Latrophilin-3 as a downstream effector of the androgen receptor induces urothelial tumorigenesis.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.

Intravenously engrafted human multilineage-differentiating stress-enduring (Muse) cells rescue erectile function after rat cavernous nerve injury.

OBJECTIVE: To evaluate the effect of intravenous administration of human multilineage-differentiating stress-enduring (Muse) cells on rat postoperative erectile dysfunction (ED) with cavernous nerve (CN) injury without an immunosuppressant. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomised into three groups after CN crush injury. Either human-Muse cells, non-Muse mesenchymal stem cells (MSCs) (both 1.0 × 105 cells), or vehicle was infused intravenously at 3 h after CN injury without immunosuppressant. Erectile function was assessed by measuring intracavernous pressure (ICP) and arterial pressure (AP) during pelvic nerve electrostimulation 28 days after surgery. At 48 h and 28 days after intravenous infusion of Muse cells, the homing of Muse cells and non-Muse MSCs was evaluated in the major pelvic ganglion (MPG) after CN injury. In addition, expressions of C-X-C motif chemokine ligand (Cxcl12) and glial cell line-derived neurotrophic factor (Gdnf) in the MPG were examined by real-time polymerase chain reaction. Statistical analyses and comparisons among groups were performed using one-way analysis of variance followed by the Tukey test for parametric data and Kruskal-Wallis test followed by the Dunn-Bonferroni test for non-parametric data. RESULTS: The mean (SEM) ICP/AP values at 28 days were 0.51 (0.02) in the Muse cell group, 0.37 (0.03) in the non-Muse MSC group, and 0.36 (0.04) in the vehicle group, showing a significant positive response in the Muse cell group compared with the non-Muse and vehicle groups (P = 0.013 and P = 0.010, respectively). In the MPG, Muse cells were observed to be engrafted at 48 h and expressed Schwann cell markers S100 (~46%) and glial fibrillary acidic protein (~24%) at 28 days, while non-Muse MSCs were basically not engrafted at 48 h. Higher gene expression of Cxcl12 (P = 0.048) and Gdnf (P = 0.040) was found in the MPG of the Muse group than in the vehicle group 48 h after infusion. CONCLUSION: Intravenously engrafted human Muse cells recovered rat erectile function after CN injury in a rat model possibly by upregulating Cxcl12 and Gdnf.

Impact of cancer therapy on post-treatment ejaculation disorder and sexual life in testicular cancer survivors.

OBJECTIVE: To evaluate the impact of cancer therapy on post-treatment ejaculation in patients with testicular cancer. METHODS: A total of 74 testicular cancer survivors provided completed International Index of Erectile Function-15 questionnaires before and after treatment between 2010 and 2017. Sexual function, particularly ejaculatory function, was evaluated before and after treatment. In this study, patients who answered "1 = almost never/never" or "2 = a few times" for questionnaire number 9 (ejaculation frequency) were defined as having "ejaculation disorder." RESULTS: Of 74 testicular cancer survivors, 50 (68%) had no ejaculation disorders before treatment. Four (44%) of nine survivors, who received chemotherapy and retroperitoneal lymph node dissection, developed ejaculation disorders after treatment. On multivariate analysis, retroperitoneal lymph node dissection was a significant predictor of post-treatment ejaculation disorder (P = 0.042). Of 60 survivors with evaluable ejaculation function after treatment, 24 (40%) did not attempt sexual intercourse, and multivariate analysis showed ejaculation disorder had a significant negative impact on having sexual intercourse (P = 0.035). Furthermore, the mean International Index of Erectile Function-15 scores in the groups with and without ejaculation disorders after treatment were 24.0 and 51.9, respectively (P < 0.001). CONCLUSION: Ejaculation disorders occur at high rate after retroperitoneal lymph node dissection. Many testicular cancer survivors reporting no sexual intercourse have ejaculation disorders, suggesting an adverse impact on sexual life. Urologists should provide proper counselling regarding the risk of ejaculation disorder and its possible impact on sexual life.

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer.

The underlying molecular mechanisms of resistance to cisplatin-based systemic chemotherapy in bladder cancer patients remain to be elucidated, while the link between androgen receptor (AR) activity and chemosensitivity in urothelial cancer has been implicated. Our DNA microarray analysis in control vs. AR knockdown bladder cancer lines identified GULP1 as a potential target of AR signaling. We herein determined the relationship between AR activity and GULP1 expression in bladder cancer cells and then assessed the functional role of GULP1 in cisplatin sensitivity. Androgen treatment in AR-positive cells or AR overexpression in AR-negative cells considerably reduced the levels of GULP1 expression. Chromatin immunoprecipitation further showed direct interaction of AR with the promoter region of GULP1. Meanwhile, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment compared with respective controls. GULP1 knockdown also resulted in a significant decrease in apoptosis, as well as a significant increase in G2/M phases, when treated with cisplatin. In addition, GULP1 was immunoreactive in 74% of muscle-invasive bladder cancers from patients who had subsequently undergone neoadjuvant chemotherapy, including 53% of responders showing moderate (2+)/strong (3+) expression vs. 23% of non-responders showing 2+/3+ expression (P = 0.044). These findings indicate that GULP1 represents a key downstream effector of AR signaling in enhancing sensitivity to cisplatin treatment.

FOXO1 inactivation induces cisplatin resistance in bladder cancer.

We found that FOXO1-shRNA sublines or FOXO1-positive cells co-treated with a FOXO1 inhibitor were significantly more resistant to cisplatin treatment at pharmacological concentrations, compared with respective control sublines or those with mock treatment. Western blot demonstrated considerable increases in the expression levels of a phosphorylated inactive form of FOXO1 (p-FOXO1) in cisplatin-resistant sublines established by long-term culture with low/increasing doses of cisplatin, compared with respective controls. Immunohistochemistry in surgical specimens from patients with muscle-invasive bladder cancer undergoing cisplatin-based neoadjuvant therapy further showed a strong trend to associate between p-FOXO1 positivity and unfavorable response to chemotherapy.

Trends in Age and Histology of Testicular Cancer from 1980-2019: A Single-Center Study.

Testicular cancer occurs in the testes of the male reproductive system and is the most common cancer in adolescent and young adult (AYA) men. However, recently, there have been more cases of testicular cancer in men older than 40 years. Therefore, trends of testicular cancer during the past 40 years were retrospectively examined, focusing on age and histology. Patients who were diagnosed with testicular cancer at our institution between 1980 and 2019 were enrolled in this study. The patients were divided into groups by the year of diagnosis (1980s, 1990s, 2000s, and 2010s), age at diagnosis (14, 15 to 39, and older than 40 years), and histological type (seminoma and non-seminoma). A total of 563 patients were diagnosed with testicular cancer over the 40-year period. The median age at diagnosis increased continuously, from 28 years to 31 years, 34 years, and 38 years in each period, respectively (p < 0.001). Moreover, most testicular cancer patients were of the AYA generation, whereas the ratio of patients older than 40 years increased significantly since 2000 (p < 0.001). The relative proportion of seminoma also increased more than 50% since 2000. In the seminoma group, median age increased from 31 years to 41 years during the 40-year period (p < 0.001). In conclusion, the age at diagnosis is rising for testicular cancer patients. Clinicians should recognize that testicular cancer affects not only the AYA generation, but there has been a shift to older than 40 years, especially in seminoma.

Phosphodiesterase type 5 inhibitor attenuates chronic ischemia-induced prostatic hyperplasia in a rat model.

BACKGROUND: Many elderly men suffer from benign prostatic hyperplasia (BPH). Recently, chronic ischemia in the prostate has been suggested to be related to BPH. Thus, the impact of chronic ischemia on the development of prostatic hyperplasia and the efficacy of phosphodiesterase type 5 (PDE5) inhibitor for hyperplasia were evaluated in a rat model with chronic ischemia induced by local atherosclerosis. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups: sham operation, regular diet, placebo (SRP); arterial endothelial injury, high cholesterol diet, placebo (AHP); or arterial endothelial injury, high cholesterol diet, and tadalafil as a PDE5 inhibitor (AHT). The endothelial injury in the common iliac arteries was performed using a 2-Fr Fogarty arterial embolectomy catheter through an incision in the femoral artery into the common iliac artery. Diet and oral drugs were administrated for 8 weeks after surgery. At 8 weeks, blood flow to the ventral prostate (VP) was measured using laser speckle blood flow analysis, and the VP was histologically evaluated. RESULTS: In the AHP group, prostatic blood flow was reduced, and mean VP weight and the interstitial area were significantly enlarged compared with the SRP group. In the AHT group, tadalafil administration obviously ameliorated the reduction of prostatic blood flow relative to the AHP group. Importantly, mean VP weight and the morphological changes in the AHT group were significantly smaller than those in the AHP group. CONCLUSIONS: Enlargement of the VP resulted from chronic ischemia induced by local arteriosclerosis. Also, administration of tadalafil attenuated VP enlargement. Chronic ischemia in the prostate might thus contribute to the development of BPH, and PDE5 inhibitors might provide an innovative approach to preventing BPH.

The impact of perivesical lymph node metastasis on clinical outcomes of bladder cancer patients undergoing radical cystectomy.

BACKGROUND: Perivesical lymph nodes (PVLNs) are occasionally isolated during grossing of cystectomy specimens. However, the prognostic implications of the involvement of PVLNs in bladder cancer patients, especially those with comparisons to pN0 disease, remain poorly understood. METHODS: A retrospective review identified 115 radical cystectomy cases where PVLNs had been histologically assessed. These cases were then divided into 4 groups - Group 1 (n = 76): PVLN-negative/other pelvic lymph node (non-PVLN)-negative; Group 2 (n = 5): PVLN-positive/non-PVLN-negative; Group 3 (n = 17): PVLN-negative/non-PVLN-positive; and Group 4 (n = 17): PVLN-positive/non-PVLN-positive. RESULTS: pT stage at cystectomy was significantly higher in Group 3 (P = 0.013), Group 4 (P < 0.001), Groups 2 and 4 (P < 0.001), or Groups 2-4 (P < 0.001) than in Group 1. However, the number of positive PVLNs (mean: 1.8 vs. 2.1; P = 0.718) or the rate of extracapsular extension in the PVLNs (40% vs. 65%, P = 0.609) was not significantly different between Group 2 and Group 4. Kaplan-Meier analysis and log-rank test revealed significantly (P < 0.05) higher risks of disease progression (Group 3/Group 4), cancer-specific mortality (Group 2/Group 3/Group 4), and overall mortality (Group 4), compared with Group 1. Multivariate analysis further showed metastasis to both PVLN and non-PVLN (Group 4), PVLN (Groups 2 and 4), or PVLN and/or non-PVLN (Groups 2-4) as an independent prognosticator for cancer-specific mortality and overall survival. There were also insignificant (P = 0.096) and significant (P = 0.036) differences in cancer-specific survival and overall survival, respectively, between Group 3 versus Group 4, and the trend of the latter was confirmed by subset multivariate analysis (hazard ratio = 3.769; P = 0.099). CONCLUSIONS: Worse prognosis was observed in bladder cancer patients with isolated PVLN metastasis (vs. pN0 disease especially for cancer-specific survival), PVLN metastasis with or without non-PVLN metastasis (vs. pN0 disease), and concurrent PVLN and non-PVLN metastases (vs. PVLN-negative/non-PVLN-positive disease especially for overall survival). These findings indicate the importance of thorough histopathological assessment of PVLNs in radical cystectomy specimens.

Evaluating estimated glomerular filtration rates of creatinine and cystatin C for male patients with chronic spinal cord injury.

STUDY DESIGN: Retrospective study OBJECTIVES: To compare the accuracy of estimated serum creatinine (Cre)-based glomerular filtration rates (eGFRcre) and serum cystatin C (CysC)-based eGFR (eGFRcys) for determining renal function in patients with spinal cord injury (SCI). SETTING: Department of Urology, Tohoku Rosai Hospital, Japan METHODS: Male patients with SCI for longer than 5 years after injury were eligible for inclusion in this study. eGFRcre and eGFRcys were calculated using the following formulas: eGFRcre = 194 × Cre-1.094 × age-0.287; eGFRcys = (104 × CysC-0.1019 × 0.996age) - 8. The eGFRcre/eGFRcys ratio between 0.8 and 1.2 was considered to be equal, and a relationship between them was investigated. Demographic data, degree of spinal cord damage, management of bladder emptying, post-injury period, and ambulatory status were evaluated. RESULTS: A total of 115 male patients were included. eGFRcre overestimated renal function in 87 (76%) patients with SCI compared with eGFRcys. On univariate analysis, renal function by eGFRcre was overestimated in patients with an eGFRcre of more than 60 ml min-1 per 1.73 m2 (P < 0.001), in non-ambulatory patients (P < 0.001) and, in patients with complete paralysis (P < 0.001). On multivariate analysis, an eGFRcre of more than 60 ml min-1 per 1.73 m2 (P < 0.001), non-ambulatory status (P < 0.001), complete paralysis (P = 0.17), and age (P < 0.001) were independent factors for overestimated renal function by eGFRcre. CONCLUSIONS: eGFRcre overestimates renal function compared with eGFRcys. eGFRcys is beneficial, particularly in patients with an eGFRcre of more than 60 ml min-1 per 1.73 m2, in non-ambulatory patients, and in older patients with SCI.

[Availability of Local Therapy to Castration-Resistant Prostate Cancer for M0 Patients with Initial Prostate Specific Antigen 100 ng/ml or Higher].

Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.

[A CASE OF PRIMITIVE NEUROECTODERMAL TUMOR OF THE TESTIS].

A 44-year-old man discovered a swollen right testis more than 4 years earlier. He was brought to our hospital because of abdominal pain and vomiting. Enhanced computed tomography (CT) showed a swollen right testis, lung nodules, and swollen retroperitoneal and mediastinal lymph nodes. The swollen lymph nodes compressed the duodenum, causing ileus. HCG, HCG-ß, and AFP levels were normal, but the LDH level was high (2,933 IU/L). A diagnosis of testicular cancer with lung and lymph node metastases was made, and a right orchidectomy was performed. However, the pathological diagnosis was unclear, and it was necessary to consult another pathologist, but this took .6 weeks. While awaiting the pathological diagnosis, the patient was given chemotherapy with two 3-week courses of BEP. On pathological examination, the tumor consisted of small round cells with a rosette-like arrangement. Cartilage and keratinized tissues were also present. Immunohistochemical staining was positive for CD56, synaptophysin, vimentin, GFAP, and CD99 (MIC2), but negative for AE1/AE3, OCT-4, chromogranin, INI-1, and desmin. The patient was then diagnosed as having a primitive neuroectodermal tumor and teratoma. The metastatic lymph nodes decreased in size after chemotherapy; therefore, two further courses of BEP were added. However, CT showed disease progression. The patient refused further therapy and returned home. Eight months later, he was hospitalized because of swollen retroperitoneal and mediastinal lymph nodes and ileus. Despite treatment with radiation therapy, which resulted in decreased lymph nodes, the patient died. This was a very rare case, the first such case in Japan.

Mineralocorticoid receptor signaling inhibits bladder cancer progression.

The biological or clinical significance of mineralocorticoid receptor (MR) in urothelial cancer remains largely unknown. The present study aimed to determine the functional role of MR in bladder cancer progression. In two of the human bladder cancer lines expressing MR, treatment with a natural MR ligand, aldosterone, significantly reduced cell proliferation and migration, which was restored by three MR antagonists clinically used, spironolactone (except colony formation of androgen receptor-positive cells cultured in the presence of androgens), eplerenone, and esaxerenone. Similarly, MR knockdown via shRNA virus infection resulted in significant increases in cell viability/migration, as well as colony formation, compared with control sublines. In addition, MR knockdown augmented the expression of ß-catenin, c-fos, and N-cadherin, and lowered that of E-cadherin and p53, indicating the induction of the cadherin switching. Immunohistochemistry in surgical specimens detected MR signals in 58 (92.1%; 36.5% weakly-positive/1+, 44.4% moderately-positive/2+, and 11.1% strongly-positive/3+) of 63 muscle-invasive bladder cancers, which was significantly lower than in adjacent non-neoplastic urothelial tissues (100%; 15.7% 1+, 37.3% 2+, and 47.1% 3+). Moreover, patients with MR-high (3+) tumor had a significantly lower risk of cancer-specific mortality (P=0.039). Multivariable analysis further showed that strong MR expression was an independent predictor of cancer-specific survival in patients with muscle-invasive bladder cancer (hazard ratio 0.117, P=0.039). These findings suggest that MR signaling functions as a tumor suppressor in urothelial carcinoma and prevents tumor growth. Accordingly, there is a possibility that the concurrent use of anti-mineralocorticoids, particularly eplerenone and esaxerenone, in patients with bladder cancer rather contributes to the promotion of disease progression.

The Clinical Impact of Comedonecrosis Within Intraductal Carcinoma of the Prostate.

CONTEXT.­: Intraductal carcinoma of the prostate (IDC-P) is considered a distinct form of aggressive prostate cancer where comedonecrosis, a grade 5 pattern, is occasionally present. Meanwhile, assigning a Gleason grade to IDC-P remains controversial. OBJECTIVE.­: To assess the clinical significance of necrosis associated with IDC-P. DESIGN.­: We compared radical prostatectomy (RP) findings and oncologic outcomes in men with prostate cancer exhibiting IDC-P with (IDC-P+/N+) versus without (IDC-P+/N-) comedonecrosis. RESULTS.­: Of the 558 RPs examined, IDC-P was present in 213 cases (38.2%), including 167 (78.4%) with IDC-P+/N- and 46 (21.6%) with IDC-P+/N+. When comparing IDC-P+/N- versus IDC-P+/N+ cases, the presence of necrosis was significantly associated with higher tumor grade, higher incidence of pT3/pT3b or pN1 disease, and larger estimated tumor volume. Outcome analysis revealed a significantly higher risk of disease progression in IDC-P+/N+ patients than in IDC-P+/N- patients (P < .001). Significant differences in progression-free survival between IDC-P+/N- and IDC-P+/N+ patients were also seen in subgroups, such as those without (P = .01) or with (P = .03) adjuvant therapy immediately after RP, those with pN0 disease (P < .001), and, more interestingly, those exhibiting conventional Gleason pattern 5 component (P = .02). Multivariate analysis showed significance for IDC-P+/N+ when IDC-P (grade 4) and IDC-P+/N+ (grade 5) were (hazard ratio, 1.768; P = .049) or were not (hazard ratio, 2.000; P = .008) incorporated into the Gleason score. CONCLUSIONS.­: IDC-P+/N+ was found to be associated with worse histopathologic features on RP and poorer prognosis as an independent predictor. Pathologists may thus need to report the presence or absence of not only IDC-P but also comedonecrosis within IDC-P.

Protective role of mineralocorticoid receptor signaling in urothelial tumorigenesis.

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The in vitro system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of ß-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (P<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (P=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (P=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.

A case of testicular cancer with retroperitoneal lymph node metastasis of teratoma with somatic-type malignancy 18 years after initial treatment.

Introduction: In testicular cancer, late relapse of teratoma with somatic-type malignancy is rare and associated with a poor survival. A case of retroperitoneal lymph node metastasis of teratoma with somatic-type malignancy 18 years after initial treatment for testicular cancer is reported. Case presentation: A 46-year-old man had a 15-mm-sized mass in the para-aortic region 18 years after initial treatment for testicular cancer, without elevated serum alfa-fetoprotein or human chorionic gonadotropin levels. Laparoscopic retroperitoneal lymph node dissection was performed. The pathological findings showed teratoma with somatic-type malignancy, and the findings of primary testicular cancer reported a yolk sac tumor, not teratoma. Conclusion: Late relapse of teratoma with somatic-type malignancy was resected by laparoscopic retroperitoneal lymph node dissection. Therefore, long-term follow-up should be considered if patients with small retroperitoneal masses did not undergo retroperitoneal lymph node dissection, and early detection and surgical resection for relapse might be effective.

Association of second-hand smoke exposure, quantified by salivary cotinine, with dental caries in Japanese adolescents.

PURPOSE: Second-hand smoke has adverse effects on oral health. This cohort study used a multilevel approach to investigate the association of second-hand smoke exposure, as determined by salivary cotinine level, with dental caries in adolescents. METHODS: Data from 75 adolescents aged 11 or 12 years and 2,061 teeth without dental caries were analyzed in this study. Annual dental examinations to assess dental caries were conducted between 2018 and 2021. Salivary cotinine and Dentocult SM-Strip level were measured at baseline. Information on the smoking habits of parents, snack frequency, regular dental visits, and use of fluoride toothpaste was collected at baseline from parent-reported questionnaires. RESULTS: During the 3-year follow-up, dental caries was noted in 21 adolescents and 43 teeth. Participants exposed to parental smoking had higher salivary cotinine levels than those whose parents did not smoke. The multilevel Cox regression model showed that a high salivary cotinine level was associated with the incidence of dental caries, after adjusting for potential confounding factors (hazard ratio, 3.39; 95% confidence interval 1.08-10.69). CONCLUSION: This study suggests that the risk of dental caries is higher for adolescents who have high salivary cotinine levels attributable to second-hand smoke exposure.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Clinical significance of perineural invasion by prostate cancer on magnetic resonance imaging-targeted biopsy.

Perineural invasion (PNI) by prostate cancer detected on systematic sextant biopsy (S-Bx) has been considered as a key prognosticator. However, the clinical significance of PNI on magnetic resonance imaging-targeted biopsy (T-Bx) needs to be further investigated. We assessed 169 patients undergoing T-Bx with concurrent S-Bx, followed by radical prostatectomy (RP) from 2015 to 2019. In all cases where cancer was detected on T-Bx only (n = 34) or both S-Bx and T-Bx (B-Bx; n = 135), PNI was found in 33 (19.5%) T-Bxs. Compared with no PNI, PNI on T-Bx was associated with higher Grade Group on biopsy/RP, higher pT stage, and lymph node metastasis. Outcome analysis revealed a significant difference in the risk of biochemical recurrence after RP between cases with and without PNI on T-Bx (P = 0.021). Next, in the 135 B-Bx cases, PNI was found on S-Bx only (n = 31), T-Bx only (n = 15), or B-Bx (n = 16). Compared with PNI on S-Bx, B-Bx PNI was associated with higher preoperative prostate-specific antigen, higher biopsy GG, higher pT stage, and larger tumor volume. There were no significant differences in any of the clinicopathologic features examined between cases with PNI on T-Bx only vs. B-Bx. Moreover, in this subgroup of patients, PNI on B-Bx was associated with significantly higher risks of biochemical recurrence, compared with PNI on S-Bx only (P = 0.024) or T-Bx only (P = 0.033). In multivariate analysis, PNI on B-Bx showed significance for recurrence (hazard ratio = 2.787, P = 0.034). The presence of PNI on T-Bx, particularly B-Bx, associated with worse histopathologic features on RP and poorer outcomes might thus be useful for risk stratification.

The Clinical Impact of pT3a Lesions in Patients With pT3b Prostate Cancer Undergoing Radical Prostatectomy.

CONTEXT.­: Seminal vesicle invasion (SVI) by prostate cancer (pT3b disease) has been considered as a key prognostic factor. OBJECTIVE.­: To assess the clinical impact of T3a lesions (ie, extraprostatic extension other than bladder neck invasion [BNI] or SVI [EPE], microscopic bladder neck invasion [mBNI]) in pT3b disease. DESIGN.­: We compared radical prostatectomy findings and long-term oncologic outcomes in 248 patients with pT3b disease, with versus without EPE/mBNI. RESULTS.­: Extraprostatic extension/mBNI was found in 219 (88.3%)/48 (19.4%) cases, respectively. Extraprostatic extension was significantly associated with higher preoperative prostate-specific antigen (PSA) level, higher rates of positive surgical margin (pSM) and lymphovascular invasion (LVI), and larger tumor volume. Similarly, mBNI was significantly associated with higher PSA level, higher rates of Grade Group(s) 4-5 or 5, pSM, LVI, and pN1, and larger tumor volume. Significant differences in all of these clinicopathologic features (except lymph node metastasis) between EPE-/mBNI+ or EPE+/mBNI- and EPE+/mBNI+ cases were also observed. Outcome analysis revealed that patients with EPE (P < .001) or mBNI (P < .001) had a significantly higher risk of disease progression than respective controls. Notably, there were significant differences in progression-free survival between EPE-/mBNI+ or EPE+/mBNI- cases and EPE-/mBNI- (P = .001) or EPE+/mBNI+ (P < .001) cases. In multivariate analysis, EPE (hazard ratio [HR] = 6.53, P = .009) and mBNI (HR = 2.33, P = .003), as well as EPE-/mBNI+ or EPE+/mBNI- (HR = 11.7, P = .01) and EPE+/mBNI+ (HR = 25.9, P = .002) versus EPE-/mBNI-, showed significance for progression. CONCLUSIONS.­: From these significant findings, we propose a novel pT3b subclassification: pT3b1 (SVI alone without EPE or mBNI), pT3b2 (SVI with either EPE or mBNI), and pT3b3 (SVI with both EPE and mBNI).

The Role of Estrogen Receptors in Urothelial Cancer.

Epidemiological data have indicated that there are some sex-related differences in bladder cancer. Indeed, the incidence of bladder cancer in men has been substantially higher than that in women throughout the world, while women tend to have higher stage disease and poorer prognosis. These gender disparities have prompted to investigate sex hormones and their cognitive receptors in bladder cancer. Specifically, estrogen receptors, including estrogen receptor-α and estrogen receptor-ß, have been shown to contribute to urothelial carcinogenesis and cancer progression, as well as to modulating chemosensitivity in bladder cancer, although conflicting findings exist. Meanwhile, immunohistochemical studies in surgical specimens have assessed the expression of estrogen receptors and related proteins as well as its associations with clinicopathologic features of bladder cancer and patient outcomes. This review article summarizes and discusses available data indicating that estrogen receptor signaling plays an important role in urothelial cancer.