The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: a multi-institutional retrospective study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a well-known prognostic marker in various cancers. However, its role as a predictive marker for the effectiveness of nivolumab in patients with metastatic RCC (mRCC) remains unclear. We evaluated the relationships between the NLR and progression-free survival (PFS) or overall survival (OS) in mRCC patients treated with nivolumab. METHODS: The data of 52 mRCC patients who received nivolumab therapy were collected from seven institutes and evaluated. The median follow-up period from treatment with nivolumab was 25.2 months (IQR 15.5-33.2). RESULTS: The median duration of nivolumab therapy was 7.1 months (IQR 2.9-24.4). The objective response rate was 25% and the 1- and 2-year PFS rates were 46.2 and 25.2%, respectively. The median NLR values at baseline and 4 weeks were 3.7 (IQR 2.7-5.1) and 3.3 (IQR 2.4-5.7), respectively. In the multivariate analysis, an NLR of ≥3 at 4 weeks was an independent predictor of PFS (P = 0.013) and OS (P = 0.034). The 1-year PFS of patients with an NLR of < 3 at 4 weeks was better than that of those with an NLR of ≥3 (75% versus 29%, P = 0.011). The 1-year OS of patients with an NLR of < 3 at 4 weeks was also better than that of those with an NLR of ≥3 (95% versus 71%, P = 0.020). CONCLUSIONS: Although the baseline NLR was not associated with PFS or OS, an NLR of ≥3 at 4 weeks after the initiation of therapy might be a robust predictor of poor PFS and OS in mRCC patients undergoing sequential treatment with nivolumab.

Genomic characterization for familial cases with urothelial carcinoma.

In this report, we present familial cases of urothelial carcinoma. To investigate the possibility of hereditary urothelial cancer, we performed semiconductor-based next-generation DNA sequencing. A woman in her 80s who had bladder and left ureteral cancer was hospitalized in Sapporo Shirakaba-dai Hospital due to consciousness disturbance. Radiographic evaluation revealed multiple liver metastases and she died 38 days later. Needle necropsy was done for a left ureteral tumor that continued to her bladder tumor and for liver metastases. At the same time, her son in his 60s, who also had muscle-invasive bladder cancer, was admitted to Sapporo Medical University Hospital and underwent neoadjuvant chemotherapy followed by laparoscopic radical cystectomy. DNA was isolated from both cancers and normal controls in each case and analyzed by massive parallel sequencing of 409 cancer-related genes using a targeted, multiplex PCR approach followed by semiconductor sequencing. Somatic mutations of KMT2C and KMT2D were detected in the mother's tumor. Copy number gains of FGFR1, IkBKB, NFkB2, FGFR2, and FLT3 and copy number losses of IGF2R and TP53 were also found in her cancer. In her son's tumor, somatic mutations of FGFR3 and EP300 were identified. Copy number gains of IkBKE/MAPK1/PARP1, EGFR, BRAF, IRS2, MAPK2K1, IGF1R, and ERBB2 and copy number loss of TP53 were also found in his cancer. There were no germline gene mutations related to familial urothelial carcinoma. Although somatic mutation of TP53 was a common feature, these cases with urothelial carcinoma might not be the result of a heredity syndrome.

Long-term follow-up of penile glans necrosis due to paraphimosis.

INTRODUCTION: Paraphimosis is a urologic emergency in which the foreskin of the penis becomes trapped behind the coronal sulcus and forms a tight band of constricting tissue. Surgical or conservative release of this constriction is required for the treatment. Delayed treatment will cause devastating outcomes, such as penile glans necrosis. A few studies have reported penile glans necrosis/gangrene, but long-term follow-up of the recovery from glans necrosis due to paraphimosis has not been previously reported. CASE PRESENTATION: A 25-year-old man who experienced glans necrosis following paraphimosis was not treated promptly with circumcision. The patient underwent conservative treatment with debridement of necrotic tissue and cystostomy for urethral meatal necrosis. We were able to prevent partial penectomy. His penile glans was covered with healthy epithelium and retained its natural shape and voiding and erectile functions were normal 2 years after the treatment. CONCLUSION: We report successful conservative management of penile glans necrosis.

[A Case of General Fatigue Caused by Enzalutamide that was Evaluated Using the Cancer Fatigue Scale and Overcome by Switching to Nighttime Treatment].

An 81-year-old man with castration-resistant prostate cancer experienced general fatigue while receiving enzalutamide treatment. In some patients we encountered the enzalutamide treatment had to be interrupted or the dose decreased because of this adverse effect. We evaluated the patient's general fatigue using the Cancer Fatigue Scale (CFS) score and clarified the quantitative information about his general fatigue. In order to maintain the optimal dose, we advised the patient to take enzalutamide at night. This alleviated the adverse effect, and he could maintain the optimal dose of this medicine. We compared the CFS score before and after switching to nighttime treatment and found improvement. This is the first report of a CFS-based evaluation of the improvement in general fatigue caused by enzalutamide by switching to nighttime treatment.

Laparoscopic Surgery for Seminal Vesicle Cysts and Ureterocele with Urination Disorder: A Case Report of Zinner Syndrome.

Background: Zinner syndrome is defined as seminal vesicle cysts with ipsilateral renal agenesis and an ectopic ureter. Symptomatic cases are very rare. In this article, we present a laparoscopic approach for a case of Zinner syndrome. Case Presentation: The patient was a 21-year-old male with difficult urination. A right seminal vesicle cyst and right kidney agenesis associated with ureterocele were found on examination and he was diagnosed with Zinner syndrome. First, we performed transperineal puncture of the ureterocele because it closed the bladder neck during voiding. Although voiding symptoms temporarily improved, the ureterocele recurred soon and the urination disorder was reexacerbated. Next, we selected laparoscopic removal of the ureterocele and the seminal vesicle cyst. The procedure was performed with transperitoneal access using four trocars. Perioperative and postoperative complications were not observed, and micturition was satisfactory after surgery. Conclusion: Treatment for difficult urination because of Zinner syndrome is mostly selected puncture of the ureterocele or seminal vesicle cyst. However, some patients experience recurrence. The laparoscopic approach is minimally invasive and provides a satisfactory surgical field. Therefore, it should be considered the method of treatment for symptomatic Zinner syndrome.

Complications within 90 days after radical cystectomy for bladder cancer: results of a multicenter prospective study in Japan.

PURPOSE: We prospectively evaluated the 90-day postoperative mortality and morbidity of open radical cystectomy by using a standardized reporting methodology. Additionally, we assessed the preoperative characteristics to determine risk factors for major complications. METHODS: This multicenter prospective study included 185 consecutive patients undergoing open radical cystectomy from October 2010 through March 2014. Postoperative complications within 90 days were recorded and graded according to the modified Clavien-Dindo classification. RESULTS: Totally, 328 postoperative complications were observed in 149 patients (80.5%). Of these events, 73 (22.2%) were high grade (≥ Grade III), and developed in 46 patients (24.9%). Three patients (1.6%) died postoperatively. Urinary tract infection, wound complications, and paralytic ileus were common complications that occurred in 55 (29.7%), 42 (22.7%) and 41 (22.2%) patients, respectively. Ureteroenteric stricture was diagnosed in 13 of the 151 patients (8.6%) undergoing intestinal urinary diversion. Emergency room visits were required for 13 patients (7.0%) and readmission after discharge was needed for 36 (19.5%). A body mass index ≥ 25 kg/m2, smoking history and Charlson Comorbidity Index ≥ 2 were independent risk factors for high-grade complications, and their odds ratios (95% confidence intervals) were 2.357 (1.123-4.948), 2.843 (1.225-6.596) and 3.025 (1.390-6.596), respectively. CONCLUSIONS: Open radical cystectomy is associated with a high incidence of postoperative complications. Most, however, are of low grade. Our results suggest that obesity, a smoking history, and increasing comorbidity are risk factors for major complications.

Clinicopathological characteristics of Xp11.2 translocation renal cell carcinoma in adolescents and adults: Diagnosis using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis.

OBJECTIVES: To determine the rate and clinicopathological features of Xp11.2 translocation carcinoma using immunostaining of transcription factor E3 and fluorescence in situ hybridization analysis. METHODS: We evaluated 638 patients with renal cell carcinoma treated at Sapporo Medical University Hospital, Sapporo, Japan, from 1990 to 2009 by reviewing all hematoxylin-eosin-stained sections and carrying out immunostaining of transcription factor E3 for all cases. Fluorescence in situ hybridization analysis was carried out for patients with positive immunostaining or with findings suspicious for Xp11.2 translocation carcinoma on hematoxylin-eosin-stained sections. In this analysis, we set a cut-off level for split signals of at least 10% of nuclei. RESULTS: Of the 631 patients, 20 (3.2%) were positive for immunostaining. Finally, five patients were diagnosed with Xp11.2 translocation carcinoma (0.8%). Four of these patients were female and aged less than 50 years, and three cases were diagnosed as stage IV with multiple regional lymph nodal or visceral metastases. The positive predictive value of immunostaining was 25%. CONCLUSION: Patients with Xp11 translocation renal cell carcinoma tend to be younger, more frequently female and diagnosed at a more advanced stage. Immunostaining followed by fluorescence in situ hybridization analysis is an accurate and cost-effective approach for diagnosis of Xp11 translocation renal cell carcinoma.

How do we understand the disagreement in the frequency of surgical site infection between the CDC and Clavien-Dindo classifications?

To clarify the discrepancy in the incidence and severity of surgical site infections (SSI) for radical cystectomy between reports based on the CDC guideline and those using the Clavien-Dindo classification we evaluated 449 consecutive patients who underwent radical cystectomy for bladder cancer between 1990 and 2012. Of the 115 (25.6%) patients with SSI defined by the CDC guideline, 89 could be analyzed. We compared the SSI rates and severity defined by the CDC guideline and Clavien-Dindo classifications. There were 58 patients with superficial SSI, 16 with deep SSI, and 15 with organ/space SSI according to the CDC guideline. All patients with organ/space SSI were judged as "not having SSI" by the Clavien-Dindo classification. They were classified as having "intestinal prolapse", "intestinal fistula", "abdominal abscess" and "pelvic abscess." There was a significant association between the treatment duration and depth of SSI based on the CDC guideline by Spearman's rank-correlation coefficient (p < 0.001, r = 0.614) and with the grade of complications (p < 0.001, r = 0.632) in the Clavien-Dindo classification. Multivariate analysis showed that patients with grade III SSI in the Clavien-Dindo classification needed a significantly longer treatment duration. It is necessary to be aware that a discrepancy can occur automatically due to the different natures of the definitions. Using the CDC guideline, we can effectively estimate the future treatment period when SSI occurs. With the Clavien-Dindo classification, grade III SSI requires a longer treatment duration.

Evaluation of long-term outcome for patients with renal cell carcinoma after surgery: analysis of cancer deaths occurring more than 10 years after initial treatment.

OBJECTIVE: We evaluated the outcome of renal cell carcinoma (RCC) after surgery in a long-term follow-up study to elucidate the specific biological behaviors of RCC, such as late recurrence and late cancer-specific death. MATERIALS AND METHODS: We retrospectively reviewed the clinical and pathological features of 625 patients who were diagnosed as having renal cell carcinoma at our institution from 1975 to 2006. We analyzed the parameters and outcomes for the patients who had received radical or partial nephrectomy. Pathological staging was reviewed again by two pathologists. RESULTS: The median age of the patients was 61 years (range 16-87). The median follow-up was 7.0 years (range 0.1-30.3). Of the 516 patients with localized or locally advanced RCC, 124 (24.0 %) had recurrence after surgery. Lung metastasis was observed most frequently. The 10-year cancer-specific survival rates were 92.4, 91.0, 64.1 and 11.8 % for stages I, II, III and IV, respectively. The late recurrence rates in patients with localized and locally advanced RCC 5 and 10 years after initial surgery were 8.5 and 3.7 %, respectively. Cancer death more than 10 years after initial treatment of the disease occurred in 16 patients. Of the 16 patients, 9 had localized disease at the time of the initial surgery. Specific findings that characterized them were not identified in these patients. CONCLUSIONS: Late recurrence of RCC is not rare. Cancer-specific death more than 10 years after the initial treatment was observed in 16 patients with localized or advanced disease. No specific findings were identified to characterize these patients with late cancer death.

[Bilateral urolithiasis with zonisamide developed for a short period of time in a 10-year-old girl with intractable epilepsy].

Zonisamide is an antiepileptic drug mainly used in patients with refractory epilepsy. One of the urological adverse effects caused by zonisamide is urinary lithiasis. We reported bilateral urinary lithiasis with zonisamide developed for a short period of time. A 10 year-old girl had been treated with zonisamide for intractable epilepsy for nine years. She progressively developed microscopic hematuria as well as crystalluria while being hospitalized for ventriculoperitoneal shunt infection. A computed tomography (CT) showed bilaterally hydronephrotic kidneys obstructed by multiple ureteral calculi. What was impressive was the fact that any single urinary calculus was not identified in a CT image taken just three weeks prior to this event. Then the diagnosis was made of zonisamide-induced bilateral urinary calculi and zonisamide treatment was discontinued. However, since the deterioration of renal function and left-sided hydronephrosis progressed, we performed the construction of right-sided percutaneous nephrostomy (PNS) and the transurethral placement of a left ureteral stent. Subsequently her condition was stabilized and all of these stones were discharged. The analysis of these stones showed mainly calcium phosphatic calculus. We eventually removed both the right PNS and the left ureteral stent. Since then, there has not been any recurrence thus far. We need to recognize the risk of progressively developing renal calculi during zonisamide treatment for a relatively short period of time in the face of dehydration.

Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE).

Xp11 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. Various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome X cause the tumor. We established an Xp11 translocation renal cell carcinoma cell line from a renal tumor in a 18-y-old Japanese female and named it "S-TFE." The cell line and its xenograft demonstrated definite gene fusion including TFE3. They showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis and ASPL-TFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. S-TFE will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.

Long-term outcome of small, organ-confined renal cell carcinoma (RCC) is not always favourable.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Small, organ-confined renal cell carcinoma (RCC) generally has favourable pathological characteristics and a good prognosis. However, late recurrence is a known characteristic of the biological behaviour of RCC and no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy. In the present study with long-term follow-up of patients with small RCCs, 18 of 172 patients (10.5%) with pT1a RCC developed recurrence and eight of these (4.7%) died from cancer. Patients with microvascular invasion had a higher risk for cancer death than those without (P < 0.001, Log-rank test). Therefore long-term follow-up is required after surgery, particularly when the disease has microvascular invasion. OBJECTIVES: To identify the long-term clinical course of small, organ-confined renal cell carcinoma (RCC). To detect the risk factors of recurrence and of cancer death in small RCC. PATIENTS AND METHODS: Retrospectively reviewed 172 patients who were pathologically diagnosed as having pT1a RCC without metastasis at our institution from 1980 to 2005. All pathology slides were re-reviewed by a single experienced pathologist. Associations of microvascular invasion (MVI), development of metastasis, and cancer death were evaluated using Cox proportional hazards analysis. RESULTS: During a median (range) follow-up of 104.5 (8-308) months, 18 patients (10.5%) developed progression and eight patients (4.7%) died from cancer. Kaplan-Meier curves showed higher cancer-specific survival (CSS) in patients without MVI (P < 0.001). In multivariate analysis, MVI was the only factor that reached statistical significance (P = 0.006). The 10-year CSS rates were 85.1% and 96.5% in patients with and without MVI, respectively. CONCLUSIONS: Patients with MVI have worse survival than those without MVI. This suggests that long-term follow-up of patients with small RCCs is needed because of the risk of recurrence and cancer death even 10 years after surgery, particularly when the disease has apparent MVI.

[Retrospetive analysis of early postoperative complications of radical cystectomy and urinary diversion performed during a 17-year period].

We retrospectively analyzed early postoperative complications in 293 consecutive patients withbladder cancer who underwent radical cystectomy with urinary diversion from 1990 to 2007 at the Department of Urology of the Sapporo Medical University School of Medicine. The Common Terminology Criteria for Adverse Events (ver 3.0) was used to evaluate complications that occurred within 30 days after surgery, and grade 3 and higher grades according to the criteria were defined as complications in this study. The guidelines of the Centers for Disease Control and Prevention were used for the classification of surgical site infection. Early postoperative complications were found in 158 cases (54%). Acute pyelonephritis (APN), which was related to the removal of the ureteral catheter, was the most frequent complication, found in 96 (33%), followed by surgical site infection in 39 (13%), and ileus in 33 (11%). When transient APN was excluded, the rate for complications was 30%. Possible life-threatening complications were experienced in 15 patients (5%) including 2 (0.7%) who eventually died of the complications. The preoperative grade 3 score of the American Society of Anesthesiologists (ASA score) was significantly related to development of early postoperative complications in univariate analysis. In multivariate analysis, a grade 3 ASA score and the estimated blood loss were independent factors to predict development of early complications. Postoperative nasogastric tubing was not related to ileus after surgery, suggesting that postoperative indwelling of the tube is not routinely needed. Although about half of the patients experienced early postoperative complications, they were usually transient and manageable. Thus, careful evaluation of the preoperative ASA score and a reduction in the amount of bleeding during surgery may lower the development of early postoperative complications.

[Use of 2-octylcyanoacrylate tissue glue for skin closure in radical retropubic prostatectomy].

2-Octylcyanoacrylate tissue adhesive (2-OCA ; Dermabond® , Ethicon, Inc., Sommerville, New Jersey) is a synthetic tissue adhesive recently used for skin closure in the treatment of minor lacerations and minor surgical incisions. We have been using this adhesive for wound closure in radical retropubic prostatectomy (RRP) since August 2006. Before that we used a skin stapler. We assessed the effectiveness of the adhesive as a sole dressing after open radical prostatectomy and compared the economic outcomes of 2-OCA and stapled repair. We retrospectively evaluated patients undergoing RRP for whom 2-OCA (101 patients) and a skin stapler (133 patients) were used at our institution. Superficial surgical site infection (SSI) was seen in 3 patients in the glue group and 3 patients in the staple group (p=0.99). Wound dehiscence without SSI was seen in 1 patient in the glue group. The cost of surgery with 2-OCA was much lower than that with the skin stapler. Wound closure using 2-OCA following RRP is acceptable and has benefits in terms of surgical costs.

[Case of urinary mycobacterium fortuitum in a patient with urinary tract tuberculosis posttreatment].

A 70-year-old male who complained of urinary frequency and a feeling of incomplete emptying was admitted to our hospital. Imaging findings showed dilation of the left renal pelvis and ureter. He was diagnosed as having urinary tuberculosis because a positive urinary Mycobacterium tuberculosis result was obtained by polymerase chain reaction (PCR). He was treated with a combination of the antituberculosis agents isoniazid, rifampicin, pyrazinamide and ethambutol for six months. The symptoms and pyuria disappeared and M. tuberculosis was negative by PCR; however, Mycobacterium fortuitum was isolated by culture. Due to asymptomatic urinary tract infection by the multidrug resistant M. fortuitum, he was followed up with observation. Currently, he remains unchanged with regard to symptoms and imaging examination. M. fortuitum is a nontubercular mycobacterium, and clinical relevance between urinary tract infection and M. fortuitum has rarely emerged. However, we should be aware that nontubercular mycobacteria such as M. fortuitum can infect the urinary tract, especially in immunocompromised patients.

Measurement of plasma concentration of gemcitabine and its metabolite dFdU in hemodialysis patients with advanced urothelial cancer.

OBJECTIVE: We investigated the pharmacokinetics of gemcitabine and its metabolite in two male patients (52 and 56-year-old) with advanced urothelial cancer receiving hemodialysis three times a week. METHODS: Gemcitabine, 1000 mg/m(2) in 100 ml of saline, was intravenously administered for 30 min. The concentration of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was measured at several given time points using a high-pressure liquid chromatography assay. Pharmacokinetic parameters were determined using the two-compartment modeling program. RESULTS: Gemcitabine was rapidly eliminated from plasma even in patients with renal dysfunction. No obvious differences in pharmacokinetic parameters such as the t(1/2), AUC and C(max) of gemcitabine were observed between the patients on hemodialysis and those with normal renal function in previous reports. On the other hand, dFdU showed a sustained level until hemodialysis was initiated. Hemodialysis could reduce the plasma dFdU level by approximately 50%. CONCLUSIONS: According to the previous information, no dose modification of gemcitabine may be required for patients with renal impairment or hemodialysis. However, gemcitabine should be given with caution because only limited information is available, and the clinical effect of sustained and/or accumulated dFdU is unknown.

Bone scanning--who needs it among patients with newly diagnosed prostate cancer?

BACKGROUND: We evaluated the relationship between serum PSA and clinical variables to eliminate bone scanning in patients with prostate cancer having a low probability of bone metastasis. METHODS: The study included 366 patients with newly diagnosed prostate cancer between 1999 and 2005. Bone metastasis was studied for its correlation with various clinical and pathological variables in these patients. RESULTS: Bone metastasis was found in 28 (7.7%) of 366 patients. Fourteen patients had skeletal symptoms related to bone metastasis. The risk for bone metastases increased considerably with increases of PSA level, clinical T stage and Gleason score. The metastasis was not found in 161 patients with serum PSA concentration of 10 ng/ml or lower. In 95 patients with the concentration between 10 and 20 ng/ml only two had the metastasis. These two patients had T2 disease and Gleason scores of 7 or greater. In 204 patients with clinical stage T1 disease, one (0.5%) had the metastasis. In 117 patients with Gleason scores of 6 or less, the metastasis was found in two (1.7%). CONCLUSIONS: For patients with serum PSA levels of 10 ng/ml or lower, bone scanning may be eliminated because of the negligible risk of bone metastases. In addition, scanning may not be necessary for those with PSA levels between 10 and 20 ng/ml, when they have T1 disease and Gleason scores of 6 or lower.

[Early postoperative complications of radical cystectomy and urinary diversion in elderly patients].

Clinical and operative features and early postoperative complications were reviewed in 26 patients 75 years old and older who were treated with radical cystectomy including pelvic lymphadenectomy and urinary diversion in our hospital from 1994 to 2005. These findings were compared with those in 170 patients younger than 75 years old who received the same surgery and in 26 patients 75 years old and older who were not surgically treated. Early postoperative complications were found in 9 elderly patients (34%), but there were no deaths in the preoperative and early postoperative periods. There was no significant difference in the rate of early postoperative complications between patients 75 years old and older and those younger than 75. Preoperative performance status (PS) and the American Society of Anesthesiologists Score (ASA score) were significantly better in elderly patients with the surgery than those without surgery. Therefore, evaluation with PS and the ASA score may allow urologists to appropriately select elderly candidates for radical cystectomy and urinary diversion. Chronological age alone is not a determinant for indicating the surgery.

[Patients with clinically unconfirmed positive urinary cytology --retrospective analysis of clinical courses].

We retrospectively analyzed the clinical courses of 7 patients with clinically unconfirmed positive urine cytology characterized by persistent positive urine cytology but without any evidence of tumor by endoscopy or image diagnosis during the time from January 1999 to June 2004. A past history of urothelial cancer was found in 5 patients. In 2 of these 5 patients, transurethral resection of the bladder mucosa and ureteroscopy done as the initial examination identified bladder cancer and ureteral cancer, respectively. Urothelial cancer was found in the remaining 3 patients by subsequent endoscopy, image diagnosis and surgical resection that were done in the follow-up period of 8 months. Two patients who did not have a history of urothelial cancer were diagnosed as having bladder cancer and ureteral cancer in the initial or subsequent examination. Patients with clinically unconfirmed positive urine cytology should be carefully followed up with endoscopy and image diagnosis since the subsequent examinations tend to identify urothelial cancer in the upper urinary tract or bladder.