Improving compliance with guidelines may lead to favorable clinical outcomes for patients with non-muscle-invasive bladder cancer: A retrospective multicenter study.

OBJECTIVES: Clinical guidelines recommend that patients with non-muscle-invasive bladder cancer (NMIBC) should be treated with appropriate adjuvant therapy. However, compliance with guideline recommendations is insufficient, and this may lead to unfavorable outcomes. We aimed to investigate the level of adherence to guideline recommendations in patients with NMIBC and evaluate the outcomes of those who did and did not receive guideline-recommended therapies. METHODS: We performed a retrospective analysis of patients with histologically diagnosed NMIBC. The percentage of patients with intermediate- and high-risk tumors who received adjuvant intravesical therapy or second transurethral resection (TUR) was calculated. Recurrence-free survival was assessed in patients who did and did not receive the therapies. We conducted a propensity score-matched analysis to compare outcomes between patients with intermediate-risk and T1 NMIBC who did and did not undergo guideline-recommended therapies. RESULTS: Overall, 1204 patients from the Tohoku Urological Evidence-Based Medicine Study Group and Kyoto University Hospital were included. Of patients with intermediate- and high-risk tumors, 91.0% and 74.0% did not receive maintenance bacillus Calmette-Guérin (BCG), respectively. In both groups, significantly better recurrence-free survival was found for patients treated with maintenance BCG. Among patients with T1 NMIBC, only 16.7% underwent guideline-recommended therapies, that is, a second TUR and maintenance BCG. Significantly greater recurrence-free survival was observed in patients who received guideline-recommended therapies compared with propensity-matched patients who did not. CONCLUSIONS: Guideline-recommended therapies may contribute to improvements in outcomes for patients with NMIBC, suggesting that improvements in adherence to clinical guidelines may lead to favorable outcomes.

Penile blood pressure is useful to identify candidates for tadalafil treatment in patients with lower urinary tract symptoms.

OBJECTIVES: To determine whether penile blood pressure (PBP) can be used to identify patients who can benefit from tadalafil treatment, the correlation between PBP at baseline and changes in lower urinary tract symptoms (LUTS) induced by tadalafil treatment was studied prospectively. PATIENTS AND METHODS: Patients with BPH who were poor responders to α1 -blockers and took tadalafil instead of an α1 -blocker were registered between 2014 and 2016. The patients were divided into two groups (low- and high-PBP groups) using the median baseline PBP of 110 mmHg as the threshold. The changes in the International Prostate Symptom Score (IPSS) between before and at 4 and 12 weeks after tadalafil treatment were compared between the low- and high-PBP groups. Multivariate analysis was performed to identify parameters associated with IPSS improvement with tadalafil treatment. RESULTS: In all, 51 patients were investigated. The IPSS in the low-PBP group decreased immediately after the start of treatment, and there was significant improvement in the IPSS from baseline at 4 and 12 weeks after the start of treatment, whilst the IPSS in the high-PBP group did not show significant changes. On multivariate analysis, PBP at baseline, anticholinergic drug use, and IPSS at baseline were significant predictors of a good IPSS response to tadalafil treatment. CONCLUSIONS: This study demonstrated that PBP could reliably identify patients with BPH who could benefit from tadalafil treatment. Patients with low PBP could be better responders to tadalafil.

Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the THPMG trial.

OBJECTIVE: The Pirarubicin Monotherapy Study Group trial was a randomized Phase II study that evaluated the efficacy of intravesical instillation of pirarubicin in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. This study conducted further analysis of the Pirarubicin Monotherapy Study Group cohort, focusing on intravesical seeding of cancer cells. METHODS: Using the data from the Pirarubicin Monotherapy Study Group trial, bladder recurrence-free survival rates and factors associated with bladder recurrence in the control group were analyzed. RESULTS: Of 36 patients in the control group, 14 with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative cytology (P = 0.004). Based on the multivariate analysis in the control group, voided urine cytology was an independent predictive factor of bladder recurrence (hazard ratio, 5.54; 95% confidence interval 1.12-27.5; P = 0.036). Of 72 patients in the Pirarubicin Monotherapy Study Group trial, 31 had positive urine cytology. Among the 31 patients, 17 patients who received pirarubicin instillation had fewer recurrences when compared with 14 patients who received control treatment (P = 0.0001). On multivariate analysis, pirarubicin instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (hazard ratio, 0.02; 95% confidence interval, 0.00-0.53; P = 0.018). Of 21 patients with bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium. CONCLUSIONS: Intravesical instillation of pirarubicin immediately after nephroureterectomy significantly reduced the bladder recurrence rate in patients with positive voided urine cytology. The results suggest that intravesical seeding of upper urinary tract urothelial carcinoma occurs during nephroureterectomy.

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.

Core 2 N-acetylglucosaminyltransferase-1 expression induces aggressive potential of testicular germ cell tumor.

We studied orchiectomy specimens from 130 patients immuhistochemically with testicular germ cell tumor (TGCT) using anti-core 2 N-acetylglucosaminyltransferase-1 (C2GnT-1) antibody. The incidence of C2GnT-1 positivity in stage I disease (29.5%, 21/71) was significantly lower than that in higher stages (84.7%, 50/59) (P < 0.001, chi(2) test). This significant difference was also found when the cases were divided into seminoma and NSGCT according to histopathological classification. Kaplan-Meier plots and the log rank test showed that in the patients with stage I seminoma, C2GnT-1-positive cases had a higher risk for recurrence (P < 0.001). This was also the case with the patients with stage I NSGCT (P < 0.001). To determine whether C2GnT-1 promotes aggressive behavior of cancer cells, a C2GnT-1-negative human TGCT cell line, JKT-1, was stably transfected with a mammalian expression vector containing C2GnT-1 cDNA. In vitro assays revealed that JKT-1-C2 cells are more invasive than mock transfectants, although there are no differences in proliferation activity. When orthotopically inoculated into athymic nude mice, JKT-1-C2 cells produced larger testicular tumors extending to the retroperitoneum with mesenteric metastasis, while mock transfectants produced small tumors without metastasis (P < 0.01, Mann-Whitney's U-test). When injected via the tail vein, JKT-1-C2 cells produced a number of metastatic lung foci. In contrast, mock transfectants produced a small number of nodules (p < 0.01, Mann-Whitney's U-test). These results strongly suggest that C2GnT-1 enhances the metastatic potential of TGCT and may be a reliable biomarker for aggressive potential of TGCT.

Two cases of anaphylaxis due to contrast media during administration of nivolumab and ipilimumab in metastatic renal cell carcinoma.

A combination therapy of nivolumab and ipilimumab is effective for advanced renal cell carcinoma, but there are concerns about immune-related adverse events. A 46-year-old man was hospitalized for metastatic renal cell carcinoma. On day 9, he received nivolumab and ipilimumab. On days 16 and 49, he presented with fever, skin rash, and hypotension after contrast-enhanced computed tomography. A 70-year-old man was hospitalized for metastatic renal cell carcinoma. On day 9, he received nivolumab and ipilimumab. On day 44, he presented with fever, skin rash, and hypotension after contrast-enhanced computed tomography. Both patients were diagnosed with anaphylaxis due to the contrast agent.

Systemic treatment for coexisting mucinous urethral adenocarcinoma and prostate adenocarcinoma.

INTRODUCTION: Mucinous urethral adenocarcinoma is a rare and progressive cancer of the prostatic urethra. Reports on palliative systemic treatment for mucinous urethral adenocarcinoma are few. We present a case of coexisting mucinous urethral and prostate adenocarcinomas managed with systemic treatment. CASE PRESENTATION: A 66-year-old man presented with gross hematuria and urinary retention. Prostate-specific antigen level was elevated, at 99 ng/mL, and prostate biopsy revealed moderately to poorly differentiated adenocarcinoma. Hormone therapy and standard chemotherapy for prostate adenocarcinoma were ineffective. Prostate re-biopsy revealed coexisting mucinous urethral and prostate adenocarcinomas. Gemcitabine + cisplatin chemotherapy and folinic acid + 5-fluorouracil + irinotecan chemotherapy temporarily suppressed the cancer, but 14 months after presentation, he developed liver metastasis and died. Autopsy revealed metastasis of both mucinous urethral adenocarcinoma and carcinosarcoma. CONCLUSION: Mucinous urethral adenocarcinoma is difficult to diagnose in coexistence with prostate adenocarcinoma. This was an extremely rare case showing chemoresistance due to epithelial-mesenchymal transition.

Case of atypical femoral fractures that mimicked the typical imaging findings of prostate cancer-induced bone metastasis.

INTRODUCTION: Atypical femoral fractures are atraumatic or minimally traumatic fractures and rare side effects of bone resorption inhibitors. Bone resorption inhibitors are frequently used in the treatment of prostate cancer. CASE PRESENTATION: A 62-year-old man complained of difficulty in walking and left lower limb pain. Androgen deprivation and denosumab therapy for prostate cancer-induced bone metastasis was initiated 27 months ago. Even though the prostate-specific antigen level did not increase, imaging studies indicated the possibility of bone metastasis. The patient underwent bone biopsy; however, no malignancy was detected. Afterward, he had a fall, causing a complete fracture in his left femur. CONCLUSION: Atypical femoral fractures occasionally mimic typical imaging findings and outcomes of bone metastasis. This case is important for recognizing such cases.

Positive expressions of N-acetylglucosaminyltransferase-V (GnT-V) and beta1-6 branching N-linked oligosaccharides in human testicular germ cells diminish during malignant transformation and progression.

N-acetylglucosaminyltransferase-V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagines (N)-linked oligosaccharides of cell proteins. We examined the implication of GnT-V and beta1-6 branching N-linked oligosaccharide expression in human testicular germ cells during malignant transformation and cancer progression. We analyzed immuhistochemically orchiectomy specimens of 130 patients with testicular germ cell tumors (TGCT) using anti-GnT-V monoclonal antibody, and compared GnT-V expression with clinicopathological features. N-linked oligosaccharide structural analysis was also performed to confirm the oligosaccharide profile produced by GnT-V. GnT-V was positive in all normal testis samples. This positive incidence declined in TGCT according to clinical stage; 16/71 (22.5%) in stage I, and 3/59 (5.1%) in stage II/III (p=0.015, chi(2) test). When divided into pathological subtypes, GnT-V positive incidences in stage I seminoma, stage II/III seminoma, stage I non-seminomatous germ cell tumor (NSGCT), and stage II/III NSGCT were 3/43 (7%), 0/22 (0%), 13/28 (46.4%), and 3/37 (8.1%), respectively. In stage I NSGCT, patients with GnT-V-negative tumor samples were at a significantly higher risk of recurrence than those with GnT-V-positive tumors (p=0.015, log-rank test). N-linked oligosaccharide structural analysis revealed that a normal testis has three kinds of beta1-6 branching N-linked oligosaccharides, all of which are downregulated in TGCT tissues. These results suggest that GnT-V and beta1-6 branching N-linked oligosaccharide expressions are downregulated during carcinogenesis and progression of human TGCT. GnT-V may be a promising recurrence predictor for stage I NSGCT.

N-acetylglucosaminyltransferase V and beta1-6 branching N-linked oligosaccharides are associated with good prognosis of patients with bladder cancer.

PURPOSE: N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. We examined the relationship between GnT-V expression and clinicopathologic features of the patients with bladder cancer. EXPERIMENTAL DESIGN: We immunohistochemically examined GnT-V expression in paraffin-embedded bladder cancer specimen using anti-GnT-V monoclonal antibody. We compared GnT-V expression with cause-specific survival of the patients with bladder cancer treated by radical cystectomy. Kaplan-Meier survival curves were generated to show the cause-specific survival. Univariate and multivariate analyses were carried out to compare GnT-V expression with other clinical and pathologic variables. We also evaluated mRNA expression of GnT-V and N-linked oligosaccharide structure in bladder cancer specimens. RESULTS: Immunohistochemistry revealed that GnT-V expression inversely correlated with tumor grade and stage. The incidence of positive GnT-V expression in bladder cancer was significantly higher in low-grade/superficial cancer than in high-grade/invasive cancer. The patients whose tumor was positive for GnT-V survived significantly longer than those whose tumor was negative for GnT-V. Univariate and multivariate analyses revealed that GnT-V expression was an independent predictor of prognosis of the patient. The expression of GnT-V mRNA determined by reverse transcription-PCR was consistent with the results with immunohistochemistry for tumor samples. Carbohydrate structural analysis revealed that superficial bladder cancer is rich in branched N-linked oligosaccharides, for which biosynthesis GnT-V is responsible. CONCLUSIONS: GnT-V and its resultant beta1-6 branching N-linked oligosaccharides are closely related to low malignant potential and good prognosis of the patients with bladder cancer.

Clinical predictors of the estimated glomerular filtration rate 1 year after radical nephrectomy in Japanese patients.

PURPOSE: To evaluate renal function 1 year after radical nephrectomy (RN) for renal cell carcinoma, the preoperative predictors of postnephrectomy renal function were investigated by sex, and equations to predict the estimated glomerular filtration rate (eGFR) 1 year after RN were developed. MATERIALS AND METHODS: A total of 525 patients who underwent RN between May 2007 and August 2011 at Tohoku University Hospital and its affiliated hospitals were prospectively evaluated. Overall, 422 patients were analyzed in this study. RESULTS: Independent preoperative factors associated with postnephrectomy renal function were different in males and females. Preoperative eGFR, age, tumor size, and body mass index (BMI) were independent factors in males, while tumor size and BMI were not independent factors in females. The equations developed to predict eGFR 1 year after RN were: Predicted eGFR in males (mL/min/1.73 m2)=27.99-(0.196×age)+(0.497×eGFR)+(0.744×tumor size)-(0.339×BMI); and predicted eGFR in females=44.57-(0.275×age)+(0.298×eGFR). The equations were validated in the validation dataset (R2=0.63, p<0.0001 and R2=0.31, p<0.0001, respectively). CONCLUSIONS: The developed equations by sex enable better prediction of eGFR 1 year after RN. The equations will be useful for preoperative patient counseling and selection of the type of surgical procedure in elective partial or RN cases.

Functional correlation of trophinin expression with the malignancy of testicular germ cell tumor.

Trophinin is a membrane protein that is potentially involved in human embryo implantation by mediating homophillic cell adhesion between trophoblastic cells and endometrial cells. Trophinin expression by maternal cells may be induced by the embryo that secretes human chorionic gonadotropin (hCG). Because the process of tumor metastasis resembles that of trophoblast invasion and proliferation during embryo implantation, we hypothesized that testicular cancers that synthesize hCG express trophinin thus becoming aggressive trophoblast-like cells. We screened paraffin-embedded orchiectomy specimens of 158 patients with testicular germ cell tumor by immunohistochemistry using antitrophinin antibody. This screening identified trophinin-positive specimens with the frequencies 39 of 91 (43%) in stage I, 14 of 24 (58%) in stage II, and 41 of 43 (95%) in stage III (P < 0.001). Thus, trophinin expression positively correlates with clinical stage. Remarkably, trophinin was found in all of the cases (33 of 33) with lung metastasis. The levels of serum hCG-beta were significantly higher in the patients with trophinin-positive tumors than those with trophinin-negative tumors (P = 0.004). To determine whether trophinin promotes aggressiveness of the cell, trophinin-negative human seminona cell line JKT-1 was stably transfected with a mammalian expression vector containing trophinin cDNA. In vitro assays revealed that trophinin-expressing JKT-1-Tro cells are more invasive than JKT-1-mock cells, whereas there are no differences between JKT-1-Tro and JKT-1-mock in their proliferation activity. Upon orthotopic inoculation to athymic nude mice, JKT-1-Tro cells exhibited i.p. metastases in all of the mice (n = 5), whereas JKT-1-mock produced no metastases (n = 5). These results suggest strongly that trophinin enhances invasiveness of the cells and promotes metastasis of testicular germ cell tumor.

[Renal cell carcinoma metastatic to the base of tongue: a case report].

A 66-year-old male patient underwent left radical nephrectomy for stage III renal cell carcinoma (RCC) two years and eight months previously. He complained of discomfort at his pharynx. An otolaryngeal examination revealed a tumor about 1.3 cm in size at the base of tongue, and the tumor was resected. It was pathologically diagnosed as clear cell carcinoma and as tongue metastasis of RCC. The subsequent appearance of a minute pulmonary metastasis caused the administration of interferon-alpha and interleukin-II. At present, two years after the treatment, neither growth of lung metastasis nor recurrence of tongue tumor are noticed. Tongue metastasis of RCC is rare and its prognosis is poor. This is the 17th case reported in Japan.

Prospective randomized phase II trial of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma: the THP Monotherapy Study Group Trial.

PURPOSE: We evaluated the efficacy of a single early intravesical instillation of pirarubicin (THP) in the prevention of bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: From December 2005 to November 2008, 77 patients clinically diagnosed with UUT-UC from 11 institutions participating in the Tohoku Urological Evidence-Based Medicine Study Group were preoperatively enrolled in this study. Patients were randomly assigned to receive or not receive a single instillation of THP (30 mg in 30 mL of saline) into the bladder within 48 hours after nephroureterectomy. Cystoscopy and urinary cytology were repeated every 3 months for 2 years or until the occurrence of first bladder recurrence. RESULTS: Seventy-two patients were evaluable for efficacy analysis, 21 of whom had a subsequent bladder recurrence. Significantly fewer patients who received THP had a recurrence compared with the control group (16.9% at 1 year and 16.9% at 2 years in the THP group v 31.8% at 1 year and 42.2% at 2 years in the control group; log-rank P = .025). No remarkable adverse events were observed in the THP-treated group. Based on multivariate analysis, THP instillation (hazard rate [HR], 0.26; 95% CI, 0.07 to 0.91; P = .035) and open surgery (HR, 0.28; 95% CI, 0.09 to 0.84; P = .024) were independently predictive of a reduced incidence of bladder recurrence. CONCLUSION: In this prospective randomized phase II study, a single intravesical instillation of THP seemed to reduce bladder recurrence after nephroureterectomy. A phase III, large-scale, multicenter study is needed to confirm these observations.

Bilateral testicular tumors: a report of nine cases with long-term follow-up.

BACKGROUND: The incidence and clinical features of bilateral germ cell testicular tumor (GCTT) in the Japanese population are not fully characterized. We examined the incidence, clinical features, management and outcome, sexual status, hormonal environment, implication of androgen replacement, and human leukocyte antigen (HLA) typing of bilateral GCTT. METHODS: We treated nine consecutive patients with bilateral GCTT from 1980 through to 1999, and reviewed their hospital and clinic charts. Testosterone, luteinizing hormone, follicle stimulating hormone, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate were measured in bilateral orchiectomized patients. Human leukocyte antigen typing was assessed with peripheral lymphocyte. RESULTS: The incidence of bilateral GCTT against the total number of patients with GCTT was 9/274 (3.3%). The median age of the first tumor was 29 (range 21-75) years. Three cases were synchronous and the remaining six cases were metachronous. In the case of metachronous tumor, the median interval between first and contralateral tumor was 8 (range 2-25) years. Standard treatment was defined as surveillance policy in stage I, chemotherapy for higher stages of non-seminoma, and radiotherapy for stage II seminoma. Human leukocyte antigen typing was examined for seven cases. Five cases were positive for HLA-A24. The incidence of HLA-A24 in bilateral GCTT was identical to that of the Japanese population. The relapsing incidence of stage I disease with surveillance policy was almost identical to unilateral GCTT. A 74-year-old patient with stage II seminoma died of the disease at 1.3 years. The other eight patients remained well without any evidence of recurrence at a median follow-up period of 78 (range 12-204) months. Four patients with bilateral orchiectomy did not require androgen replacement without easy fatigability. Sexual status was conserved using androgen replacement. CONCLUSIONS: Long-term follow-up, as long as 25 years, is recommended for contralateral relapse. Some patients with bilateral orchiectomy do not require androgen replacement. The significance of HLA-A24 for bilateral testicular tumor is equivocal in the Japanese population.