the injection, LPP and histology of the urethral sphincter were evaluated. RESULTS: The VD + OVX group retained a decrease in LPP with sphincter muscle atrophy at least until 6 weeks after injury. The LPP and urethral sphincter muscle atrophy in the DFAT group recovered better than those in the fibroblast group. CONCLUSIONS: The persistence SUI model was created by a combination of VD and bilateral OVX in rats. Urethral injection of DFAT cells inhibited sphincter muscle atrophy and improved LPP in the persistence SUI model. These findings suggest that the DFAT cells may be an attractive cell source for cell-based therapy to treat SUI.

Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis.

BACKGROUND: Several studies have reported the incidence of immune-related adverse events (irAEs) as a predictor of the efficacy of anti-programmed cell death protein 1 antibodies in patients with cancer. However, immortal time bias has not always been fully addressed in these studies. In this retrospective multicenter study, we assessed the association between the incidence of irAEs and the efficacy of pembrolizumab in urothelial carcinoma (UC) using time-dependent analysis, an established statistical method to minimize immortal time bias. METHODS: The study included 176 patients with advanced UC who underwent pembrolizumab treatment at seven affiliated institutions between January 2018 and July 2020. Patients with irAEs were compared with those without irAEs in terms of overall survival (OS) and cancer-specific survival (CSS). Immortal time bias was eliminated by using time-dependent analysis. RESULTS: Of the 176 patients, irAEs occurred in 77 patients (43.8%), with a median of 60 days. The irAEs (+) cohort showed significantly favorable OS and CSS compared with the irAEs (-) cohort (p=0.018 and p=0.005, respectively), especially in the cohort with grade 1-2 irAEs (OS and CSS; p=0.003 and p=0.002, respectively). Multivariate analyses identified any irAEs and grade 1-2 irAEs as independent favorable prognostic factors for OS and CSS. CONCLUSION: Even after minimizing immortal time bias by time-dependent analysis, the incidence of irAEs, especially grade 1-2 irAEs, could be a significant predictor of favorable prognoses in patients with UC who have undergone pembrolizumab treatment.