Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

PURPOSE: Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. RESULTS: Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION: Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

The Relationship between Children's School Adaptation, Academic Achievement, Happiness, and Problematic Smartphone Usage: A Multiple Informant Moderated Mediating Model.

The school environment is a primary realm of life for school-aged children and thus their adaptation to school and academic performance may affect their degree of happiness. The age of smartphone users has declined, and problematic smartphone usage has widely expanded such that young children are also affected by such devices. This study assessed adaptation to school, academic achievement, problematic smartphone usage, and general happiness in a panel data sample of 695 Korean 10-year-old children and their teachers and mothers, and a moderated mediation model of these variables was tested. Results revealed that school adaptation affected general happiness of children through academic performance, and problematic smartphone usage demonstrated significant moderating effects on the relationship between school adaptation and academic achievement. Specifically, in children with a high level of adaptation to school life, the difference in problematic smartphone usage did not affect academic performance. However, lower level of adaptation led to greater differences in academic performance depending on problematic smartphone usage, and children with high problematic smartphone usage showed poorer academic performance. This study is meaningful because variables related to adaptation of 10-year-old children were collected from multiple informants. In addition, this study focused on general happiness, a positive factor, as the outcome variable to test the effects of variables related to school and problematic smartphone usage. Limitations include that a causal relationship cannot be examined, and qualitative differences in smartphone usage were not measured. Supplementary Information: The online version contains supplementary material available at 10.1007/s11482-022-10080-w.

Long-term oncologic outcomes after radical prostatectomy in clinically localized prostate cancer: 10-year follow-up in Korea.

Purpose: The clinical behavior of prostate cancer differs by race and ethnicity; however, data on the Korean population are scarce. We assessed the long-term oncologic outcomes of clinically localized prostate cancer after radical prostatectomy in Korean men. Materials and Methods: We analyzed 786 clinically localized prostate cancer patients who underwent radical prostatectomy, from June 1993 to June 2008. Kaplan-Meier survival curve analysis and log-rank test were used to assess the oncologic outcomes. Results: The mean age of the patients was 64.9±6.6 years. Pelvic lymph node dissection was performed in 373 patients. Pathologic T and N stage cancer with local advancement and invasion were detected by radical prostatectomy in 307 and 22 patients, respectively. In total, 38 patients who underwent adjuvant therapy were excluded from the analysis of progression after biochemical recurrence (BCR), which occurred in 261 men. In total, 219 patients underwent salvage treatment. Local recurrence and distant metastasis occurred in 109 and 42 patients, respectively; 36 patients experienced metastasis with local recurrence. Castration-resistant prostate cancer developed in 22 patients, and overall and disease-specific mortality was noted in 148 and 23 patients, respectively. The median duration from operation to BCR, BCR to metastasis, and metastasis to disease-specific death was 25, 40, and 22 months, respectively. Conclusions: We demonstrated the long-term prognosis of localized prostate cancer after radical prostatectomy among Koreans. Our results differ from those reported in the Western literature, with a lower prevalence of distant metastasis and shorter time to metastasis after BCR.

Antitumor effects of MutT homolog 1 inhibitors in human bladder cancer cells.

As standard second-line regimen has not been established for patients who are refractory to or relapse with cisplatin-based chemotherapy, an effective class of novel chemotherapeutic agents is needed for cisplatin-resistant bladder cancer. Recent publications reported that MutT homolog 1 (MTH1) inhibitors suppress tumor growth and induce impressive therapeutic responses in a variety of human cancer cells. Few studies investigated the cytotoxic effects of MTH1 inhibitors in human bladder cancer. Accordingly, we investigated the antitumor effects and the possible molecular mechanisms of MTH1 inhibitors in cisplatin-sensitive (T24) and - resistant (T24R2) human bladder cancer cell lines. These results suggest that TH588 or TH287 may induce cancer cell suppression by off-target effects such as alterations in the expression of apoptosis- and cell cycle-related proteins rather than MTH1 inhibition in cisplatin-sensitive and - resistant bladder cancer cells.Abbreviations: MTH: MutT homolog; ROS: reactive oxygen species; CCK-8: cell counting kit-8; DCFH-DA: dichlorofluorescein diacetate; PARP: poly (ADP-ribose) polymerase.

Suberoylanilide Hydroxamic Acid Can Re-sensitize a Cisplatin-Resistant Human Bladder Cancer.

Cisplatin chemotherapy is the standard treatment for metastatic urothelial carcinoma. Although there are second-line chemotherapeutic agents approved by the U.S. Food and Drug Administration (FDA) such as those targeting programmed death-ligand 1 (PD-L1), more effective pharmacotherapy is required for cisplatin-resistant bladder cancer due to its limited overall survival and progression-free survival. The synergistic anti-cancer effect of cisplatin and suberoylanilide hydroxamic acid (SAHA) in cisplatin-resistant bladder cancer cells (T24R2) was examined. Tumor cell proliferation and cell cycle was examined using the cell counting kit (CCK)-8 assays and flow cytometry, respectively. Synergism was examined using the combination index (CI). CCK-8 assay and CI test were used to observe the strong synergistic anti-cancer effect between SAHA and cisplatin. Activation of caspase mediated apoptosis, down-regulated expression of the anti-apoptotic B-cell lymphoma-2 (Bcl-2) and up-regulated expression of pro-apoptotic Bcl-2-associated death promoter (BAD) were observed in Western blot. SAHA synergistically could partially re-sensitize cisplatin-resistant bladder cancer cells (T24R2) through the cell cycle arrest and induction of apoptosis pathway. SAHA-based treatment could be a potential treatment regimen in patients with cisplatin resistant bladder cancer.

Analysis of resistance-associated gene expression in docetaxel-resistant prostate cancer cells.

Docetaxel-based chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (CRPC). However, a number of patients with metastatic CRPC are refractory to docetaxel or develop docetaxel resistance. The underlying molecular mechanisms of docetaxel resistance remain unclear, which is a significant burden to the management of metastatic prostate cancer. In the present study, the differential gene expression between docetaxel-sensitive (PC3) and docetaxel-resistant (PC3DR2) prostate cancer cells was identified using DNA microarrays, western blot analysis and reverse transcription-quantitative polymerase chain reaction. Of the genes implicated in cancer-associated pathways, insulin-like growth factor 1 receptor, DBF4 homolog, sterile α motif and leucine zipper-containing kinase AZK, Patched 1, serpin peptidase inhibitor, clade E, member 1 and breast cancer 2 (BRCA2) were >3-fold upregulated in PC3DR2 cells compared with PC3 cells. BRCA2 knockdown with small interfering RNA decreased the docetaxel resistance of PC3DR2 cells. These results suggest that BRCA2 serves an important role in the docetaxel resistance of prostate cancer cells. In addition, BRCA2 modulation may be a strategy to partially reverse docetaxel resistance in prostate cancer.

The establishment of KORCC (KOrean Renal Cell Carcinoma) database.

PURPOSE: The purpose of this article is to report establishment of the 1st Web-based database (DB) system to collect renal cell carcinoma (RCC) data in Korea. MATERIALS AND METHODS: The new Web-based DB system was established to collect basic demographic and clinicopahtological characteristics of a large cohort of patients with RCC in Korea. Data from a total of 6,849 patients were collected from 8 tertiary care hospitals that agreed to participate in organizing the Korean Renal Cell Carcinoma (KORCC) study group as of 1 July 2015. Basic demographic and clinicopathological characteristics were collected. The data of patients who underwent surgical treatments were analyzed to characterize Korean RCC. RESULTS: We established the 1st Web-based DB of Korean RCC, a database comprising renal mass management cases from multiple centers in Korea. The data of 5,281 patients who underwent surgical management (mean follow-up, 32 months) were analyzed. The most common symptom was incidentally detected renal mass (76.9%). Clinical T1a was the most common (54.3%) stage and mean tumor size was 4.8±4.2 cm. Radical nephrectomy accounted for 62.7% of cases and an open approach was used in 50.7% and 52.2% of radical and partial nephrectomies, respectively. The 5-year overall, cancer-specific and recurrence-free survival rates were 88.1%, 92.2%, and 88.0%, respectively. CONCLUSIONS: We report the 1st establishment of a Web-based DB system to collect RCC data in Korea. This DB system will provide a solid basis for the characterization of Korean RCC.

Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines.

PURPOSE: The mechanism of resistance to cisplatin during treatment of bladder cancer (BC) has been a subject of intense investigation in clinical research. This study aims to identify candidate genes associated with resistance to cisplatin, in order to understand the resistance mechanism of BC cells to the drug, by combining the use of microarray profiling, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. MATERIALS AND METHODS: The cisplatin sensitive human BC cell line (T24) and the cisplatin resistant BC cell line, T24R2, were used for microarray analysis to determine the differential expression of genes that are significant in cisplatin resistance. Candidate upregulated genes belonging to three well-known cancer-related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (p53 tumor suppressor, apoptosis, and cell cycle) were selected from the microarray data. These candidate genes, differentially expressed in T24 and T24R2, were then confirmed by quantitative RT-PCR and western blot. A fold change ≥2 with a p-value <0.05 was considered significant. RESULTS: A total of 18 significantly upregulated genes were detected in the three selected cancer-related pathways in both microarray and RT-PCR analyses. These genes were PRKAR2A, PRKAR2B, CYCS, BCL2, BIRC3, DFFB, CASP6, CDK6, CCNE1, STEAP3, MCM7, ORC2, ORC5, ANAPC1, and ANAPC7, CDC7, CDC27, and SKP1. Western blot analyses also confirmed the upregulation of BCL2, MCM7, and CCNE1 at the protein level, indicating their crucial association with cisplatin resistance. CONCLUSIONS: The BCL2, MCM7, and CCNE1 genes might play distinctive roles in cisplatin resistance in BC.

Effect of preoperative urodynamic detrusor overactivity on post-prostatectomy incontinence: a systematic review and meta-analysis.

PURPOSE: To investigate whether preoperative urodynamic detrusor overactivity (DO) contributes to post-prostatectomy incontinence (PPI). METHODS: We systematically searched the online PubMed, Embase, and Cochrane Library databases spanning the period of January 1989 to December 2014. RESULTS: A total of nine articles met the eligibility criteria for this systematic review. The eligible studies included a total of 457 patients with a median number of 58 patients per study (range 17-92). Of the nine studies, five conducted open retropubic radical prostatectomy (RRP), two performed robot-assisted laparoscopic prostatectomy (RALP), and two others utilized multiple modalities. PPI was more likely to occur in patients with preoperative DO [pooled odds ratio (OR) 2.30; 95 % confidence interval (CI) 1.39-3.82; studies 9; participants 419], as compared to patients who were DO negative. Sensitivity analysis using the subgroups of RRP (OR 2.32; 95 % CI 1.11-4.85), RALP (OR 3.41; 95 % CI 1.55-7.47), DO defined as any amplitude of involuntary contraction (OR 2.32; 95 % CI 1.11-4.85), no postoperative intervention (OR 2.32; 95 % CI 1.11-4.85), and outcome evaluation after 6 months (OR 2.32; 95 % CI 1.11-4.85) demonstrated consistent results. Although some comparisons showed inter-study heterogeneity, there was no clear evidence of publication bias in this meta-analysis. CONCLUSIONS: Our meta-analysis results suggest that preoperative DO is another possible underlying mechanism for PPI.

Predictive and Prognostic Value of Ribonucleotide Reductase Regulatory Subunit M1 and Excision Repair Cross-Complementation Group 1 in Advanced Urothelial Carcinoma (UC) Treated with First-Line Gemcitabine Plus Platinum Combination Chemotherapy.

Preclinical and clinical studies have suggested that expression of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) is associated with resistance to gemcitabine and cisplatin, respectively. We evaluated the significance of RRM1 and ERCC1 expression to predict tumor response to gemcitabine plus platinum chemotherapy (GP) and survival in advanced UC. We retrospectively collected tumor samples and reviewed clinical data of 53 patients with unresectable or metastatic UC, who were treated with first-line GP. RRM1 and ERCC1 expression were measured by immunohistochemistry. Among 53 patients, 12 (22.6%) and 26 (49.1%) patients had tumors that demonstrated a high expression for RRM1 and ERCC1, respectively. Twenty-nine (70.7%) of 41 patients with low RRM1 expression achieved a clinical response (complete + partial responses), but only 3 (25.0%) of 12 patients with high RRM1 expression achieved a clinical response after GP (P=0.007). Nineteen (70.4%) of 27 patients with low ERCC1 expression achieved a clinical response, while 13 (50.0%) of 26 patients with high ERCC1 expression achieved a clinical response (P=0.130). High RRM1 expression was associated with shorter progression free survival and overall survival (PFS P=0.006, OS P=0.006). Multivariate analysis confirmed that patients with high RRM1 expression had a significantly greater risk of progression and death than those with low RRM1 expression. ERCC1 status was not a significant predictor for PFS and OS. RRM1 expression was predictive and prognostic of clinical outcome in advanced UC treated with gemcitabine plus platinum combination chemotherapy.

A propensity-matched comparison of perioperative complications and of chronic kidney disease between robot-assisted laparoscopic partial nephrectomy and radiofrequency ablative therapy.

OBJECTIVE: The study presents a matched-pair analysis of robot-assisted laparoscopic partial nephrectomy (RALPN) versus radiofrequency ablation (RFA) to compare the perioperative incidence of complications and chronic kidney disease (CKD). METHODS: All 46 RFA and 206 RALPN cases from June 2005 to December 2011 were retrospectively reviewed from the medical records and were matched 1:1 based on propensity scores by sex, tumor size, tumor laterality of kidney, tumor location within the kidney, and clinical T stage. Hilar vessel clamping was performed in all RALPN patients. The estimated glomerular filtration rate was used to define the CKD of < 60 mL/minute/1.73 m(2) by the Modification of Diet in Renal Disease equation. All patients with baseline CKD or solitary kidney were excluded prior to the matching analysis. The complication was noted with modified Clavien grades ≥ 3. Statistical analysis was performed to compare the perioperative incidence of complications and CKD. RESULTS: A total of 27 matched pairs of RFA and RALPN patients were enrolled for analyzing CKD and perioperative complications. The better general conditions, higher estimated blood loss and transfusion rates, and longer operative time and hospital stay were observed significantly in RALPN patients (p < 0.05). Matched analysis demonstrated that the incidences of both perioperative complications (p = 0.434) and of CKD (p = 0.500) were not significantly different. No complication higher than Grade 4 was detected in either group. CONCLUSION: Despite the intraoperative renal ischemia and invasiveness of the procedure associated with RALPN, the incidence of perioperative complication and of CKD developing rates were statistically similar.

Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin­resistant bladder tumor cell line.

Cisplatin-based chemotherapy is the first­line treatment for metastatic urothelial cell carcinoma. However, for cisplatin­resistant cases, no chemotherapeutic agent has been established as a standard of treatment. This study aimed to investigate the synergistic antitumor effect of ginsenoside Rg3 on cisplatin in cisplatin­resistant bladder cancer cells (T24R2). T24R2 cells were treated with cisplatin and/or ginsenoside Rg3. Cell viability was assessed by the Cell Counting Kit-8 and clonogenic assays. Synergism between ginsenoside Rg3 and cisplatin was determined when the combination index was <1.0. Flow cytometry was used to evaluate the cell cycle distribution. To estimate the changes of proteins associated with the cell cycle and apoptosis following the treatment of ginsenoside Rg3, western blotting and densitometric assays were performed for caspase-3, -8 and -9, cyclin B1, Bcl-2, Bad, p21 and cytochrome c. The Cell Counting Kit-8 and clonogenic assays showed the synergistic antitumor effect of ginsenoside Rg3 on cisplatin, while the combination index was <1.0, confirming the synergism. Cell cycle alterations at the G2/M phase caused by cisplatin were greater after the combination with ginsenoside Rg3. Western blotting and densitometric assay showed that the expression of Bcl-2 was decreased after the combined treatment of ginsenoside Rg3 and cisplatin, whereas the expression of cytochrome c and caspase-3 were increased, suggesting the activation of the intrinsic apoptotic pathway. In conclusion, ginsenoside Rg3 inhibited the proliferation of cisplatin­resistant bladder cancer cells in a synergistic manner with cisplatin. Activation of the intrinsic apoptotic pathway and the enhancement of cell cycle alterations are possible explanations for this result.

Pre- and post-operative nomograms to predict recurrence-free probability in korean men with clinically localized prostate cancer.

OBJECTIVES: Although the incidence of prostate cancer (PCa) is rapidly increasing in Korea, there are few suitable prediction models for disease recurrence after radical prostatectomy (RP). We established pre- and post-operative nomograms estimating biochemical recurrence (BCR)-free probability after RP in Korean men with clinically localized PCa. PATIENTS AND METHODS: Our sampling frame included 3,034 consecutive men with clinically localized PCa who underwent RP at our tertiary centers from June 2004 through July 2011. After inappropriate data exclusion, we evaluated 2,867 patients for the development of nomograms. The Cox proportional hazards regression model was used to develop pre- and post-operative nomograms that predict BCR-free probability. Finally, we resampled from our study cohort 200 times to determine the accuracy of our nomograms on internal validation, which were designated with concordance index (c-index) and further represented by calibration plots. RESULTS: Over a median of 47 months of follow-up, the estimated BCR-free rate was 87.8% (1 year), 83.8% (2 year), and 72.5% (5 year). In the pre-operative model, Prostate-Specific Antigen (PSA), the proportion of positive biopsy cores, clinical T3a and biopsy Gleason score (GS) were independent predictive factors for BCR, while all relevant predictive factors (PSA, extra-prostatic extension, seminal vesicle invasion, lymph node metastasis, surgical margin, and pathologic GS) were associated with BCR in the post-operative model. The c-index representing predictive accuracy was 0.792 (pre-) and 0.821 (post-operative), showing good fit in the calibration plots. CONCLUSIONS: In summary, we developed pre- and post-operative nomograms predicting BCR-free probability after RP in a large Korean cohort with clinically localized PCa. These nomograms will be provided as the mobile application-based SNUH Prostate Cancer Calculator. Our nomograms can determine patients at high risk of disease recurrence after RP who will benefit from adjuvant therapy.

A retrospective analysis of incidence and its associated risk factors of upper urinary tract recurrence following radical cystectomy for bladder cancer with transitional cell carcinoma: the significance of local pelvic recurrence and positive lymph node.

OBJECTIVE: The aim of this study is to examine the incidence and risk factors of upper urinary tract recurrence (UUTR) following radical cystectomy (RC) in bladder cancer and to evaluate its relationship with neobladder (Neo) or ileal conduit (IC). MATERIALS AND METHODS: All clinicopathologic parameters and perioperative parameters of 311 patients who underwent RC with either Neo or IC by a single surgeon from 1999 to 2012 were retrospectively included in this study. Patients with a history of renal surgery, concomitant UUTR, or a histopathology of non-transitional cell carcinoma were excluded. For statistical analyses of predictive risk factors of UUTR, a multivariate analysis was performed with known risk factors of UUTR, including type of urinary diversion with significance defined as P < 0.05. RESULTS: During the median follow-up period of 53 months, 143 (46.0%) IC and 168 (54.0%) Neo were performed, resulting in 11 (3.5%) cases of UUTR (Neo 7 and IC 4) after RC and all patients then underwent nephroureterectomy. No significant differences in incidence and overall survival in UUTR were observed according different types of urinary diversion (p = 483), and the prognosis for survival of Neo was insignificantly better than that of IC (5-year overall survival 78% vs 74%, respectively, p>0.05). Higher number of positive lymph nodes (HR 9.03) and the presence of pelvic local recurrence (HR 7286.08) were significant predictive factors of UUTR (p<0.05). CONCLUSION: This study reports a UUTR rate of 3.5%, and positive lymph nodes and presence of local recurrence at the pelvis as important risk factors. No significant differences in incidence and survival were observed between Neo and IC.

Incidence and risk factors of 30-day early and 90-day late morbidity and mortality of radical cystectomy during a 13-year follow-up: a comparative propensity-score matched analysis of complications between neobladder and ileal conduit.

OBJECTIVE: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors. METHODS: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post-operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder. RESULTS: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n=91) and 19.8% (n=61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P=0.096; late: neobladder 67 vs. ileal conduit 37, P<0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P<0.05). CONCLUSIONS: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit.

Is high-dose leuprorelin acetate effective and safe in asian men with prostate cancer? An open-label, non-comparative, multi-center clinical trial.

PURPOSE: Leuprorelin is a well known luteinizing hormone releasing hormone agonist. However, there are insufficient data on the efficacy and safety of high dose leuprorelin acetate, especially in Asian patients with prostate cancer. We aimed to investigate the safety and efficacy of leuprorelin acetate 22.5 mg administered at three-month intervals in patients with prostate cancer. MATERIALS AND METHODS: In an open, prospective clinical trial enrolling 47 patients, we aimed to assess the efficacy and safety of leuprorelin acetate 22.5 mg in treating patients with histologically confirmed prostate cancer. The primary objective of this study was to evaluate the efficacy of the leuprorelin acetate 22.5 mg in producing and maintaining castration levels of testosterone over a 6-month follow-up period and to determine its safety profile. RESULTS: All 42 patients achieved serum testosterone levels within the castration range by 4 weeks. A breakthrough response was observed in one of 36 patients by 8 weeks. However, this patient was medically castrated by 12 weeks. There were no significant prostate-specific antigen (PSA) or testosterone changes according to clinical stage or body mass index. Twenty adverse events (AEs) in 15 of 42 patients (35.7%) were observed during this study. The most common AEs were hot flushes (n=4, 20.0%) with mild intensity, pain (n=2, 10.0%), and infection (n=2, 10.0%). No patient withdrew from the study due to AEs. CONCLUSION: Leuprorelin acetate 22.5 mg was shown to be effective and safe in Asian patients with prostate cancer, even though sexual function decreased.

Is neoadjuvant androgen deprivation therapy beneficial in prostate cancer treated with definitive radiotherapy?

PURPOSE: To determine whether neoadjuvant androgen deprivation therapy (NADT) improves clinical outcomes in patients with prostate cancer treated with definitive radiotherapy. MATERIALS AND METHODS: We retrospectively reviewed medical records of 201 patients with prostate cancer treated with radiotherapy between January 1991 and December 2008. Of these, 156 patients with more than 3 years of follow-up were the subjects of this study. The median duration of follow-up was 91.2 months. NADT was given in 103 patients (66%) with median duration of 3.3 months (range, 1.0 to 7.7 months). Radiation dose was escalated gradually from 64 Gy to 81 Gy using intensity-modulated radiotherapy technique. RESULTS: Biochemical relapse-free survival (BCRFS) and overall survival (OS) of all patients were 72.6% and 90.7% at 5 years, respectively. BCRFS and OS of NADT group were 79.5% and 89.8% at 5 years and those of radiotherapy alone group were 58.8% and 92.3% at 5 years, respectively. Risk group (p = 0.010) and radiation dose ≥70 Gy (p = 0.017) affected BCRFS independently. NADT was a significant prognostic factor in univariate analysis, but not in multivariate analysis (p = 0.073). Radiation dose ≥70 Gy was only an independent factor for OS (p = 0.007; hazard ratio, 0.261; 95% confidence interval, 0.071-0.963). CONCLUSION: NADT prior to definitive radiotherapy did not result in significant benefit in terms of BCRFS and OS. NADT should not be performed routinely in the era of dose-escalated radiotherapy.

Localized non-conventional renal cell carcinoma: prediction of clinical outcome according to histology.

OBJECTIVE: A wide variety of parameters have been investigated in the prognostic significance of non-conventional clear cell renal cell carcinoma. Aim of the present study was to compare its clinical outcome and to determine the independent prognostic factors according to the histology. METHODS: This retrospective study enrolled localized non-conventional clear cell renal cell carcinomas (T1a-T4N0M0), including Xp11.2 translocation (Xp11.2t), all surgically treated in a single institution between 1988 and 2011. The study statistically analyzed the clinicopathological parameters to compare the prognostic outcomes among the different histological subtypes of non-conventional clear cell renal cell carcinoma and to define any independent prognostic factors. RESULTS: A total of 374 cases were examined, including 126 papillary (33.7%), 164 chromophobe (43.9%), eight collecting duct (2.1%), 40 unclassified (10.7%), 16 Xp11.2t (4.3%), seven mucinous tubular and spindle cell (1.8%) renal cell carcinomas and 13 oncocytomas (3.5%). The mean follow up was 56.4 months, with s mean tumor size of 4.9 ± 3.4 cm. The 4-year recurrence-free survival, overall survival and cancer-specific survival were inversely related to the increase of pathological T stages (P < 0.001). For histological type other than 13 oncocytomas and seven mucinous tubular and spindle cell renal cell carcinomas, the chromophobe showed the best prognosis of survival, followed by papillary, Xp11.2t, unclassified and collecting duct renal cell carcinomas, in this order. All survival rates were significantly different, as according to the histology (P = 0.009). The significant prognostic factors were preoperative body mass index (hazard ratio 0.76), serum albumin (hazard ratio 0.64), T stage (hazard ratio 2.28), the sarcomatoid differentiation (hazard ratio 33.45) and lymphovascular invasion (hazard ratio 12.40) in pathology (P < 0.05). CONCLUSIONS: Different non-conventional clear cell renal cell carcinoma subtypes have significantly different clinical characteristics of prognosis with many suggestive predictive factors of survival.

The role of c-FLIP in cisplatin resistance of human bladder cancer cells.

PURPOSE: We investigated the mechanisms underlying cisplatin resistance in human bladder cancer cells to provide novel molecular targets for the treatment of cisplatin resistant bladder cancer. MATERIALS AND METHODS: The differential gene expression of cisplatin sensitive (T24) and resistant (T24R2) human bladder cancer cell lines was analyzed and validated by microarray and Western blot analysis. Changes in cisplatin sensitivity by c-FLIP knockdown and related mechanisms in T24R2 cells were assessed using the Cell Counting Kit-8 assay (Dojindo Molecular Technologies, Gaithersburg, Maryland) and Western blot. siRNA oligonucleotides that specifically target c-FLIP were prepared and siRNA transfection was done. RESULTS: Microarray analysis revealed that the expression of 1,086 and 322 genes showed more than twofold and fourfold changes in the T24R2 and T24 cell lines, respectively. Especially genes involved in the c-FLIP related death receptor apoptosis pathway, including caspase 2 and 9, NF-kB, BID, c-FLIP, XIAP, and cIAP1 and 2, showed differential expression in the 2 cell lines. Western blot demonstrated complete cisplatin mediated suppression of c-FLIP expression in T24 cells but no change in c-FLIP expression was observed in T24R2 cells after cisplatin treatment in the same dose range. Suppression of c-FLIP expression in T24R2 cells by siRNA transfection rendered these cells significantly more sensitive to cisplatin treatment than untransfected T24R2 cells (p <0.05). CONCLUSIONS: Results reveal that c-FLIP has an important role in the cisplatin resistance of human bladder cancer cells and c-FLIP modulation may at least partially reverse cisplatin resistance in bladder cancer cells.

A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update.

BACKGROUND: In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. METHODS: Treatment-naive or cytokine-pretreated mRCC patients (n=435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. FINDINGS: The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR]=0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P=.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR=0.504; 95% CI, 0.315-0.762; two-sided P=.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR=0.43; 95% CI, 0.215-1.388; two-sided P=.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. INTERPRETATION: Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.