Risk stratification for bladder recurrence of upper urinary tract urothelial carcinoma after radical nephroureterectomy.

OBJECTIVES: To identify risk factors and develop a model for predicting recurrence of upper urinary tract urothelial carcinoma (UTUC) in the bladder in patients without a history of bladder cancer after radical nephroureterectomy (RNU). PATIENTS AND METHODS: We retrospectively reviewed 754 patients with UTUC without prior or concurrent bladder cancer or distant metastasis at 13 institutions in Japan. Univariate and multivariate Fine and Gray competing risks proportional hazards models were used to examine the cumulative incidence of bladder recurrence of UTUC. A risk stratification model and a nomogram were constructed. Two prediction models were compared using the concordance index (c-index) focusing on predictive accuracy and decision-curve analysis, which indicate whether a model is appropriate for decision-making and determining subsequent patient prognosis. RESULTS: The cumulative incidence rates of bladder UTUC recurrence at 1 and 5 years were 15 and 29%, respectively; the median time to bladder UTUC recurrence was 10 months. Multivariate analysis showed that papillary tumour architecture, absence of lymphovascular invasion and higher pathological T stage were both predictive factors for bladder cancer recurrence. The predictive accuracy of the risk stratification model and the nomogram for bladder cancer recurrence were not different (c-index: 0.60 and 0.62). According to the decision-curve analysis, the risk stratification was an acceptable model because the net benefit of the risk stratification was equivalent to that of the nomogram. The overall cumulative incidence rates of bladder cancer 5 years after RNU were 10, 26 and 44% in the low-, intermediate- and high-risk groups, respectively. CONCLUSIONS: We identified risk factors and developed a risk stratification model for UTUC recurrence in the bladder after RNU. This model could be used to provide both an individualised strategy to prevent recurrence and a risk-stratified surveillance protocol.

Development of a novel interferon-α2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro.

BACKGROUND: Despite the advent of targeted therapies, interferon-alpha (IFN-α) remains a therapeutic option for advanced renal cell carcinoma (RCC), especially in Japan, with a treatment response rate of 15-20 %. To improve the efficacy of IFN-α-based therapies, we evaluated a novel treatment strategy for RCC using an IFN-α2b gene construct with a repetitive hypoxia-inducible factor binding site. METHODS: We constructed an expression plasmid designated 5HREp-IFN-α2b containing the coding region of the IFN-α2b gene. Five copies of the hypoxia-response element (HRE) sequences were inserted upstream of the IFN-α2b gene, and the construct was transfected into human RCC cell lines ACHN, 786-O and KU19-20. The concentrations of IFN-α2b in the conditioned media were measured by enzyme-linked immunosorbent assay. Cell viabilities were determined by MTS assays. RESULTS: Construct-induced IFN-α secretion was confirmed in all three cell lines. IFN-α production was significantly enhanced by the hypoxia-mimicking agent deferoxamine mesylate in cell lines expressing the wild-type von Hippel-Lindau (VHL) gene (KU19-20 and ACHN) compared with cells expressing the mutant VHL gene (786-O). The construct exerted significant suppressive effects on the viabilities of all RCC cell lines. CONCLUSION: This is the first study to report on the construction of a cytokine gene with a repetitive hypoxia-inducible factor binding site and its application in the suppression of human cancer cells. Gene therapy using this IFN-α2b gene construct with HREs may represent a novel treatment modality for advanced RCC.

Equivalent survival and improved preservation of renal function after distal ureterectomy compared with nephroureterectomy in patients with urothelial carcinoma of the distal ureter: a propensity score-matched multicenter study.

OBJECTIVES: To investigate the oncological and functional outcome of distal ureterectomy compared with nephroureterectomy in the management of distal ureteral urothelial carcinoma. METHODS: Using a database including upper urinary tract urothelial carcinoma patients (n = 1329), 282 patients were identified with urothelial carcinoma localized in the distal ureter on clinical evaluation. To adjust for potential baseline differences between groups, 43 patients undergoing distal ureterectomy were matched with 86 patients undergoing nephroureterectomy using propensity scoring. Cox regression models tested the effect of surgery type on recurrence-free survival and cancer-specific survival. Estimated glomerular filtration rate was measured before and after surgery. RESULTS: The median follow-up period was 50 months. There were no significant differences in 5-year recurrence-free survival and cancer-specific survival rates between the distal ureterectomy and nephroureterectomy groups (P = 0.22 and P = 0.70, respectively). Multivariate analysis showed that surgery type was not associated with recurrence-free survival and cancer-specific survival (P = 0.90 and P = 0.28, respectively). In the subanalysis, recurrence-free survival and cancer-specific survival in the distal ureterectomy group were equivalent to those of the nephroureterectomy group in both pTa-1 and pT2-4 patients. Renal function was better preserved in the distal ureterectomy group than in the nephroureterectomy group (rate of change in estimated glomerular filtration rate 2% vs -20%; P < 0.001). CONCLUSIONS: The oncological outcome of distal ureterectomy is comparable with that of nephroureterectomy in distal ureteral urothelial carcinoma patients, and distal ureterectomy provides better preservation of renal function. Distal ureterectomy would be feasible for carefully selected patients with distal ureteral urothelial carcinoma.

[Transurethral resection of a intravesical recurrence of a tumor after resection of sigmoid colon cancer].

A 66-year-old man presented to the urology clinic with hematuria. Cystoscopy with biopsy was performed for suspected bladder cancer, and a pathological diagnosis of adenocarcinoma was made. Colonoscopy revealed sigmoid colon cancer, and he was referred to our hospital. Computed tomography (CT) and magnetic resonance imaging (MRI) showed sigmoid colon cancer with urinary bladder invasion. Sigmoidectomy with lymph node dissection and partial cystectomy were performed under laparotomy. The pathological diagnosis was moderately differentiated adenocarcinoma: T4b (bladder), N1, M0, and the bladder margin was negative. Four months after surgery, CT revealed a small mass in the bladder. Cystoscopy showed a papillary pedunculated tumor at the bladder trigone, and a transurethral resection was performed. Pathological examination revealed a moderately differentiated adenocarcinoma, similar to the prior sigmoid colon cancer, which was diagnosed as an intravesical recurrence of the tumor. More than 8 years after the transurethral resection, the patient has shown no signs of recurrence.

Treatment outcome of patients with extragonadal nonseminomatous germ cell tumors: the Saitama Cancer Center experience.

BACKGROUND: Survival of patients with extragonadal nonseminomatous germ cell tumors remains inferior to that of patients with advanced testicular cancer, although treatment is often the same for both conditions. In addition, the prognosis for nonseminomatous tumors has been shown to be worse than for seminoma. METHODS: Thirteen patients with extragonadal nonseminomatous germ cell tumors were treated between 1998 and 2011; the primary tumors were located in the mediastinum in six and in the retroperitoneum in seven. At initial diagnosis seven patients had distant metastases. According to the IGCCC, eleven patients had poor prognosis and two were intermediate. All 13 patients received cisplatin or carboplatin-based chemotherapy as initial treatment. The patients were further treated by use of a multi-modal strategy which included high-dose chemotherapy, aggressive surgery, and early introduction of salvage regimens. RESULTS: Complete response was obtained for eight patients. Among these complete responders, one patient remained relapse-free after post-chemotherapy surgical excision of viable cancer tissue. In the course of the chemotherapy, four patients died from cancer progression and one patient died as a result of post-chemotherapeutic sepsis. The other eight patients were alive at the end of the observation period. At the last observation all surviving patients were without evidence of disease. Five-year overall survival for all 13 patients was 62 %, and 5-year cancer-specific survival was 68 %. CONCLUSION: Our results indicate that even patients with far-advanced extragonadal nonseminomatous germ cell tumors can be cured by intensive chemotherapy plus surgery.

[Case of septic shock caused by extended spectrum ß-lactamase producing Escherichia coli after transrectal prostate biopsy, successfully treated by endotoxin adsorption therapy].

A 62-year-old man, with a family history of prostate cancer, referred to our hospital because of elevated prostate-specific antigen (PSA) (6.02 ng/ml). After prophylactic administration of antibiotics (cefotiam), transrectal needle biopsy of the prostate was performed. He was admitted to the hospital due to high fever the next evening. His blood pressure was below the shock level, and his renal function deteriorated progressively. Suspecting septic shock, the patient was treated with Meropenem, γ-globulin, and dopamine, which were not effective. Then, endotoxin adsorption therapy was employed and the condition of the patient recovered soon after the initiation of the therapy. Extended spectrum ß -lactamase-producing Escherichia coli was found in his urine. Pathological diagnosis of the biopsy specimen was atypical glands.

[Outcome of simple prophylactic procedure of inguinal hernia after radical prostatectomy].

Blunt dissection of the peritoneum at the internal inguinal ring and isolation of the spermatic cord from the peritoneum have been demonstrated to be effective for the prevention of post radical prostatectomy (RRP) inguinal hernia. We tested the efficacy of this simple procedure and analyzed the factors affecting the incidence of inguinal hernia. Of the 298 patients who underwent open RRP for clinically localized prostate cancer between February 2005 and March 2011 at Saitama Cancer Center hospital, 186 patients received the simple prophylactic procedure of inguinal hernia. We evaluated the risk factors of inguinal hernia (age, time of operation, intraoperative bleeding, prophylactic procedure of inguinal hernia, previous history of abdominal surgery, previous history of inguinal hernia surgery, nerve sparing, lymph node dissection, body-mass-index (BMI), hypertension, diabetes, and smoking) by univariate and multivariate analysis. Effects of the simple prophylactic procedure on incidence of inguinal hernia were analyzed using Kaplan-Meier plots. The incidence of inguinal hernia was 29.6% in those without the prophylactic procedure, and 11.4% in those with the prophylactic procedure. In univariate and multivariate analysis, only low BMI was a significant risk factor for inguinal hernia after RRP. Accordingly, the incidence of inguinal hernia was not affected by the prophylactic procedure in Kaplan-Meier analysis. Though the simple prophylactic procedure might be useful for prevention of post-radical prostatectomy inguinal hernia, its efficacy was demonstrated to be limited.

[Result of treatment for advanced germ cell tumor in the last decade].

PURPOSE: We retrospectively analyzed our therapeutic results of advanced male germ cell tumors in terms of efficacy and feasibility of our treatment strategy. PATIENTS AND METHODS: Fifty-one new cases were treated in Saitama Cancer Center between April 1997 and August 2007. Patients age ranged from 16 to 58 (median 33). Primary site of the tumor was testis in 41 (80%) patients, retroperitoneum in 6 (12%), and mediastinum in 4 (8%). Histology of the primary germ cell tumor was pure seminoma in 14 (27%), and non-seminoma in 30 (59%). Twenty (39%), 14 (27%) and 17 (33%) were classified as good-, intermediate-, and poor-risk, retrospectively, based on The International Germ Cell Consensus Classification (IGCCC) criteria. The initial treatment for good-risk patients was BEP x 3. Intermediate- or poor-risk patients were treated by VIP from 1997 to 2000, VIPVB from 2001 to 2004, and BEP from 2005 to 2007. Second line salvage treatments were high-dose VIP or ICE from 1997 to 2000. TIP x 4 has been employed since. Marker-negative cases with residual tumors underwent surgical resection of the mass lesion. RESULTS: Five-year survival rate was 100%, 74%, and 76% in patients with good-, intermediate- and poor-risk characteristics, respectively. After two courses of initial chemotherapy, tumor marker decline was satisfactory in 37 patients (73%) and unsatisfactory in 14 (27%). Of these 14 patients, 12 (86%) had unsatisfactory hCG decline, 4 (29%) had unsatisfactory AFP decline, and 2 (14%) had unsatisfactory decline in both markers. Five-year overall survival was 94% in cases with satisfactory maker decline and 71% in those with unsatisfactory marker decline (p = 0.03). CONCLUSIONS: In this IGCCCG era, 5 year survival rates of the advanced germ cell tumors have improved by the earlier administration of second line chemotherapies based on both the prognostic factor-based staging system and the tumor marker decline in initial chemotherapy. Development of effective treatment for cases with unfavorable tumor maker decline is the most challenging issue to be addressed.

Yolk sac tumor but not seminoma or teratoma is associated with abnormal epigenetic reprogramming pathway and shows frequent hypermethylation of various tumor suppressor genes.

Germ cell tumors (GCTs) are thought to arise from primordial germ cells (PGCs) that undergo epigenetic reprogramming: erasure of the somatic imprint in the genital ridge, and re-establishment of the sex-specific imprint at gametogenesis in the developing gonad. Previous studies suggested that GCTs show epigenetic patterns reflecting the reprogramming process of PGCs; however, epigenetic alterations of imprinted genes and their relationship with the methylation status of tumor suppressor genes (TSGs) have not been comprehensively studied. We analyzed the methylation status of the H19 and SNRPN differential methylated regions (DMRs) and the promoter region of 17 TSGs, and the expression status of H19, IGF2 and SNRPN in 45 GCTs, and found that 25 and 20 were in the normal and abnormal reprogramming pathways, respectively, defined on the basis of the methylation status of the two DMRs and the anatomical tumor site. The methylation pattern of the H19 and SNRPN DMRs was total erasure in seminomas, mostly physiological in teratomas, and various in yolk sac tumors. There were no correlations between the methylation status of the H19 DMR and mono- or biallelic expression of H19 or IGF2. Furthermore, we found that yolk sac tumors had a higher number of methylated TSGs than seminomas (P < 0.001) teratomas (P = 0.004) or other childhood tumors. While TSG methylation was known to have prognostic implications in various cancers, it did not affect the outcomes of patients with yolk sac tumor, suggesting that mechanisms of TSG methylation may be different between yolk sac tumor and other cancers.

Prognostic model for predicting survival after palliative urinary diversion for ureteral obstruction: analysis of 140 cases.

PURPOSE: We identified patients with ureteral obstruction likely to benefit from palliative urinary diversion so that they can be advised appropriately. MATERIALS AND METHODS: A total of 140 patients with obstructive nephropathy secondary to advanced incurable malignant disease underwent percutaneous nephrostomy urinary diversion. Several variables were investigated including sex, age, type of primary malignancy, events related to malignant dissemination (metastasis, ascites and pleural effusion), number of events related to malignant dissemination, degree of hydronephrosis, location of obstruction, interval from initial diagnosis of bilateral hydronephrosis to percutaneous nephrostomy, and serum creatinine, hemoglobin and serum albumin levels before nephrostomy. RESULTS: Median overall survival was 96 days (range 2 to 1,283). The 1, 6 and 12-month survival rates were 78%, 30% and 12%, respectively. On multivariate analysis the number of events related to malignant dissemination (3 or more), degree of hydronephrosis (grade 1 or 2) and serum albumin before nephrostomy (3 gm/dl or less) were significantly associated with a short survival time. The patients were divided into 3 risk groups of favorable-0 risk factors (34 patients), intermediate-1 risk factor (60) and poor-2 or 3 risk factors (41). There were significant differences in the survival profiles of the 3 risk groups (p <0.0001). The 6-month survival rates for the favorable, intermediate and poor risk groups were 69%, 24% and 2%, respectively. CONCLUSIONS: The current stratification model may represent a useful tool for clinicians treating patients with ureteral obstruction due to advanced cancer.

Clinical outcome of chemoradiotherapy for T1G3 bladder cancer.

The aim of this study was to determine the clinical outcome of a bladder-sparing approach using chemoradiotherapy (CRT) for T1G3 bladder cancer. Between May 2000 and August 2007, 11 patients with T1G3 bladder cancer and who were negative for macroscopic residual tumor were treated by CRT after transurethral resection of bladder tumor (TUR-Bt). Pelvic irradiation was given at a dose of 40 Gy in 4 weeks. Intra-arterial administration of cisplatin and systemic administration of methotrexate were carried out in the first and third weeks of radiotherapy. One month after CRT, response was evaluated by restaging TUR-Bt. For persistent tumor after CRT or tumor recurrence, patients received additional treatment. Median follow-up was 21.2 months. Complete response was achieved in 10 of 11 patients (90.9%). Local recurrence for the entire group of 11 patients was 22.1% at both 2 and 5 years. Tumor progression was 0% at 5 years. Disease-specific survival rates were 100% at 5 years. All of survivors retained functioning bladders. Bladder preservation by CRT is a curative treatment option for T1G3 bladder cancer and a reasonable alternative to intravesical treatment or early cystectomy.

Cardiovascular events in survivors of high-dose chemotherapy for germ cell tumors.

The objective was to investigate cardiovascular complications in long-term survivors treated by high-dose chemotherapy. We analyzed 13 previously successfully treated metastatic germ cell cancer patients. The patients ranged in age from 16 to 38 years (median: 27 years). Patients were treated by high-dose ifosfamide, carboplatin and etoposide (ICE) or high-dose etoposide, ifosfamide and cisplatin (VIP). In a minimal follow-up of 48 months, the incidence of cardiovascular events and the accumulated doses of platinum were analyzed from the total amounts of cisplatin and/or carboplatin. The calculated accumulated doses of platinum ranged from 487 to 4302 mg (median: 2297 mg). Cardiovascular events were observed in two patients who received cumulative doses of more than 3000 mg of platinum. Survivors of high-dose chemotherapy may have a risk of developing cardiovascular complications during the early phase of follow-up. In particular, patients who have received carboplatin-based high dose chemotherapy require careful observation.

[Primary malignant melanoma of the male urethra: a case report].

A 70-year-old man presented with hematuria and urodynia. A hemorrhagic black tumor and surrounding tan-colored flat lesions were observed at the distal urethra on urethroscopy. Atypical cells consistent with malignant melanoma were noted in urinary cytologic samples. Total penectomy and prostatectomy were performed with negative surgical margin. Because of negative sentinel biopsy of inguinal lymph nodes, further lymph nodes exploration was omitted. However, recurrent tumors at the perineal region and metastases to pelvic lymph nodes appeared four months after surgery, and he died eleven months later.

[Bladder preservation by chemoradiotherapy in combination with radical TUR-Bt in muscle invasive bladder cancer].

PURPOSE: To evaluate bladder preservation protocol by radical TUR-Bt and subsequent concurrent chemoradiotherapy in muscle invasive bladder cancer. PATIENTS AND METHODS: Twenty-six patients with muscle invasive bladder cancer (T2-T4NOM0) were treated with concurrent chemoradiotherapy after transurethral resection of the tumor as much as possible beyond muscle layers. Chemotherapy was consisted of systemic administration of methoterexete (30 mg/m2 day 1 and day 22) and intraarterial infusion of cisplatin (70 mg/m2, day 2 and day 23). The response was evaluated by TUR, urine cytology, CT and/or MRI 4 to 6 weeks after the treatment. RESULTS: Among 24 evaluable cases, pathological complete response was achieved in 13 cases (50%) and residual tumors were noted in 11 cases (pT1 in 9 and pT2 in 2). During follow-up period up to 69.8 months, invasive recurrence was observed in 2 cases, superficial recurrence was noted in 5 patients and distant metastasis without evidence of local recurrence was noted in 4 cases. Overall bladder preservation rate was 92%. CONCLUSIONS: The bladder preservation by radical TUR-Bt and chemoradiotherapy is a safe and effective treatment option for muscle invasive bladder cancer.

[A case of complete regression of metastatic renal cell carcinoma following corticosteroid treatment].

A 72-year-old man presented with hemosputum and was admitted to our hospital. Computed tomography and osseous scintigraphy revealed right renal cancer and multiple pulmonary and osseous metastases. A translumbar nephrectomy was performed. The histopathological examination demonstrated granular cell carcinoma and clear cell carcinoma. The patient complained of dyspnea on postoperative day (POD) 16, and chest X-ray showed progression of the multiple pulmonary metastases and lymphangitis carcinomatosa. Betamethasone was administered for palliative treatment. After the treatment, dyspnea improved and chest X-ray on POD 57 showed disappearance of the multiple pulmonary metastases and improvement of lymphangitis carcinomatosa. Computed tomography and osseous scintigraphy confirmed complete regression of metastases. He has been free from recurrence for 16 months after the nephrectomy and for 13 months after the complete regression. To our knowledge, this is the first case of complete regression of metastatic renal cell carcinoma following corticosteroid treatment reported in Japan, and the second case when foreign literature is included.

Young age as favorable prognostic factor for cancer-specific survival in localized renal cell carcinoma.

OBJECTIVES: To evaluate the prognostic effect of age in patients with localized renal cell carcinoma (RCC) and investigate the incidence of Xp11 translocation RCC in young patients who developed recurrence. METHODS: From 1990 to 2007, 2403 Japanese patients underwent nephrectomy for presumed RCC at 9 institutions. Of those, 1143 patients had localized RCC (Stage pT1-2N0M0). Their clinical data were retrospectively reviewed. In the present study, 131 patients (11%) were considered young (≤45 years at diagnosis). In the young patients with recurrence, the nephrectomy specimens were immunostained with TFE3 to determine the incidence of Xp11 translocation RCC. RESULTS: During the median follow-up of 47 months, 3 cancer deaths (2.2%) occurred among young patients and 51 (5.0%) among older patients. The 5-year cancer-specific survival (CSS) rate was significantly better for the younger patients than for the older patients (P = .049). Multivariate analysis showed that age was significantly associated with CSS, as were the pathologic T stage, tumor grade, and symptoms at diagnosis. The hazard ratio of young age was 0.31 (95% confidence interval 0.077-0.87). The recurrence-free survival curves revealed no difference between these 2 groups. Of the 74 patients with recurrence, the CSS after recurrence was significantly better in the younger patients than in the older patients (P = .0010). Of the 8 young patients with recurrence, 4 had Xp11 translocation RCC, and 3 survived for >5 years after recurrence. CONCLUSIONS: Compared with the older patients, the young patients with RCC had similar recurrence-free survival rates but better CSS rates. This might have been because significant numbers of the young patients had Xp11 translocation RCC.

Incorporation of TIP (paclitaxel, ifosfamide, cisplatin) into first-line therapy for intermediate to poor risk testicular germ cell tumors with unfavorable marker decline after initial two cycles chemotherapy: a report of three cases.

Three patients of advanced-non-seminomatous germ cell tumors (International Germ Cell Cancer Collaborative Group classification: poor risk, 2; intermediate, 1) without evidence of a second primary germ cell tumor were treated. The patients received two cycles of standard BEP (bleomycin, etopside, cisplatin) or VIP/VB (etoposide, ifosphamide, cisplatin/vinblastine, bleomycin) therapy first. All patients in this trial showed unfavorable marker response to these therapies and received four cycles of TIP subsequently. A complete remission was observed in all patients. No patient experienced life-threatening toxicity. During the 34-month observation period, all patients were alive without progression.