Novel germ line mutation p53-P177R in adult adrenocortical carcinoma producing neuron-specific enolase as a possible marker.

Adrenocortical cancer (ACC) is a rare and aggressive endocrine tumor. The patient presented with a large retroperitoneum tumor and lung metastases. Removal of the adrenocortical tumor with part of the transverse colon and tail of the pancreas, spleen and kidney was successfully performed following chemotherapy. Levels of serum neuron-specific enolase (NSE) were found to be markedly high before surgery and may be clinically useful markers for monitoring tumor status during management. Immunohistochemical studies showed that the cancer cells were positive for NSE and overexpression of p53. We identified a novel germ line variant of the 177 mutant (Pro to Arg; P177R) of p53 by genomic sequencing. The genetic and biochemical data presented in this case confirm the importance of screening for p53 status in ACC with inherited cancer syndrome.

Development of a nomogram for predicting high-grade prostate cancer on biopsy: the significance of serum testosterone levels.

BACKGROUND: A screening method that focuses on the early detection of high-grade prostate cancer is required. In this study, two sets of nomograms were developed, one to predict the presence of prostate cancer, and the other to predict the presence of high-grade prostate cancer (defined as Gleason Score > or =7). PATIENTS AND METHODS: Prostate biopsies were obtained from 396 men with an abnormal serum level of prostate-specific antigen (PSA). Using factors including age, PSA, follicle stimulating hormone (FSH), serum teststerone level and prostate volume of the transitional zone (TZ), nomograms were created that incorporated these factors. External validations were performed involving 174 males, including 103 normal and 71 prostate cancer cases from our institution. RESULTS: Out of the 396 patients referred for prostate biopsy, 146 were found to have prostate cancer. On logistic regression analysis, age, PSA, prostate volume of the TZ and FSH were significant predictors of prostate cancer, while serum PSA, and testosterone levels were significant predictors of high-grade prostate cancer. The pretreatment testosterone level was found to be a significant biomarker for predicting the pathological features. CONCLUSION: The testosterone level might be a useful biomarker to be included in conventional PSA screening programs to further improve the efficacy of detecting potentially lethal carcinomas.

Clinical efficacy of proton magnetic resonance spectroscopy (1H-MRS) in the diagnosis of localized prostate cancer.

BACKGROUND: The objective of this study was to evaluate the efficacy of proton magnetic resonance spectroscopy (1H-MRS) in the detection of prostate cancer. MATERIALS AND METHODS: The experimental group consisted of 20 patients with localized prostate cancer who underwent radical prostatectomy. The sensitivity, positive predictive value and accuracy of the detection of prostate cancer in the 12 sections of the peripheral zone were calculated for prostate biopsy alone, 1H-MRS alone and the combination of these methods, respectively. RESULTS: The sensitivity, the positive predictive value, and the accuracy of the preoperative diagnosis of prostate cancer were 43.7%, 68.9% and 54.6%, respectively, with prostate biopsy alone; 60.6%, 87.8% and 71.4% with 1H-MRS alone; and 88.7%, 88.7% and 87.4% with the combination of biopsy and 1H-MRS, respectively. Combined use of biopsy and 1H-MRS significantly improved the sensitivity, positive predictive value and accuracy of the diagnosis. CONCLUSION: 1H-MRS together with biopsy might improve the diagnostic accuracy in prostate cancer.

DNA damage response in prostate cancer cells after high-intensity focused ultrasound (HIFU) treatment.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a new modality that can be used for local tumor ablation therapy. In the present study, the expression of human checkpoint kinase2 (Chk2), which may have significant roles in the response to DNA damage after HIFU treatment for prostate cancer, was examined. MATERIALS AND METHODS: By immunohistochemistry, the Chk2 expression in human prostate cancer tissues was examined before and after HIFU treatment. The phosphorylation of ataxia-telangiectasia-mutated kinase (ATM), histone H2A variant (H2AX), Chk2 and p53, and the number of apoptotic cells in human prostate cancer cell lines after heat treatment was checked. RESULTS: The expression level of phosphorylated Chk2 was found to be increased after HIFU treatment. In addition, heat treatment induced the phosphorylation of Chk2 proteins examined and led to apoptosis in the prostate cancer cells. CONCLUSION: Our results suggest that DNA double-strand break formation is a possible pathway of HIFU treatment and leads to heat-induced cell killing.

Salivary 8-OHdG: a useful biomarker for predicting severe ED and hypogonadism.

INTRODUCTION: Erectile and endothelial dysfunction are common pathologies of multiple cardiovascular risk factors and are considered longitudinal predictors of cardiovascular events. Oxidative stress and decreases in testosterone levels play an important role in the pathogenesis of endothelial dysfunction. AIM: We sought to determine whether the severity of erectile dysfunction (ED) was associated with individual levels of testosterone and oxidative stress, and whether treatment with a phosphodiesterase type 5 inhibitor could reduce oxidative stress and increase testosterone availability. METHODS: We evaluated the association of salivary 8-hydroxy-2'-deoxyguanosine (8-OHdG), salivary testosterone, International Index of Erectile Function-erectile function domain (IIEF-EF) scores, and Medical Outcome Study (MOS) 36-item Short-Form Healthy Survey (SF-36) questionnaires in 128 middle-aged male volunteers. We investigated the changes in testosterone levels, salivary 8-OHdG levels, IIEF-EF scores, and SF-36 scores in 20 ED patients (according to the IIEF-EF) who took 50 mg of sildenafil once a week for 6 months. MAIN OUTCOME MEASURES: IIEF-EF scores were used to assess ED severity. Antioxidant status was defined by salivary 8-OHdG. Salivary testosterone was used to evaluate serum bioavailable testosterone availability. RESULTS: Salivary 8-OHdG (OR = 9.88, 95% CI: 1.52-64.10), salivary testosterone (Odds ratio [OR] = 0.96, 95% CI: 0.93-0.98), and vitality on the SF-36, version 2 (SF-36 v2) (OR = 0.92, 95%CI: 0.84-0.98) were significantly associated with the severity of ED in healthy volunteers. Treatment with sildenafil for 6 months significantly increased the total serum testosterone (426.4 +/- 174.8 vs. 569.6 +/- 146.1 ng/dL, P = 0.021) and salivary testosterone levels (56.1 +/- 22.3 vs. 110.0 +/- 48.4 pg/mL, P < 0.001), whereas it decreased salivary 8-OHdG levels (2.30 +/- 0.23 vs. 0.90 +/- 0.05 ng/mL, P = 0.0046). CONCLUSIONS: Salivary 8-OHdG is a useful biomarker for predicting severe ED and hypogonadism in middle-aged men. Once-a-week treatment with sildenafil can have beneficial effects on men's health by decreasing oxidative stress and increasing testosterone levels.

Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer.

BACKGROUND: We evaluated the efficacy and feasibility of high-intensity-focused ultrasound (HIFU) for localized prostate cancer. METHODS: Seventy patients received HIFU using Sonablate((R)) 500 (Focus Surgery, IN, USA). In patients whose cancer was confined to only one lobe by multi-regional biopsies, total peripheral zone and a half portion of transitional zone were ablated (focal therapy). Otherwise, patients received whole organ ablation (whole therapy). Scheduled biopsies were performed at 6 and 12 months after treatment. Pre- and post-HIFU serum testosterone levels were measured. Result The 2-year biochemical disease-free survival (DFS) rates in patients at low, intermediate and high risk were 85.9, 50.9 and 0%, respectively, (P = 0.0028). After 12 months, 81.6% (40/49) of patients were biopsy negative; 84.4% in patients who received whole therapy, whereas 76.5% in those with focal therapy. The 2-year biochemical DFS rates for the patients at low and intermediate risk was 90.9 and 49.9%, respectively, in patients with whole therapy, whereas 83.3 and 53.6% in patients with focal therapy. In patients without neoadjuvant androgen deprivation, serum testosterone levels continuously decreased after whole therapy, whereas no changes were seen in those with focal therapy. The patients whose follow-up biopsies were positive tended to have significantly higher changes in prostate-specific antigen levels than biopsy-negative patients. CONCLUSIONS: In patients with low-risk prostate cancer, HIFU monotherapy resulted in comparable immediate cancer control with other modalities. Particularly, focal therapy might offer a feasible minimally invasive therapeutic option, which maintained serum testosterone level. To our knowledge, this is the first report that whole, but not focal, therapy affects the serum testosterone level.

Inhibitory effects of nicorandil, a K ATP channel opener and a nitric oxide donor, on overactive bladder in animal models.

OBJECTIVES: To investigate the effects of nicorandil, an ATP-sensitive potassium (K(ATP)) channel opener with a nitric oxide (NO) donor property, on overactive bladder (OAB) in animal models. Nicorandil is currently used clinically to treat ischaemic heart disease. MATERIALS AND METHODS: Three animal OAB models were used: (i) C-fibre mediated bladder overactivity by infusion of a low concentration of acetic acid (AA) into the bladder in female Wistar rats; (ii) bladder outlet obstruction (BOO) created by partial urethral obstruction in female Wistar rats; and (iii) neuronal NO synthase (nNOS) knockout (KO) mice with urinary frequency. The effects of nicorandil and KRN2391, both of which act as K(ATP) channel openers and NO donors, on the OAB models were examined. RESULTS: Cystometry showed that intravesical instillation of nicorandil and KRN2391 successfully inhibited OAB induced by intravesical instillation of AA. In the BOO model compared with untreated BOO rats, both nicorandil (1 and 3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency. Compared with wild-type mice, nNOS KO mice had urinary frequency with no change in the total urine volume. Nicorandil (3 mg/kg, orally) and KRN2391 (1 mg/kg, orally) significantly reduced the voiding frequency in nNOS KO mice. CONCLUSIONS: Our in vivo results show that nicorandil, a K(ATP) channel opener with a NO donor property, can suppress OAB from both neurogenic and myogenic causes. Nicorandil appears to be a promising candidate for clinical use in patients with OAB.

Tyk2 expression and its signaling enhances the invasiveness of prostate cancer cells.

Protein tyrosine kinase plays a central role in the proliferation and differentiation of various types of cells. One of these protein kinases, Tyk2, a member of the Jak family kinases, is known to play important roles in receptor signal transduction by interferons, interleukins, growth factors, and other hormones. In the present study, we investigated Tyk2 expression and its role in the growth and invasiveness of human prostate cancer cells. We used a small interfering RNA targeting Tyk2 and an inhibitor of Tyk2, tyrphostin A1, to suppress the expression and signaling of Tyk2 in prostate cancer cells. We detected mRNAs for Jak family kinases in prostate cancer cell lines by RT-PCR and Tyk2 protein in human prostate cancer specimens by immunohistochemistry. Inhibition of Tyk2 signaling resulted in attenuation of the urokinase-type plasminogen activator-enhanced invasiveness of prostate cancer cells in vitro without affecting the cellular growth rate. These results suggest that Tyk2 signaling in prostate cancer cells facilitate invasion of these cells, and interference with this signaling may be a potential therapeutic pathway.

Real-time MRI of orthotopic ileal neobladder voiding: preliminary findings.

OBJECTIVES: The purpose of this preliminary study was to analyze the dynamic changes in the configuration of the neobladder and naïve bladder during voiding using real-time MRI. METHODS: This study included 10 male patients who had a radical cystectomy and an ileal orthotopic neobladder due to organ-confined bladder cancer and had good urinary function, and 5 male control volunteers. With the subjects in the lateral decubitus position, real-time MRI was performed during micturition. A sagittal slice orientation was used to depict the bladder and the entire length of the urethra; individual movements along the X-axis and Y-axis of the bottom and top of the neobladder and the naïve bladder were recorded and analyzed. Urodynamic studies (UDS) and video voiding cystourethrography were performed in patients. RESULTS: Five of the 10 neobladder patients could void in the lateral decubitus position. In normal controls and patients who could void, the bladder outlet bladder moved ventrocranially during micturition. The ileal bladder outlet moved a significantly longer distance than the naïve bladder during micturition (X-axis, -13.4+/-1.5 vs. -3.6+/-4.3 cm, p=0.0014; Y-axis, -10.6+/-0.5 vs. -2.0+/-6.5 cm, p=0.0187). The distance that the bladder top moved between the naïve bladders and the neobladder did not differ. UDS did not show a difference between patients who could and could not void at lateral position. CONCLUSIONS: During micturition, the neobladder was found to rotate and move more dynamically than the naïve bladder. Real-time MRI is useful for assessing dynamic voiding function of orthotopic neobladders.

Testosterone decreased urinary-frequency in nNOS-deficient mice.

To observe the effect of testosterone on the frequency of urination in mice lacking neuronal nitric oxide synthase (nNOS(-/-)), we compared the urination patterns between unanaesthetized male wild-type (n = 27) and nNOS(-/-) mice (n = 50) with or without testosterone treatment. Compared with wild-type mice, nNOS(-/-) mice showed a greater frequency of urination during a 24-h observation period (3.0 vs. 5.4 times/day, p < 0.0001) without any significant difference in the total voided volume or the functional voiding capacity. While testosterone treatment did not affect the urination patterns in wild-type, it decreased the daytime frequency of urination (5.4 vs. 3.7 times, p = 0.0198) and the nighttime urination (4.4 vs. 2.9 times, p = 0.039) in nNOS(-/-) mice. The nNOS(-/-) mice can be a useful animal model for urinary frequency. Testosterone improved the functional abnormalities in the voiding of nNOS(-/-) mice.

Spindle cell lipoma of the spermatic cord.

Spindle cell lipoma usually occurs as a solitary, subcutaneous, circumscribed lesion in the back, posterior neck or shoulders of older men. As a paratesticular tumor, spindle cell lipoma is extremely rare. Herein we report the second case of spindle cell lipoma of the spermatic cord in the published reports. The tumor comprised mature adipocytes and uniform spindle cells within thick ropey collagen bundles and mast cells. Immunohistochemical studies showed spindle cells positive for CD34, a diagnostic feature of this tumor.

Incidentally discovered adrenal myelolipoma associated with hyperthyroidism.

Adrenal myelolipomas are uncommon, nonfunctioning tumors that tend to be discovered incidentally on imaging. Such tumors are composed of mature adipose tissue and hematopoietic elements, but their etiology is still unknown. Thyroid hormones have important effects on development, growth, and metabolism, as well as tumorigenesis. We report a case of adrenal myelolipoma in a patient with hyperthyroidism; this benign tumor expressed both thyroid hormone receptor alpha and beta.

Anesthesia for extracorporeal shockwave lithotripsy: Teikyo University Hospital experience using the third generation lithotripter.

A single-board certified urologist with training and experience in anesthesiology was assigned to treat 502 patients (185 with renal stones, 317 with ureteral stones) using the Dornier Compact Delta lithotripter under general or epidural anesthesia. Data were obtained regarding stone location, stone size, shockwave use, stone-free rate, and complications. In all, 502 stones were treated with the Dornier Compact Delta lithotripter. Among renal stones, 73% were in the renal pelvis. Among ureteral stones, 60% were in the upper, 10% in the middle, and 30% in the lower ureter. Diameters of 61.8% of stones were less than 1 cm. The mean number of shocks was 3,471 at a mean power setting of 5. The stone-free rate for renal stones was 71.5%, while for ureteral stones this reached 99%. The efficiency quotient was calculated as 0.65. One patient with a renal stone developed perinephric hematoma requiring 3 units of transfusion. With a success rate higher than that reported for other lithotripters, the Dornier Compact Delta lithotripter represents a feasible treatment for urolithiasis. We stress that even in the third generation machines the lithotripsy under anesthesia can improve the treatment efficacy.

[A case of a giant adrenal myelolipoma in a man with spinal cord injury].

A 38-year-old man in a wheelchair for spinal cord injury from a traffic accident was referred to our hospital with complaint of dull right flank pain. The patient had a history of skin ulcer formation on both toes due to poor circulation. Abdominal ultrasonography and computed tomographic scan revealed a huge retroperitoneal tumor compressing the right kidney. Serum levels of cortisol, adrenocorticotropic hormone, aldosterone, adrenalin, noradrenalin, urinary levels of vanillylmandelic acid, homovanillic acid, 17-ketosteroid and 17-hydroxycorticosteroid were all within normal limits. Combining all preoperative diagnostic information, the possibility of retroperitoneal liposarcoma could not be thoroughly ruled out. The patient consented to undergo resection of the tumor with the right kidney. Prior to the scheduled operation simulation of the positioning on the operation table was done to evaluate the compressing pressure. During operation decompressing pads were used to minimize the compressing pressure and intermittent pneumatic compression was also used to prevent pressure ulcer and facilitate circulation to the lower extremities. Five thousands units of heparin (FragminR, Pfizer, USA) was used daily to prevent deep vein thrombosis until the patient could use his wheelchair. Perioperative rehabilitation was conducted by a team of physical therapists. The excised tumor weighed 1,320 g. Pathologic diagnosis was an adrenal myelolipoma. Convalescence was uneventful and the patient was discharged on the 10th post operative day. Between 1992 and 2006, 80 cases of adrenal myelolipoma were reported in Japan. Our case was found to be the second largest one. We reviewed these 80 cases and discussed the diagnosis and treatment strategy of the adrenal myelolipoma. We also discussed the perioperative management for patients with spinal cord injury.

Enumeration of bacterial cell numbers and detection of significant bacteriuria by use of a new flow cytometry-based device.

A new, automated flow cytometry-based urine bacterium analyzer (UBA) was developed. We assessed the UBA for linearity of measurement, reproducibility of results, carryover rate, and correlation of measured results with those determined by urine culture. We also evaluated its ability to screen urine samples for significant bacteriuria. The UBA showed excellent linearity and a minor carryover rate. Results from the UBA were highly reproducible, and in between-run precision assays, the coefficients of variation for the UBA results were smaller than those for the urine culture results. Two hundred seventy-three urine specimens from patients attending the outpatient clinics of two university-based hospitals were examined. The results for the UBA were compared with those for urine culture. The UBA detected significant bacteriuria with a sensitivity of 96.6%, a specificity of 79.9%, a positive predictive value of 57.0%, a negative predictive value of 98.8%, a false-positive rate of 15.8%, a false-negative rate of 0.7%, and an accuracy of 83.5%. These results were comparable to or better than those obtained with previously reported screening procedures. The UBA can perform accurate enumeration of bacterial cells automatically in 90 seconds and can be used for the screening of significant bacteriuria.

[Clinico-statistical analysis of renal cell carcinomas in patients on hemodialysis].

Eleven patients on hemodialysis that were surgically treated for renal cell carcinomas during the recent 10 years at our institutes were clinically analyzed. Patients' ages at presentation ranged from 35 to 70 years with an average of 54.8 years. Nine of the 11 patients were males and 2 were females. Periods between the introduction of hemodialysis and the presentation ranged from 1 to 21 years with an average of 11.7 years. The most frequent cause of hemodialysis was chronic glomerulonephritis. Five patients presented with macroscopic hematuria, which was the most frequent clinical manifestation. Transperitoneal nephrectomy through a lumbar oblique incision was performed in 9 of 12 surgical procedures. Transperitoneal resection and retroperitoneal endoscopic resection were performed on 2 patients and 1 patient, respectively. Blood transfusion was performed on 2 patients with retroperitoneal hemorrhage before or after operation and 2 patients with pre-existing renal anemia. Pathologically, 9 patients had pT1a disease. Patients were followed up for up to 7 years and 11 months. One patient died of the disease and 2 patients died of unknown causes. In conclusion, surgical removal of renal cell carcinomas was well tolerated, safe and effective treatment in patients under hemodialysis.

[A case of leiomyosarcoma of the spermatic cord].

A 44-year-old male was referred to our hospital for further treatment of lung and adrenal metastases from leiomyosarcoma occurring in the left spermatic cord. He had undergone high orchiectomy 5 months before, but no adjuvant therapy was done. Although systemic CYVADIC therapy (cyclophosphamide, vincristine, doxorubicin hydrochloride, dacarbazine) was performed in our hospital, he died of metastatic disease 10 months after the initial therapy. Leiomyosarcoma arising in the spermatic cord is a rare entity. We present a case of leiomyosarcoma of the spermatic cord, and to our knowledge, this is the 23rd case reported in Japan.