Polygenic risk score model for renal cell carcinoma in the Korean population and relationship with lifestyle-associated factors.

BACKGROUND: The polygenic risk score (PRS) is used to predict the risk of developing common complex diseases or cancers using genetic markers. Although PRS is used in clinical practice to predict breast cancer risk, it is more accurate for Europeans than for non-Europeans because of the sample size of training genome-wide association studies (GWAS). To address this disparity, we constructed a PRS model for predicting the risk of renal cell carcinoma (RCC) in the Korean population. RESULTS: Using GWAS analysis, we identified 43 Korean-specific variants and calculated the PRS. Subsequent to plotting receiver operating characteristic (ROC) curves, we selected the 31 best-performing variants to construct an optimal PRS model. The resultant PRS model with 31 variants demonstrated a prediction rate of 77.4%. The pathway analysis indicated that the identified non-coding variants are involved in regulating the expression of genes related to cancer initiation and progression. Notably, favorable lifestyle habits, such as avoiding tobacco and alcohol, mitigated the risk of RCC across PRS strata expressing genetic risk. CONCLUSION: A Korean-specific PRS model was established to predict the risk of RCC in the underrepresented Korean population. Our findings suggest that lifestyle-associated factors influencing RCC risk are associated with acquired risk factors indirectly through epigenetic modification, even among individuals in the higher PRS category.

Tubular damage marker as a predictive factor for pathologically upstaged renal cell carcinoma.

PURPOSE: To investigate if increased tubular damage biomarker can predict pathologically upstaged renal cell carcinoma (RCC), which may possess sub-radiologic invasive behavior, leading to surrounding tubular damage. MATERIALS AND METHODS: We examined 1563 patients with surgically resected RCC between March 2016 and June 2021 from the prospective database SUPER-RCC-Nx. Exclusion criteria were cancer not originating from the kidneys, benign renal tumor, and end-stage renal disease. RESULTS: Of 1297 patients, 131 had a clinically high T stage (T3-4), whereas 1166 had a low one. Patients with a clinically low T stage were subgrouped into identical-stage (n = 1041) and upstaged (n = 125) groups, who were confirmed as a pathologically high T stage. The upstaged group had older age (p = 0.003), larger tumor size (5.72 ± 3.24 vs. 3.12 ± 2.08, p < 0.001), higher Fuhrman grade (grades 3-4) (57.3% vs. 47.1%, p = 0.032), and higher urine N-acetyl-beta-D-glucosaminidase/creatinine (NAG/Cr) (5.13 ± 4.78 vs. 4.05 ± 2.84, p = 0.026). Tumor size (> 4 cm; odds ratio = 10.2, p < 0.001) and urine NAG/Cr (odds ratio = 1.16, p = 0.003) were independently associated with pathological upstaging in patients with normal renal function, while age and tumor size were significant risk factors in those with decreased renal function. The receiver operating characteristic curve analysis showed that the model using tumor size and urine NAG/Cr strongly predicted pathological upstaging (area under the curve, 0.84). CONCLUSION: Urine NAG/Cr may be a useful biomarker predicting pathologically upstaged RCC. Clinicians should be prudent in making management decisions when a large RCC is accompanied by an increased urine NAG/Cr.

Clinical features and Surgical Outcome of Clear Cell Papillary Renal Cell Tumor: result from a prospective cohort.

BACKGROUND: Clear cell papillary renal cell tumor (CCPRCT) was first reported in 2006 a patient with end stage renal disease. After that it was discovered in the kidney without end stage renal disease in the 2010s and started to be mentioned in pathology and urology. The incidence of CCPRCT is low and most of it is discovered incidentally, so there is a lack of reports on clinical characteristics and surgical outcome. METHODS: This study used clinical data from the Seoul National University Prospectively Enrolled Registry for Renal Cell Carcinoma-Nephrectomy (SUPER-RCC-Nx). Between August 2016 and July 2022, patients who underwent radical or partial nephrectomy with clear cell papillary RCC with pathological finding were included in this study. All patients' pathologic reports were reviewed by 1 pathologist. Clinical characteristics and surgical outcomes were presented through descriptive statistics, and Kaplan-Meier curve used for survival analysis. RESULTS: Of the 2057 patients, CCPRCT was reported in 36 patients (1.8%). The median follow up period was 26.8 months. The median age was 67 years, and there were 10 females and 26 males. The median tumor size was 1.2 cm. Twenty-nine patients underwent partial nephrectomy. Seven patients with end-stage renal disease underwent radical nephrectomy. The median operative time for patients who underwent partial nephrectomy was 97.5 min and the estimated blood loss was 100 cc. The median hospital days was 4 and 30-day complications were 2 cases with clavien-dindo classification III or higher. During the follow-up period, there was no recurrence and cancer specific mortality. CONCLUSIONS: The size of CCPRCT was small and there was no advanced stage at that time of diagnosis. There was no recurrence or cancer specific mortality during the follow-up period. A multi-center study with a large scale is needed in the future. TRIAL REGISTRATION: Seoul National University Hospital (SNUH) Institutional Review Board (IRB) (approval number: 2210-126-1371).

Clinical determinants of recurrence in pTa bladder cancer following transurethral resection of bladder tumor.

BACKGROUND: Non-muscle invasive bladder cancer can be controlled by transurethral resection of bladder (TURB), but suffers from frequent recurrences in 60-70% of cases. Although, recurrence interval after TURB influences treatment course and prognosis, its implication and risk factors have not been fully elucidated. We evaluated the risk factors of early (within 1 yr) and late (after 1 yr) recurrence of pTa bladder cancer and clinical significance of recurrence interval on disease progression and overall survival. METHODS: In this study, pTa bladder cancer patients enrolled in prospective patient registry system of Seoul National University, SUPER-UC, were retrospectively examined to determine the clinical risk factors for recurrence and its significance regarding to recurrence interval. A total of 1067 bladder cancer patients who underwent TURB between March 20 and June 2021 were included and classified into three groups of no recurrence, early, or late recurrence to be comparatively analyzed. RESULTS: Early recurrence was associated with poorer cystectomy-free survival and overall survival than late recurrence. Risk factors for early recurrence included a high number of previous TURB, tumor multiplicity, tumor location, tumor shape, incompleteness of TURB, and high tumor grade. Otherwise, late recurrence was associated with low-grade tumors with insufficient TURB depth. CONCLUSION: Patients with risk factors for early recurrence should be closely followed up with special cautions.

Association between decreased ipsilateral renal function and aggressive behavior in renal cell carcinoma.

BACKGROUND: To assess prognostic value of pre-operative ipsilateral split renal function (SRF) on disease-free survival (DFS) and its association with aggressive pathological features in renal cell carcinoma (RCC) patients.  METHODS: We examined patients registered in SNUG-RCC-Nx who underwent partial or radical nephrectomy at Seoul National University Hospital between January 1, 2010 and December 31, 2020. Patients with the following criteria were excluded from the study. 1) non-kidney origin cancer or benign renal tumor, 2) no pre-operative Tc 99 m-DTPA renal scan, 3) single kidney status or previous partial or radical nephrectomy, and 4) bilateral renal mass. Finally, 1,078 patients were included. RESULTS: Among 1,078 patients, 899 (83.4%) showed maintained ipsilateral SRF on DTPA renal scan; 179 patients (16.6%) showed decreased SRF. The decreased SRF group showed significantly large tumor size (maintained vs. decreased SRF; 3.31 ± 2.15 vs. 6.85 ± 3.25, p < 0.001), high Fuhrman grade (grade 3-4) (41.7% vs. 55.6%, p < 0.001), and high T stage (T stage 3-4) (9.0% vs. 20.1%, p < 0.001). Pathological invasive features, including invasion of the renal capsule, perirenal fat, renal sinus fat, vein, and collecting duct system, were associated with low SRF of the ipsilateral kidney. Univariate Cox regression analysis identified higher SSIGN (The stage, size, grade, and necrosis) score and decreased ipsilateral SRF as significant risk factors, while multivariate analysis showed SSIGN (5-7) (hazard ratio [HR] 11.9, p < 0.001) and SSIGN (8-10) (HR 69.2, p < 0.001) were significantly associated with shortened DFS, while decreased ipsilateral SRF (HR 1.75, p = 0.065) showed borderline significance. Kaplan-Meier analysis showed that decreased ipsilateral SRF (< 45%) group had shorter DFS than the other group (median DFS: 90.3 months vs. not reached, p < 0.001). CONCLUSIONS: Among unilateral RCC patients, those with low ipsilateral SRF showed poor prognosis with pathologically invasive features. Our novel approach may facilitate risk stratification in RCC patients, helping formulate a treatment strategy.

Efficacy of the Treatment of Intraperitoneal Bladder Perforation during Transurethral Resection of Bladder Tumor with the Urethral Catheter Alone: Retrospective Analysis of over 15 Years Using the Clinical Data Warehouse System.

INTRODUCTION: We investigated the efficacy of a urethral catheter alone for intraperitoneal perforation during transurethral resection of bladder tumor (TURBT). PATIENTS AND METHODS: We retrospectively evaluated the medical records of 4,543 patients who underwent TURBT from January 2000 to December 2017 using the Clinical Data Warehouse system. The clinicopathologic characteristics, recurrence-free survival, and progression-free survival were compared between the patient groups with intraperitoneal perforation treated with the Foley catheter alone, extraperitoneal perforation, and matched control TURBT. RESULTS: Intraperitoneal perforation and extraperitoneal perforation were observed in 16 (35.6%) and 29 (64.4%) patients, respectively. In the intraperitoneal perforation group, 11 (68.8%), 2 (12.5%), and 3 (18.8%) patients were treated with the Foley catheter alone, additional percutaneous drainage, and delayed open surgery, respectively. The use of the Foley catheter alone in patients with intraperitoneal perforation of smaller size than the cystoscope or no pelvic radiotherapy history showed improved efficacy without sequelae or therapeutic delay. One of the 2 patients with the size of the intraperitoneal perforation larger than the cystoscope was successfully treated with the Foley catheter alone, whereas the other patient underwent delayed surgical repair. There was no difference in recurrence-free survival and progression-free survival of the intraperitoneal perforation treated with the Foley catheter alone compared to those of the matched control TURBT (p = 0.909, p = 0.518) and the extraperitoneal perforation (p = 0.458, p = 0.699). CONCLUSIONS: Intraperitoneal perforation rarely occurred during TURBT. In the case of intraperitoneal perforation of size smaller than cystoscopy or without pelvic radiotherapy history, treatment with the Foley alone showed successful improvement and safe oncological results. Therefore, treatment with the urethral catheter alone can be carefully considered when an intraperitoneal perforation smaller than the cystoscope size or without pelvic radiotherapy history occurs.

Long-term Mortality Risks Among Living Kidney Donors in Korea.

RATIONALE & OBJECTIVE: Living kidney donors may have a higher risk for death and kidney failure. This study aimed to investigate the long-term mortality experience of living kidney donors compared with members of the general public in Korea who underwent voluntary health examinations. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: We first calculated standardized mortality ratios for 1,292 Korean living kidney donors who underwent donor nephrectomy between 1982 and 2016 and 72,286 individuals who underwent voluntary health examinations between 1995 and 2016. Next we compared survival between the 1,292 living kidney donors and a subgroup of the health examination population (n=33,805) who had no evident contraindications to living kidney donation at the time of their examinations. Last, a matched comparator group was created from the health examination population without apparent contraindication to donation by matching 4,387 of them to donors (n=1,237) on age, sex, body mass index, estimated glomerular filtration rate, urine dipstick albumin excretion, previously diagnosed hypertension and diabetes, and era. EXPOSURES: Donor nephrectomy. OUTCOMES: All-cause mortality and other clinical outcomes after kidney donation. ANALYTICAL APPROACH: First, standardized mortality ratios were calculated separately for living kidney donors and the health examination population standardized to the general population. Second, we used Cox regression analysis to compare mortality between living kidney donors versus the subgroup of the health examination population without evident donation contraindications. Third, we used Cox regression analysis to compare mortality between living kidney donors and matched comparators from the health examination population without apparent contraindication to donation. RESULTS: The living kidney donors and health examination population had excellent survival rates compared with the general population. 52 (4.0%) of 1,292 kidney donors died during a mean follow-up of 12.3±8.1 years and 1,072 (3.2%) of 33,805 in the health examiner subgroup without donation contraindications died during a mean follow-up of 11.4±6.1 years. Donor nephrectomy did not elevate the hazard for mortality after multivariable adjustment in kidney donors and the 33,805 comparators (adjusted HR, 1.01; 95% CI, 0.71-1.44; P=0.9). Moreover, living donors showed a similar mortality rate compared with the group of matched healthy comparators. LIMITATIONS: Donors from a single transplantation center. Residual confounding owing to the observational study design. CONCLUSIONS: Kidney donors experienced long-term rates of death comparable to nondonor comparators with similar health status.

Prognostic Implication of Body Mass Index on Survival Outcomes in Surgically Treated Nonmetastatic Renal Cell Carcinoma: A Single-Institutional Retrospective Analysis of a Large Cohort.

PURPOSE: Obesity is a well-known risk factor for renal cell carcinoma (RCC). However, the prognostic role of obesity in RCC has not been clearly established thus far. We aim to assess the effect of preoperative body mass index (BMI) on survival outcomes in nonmetastatic RCC patients. PATIENTS AND METHODS: We retrospectively analyzed data on 2329 patients who underwent curative surgery for RCC between 2000 and 2014 in a single institution. Patients were divided into normal (< 23 kg/m2), overweight (23-24.9 kg/m2), and obese (≥ 25 kg/m2) groups depending on cutoffs for Asian population. Kaplan-Meier analysis with log-rank test was used to estimate and compare survival outcomes, including recurrence-free, overall, and cancer-specific survival, among each BMI group. The influence of BMI on each survival outcome was evaluated using multivariate Cox regression analyses. RESULTS: Obese patients presented favorable 5-year recurrent-free (90.7% vs 84.9%, p < 0.001), overall (91.8% vs 86.8%, p = 0.002), and cancer-specific (94.8% vs 89.4%, p = 0.002) survival rates than the normal group. Multivariate analyses revealed that increasing BMI was an independent predictor of favorable survival outcomes (all p values < 0.05). In particular, overweight (p = 0.009) and obese (p = 0.009) patients showed better cancer-specific survival compared with normal patients. CONCLUSIONS: Our data suggest that overweight and obesity defined based on BMI are generally related to favorable survival outcomes after surgery for RCC. Additional basic research is required to find out the biological mechanisms explaining the correlation between BMI and survival outcomes.

A Low Geriatric Nutritional Risk Index is Associated with Aggressive Pathologic Characteristics and Poor Survival after Nephrectomy in Clear Renal Cell Carcinoma: A Multicenter Retrospective Study.

Purpose: To investigated the prognostic significance of the geriatric nutritional risk index (GNRI) in patients with surgically treated clear cell renal cell carcinoma (ccRCC).Patients and methods: We retrospectively selected 4,591 consecutive patients with surgically treated ccRCC from a multi-institutional Korean collaboration between 1988 and 2015. The clinical significance of the GNRI as a continuous and categorical variable was determined.Results: Preoperative low GNRI was significantly associated with older age, low body mass index, presence of diabetes, poor performance status, and presence of symptoms at diagnosis, as well as pathologic features such as aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, sarcomatous differentiation, and tumor necrosis. A low GNRI was significantly associated with a short recurrence-free survival (RFS) in localized (pT1-2N0M0) ccRCC and cancer-specific survival (CSS) in the entire cohort, and with short RFS and CSS in the subgroup analysis according to age categories (≤65 and >65 years). Multivariate Cox regression analysis showed that preoperative GNRI, as a continuous or categorical variable, was an independent predictor of RFS and CSS.Conclusion: Malnutrition as assessed by the preoperative GNRI is associated with aggressive tumor characteristics and poor survival in patients with surgically treated ccRCC.

Sharing the initial experience of pan-cancer panel analysis in high-risk renal cell carcinoma in the Korean population.

BACKGROUND: This study aimed to assess the feasibility of a pan-cancer panel assay for high-risk renal cell carcinoma (RCC) in the Korean population. We also analyzed the clinical and genetic factors contributing to metastasis in clear cell RCC. METHODS: Thirty-one patients with advanced RCC who underwent radical nephrectomy were analyzed. A 1.8 Mb multi-cancer panel (including 25 RCC-related genes, such as VHL, PBRM1, SETD2, and MET), comprising 181 target genes, 23 fusion genes, and 45 drug target lesions developed by Seoul National University Hospital, was used for this study. RESULTS: We extracted DNA from 30 of the 31 (96.7%) RCC specimens. Twenty-one patients (average age 63.3 ± 11.3 years) with clear cell RCC, 5 with papillary RCC, 3 with chromophobe RCC, and one patient, each with MiT family translocation carcinoma RCC and succinate dehydrogenase deficiency RCC, were analyzed. The sequencing depth was 430.8 ± 206.6 and 97 mutations (7.3 ± 2.7 mutations per patient) were detected. The most commonly mutated genes were VHL (46%), PBRM1 (30%), and BAP1, NOTCH4, and POLQ (23.33% each). Compared with TNM stage matched data from TCGA of clear cell RCC, VHL and PBRM1 are most common in both cohorts. Univariate and multivariate analyses revealed that tumor size (Hazard ratio = 2.47, p = 0.04) and PBRM1 (Hazard ratio = 28.69, p = 0.05) were related to metastasis in clear cell RCC. CONCLUSION: The pan-cancer panel comprised of RCC-related genes is a feasible and promising tool to evaluate genetic alterations in advanced RCC. However, large-scale studies and a focus on the clinical utility of this cancer panels is needed.

Intraoperative allogeneic blood transfusion is associated with adverse oncological outcomes in patients with surgically treated non-metastatic clear cell renal cell carcinoma.

BACKGROUND: The objective of this study was to provide more definitive information about the prognostic impact of perioperative blood transfusion (PBT) on patients with surgically treated renal cell carcinoma (RCC). METHODS: A database of 4019 patients with clear cell RCC, all of whom underwent radical or partial nephrectomy as primary therapy as part of a multi-institutional Korean collaboration between 1988 and 2015, was analyzed retrospectively. PBT was defined as transfusion of allogeneic red blood cells during surgery or postsurgical period. Receipt of a PBT, as well as the amount and time of blood transfusion (BT), was compared. RESULTS: Overall, 335 (8.3%) patients received a PBT: 84 received postoperative BT, 202 received intraoperative BT, and 49 received both intraoperative and postoperative BT. Patients receiving a PBT had a poor preoperative immuno-nutritional status, and aggressive tumor characteristics. Multivariate analyses identified PBT as an independent predictor of recurrence-free survival and cancer-specific survival. Prognostic impact of PBT was restricted to those with locally advanced stage (pT3-4), and who underwent radical nephrectomy. Among patients who received a PBT, intraoperative (but not postoperative) BT was a prognostic factor for survival. Among patients who received intraoperative BT, those receiving three or more transfusion units had a significantly worse survival. CONCLUSION: Receipt of a PBT was an independent predictor of RFS and CSS in patients with surgically treated RCC, specifically locally advanced disease. Regarding the prognostic impact of timing or dose of PBT on survival, intraoperative BT and ≥ 3 pRBC units were associated with adverse oncological outcomes.

Patients with Biopsy Gleason Score 3 + 4 Are Not Appropriate Candidates for Active Surveillance.

OBJECTIVE: The aim of this study was to evaluate the feasibility of including patients with biopsy Gleason score (bGS) 3 + 4 prostate cancer in an active surveillance (AS) protocol. METHODS: A total of 615 patients underwent a radical prostatectomy and satisfied the following requirements: prostate-specific antigen ≤10 ng/dL, clinical stage T1c or T2a, 2 or fewer positive biopsy cores, and bGS 6 or 3 + 4 prostate cancer. The patients were divided into two groups according to their bGS (bGS 6 group, n =534; bGS 3 + 4 group, n = 81). RESULTS: The adverse pathological features were significantly higher in the bGS 3 + 4 group (16.7 vs. 49.4%, p< 0.001). Biochemical recurrence (BCR)-free survival was also significantly lower in this group (p < 0.001). In a multivariate analysis, clinical stage (odds ratio [OR] 2.026, p =0.007), maximum percentage of biopsy core involvement (OR 1.015, p = 0.014), and bGS (OR 1.913, p = 0.030) were independent risk factors for adverse pathological features. However, the bGS was the only variable to forecast BCR (hazard ratio 3.567, p < 0.001). CONCLUSIONS: A bGS 3 + 4 was the leading risk factor for a worse postoperative prognosis. Therefore, patients with a bGS 3 + 4 are not appropriate candidates for AS.

Histone Demethylase KDM7A Regulates Androgen Receptor Activity, and Its Chemical Inhibitor TC-E 5002 Overcomes Cisplatin-Resistance in Bladder Cancer Cells.

Histone demethylase KDM7A regulates many biological processes, including differentiation, development, and the growth of several cancer cells. Here, we have focused on the role of KDM7A in bladder cancer cells, especially under drug-resistant conditions. When the KDM7A gene was knocked down, bladder cancer cell lines showed impaired cell growth, increased cell death, and reduced rates of cell migration. Biochemical studies revealed that KDM7A knockdown in the bladder cancer cells repressed the activity of androgen receptor (AR) through epigenetic regulation. When we developed a cisplatin-resistant bladder cancer cell line, we found that AR expression was highly elevated. Upon treatment with TC-E 5002, a chemical inhibitor of KDM7A, the cisplatin-resistant bladder cancer cells, showed decreased cell proliferation. In the mouse xenograft model, KDM7A knockdown or treatment with its inhibitor reduced the growth of the bladder tumor. We also observed the upregulation of KDM7A expression in patients with bladder cancer. The findings suggest that histone demethylase KDM7A mediates the growth of bladder cancer. Moreover, our findings highlight the therapeutic potential of the KMD7A inhibitor, TC-E 5002, in patients with cisplatin-resistant bladder cancer.

Histone Demethylase LSD1 Regulates Kidney Cancer Progression by Modulating Androgen Receptor Activity.

Kidney cancer is one of the most difficult cancers to treat by targeted and radiation therapy. Therefore, identifying key regulators in this cancer is especially important for finding new drugs. We focused on androgen receptor (AR) regulation by its epigenetic co-regulator lysine-specific histone demethylase 1 (LSD1) in kidney cancer development. LSD1 knock-down in kidney cancer cells decreased expression of AR target genes. Moreover, the binding of AR to target gene promoters was reduced and histone methylation status was changed in LSD1 knock-down kidney cancer cells. LSD1 knock-down also slowed growth and decreased the migration ability of kidney cancer cells. We found that pargyline, known as a LSD1 inhibitor, can reduce AR activity in kidney cancer cells. The treatment of kidney cancer cells with pargyline delayed growth and repressed epithelial-mesenchymal transition (EMT) markers. These effects were additively enhanced by co-treatment with the AR inhibitor enzalutamide. Down-regulation of LSD1 in renal cancer cells (RCC) attenuated in vivo tumor growth in a xenograft mouse model. These results provide evidence that LSD1 can regulate kidney cancer cell growth via epigenetic control of AR transcription factors and that LSD1 inhibitors may be good candidate drugs for treating kidney cancer.

Clinical outcomes of muscle invasive bladder Cancer according to the BASQ classification.

BACKGROUND: We evaluated the clinical efficacy and prognosis of muscle-invasive bladder cancer according to the basal/squamous-like (BASQ) classification system based on immunohistochemical staining [CK5/6(+), CK14(+), GATA3(-), and FOXA1(-)]. METHODS: One hundred patients diagnosed with muscle-invasive bladder cancer (cT2-4 N0-3 M0) were included in the study. All patients underwent radical cystectomy after transurethral removal of bladder tumor. Immunostaining was performed for CK5/6, CK14, FOXA1, and GATA3 antibodies on tissue microarray slides, and expression patterns were quantitatively analyzed using a scanning program. RESULTS: The median follow-up time was 77.4 (interquartile range: 39-120.9) months. The mean age of the patients was 65.1 ± 11.2 years. FOXA1 or CK14 expression greater than 1% was respectively positively and negatively correlated with overall survival (OS; p = 0.011 and p = 0.042, respectively), cancer-specific survival (CSS; p = 0.050 for both), and recurrence-free survival (RFS; p = 0.018 and p = 0.040, respectively). For CK5/6+ and GATA3- or FOXA1- expression, 10% CK5/6+ cells were negatively correlated with OS (p = 0.032 and p = 0.039, respectively) and with RFS in combination with FOXA1- only (p = 0.050). CONCLUSIONS: In this study, CK14 expression was associated with a poor prognosis. The new classification system of bladder cancer based on molecular characteristics is expected to helpful tool for the establishment of personalized treatment strategies and associated prediction of therapeutic responses.

Novel nomograms to predict recurrence and progression in primary non-muscle-invasive bladder cancer: validation of predictive efficacy in comparison with European Organization of Research and Treatment of Cancer scoring system.

PURPOSE: To develop and validate novel nomograms to predict recurrence and progression after transurethral resection of bladder tumor (TURBT) in Korean patients with non-muscle-invasive bladder cancer (NMIBC). METHODS: We retrospectively analyzed the clinical data on 970 newly diagnosed NMIBC patients after TURBT between 2000 and 2013 in a single institution. We used multivariate Cox proportional hazard models to identify the significant predictors of recurrence and progression, which resulted in the construction of the nomograms predicting the 5-year probability of recurrence and progression. We internally validated the nomograms using the area under the receiver-operating characteristics' curves and calibration plots. In addition, the clinical usefulness of each nomogram was assessed and compared with that of the European Organization of Research and Treatment of Cancer (EORTC)-scoring system using decision curve analysis (DCA). RESULTS: The significant factors related to recurrence were gross hematuria at diagnosis, previous or concomitant upper urinary tract urothelial carcinoma (UTUC), pT1 tumor, high tumor grade, multiple tumors, and intravesical therapy. The significant predictors of progression were previous or concomitant UTUC, pT1 tumor, high tumor grade, carcinoma in situ, and lymphovascular invasion. The 5-year predictive accuracy of each nomogram was 65% for recurrence and 70% for progression, respectively. Compared with the EORTC-scoring system, the nomograms were generally well calibrated. On DCA, each nomogram presented better net benefit gains than did the EORTC-scoring system across a wide range of threshold probabilities. CONCLUSIONS: Our novel nomograms are not completely accurate, but they show a reasonable level of discriminative ability, adequate calibration, and meaningful net benefit gain for the prediction of recurrence and progression after TURBT in Korean NMIBC patients. Additional external validation will be required to generalize the nomograms which we developed.

Late Recurrence of Bladder Cancer following Radical Cystectomy: Characteristics and Outcomes.

PURPOSE: There are only a few studies on characteristics and outcomes of late recurrence (LR) of urothelial carcinoma of bladder (UCB) after radical cystectomy (RC). The objective of this study was to assess characteristics and oncological outcomes of such LR that developed 5 years after RC. MATERIALS AND METHODS: We retrospectively reviewed 570 patients who underwent RC and bilateral regional lymphadenectomy for UCB at our institution. Comparisons of post-recurrence disease-specific survival (DSS) according to the timing of recurrence and the site of recurrence were performed using Kaplan-Meier survival curves and log-rank test. Cox regression model was fitted to assess factors for post-recurrence DSS. RESULTS: Disease recurrence occurred in 214 (37.5%) patients, including 20 (9.3%) who had LRs. Median time from RC to recurrence was 13.0 (interquartile range 6.0-32.0) months. There were no significant differences in clinicopathological factors between early- and late-recurrence groups. Post-recurrence 5-year DSS was not significantly different (21.6 vs. 14.1%, p = 0.344) between early- and late-recurrence groups. However, it was worse in the nonurothelial recurrence group compared to that in the urothelial recurrence group (14.0 vs. 19.4%, p = 0.056). Older age (HR 1.03, 95% CI 1.01-1.05, p = 0.001), nonorgan-confined disease at RC (HR 1.73, 95% CI 1.15-2.61, p = 0.008), and lymph node invasion (HR 1.58, 95% CI 1.01-2.45, p = 0.043) were significant predictors for post-recurrence 5-year DSS. CONCLUSIONS: LR after RC with lymphadenectomy is not common. However, it cannot be overlooked. LR had similar characteristics to early recurrence. Interestingly, the time to recurrence did not affect post-recurrence survival.

Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer.

Prostate cancer can be controlled by androgen-hormone treatment until the cancer becomes refractory. It is believed that hormone sensitivity is largely dependent on androgen receptor (AR) activity. Here, we found the histone demethylase KDM7A which demethylates histone H3K27 to be overexpressed in enzalutamide resistant castration-resistant prostate cancer cell line C4-2b, and investigated the molecular mechanism whereby androgen receptor activity is regulated by KDM7A. We engineered AR-positive LNCaP cells to stably express a short-hairpin RNA against KDM7A mRNA from a lentiviral vector. By measuring AR downstream gene expression after androgen stimulation, we found that a KDM7A-deficient cell line showed lower AR downstream gene expression compared to a control cell. KDM7A knock-down in LNCaP cell line caused decreased cell proliferation. Western blot analysis with modified-histone antibody revealed that the KDM7A-knock-down LNCaP cell line had increased H3K27 di-methylation. We confirmed KDM7A binding on AR target-gene promoters after hormone stimulation in chromatin-immunoprecipitation experiments. And increased H3K27 di-methylation was observed in KDM7A knock-down LNCaP stable cell. Treatment with KDM7A inhibitor, TC-E 5002, reduced proliferation and induced apoptosis of prostate cancer cells. Finally, we observed that the KDM7A protein was significantly upregulated in prostate cancer tissue, and that this difference correlated with the Gleason score. These data suggested that KDM7A is potentially a good therapeutic target for prostate cancer drugs and can be used as potentially a good prognostic indicator for prostate cancer and related treatment strategies.

Outcomes of pathologic stage T3a renal cell carcinoma up-staged from small renal tumor: emphasis on partial nephrectomy.

BACKGROUND: The prognosis of patients with pathologic stage T3a renal cell carcinoma (RCC) that is up-staged from a small renal tumor remains controversial. We evaluated the prognosis of patients with RCC who were up-staged from clinical stage T1 to pathologic stage T3a. METHODS: We retrospectively reviewed the data of 3431 patients who were surgically treated for clinical stage T1 RCC. The survival outcomes were compared using Kaplan-Meier and Cox proportional analyses. RESULTS: Among the clinical stage T1 patients, 215 (6.3%) were finally up-staged to pathologic stage T3a. Patient age (HR 1.302, 95% CI 1.018-1.046, p <  0.001), tumor diameter (HR 1.686, 95% CI 1.551-1.834, p <  0.001), and hilar location (HR 1.765, 95% CI 1.147-2.715, p = 0.010) were significantly associated with upstaging. Kaplan-Meier analyses showed significantly shorter recurrence-free, cancer-specific and overall survivals (all p <  0.001) in patients who were up-staged. Multivariate Cox analyses revealed pathologic upstaging as an independent predictor of shorter recurrence-free (HR 2.195, 95% CI 1.459-3.300, p <  0.001), cancer-specific (HR 2.238, 95% CI 1.252-4.003, p = 0.007), and overall survivals (HR 1.632, 95% CI 1.029-2.588, p = 0.037). Subgroup analysis of pathologic stage T3a showed no significant difference in survival of the partial nephrectomy group when compared to the radical nephrectomy group (all p > 0.5). CONCLUSIONS: Patients up-staged from clinical stage T1 to pathologic stage T3a RCC showed shorter survival outcomes than those without upstaging. However, partial nephrectomy, compared with radical nephrectomy, showed comparable outcomes in patients who were up-staged.

Predictors for the detection of prostate cancer and clinically significant prostate cancer using TRUS-guided biopsy in patients with negative initial biopsy results.

PURPOSE: We aimed to determine the predictors for the detection of prostate cancer and clinically significant prostate cancer in the setting of repeat prostate biopsy using trans-rectal ultrasonography-guided biopsy. METHODS: A total of 636 patients who underwent repeat prostate biopsy were included. The patients were divided into two groups according to the repeat biopsy results (with vs. without prostate cancer). A multivariable analysis was performed to assess the predictors for the detection of prostate cancer and clinically significant prostate cancer. RESULTS: Prostate cancer was detected in 98 patients (15.4%). Although there was no difference in the prostate-specific antigen velocity, the prostate-specific antigen density was higher in the patients with prostate cancer at the initial (0.14 vs. 0.17 ng/mL/cc, p = 0.049) and repeat biopsies (0.17 vs. 0.26 ng/mL/cc, p < 0.001). The proportions of the patients who met the active surveillance criteria were as follows: 22.4% (Johns Hopkins), 30.6% (University of Toronto), 32.7% (University of California at San Francisco), 30.6% (Prostate Cancer Research International Active Surveillance), 27.6% (Memorial Sloan Kettering Cancer Center), and 13.3% (University of Miami). In the multivariable analysis, age, hypoechoic lesion on trans-rectal ultrasonography, and prostate-specific antigen density at the repeat biopsy were the significant predictors for prostate cancer and clinically significant prostate cancer. CONCLUSIONS: Trans-rectal ultrasonography before repeat prostate biopsy and the prostate-specific antigen density are useful for selecting patients with a high probability for prostate cancer if repeat trans-rectal ultrasonography-guided biopsy is considered. In addition, these are also helpful for detecting clinically significant prostate cancer.