Real-world outcomes of patients with renal cell carcinoma, surgically treated at regional hospitals, based on a prospective long-term survey of the pre-robotic era.

PURPOSE: Renal cancer surgery is frequently performed in small regional hospitals in Japan. This study evaluated the outcomes of renal cancer surgery, comparing results from the pre-robotic surgery era with those obtained with robotic surgery. METHODS: This prospective cohort study was conducted on patients who underwent renal cancer surgery between 2008 and 2013 at 14 hospitals, comprising 13 regional hospitals and a university hospital, registered in the Tohoku Urological Evidence-Based Medicine Study Group. The patients' backgrounds; perioperative data; annual postoperative renal function; and prognostic surveys, performed over a median follow-up period of 10 years were obtained. RESULTS: In 930 surgical cases at the 14 registered hospitals, the 10-year recurrence-free survival rates of cT1a, cT1b, cT2, and cT3 were 0.9326, 0.8501, 0.5786, and 0.5101, respectively. Meanwhile, the 10-year overall survival rates were 0.9612, 0.8662, 0.7505, and 0.7209, respectively. Long-term observation in patients with cT1 showed that vessel involvement and high tumor grade were prognostic factors for recurrence. As a noteworthy fact, radical nephrectomy was performed in 53.3% of patients with cT1a at the regional hospitals. However, even in patients with preoperative chronic kidney disease stage 3, radical nephrectomy was not a prognostic factor of renal function. This indicates that compensatory mechanisms had been working for a long time in many patients who underwent radical nephrectomies without hypertension and preoperative proteinuria, which were predictors of end-stage renal disease. CONCLUSION: Based on a prospective long-term survey of the pre-robotic era, our results suggested no difference of the survival outcomes between the university hospital and regional hospitals. Our study provides baseline data to evaluate the outcomes of renal cancer robotic surgery, performed at regional hospitals.

Impact of Gleason pattern 5 on prognosis for newly diagnosed metastatic hormone-sensitive prostate cancer with Gleason score ≥8.

OBJECTIVE: We evaluated the impact of Gleason pattern 5 presence on prognosis among de novo metastatic hormone-sensitive prostate cancer patients with a Gleason score ≥8. METHODS: The data of 559 patients diagnosed as metastatic hormone-sensitive prostate cancer with a Gleason score ≥8, who were initially treated with androgen deprivation therapy from 2008 to 2016, were retrospectively collected. Patients were divided into two groups as high and low volume based on the CHAARTED trial criteria. RESULTS: The median overall survival of the 559 metastatic hormone-sensitive prostate cancer patients with Gleason score ≥8 was 70 months, with a median follow-up period of 36 months. Gleason pattern 5 was confirmed in 341 patients (61.0%), in which primary Gleason pattern 5 was confirmed in 164 patients (29.3%). The number of patients with high metastatic volume group was 363 (64.9%). In total and high metastatic volume groups, hemoglobin and lactate dehydrogenase were significant factors for predicting overall survival, but both Gleason pattern 5 and primary Gleason pattern 5 did not show a statistically significant difference. In the low-volume metastatic group, the median overall survival in patients with or without primary Gleason pattern 5 was 40 and 78 months, respectively. In multivariate analysis, only primary Gleason pattern 5 was an independent predictive factor for overall survival in the low-volume metastatic group (hazard ratio 2.76, 95% confidence interval 1.88-8.67; P = 0.0026). CONCLUSION: The presence of Gleason pattern 5 was not associated with overall survival in metastatic hormone-sensitive prostate cancer with a Gleason score ≥8. In low-metastatic volume metastatic hormone-sensitive prostate cancer, primary Gleason pattern 5 was a poor prognostic factor, which might show a separate treatment option for this group.

Impact of Nerve-Sparing Status on Positive Surgical Margin Location and Biochemical Recurrence in Patients with Prostate Cancer Post Radical Prostatectomy.

PURPOSE: This study was designed to assess the relationship between nerve-sparing (NS) status, positive surgical margin (PSM) location, and biochemical recurrence (BCR) based on a multicenter, radical prostatectomy (RP) database. METHODS: We retrospectively reviewed data from 726 patients who underwent RP without any neoadjuvant or adjuvant treatment between 2010 and 2014. We statistically assessed the impact of NS sides on PSM location and BCR. RESULTS: PSM rates were 21.9% in the 726 patients studied, 13.2% in patients with ≤pT2, and 46.8% in patients with ≥pT3. Regarding PSM locations, the anterior-apex (AA) was the most common site for PSM (43.3%). After adjusting for confounding factors, bilateral nerve sparing (BNS) had a significantly higher odds ratio of PSM than the absence of NS did (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.85-4.99). In the UNS RP in patients with ≤pT2, non-AA PSM on the non-NS side was significantly higher than that on the NS side (92.9% vs. 45.5%, p = 0.009). In all patients, 5.8% experienced BCR during a median follow-up of 43.5 months. PSM was significantly associated with BCR-free survival in patients with ≤pT2 (p = 0.013), but not in patients with ≥pT3 (p = 0.185). Non-AA PSM at the non-NS side was an independent risk factor for BCR (hazard ratio [HR] 2.56, 95% confidence interval [CI] 1.12-5.85), whereas AA PSMs, including NS/non-NS sides and non-AA PSM at the NS side, were not associated with BCR-free survival. CONCLUSIONS: Avoidance of non-AA PSM on the non-NS side may be rather important for maintaining BCR-free survival after RP.

Patient-reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial.

BACKGROUND: We evaluated patient-reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca). METHODS: A multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT-P questionnaires and EPIC urinary, bowel, and sexual bother subscales. RESULTS: The FACT-P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well-being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05). CONCLUSION: The PRO was significantly favorable in IADT on FACT-P total score at 20 M and 38 M, PWB and functional scores at 38 M.

Oncological outcomes for patients with locally advanced prostate cancer treated with neoadjuvant endocrine and external-beam radiation therapy followed by adjuvant continuous/intermittent endocrine therapy in an open-label, randomized, phase 3 trial.

BACKGROUND: To date, research has not determined the optimal procedure for adjuvant androgen deprivation therapy (ADT) in patients with locally advanced prostate cancer (PCa) treated for 6 months with neoadjuvant ADT and external-beam radiation therapy (EBRT). METHODS: A multicenter, randomized, phase 3 trial enrolled 303 patients with locally advanced PCa between 2001 and 2006. Participants were treated with neoadjuvant ADT for 6 months. Then, 280 patients whose prostate-specific antigen levels were less than pretreatment levels and less than 10 ng/mL were randomized. All 280 participants were treated with 72 Gy of EBRT in combination with adjuvant ADT for 8 months. Thereafter, participants were assigned to long-term ADT (5 years in all; arm 1) or intermittent ADT (arm 2). The primary endpoint was modified biochemical relapse-free survival (bRFS) with respect to nonmetastatic castration-resistant prostate cancer (nmCRPC) progression, clinical relapse, or any cause of death. RESULTS: The median follow-up time after randomization was 8.2 years. Among the 136 and 144 men assigned to trial arms 1 and 2, respectively, 24 and 30 progressed to nmCRPC or clinical relapse, and 5 and 6 died of PCa. The 5-year modified bRFS rates were 84.8% and 82.8% in trial arms 1 and 2, respectively (hazard ratio, 1.132; 95% confidence interval, 0.744-1.722). CONCLUSIONS: Although modified bRFS data did not demonstrate noninferiority for arm 2, intermittent adjuvant ADT after EBRT with 14 months of neoadjuvant and short-term adjuvant ADT is a promising treatment strategy, especially in a population of responders after 6 months of ADT for locally advanced PCa.

Clinical outcomes and prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy: a retrospective multicenter study in Japan.

PURPOSE: Clinical outcomes of patients with newly diagnosed metastatic hormone-naïve prostate cancer (mHNPC) and initially treated with androgen deprivation therapy (ADT) were evaluated. METHODS: The medical records of 605 consecutive mHNPC patients with initial ADT or combined androgen blockade (CAB) at nine study centers between 2008 and 2016 were retrospectively reviewed. Castration-resistant prostate cancer (CRPC)-free and overall survival (OS) were estimated by the Kaplan-Meier method. The association of pretreatment risk factors with CRPC-free survival and OS was evaluated by Cox proportional hazard models and differences in survival were classified by the number of risk factors. RESULTS: Median follow-up was 2.95 years, median CRPC-free survival was 21.9 months and median OS was 5.37 years. Multivariable analysis found that four risk factors, a Gleason score ≥ 9, lymph node metastasis, an extent of disease score ≥ 2, and serum LDH of > 220 IU were independently associated with both CRPC-free survival and OS. Median CRPC-free survival of low-risk patients with no or one factor was 86.5 months, 17.9 months in intermediate-risk patients with two or three factors, and 11.0 months in high-risk patients with four factors. Median OS was 4.72 years in intermediate- and 2.44 years in high-risk patients. It was not reached in low-risk patients. CONCLUSION: In this series, CRPC-free and OS of a subset of mHNPC patients in Japan who were treated with ADT or CAB had better CRPC-free and overall survivals in Japan. Risk-adapted treatment based on the presence of novel prognostic factors may be beneficial for selected mHNPC patients.

Clinical Characterization of Low Prostate-specific Antigen on Prognosis in Patients With Metastatic Castration-naive Prostate Cancer.

INTRODUCTION: This study aimed to investigate the effect of low prostate-specific antigen (PSA) on prognosis, as the association of initial PSA level with prognosis in patients with metastatic castration-naive prostate cancer (mCNPC) remains unclear. PATIENTS AND METHODS: We evaluated 575 patients with mCNPC from 10 hospitals. Patients were stratified into 2 groups according to their initial PSA: PSA < 100 and PSA ≥ 100 groups. We compared castration-resistant prostate cancer (CRPC)-free survival, overall survival (OS), and OS from the CRPC diagnosis between the groups. Multivariate Cox regression analysis was performed to evaluate the effect of initial PSA level on prognosis. RESULTS: Of the 575 patients, 196 (34%) patients belonged to the PSA < 100 group. No significant difference was found in patients' backgrounds except for PSA, the extent of disease, and high tumor burden between the groups. CRPC-free survival was significantly shorter in the PSA ≥ 100 group than in the PSA < 100 group. However, the OS after CRPC diagnosis was significantly shorter in the PSA < 100 group than that of the PSA ≥ 100 group. Multivariate analyses showed that PSA < 100 ng/mL was an independent factor for OS after CRPC, whereas no significant association was observed in the CRPC-free survival and OS. CONCLUSIONS: A significant effect of initial PSA < 100 ng/mL on OS after CRPC was observed. PSA < 100 ng/mL might be a poor prognostic factor in patients with mCNPC after CRPC.

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy.

BACKGROUND: The purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone-naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT). METHODS: At nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer-specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models. RESULTS: During a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5-year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5-year net CSS and OS survival gradually increased for all the patients. In patients given a 5-year survivorship, the conditional 5-year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) ≥2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors. CONCLUSIONS: The conditional 5-year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient's risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5-year follow-up. Conditional net survival can play a role in clinical decision-making, providing intriguing information for cancer survivors.

Prognostic significance of early changes in serum biomarker levels in patients with newly diagnosed metastatic prostate cancer.

We evaluated the impact of early changes in serum biomarker levels on the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC) who were initially treated with androgen deprivation therapy (ADT). We retrospectively investigated 330 patients with mHSPC whose serum maker levels were at baseline and at 2-4 months. An optimal Cox regression model was established with the highest optimism-corrected concordance index based on 10-fold cross-validation. The median cancer-specific survival (CSS) and overall survival (OS) were 7.08 and 6.47 years (median follow-up, 2.53 years), respectively. In the final optimal Cox model with serum biomarker levels treated as time-varying covariates, prostate-specific antigen (PSA), hemoglobin (Hb), and alkaline phosphatase (ALP) significantly increased the risk of poor survival in the context of both CSS and OS. Kaplan-Meier curves stratified by the three risk factors of high PSA, low Hb and high ALP desmondtated that median OS were not reached with none of these factors, 6.47 years with one or two factors, and 1.76 years with all three factors.Early changes in serum biomarker levels after ADT may be good prognostic markers for the survival of patients with mHSPC.

Impact of nadir PSA level and time to nadir during initial androgen deprivation therapy on prognosis in patients with metastatic castration-resistant prostate cancer.

PURPOSE: We determine whether the nadir prostate-specific antigen level (PSA nadir) and time to nadir (TTN) during initial androgen deprivation therapy (ADT) are prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: We reviewed the Michinoku Japan Urological Cancer Study Group database, including 321 mCRPC patients. Optimal cutoff values for PSA nadir and TTN on survival were calculated with the receiver operating characteristic (ROC) curve. Patients were stratified into unfavorable (higher PSA nadir and/or shorter TTN) and favorable (lower PSA nadir and longer TTN) groups. The inversed probability of treatment weighing (IPTW)-adjusted Cox proportional hazard model was performed to evaluate the impact of the unfavorable group on overall survival (OS) after CRPC diagnosis. RESULTS: Median age and follow-up period were 71 years and 35 months, respectively. ROC curve analysis demonstrated cutoffs of PSA nadir > 0.64 ng/mL and TTN < 7 months. The unfavorable group included 248 patients who had significantly shorter OS after mCRPC. The IPTW-adjusted multivariate model revealed that the unfavorable group had a negative impact on OS in mCRPC patients [hazards ratio (HR) 2.98, P < 0.001]. CONCLUSIONS: Higher PSA nadir and shorter TTN during the initial ADT are poor prognostic factors in patients with mCRPC.

Transient increase in lactate dehydrogenase after granulocyte colony-stimulating factor administration during chemotherapy in a patient with advanced seminoma.

INTRODUCTION: Granulocyte colony-stimulating factor is often reported to induce increases in lactate dehydrogenase, complicating the evaluation of treatment effects on germ cell tumors. CASE PRESENTATION: A 30-year-old patient was diagnosed with left testicular seminoma showing enlarged para-aortic lymph nodes and a retroperitoneal tumor. Serum levels of lactate dehydrogenase were elevated. Three cycles of bleomycin, etoposide, and cisplatin were administered. After chemotherapy, computed tomography showed marked reduction in the metastatic sites. However, serum lactate dehydrogenase levels increased transiently at the end of each course of chemotherapy. In consideration of the residual tumors, one cycle of another chemotherapy was added. Five months after final chemotherapy, lactate dehydrogenase remained within normal limits with no evidence of tumor recurrence. CONCLUSION: In our case, transient elevation of lactate dehydrogenase was considered relevant to granulocyte colony-stimulating factor use. Examination of lactate dehydrogenase isoenzymes may be helpful to estimate the cause of serum lactate dehydrogenase elevation.

Radical Prostatectomy With and Without Neoadjuvant Chemohormonal Pretreatment for High-Risk Localized Prostate Cancer: A Comparative Propensity Score Matched Analysis.

BACKGROUND: To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP). PATIENTS AND METHODS: Our NCHT protocol involved complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) plus estramustine phosphate (560 mg). NCHT was provided to 60 patients with PCa before RP, and we compared the clinical and pathologic outcomes with those of 349 patients with high-risk PCa who underwent RP alone using propensity score matching. The data for those who underwent RP alone were obtained from the Michinoku Japan Urological Cancer Study Group database. RESULTS: In the NCHT group, 10.0% experienced pathologic complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien-Dindo grade III or higher) after RP. The median follow-up duration was 42.5 months, and the 5-year biochemical recurrence (BCR)-free survival was 60.1%. In multivariate analysis, pN+ was an independent prognostic factor for BCR (hazard ratio = 5.251, 95%CI 1.300-21.201; P = .020). In propensity score matching, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = .021). In subgroup analyses, the BCR rate in patients with a single high-risk factor was significantly lower in the NCHT group than in the RP-alone group (P = .027). CONCLUSION: NCHT before RP can reduce the risk of BCR in patients with high-risk PCa, particularly if a single high-risk factor is present. However, the potential for perioperative complications should be considered.

Impact of nutritional status on the prognosis of patients with metastatic hormone-naïve prostate cancer: a multicenter retrospective cohort study in Japan.

PURPOSE: To investigate the association between the Geriatric Nutritional Risk Index (GNRI) and prognosis of patients with metastatic hormone-naïve prostate cancer (mHNPC) and to design the optimal risk score predicting for prognosis. METHODS: We retrospectively reviewed data from the Michinoku Japan Urological Cancer Study Group database, containing information about 656 patients with mHNPC who initially received androgen-deprivation therapy between 2005 and 2017. The baseline GNRI was calculated using serum albumin level and body mass index. Poor nutrition was defined as GNRI < 92.0. The impact of GNRI, CHAARTED criteria, and laboratory parameters on oncological outcomes was investigated using the multivariable Cox regression models. We developed the risk comprising GNRI and laboratory parameters and compared its prognostic performance with the CHAARTED criteria using the receiver operating characteristic curve with the DeLong method. RESULTS: Of 339 patients with sufficient data, 66 (19%) were diagnosed with poor nutrition. Multivariate analyses showed that GNRI < 92.0 was an independent prognostic factor of cancer-specific survival [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.04-2.98, P = 0.035] and overall survival (HR 1.80; 95% CI 1.13-2.89, P = 0.013), in addition to hemoglobin (Hb) and lactic dehydrogenase (LDH) levels. We designed the risk score comprising GNRI < 92.0, Hb < 13.0 g/dL, and LDH > 222 IU/L. The predictive value of the risk score was significantly superior to that of the CHAARTED criteria. CONCLUSIONS: Poor nutrition may predict mortality in patients with mHNPC. Risk factors, such as nutritional status and laboratory parameters, may be useful in decision-making regarding aggressive treatments for patients with mHNPC.

Can single positive core prostate cancer at biopsy be considered a low-risk disease?

PURPOSE: Prostate cancer (PCa) may be a multifocal or bilateral disease. A single positive biopsy core is usually associated with indolent PCa, and doctors may choose to perform active surveillance or focal therapy. We investigated the correlation between finding a single positive biopsy core and the pathological outcome after radical prostatectomy (RP). METHODS: Data from the Michinoku Japan Urological Cancer Study Group database including pre- and post-operative information, on 1928 consecutive patients with PCa treated with RP alone at four institutions was used. Among them, 503 patients with a single positive core PCa were followed up, and the clinical and pathological parameters influencing prognosis were analyzed. RESULTS: Of the 503 patients, 258 (51.3%) had pathological findings ≥ pT2c and 160 (32%) had an undergraded Gleason Score (GS) based on their biopsy findings. A total of 112 patients (39.5%) with clinical T1c developed bilateral tumors (pT2c-T3). The rate of developing pT3 tumors in the single positive core group was significantly higher than that of the multiple positive core group. Moreover, there was no significant difference in the number of pT3b patients between the single and multiple positive core PCa groups. CONCLUSIONS: Based on analysis of radical prostatectomy specimens, positive core PCa can lead to clinically significant disease, with considerable rates of pT3. For patients with PCa and a positive prostate biopsy core, definitive therapy such as RP should be considered.

Cost-effectiveness comparison between neoadjuvant chemohormonal therapy and extended pelvic lymph node dissection in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis.

The aim of the present study was to assess the cost-effectiveness of extended pelvic lymph node dissection (ePLND) compared to neoadjuvant chemohormonal therapy using gonadotropin-releasing hormone agonist/antagonist and estramustine. We retrospectively analyzed data within Michinoku Urological Cancer Study Group database containing 2971 PC patients treated with radical prostatectomy (RP) at four institutes between July 1996 and July 2017. We identified 237 and 403 high-risk patients who underwent RP and ePLND (ePLND group), and neoadjuvant chemohormonal therapy followed by RP and limited PLND (neoadjuvant group), respectively. The oncological outcomes and cost-effectiveness were compared between groups. Medical cost calculation focused on PC-related medication and adjuvant radiotherapy. Biochemical recurrence-free and overall survival rates in the neoadjuvant group were significantly higher than those in the ePLND group. Significantly higher number of patients progressed to castration-resistant PC in the ePLND group than in the neoadjuvant group. Background-adjusted multivariate Cox regression analysis using inverse probability of treatment weighting (IPTW) revealed that neoadjuvant chemohormonal therapy independently reduced the risk of biochemical recurrence after RP. The 5-year cost per person was significantly higher in the ePLND group than in the neoadjuvant group. Although the present study was retrospective, neoadjuvant chemohormonal therapy followed by RP as a concurrent strategy has potential to improve oncological outcome and cost-effectiveness.

Long non-coding RNA HOTAIR promotes cell migration by upregulating insulin growth factor-binding protein 2 in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most lethal urologic cancers. About one-third of RCC patients already have distal metastasis at the time of diagnosis. There is growing evidence that Hox antisense intergenic RNA (HOTAIR) plays essential roles in metastasis in several types of cancers. However, the precise mechanism by which HOTAIR enhances malignancy remains unclear, especially in RCC. Here, we demonstrated that HOTAIR enhances RCC-cell migration by regulating the insulin growth factor-binding protein 2 (IGFBP2) expression. HOTAIR expression in tumors was significantly correlated with nuclear grade, lymph-node metastasis, and lung metastasis. High HOTAIR expression was associated with a poor prognosis in both our dataset and The Cancer Genome Atlas dataset. Migratory capacity was enhanced in RCC cell lines in a HOTAIR-dependent manner. HOTAIR overexpression accelerated tumorigenicity and lung metastasis in immunodeficient mice. Microarray analysis revealed that IGFBP2 expression was upregulated in HOTAIR-overexpressing cells compared with control cells. The enhanced migration activity of HOTAIR-overexpressing cells was attenuated by IGFBP2 knockdown. IGFBP2 and HOTAIR were co-expressed in clinical RCC samples. Our findings suggest that the HOTAIR-IGFBP2 axis plays critical roles in RCC metastasis and may serve as a novel therapeutic target for advanced RCC.

Efficacy of early ureteral ligation on prevention of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: a prospective single-arm multicenter clinical trial.

OBJECTIVE: The rate of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma is high. Seeding upper urinary tract urothelial carcinoma cells onto the damaged bladder wall is considered to be one of the causes of intravesical recurrence after radical nephroureterectomy. We evaluated the utility of early ureteral ligation in preventing the intravesical recurrence. METHODS: This prospective single-arm clinical trial included patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma in the Tohoku Urological Evidence-Based Medicine Study Group between 2012 and 2013. Early ureteral ligation was defined as ligation of the ureter as quickly as possible after expanding the retroperitoneal space. A historical control was extracted from 454 patients who underwent radical nephroureterectomy in the same group, using propensity score-matched analysis. Intravesical recurrence-free survival rates were analyzed using Kaplan-Meier curves. Factors predicting intravesical recurrence were assessed using multivariate analyses. RESULTS: Seventy-four patients underwent early ureteral ligation. Seventeen (23%) patients had intravesical recurrence with a median follow-up period of 24 months. The 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 81% and 76%, and in the control group 75% and 63%, respectively (P = 0.160). In patients with renal pelvic cancer, the 1- and 2-year intravesical recurrence-free survival rates in the early ureteral ligation group were 89% and 86%, but in the control group 74% and 64%, respectively (P = 0.025). However, intravesical recurrence-free survival rates were similar in patients with ureteral cancer. Multivariate analyses of a subset of patients with renal pelvic cancer identified early ureteral ligation as an independent predictor of intravesical recurrence. CONCLUSIONS: Early ureteral ligation decreases the rate of intravesical recurrence after radical nephroureterectomy in patients with renal pelvic cancer. Thus, early ureteral ligation might help in prevention of intravesical recurrence for renal pelvic cancer.

Clinical implications of serum N-glycan profiling as a diagnostic and prognostic biomarker in germ-cell tumors.

Serum biomarker monitoring is essential for management of germ-cell tumors (GCT). However, not all GCT are positive for conventional tumor markers. We examined whether serum N-glycan-based biomarkers can be applied for detection and prognosis in patients with GCT. We performed a comprehensive N-glycan structural analysis of sera from 54 untreated GCT patients and 103 age-adjusted healthy volunteers using glycoblotting methods and mass spectrometry. Candidate N-glycans were selected from those with the highest association; cutoff concentration values were established, and an N-glycan score was created based on the number of positive N-glycans present. The validity of this score for diagnosis and prognosis was analyzed using a receiver operating characteristic (ROC) curve. We identified five candidate N-glycans significantly associated with GCT patients. The accuracy of the N-glycan score for GCT was significant with an area-under-the-curve (AUC) value of 0.87. Diagnostically, the N-glycan score detected 10 of 12 (83%) patients with negative conventional tumor markers. Prognostically, the N-glycan score comprised four candidate N-glycans. The predictive value of the prognostic N-glycan score was significant, with an AUC value of 0.89. A high value prognostic N-glycan score was significantly associated with poor prognosis. Finally, to identify a potential carrier protein, immunoglobulin (Ig) fractions of sera were subjected to N-glycan analysis and compared to whole sera. Candidate N-glycans in Ig-fractions were significantly decreased; therefore, the carrier protein for candidate N-glycans is likely not an immunoglobulin. In summary, our newly developed N-glycan score seems to be a practical diagnostic and prognostic method for GCT.

The impact of extended lymph node dissection versus neoadjuvant therapy with limited lymph node dissection on biochemical recurrence in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis.

The optimal treatment for high-risk prostate cancer (Pca) remains to be established. The current guidelines recommend extended pelvic lymph node dissection (e-PLND) for selected intermediate- and high-risk patients treated with RP. However, the indications, optimal extent, and therapeutic benefits of e-PLND remain unclear. The aim of this study was to assess whether e-PLND confers an oncological benefit for high-risk Pca compared to neoadjuvant luteinizing hormone-releasing hormone and estramustine (LHRH + EMP). The Michinoku Urological Cancer Study Group database contained the data of 2403 consecutive Pca patients treated with RP at four institutes between March 2000 and December 2014. In the e-PLND group, we identified 238 high-risk Pca patients who underwent RP and e-PLND, with lymphatic tissue removal around the obturator and the external iliac regions, and hypogastric lymph node dissection. The neoadjuvant therapy with limited PLND (l-PLND) group included 280 high-risk Pca patients who underwent RP and removal of the obturator node chain between September 2005 and June 2014 at Hirosaki University. The outcome measure was BRFS. The 5-year biochemical recurrence-free survival rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9 and 54.7%, respectively (P < 0.0001). The operative time was significantly longer in the e-PLND group compared to that of the neoadjuvant therapy with l-PLND group. Grade 3/4 surgery-related complications were not identified in both groups. Although the present study was not randomized, neoadjuvant LHRH + EMP therapy followed by RP might reduce the risk of biochemical recurrence.

Clinical implications of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

OBJECTIVES: To characterize the site and clinical implications of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: Patients who underwent radical nephroureterectomy for upper urinary tract urothelial carcinoma between 2000 and 2011 at 12 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were included in the present study. Those who underwent prior or simultaneous radical cystectomy were excluded. The site of intravesical recurrence was investigated, and the survival curves after radical nephroureterectomy were analyzed retrospectively using the Kaplan-Meier method. Multivariate analyses of factors predicting survival were carried out. RESULTS: A total of 534 patients were eligible for the present study. With a median follow up of 47 months, 205 patients (38.4%) had intravesical recurrence. The intravesical recurrence-free survival rates at 1, 2, and 5 years were 74.6%, 62.5% and 56.3%, respectively. In a subset of 137 patients with intravesical recurrence who did not have bladder cancer before or at the diagnosis of upper urinary tract urothelial carcinoma, the most frequent site of intravesical recurrence was around the cystotomy (52.6%), followed by at the posterior wall (39.4%) and at the bladder neck (35.8%). A total of 36 patients (17.6%) developed muscle-invasive bladder cancer after radical nephroureterectomy. On multivariate analyses for the subset of patients with non-muscle invasive (≤pT1) upper urinary tract urothelial carcinoma, intravesical recurrence was an independent predictor of cancer-specific survival (HR 4.27, P = 0.016) and overall survival (HR 3.00, P = 0.018). CONCLUSIONS: Most intravesical recurrences occur around the site of bladder mucosal injury within 1 year after radical nephroureterectomy, providing important insight into the mechanism of intravesical recurrence. Intravesical recurrence after radical nephroureterectomy had an impact on oncological outcomes of patients with non-muscle invasive upper urinary tract urothelial carcinoma.