Yusuke Imamura

Combination of Gemcitabine and Paclitaxel as Second-line Chemotherapy for Advanced Urothelial Carcinoma

OBJECTIVE The aim of this study was to evaluate the efficacy and toxicities of the gemcitabine and paclitaxel combination regimen as second-line chemotherapy for patients with advanced or metastatic urothelial carcinoma (UC) who have previously been treated with platinum-based chemotherapy for the metastatic disease. METHODS Thirty-three patients with advanced or metastatic UC who had received platinum-based chemotherapy were treated with an outpatient gemcitabine and paclitaxel combination regimen. A dose of 180 mg/m(2) paclitaxel was administered by intravenous (IV) infusion on Day 1, and 1000 mg/m(2) gemcitabine was administered by IV on Days 1, 8 and 15.The course was repeated every 28 days. Patients were evaluated after every 2 cycles of therapy using computed tomography. RESULTS Of the 33 patients enrolled in this study, 30 could be evaluated to determine treatment efficacy; 10 had an objective response [overall response rate: 33.3%, 95% confidence interval (CI), 19.2-51.2%]. The median overall survival was 11.3 months (95% CI, 7.2-13.6 months). The chemotherapy sensitivity differed with disease site. The response rates of lung and bone metastases were 27% and 14%, and the progressive disease (PD) rates of lung and bone metastases were 13% and 14%, respectively. On the other hand, the response rate of liver metastasis was 14%, and its PD rate was 57%. None of the patients (n = 3) with adrenal metastasis responded to this regimen. Toxicities were mild, and no life-threatening complications occurred. CONCLUSIONS Gemcitabine and paclitaxel combination therapy is a tolerable and active regimen for patients with advanced UC after failure of platinum-based chemotherapy.

FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.

Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic

The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration‐resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel‐T, cabazitaxel and Ra‐223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor‐targeting therapies inhibit the growth of prostate cancer by blocking the ligand‐binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand‐binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF‐1 region in its N‐terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor‐related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration‐resistant prostate cancer.

Treatment outcomes of sorafenib for first line or cytokinerefractory advanced renal cell carcinoma in Japanese patients

The objective of the present study was to document the treatment efficacy and safety of sorafenib in Japanese patients with advanced renal cell carcinoma (RCC). A retrospective analysis of 50 consecutive patients with metastatic RCC between January 2005 and December 2009 was carried out. Patients received sorafenib after failed cytokine therapy or first‐line sorafenib treatment. All received 400 mg of sorafenib orally twice daily. Five of 14 patients with bone metastases were also given bisphosphonates. Tumor response was evaluated every 1–2 months according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AE) were evaluated at each visit during and after treatment, and were recorded according to the National Cancer Institutes Common Terminology Criteria for Adverse Events version 3.0. Dose modification of sorafenib was permitted if grade 3 or 4 AE occurred. Treatment continued until disease progression or treatment intolerance occurred. Partial response, and stable disease as best objective responses were observed in 11 (22%) and 23 (46%) patients, respectively. Median progression‐free survival was 7.3 months and median overall survival was 11.9 months. All patients experienced AE and one or more grade 3/4 AE occurred in 43 of 50 (86%) patients. Although it requires close monitoring, sorafenib treatment seemed to be effective in the present study population.

Development of a nomogram for predicting the stone-free rate after transurethral ureterolithotripsy using semi-rigid ureteroscope.

To develop and to internally validate a novel nomogram for predicting the stone‐free rate after transurethral ureterolithotripsy.

Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain

Androgen receptor (AR) is a validated drug target for all stages of prostate cancer including metastatic castration-resistant prostate cancer (CRPC). All current hormone therapies for CRPC target the C-terminal ligand-binding domain of AR and ultimately all fail with resumed AR transcriptional activity. Within the AR N-terminal domain (NTD) is activation function-1 (AF-1) that is essential for AR transcriptional activity. Inhibitors of AR AF-1 would potentially block most AR mechanisms of resistance including constitutively active AR splice variants that lack the ligand-binding domain. Here we provide evidence that sintokamide A (SINT1) binds AR AF-1 region to specifically inhibit transactivation of AR NTD. Consistent with SINT1 targeting AR AF-1, it attenuated transcriptional activities of both full-length AR and constitutively active AR splice variants, which correlated with inhibition of growth of enzalutamide-resistant prostate cancer cells expressing AR splice variants. In vivo, SINT1 caused regression of CRPC xenografts and reduced expression of prostate-specific antigen, a gene transcriptionally regulated by AR. Inhibition of AR activity by SINT1 was additive to EPI-002, a known AR AF-1 inhibitor that is in clinical trials (NCT02606123). This implies that SINT1 binds to a site on AF-1 that is unique from EPI. Consistent with this suggestion, these two compounds showed differences in blocking AR interaction with STAT3. This work provides evidence that the intrinsically disordered NTD of AR is druggable and that SINT1 analogs may provide a novel scaffold for drug development for the treatment of prostate cancer or other diseases of the AR axis.

PD03-03 GENOTYPE CLASSIFICATION BASED ON THE MULTIPLE CYSTINE RELATED TRANSPORTERS IN JAPANESE CYSTINURIA PATIENTS

interface was dissected and analyzed via electron dispersion spectroscopy(EDS) and scanning electron microscopy(SEM). RESULTS: Intrarenal stones were identified in 20 kidneys (Fig 1). The kidney with the largest stone came from a deceased 15 year-old Bermese male cat without history of renal insufficiency. The stone was 9x4.5 mm and was attached to the papilla (Fig 2). Stone micro CT demonstrated calcium oxalate overgrowing a region of apatite closest to the papilla. Microstructure of the apatite showed lumens consistent with calcified renal tubules pathognomonic for RP (Fig 3). Mineral composition was confirmed with EDS. Micro-CT of the tissue beneath the stone showed calcium deposition along tubules extending deep within the tissue. CONCLUSIONS: Spontaneous stone formation in cats can occur via a RP mechanism indistinguishable from humans. This is the first description of naturally occurring, spontaneous RP stone overgrowth in a non-human subject and supports further investigation of cats as a model to study stone formation.

Contralateral adrenal width predicts the duration of prolonged post‐surgical steroid replacement for subclinical Cushing syndrome

To identify pre‐treatment factors affecting the duration of post‐surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome.

Duration of androgen deprivation therapy and nadir of testosterone at 20 ng/dL predict testosterone recovery to supracastrate level in prostate cancer patients who received external beam radiotherapy

To determine the predictors of testosterone recovery after termination of androgen deprivation therapy in high/intermediate‐risk prostate cancer patients receiving external beam radiation therapy with neoadjuvant and adjuvant androgen deprivation therapy.

Biparametric Prostate Imaging Reporting and Data System version2 and International Society of Urological Pathology Grade Predict Biochemical Recurrence after Radical Prostatectomy

Micro‐Abstract We found that Prostate Imaging Reporting and Data System (PI‐RADS), version 2 and International Society of Urological Pathology (ISUP) grade predict for biochemical recurrence after radical prostatectomy. Based on the score of 2 factors, we created a risk classification. The poor‐risk group had significantly worse prognosis compared with that of intermediate‐ to favorable‐risk groups. This is the first report to show the value of combining PI‐RADS and ISUP grade for predicting the prognosis of radical prostatectomy patients. Background: We retrospectively assessed the clinical significance of the Prostate Imaging Reporting and Data System (PI‐RADS), version 2, criteria based on biparametric magnetic resonance imaging (bp‐MRI), together with the International Society of Urological Pathology (ISUP) grade, for predicting biochemical recurrence (BCR) after radical prostatectomy. Materials and Methods: The data from 126 patients who had undergone radical prostatectomy were retrospectively analyzed. The prognostic significance of the PI‐RADS v2 score based on bp‐MRI was assessed with other clinical factors, including the ISUP grade. We defined a positive PI‐RADS and ISUP score as ≥ 4 and ≥ 3, respectively. Statistical analysis was performed using Cox proportional hazard models, logistic regression analysis, and the Kaplan‐Meier method. Results: The median age and median prostate‐specific antigen level were 66 years and 7.96 ng/mL, respectively. The number of positive PI‐RADS scores was 106 (84.1%) and the number of positive ISUP grade scores was 71 (56.3%). PI‐RADS ≥ 4 (P = .0031) and ISUP ≥ 3 (P = .070) were the 2 independent prognostic factors predictive of BCR. A positive PI‐RADS score was related to tumor volume (P = .014), and a positive ISUP score was related to prostate‐specific antigen level (P = .043), extraprostatic extension (P = .029), and Gleason upgrading (P < .0001). After stratifying patients into risk groups according to PI‐RADS and ISUP positivity, the poor‐risk group (PI‐RADS and ISUP grade positive) showed significantly worse BCR‐free survival compared with that of the favorable‐ and intermediate‐risk groups (P < .0001), with a median survival difference of 21 months. Conclusion: Biparametric PI‐RADS v2 and ISUP grade criteria predicted for BCR after radical prostatectomy. PI‐RADS v2 combined with the ISUP grade might be helpful in choosing the treatment modality of patients with localized prostate cancer.