The efficacy of ultrasonography for the detection of upper tract urothelial carcinoma.

PURPOSE: Ultrasonography and computed tomography urography are two commonly used modalities to image the upper tracts for the evaluation of hematuria. This study evaluated the efficacy of ultrasonography for the detection of upper tract urothelial carcinoma compared to computed tomography urography as a standard reference. METHODS: This retrospective study included patients with urothelial carcinoma of the renal pelvis and/or ureter who were diagnosed using computed tomography urography and underwent surgical treatment. We calculated the sensitivity of ultrasonography in upper tract urothelial carcinoma diagnosis, further classified the degree of hydronephrosis on ultrasonography, and analyzed the relationship between the sensitivity and the degree of hydronephrosis and tumor location. Additionally, the usefulness of the combination of the screening ultrasonography findings, the presence of gross hematuria, and/or urine cytology was analyzed. RESULTS: This study included 136 patients with upper urothelial carcinoma. Ultrasonography in the diagnosis had 45.6% sensitivity, and ultrasonography findings, including the detection of hydronephrosis, were present in 72.8%. The presence of hydronephrosis and tumor location were associated with detection by ultrasonography. The tumor was identified in a total of 134 (98.5%) patients by combining tumor detection and hydronephrosis using ultrasonography with gross hematuria and positive urine cytology as screening. CONCLUSION: Ultrasonography showed acceptable sensitivity for upper tract urothelial carcinoma diagnosis. Considering the hydronephrosis findings, ultrasonography is a useful screening tool for upper tract urothelial carcinoma. Additionally, excessive computed tomography examinations can be reduced by adding gross hematuria and positive urine cytology.

Safety and efficacy of ureteroscopy for urolithiasis in octogenarians.

OBJECTIVE: To examine the safety and efficacy of ureteroscopy (URS) for urolithiasis in octogenarians, and identify preoperative risk factors for the incidence of postoperative complications. METHODS: The patients who underwent URS for urolithiasis were divided into octogenarians and younger patients (age: <80 years), and the groups were compared regarding their clinical characteristics, intraoperative and postoperative complications, and stone-free rate. The predictors of postoperative complications were evaluated using logistic regression models. RESULTS: A total of 1207 patients were included, 166 in the octogenarian patient group and 1041 in the younger patient group. The proportion of female patients (p < 0.001), American Society of Anesthesiologists (ASA) score (p < 0.001), rate of preoperative pyelonephritis (p < 0.001), and diabetes mellitus (p = 0.003) were higher in the octogenarian group. No statistically significant differences were found between the two groups regarding stone size, location, and intraoperative complications. Postoperative complications, which reached a significant difference, were observed in 34 (20.5%) octogenarians and 117 (11.2%) younger patients (p = 0.002). However, age itself was not significantly associated with postoperative fever, the most frequent postoperative complication, in multivariate analysis. Female sex, ASA score of ≥3, history of diabetes mellitus, and prolonged operative time (≥120 min) were the significant predictors of fever. The stone-free rate in the octogenarian group was superior to that in the younger patient group (80.1% vs. 70.6%, respectively; p = 0.035). CONCLUSION: Our results suggest that URS for urolithiasis can be safely and effectively applied to octogenarians in selected cases.

Functional and genomic characterization of patient-derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma.

Resistance to the mechanistic target of rapamycin (mTOR) inhibitors, which are a standard treatment for advanced clear cell renal cell carcinoma (ccRCC), eventually develops in most cases. In this study, we established a patient-derived xenograft (PDX) model which acquired resistance to the mTOR inhibitor temsirolimus, and explored the underlying mechanisms of resistance acquisition. Temsirolimus was administered to PDX model mice, and one cohort of PDX models acquired resistance after repeated passages. PDX tumors were genetically analyzed by whole-exome sequencing and detected several genetic alterations specific to resistant tumors. Among them, mutations in ANKRD12 and DNMT1 were already identified in the early passage of a resistant PDX model, and we focused on a DNMT1 mutation as a potential candidate for developing the resistant phenotype. While DNMT1 expression in temsirolimus-resistant tumors was comparable with the control tumors, DNMT enzyme activity was decreased in resistant tumors compared with controls. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated heterozygous knockdown of DNMT1 in the temsirolimus-sensitive ccRCC (786-O) cell line was shown to result in a temsirolimus-resistant phenotype in vitro and in vivo. Integrated gene profiles using methylation and microarray analyses of PDX tumors suggested a global shift for the hypomethylation status including promotor regions, and showed the upregulation of several molecules that regulate the mTOR pathway in temsirolimus-resistant tumors. Present study showed the feasibility of PDX model to explore the mechanisms of mTOR resistance acquisition and suggested that genetic alterations, including that of DNMT1, which alter the methylation status in cancer cells, are one of the potential mechanisms of developing resistance to temsirolimus.

CCL2 as a potential therapeutic target for clear cell renal cell carcinoma.

We previously reported that the pVHL-atypical PKC-JunB pathway contributed to promotion of cell invasiveness and angiogenesis in clear cell renal cell carcinoma (ccRCC), and we detected chemokine (C-C motif) ligand-2 (CCL2) as one of downstream effectors of JunB. CCL2 plays a critical role in tumorigenesis in other types of cancer, but its role in ccRCC remains unclear. In this study, we investigated the roles and therapeutic potential of CCL2 in ccRCC. Immunohistochemical analysis of CCL2 expression for ccRCC specimens showed that upregulation of CCL2 expression correlated with clinical stage, overall survival, and macrophage infiltration. For functional analysis of CCL2 in ccRCC cells, we generated subclones of WT8 cells that overexpressed CCL2 and subclones 786-O cells in which CCL2 expression was knocked down. Although CCL2 expression did not affect cell proliferation in vitro, CCL2 overexpression enhanced and CCL2 knockdown suppressed tumor growth, angiogenesis, and macrophage infiltration in vivo. We then depleted macrophages from tumor xenografts by administration of clodronate liposomes to confirm the role of macrophages in ccRCC. Depletion of macrophages suppressed tumor growth and angiogenesis. To examine the effect of inhibiting CCL2 activity in ccRCC, we administered CCL2 neutralizing antibody to primary RCC xenografts established from patient surgical specimens. Inhibition of CCL2 activity resulted in significant suppression of tumor growth, angiogenesis, and macrophage infiltration. These results suggest that CCL2 is involved in angiogenesis and macrophage infiltration in ccRCC, and that CCL2 could be a potential therapeutic target for ccRCC.

Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.

Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

Improvement of prognosis in patients with metastatic renal cell carcinoma and Memorial Sloan-Kettering Cancer Center intermediate risk features by modern strategy including molecular-targeted therapy in clinical practice.

OBJECTIVES: To identify the patient subgroups benefitting the most from the modern strategy including molecular-targeted therapy among patients with metastatic renal cell carcinoma (mRCC) in clinical practice. METHODS: Retrospective analysis of 144 patients with mRCC diagnosed between 1992 and 2011 at Kyoto University Hospital was conducted. Multivariate analysis using the Cox proportional hazards model was conducted to identify prognostic factors associated with overall survival (OS). Subgroup analysis was conducted to identify patients who benefitted the most from molecular-targeted therapy. RESULTS: Independent factors associated with worse OS are: tumors of histological type other than clear-cell, decreased hemoglobin (Hb), elevated lactate dehydrogenase (LDH), elevated C-reactive protein (CRP), and metastases at ≥ 3 sites. Median OS of patients treated with molecular-targeted therapy alone or with prior immunotherapy and those treated with immunotherapy alone was 57, 45 and 28 months, respectively. Molecular-targeted therapy had more effect on OS than immunotherapy alone among female patients, patients with Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk features, and patients with metastatic progression less than 1 year after initial diagnosis of RCC, compared with their counterparts. CONCLUSIONS: The modern strategy including molecular-targeted therapy may improve OS in patients with mRCC and MSKCC intermediate risk features in clinical practice, relative to those with other risk features. However, the prognosis for patients with tumors of histological type other than clear-cell, decreased Hb, elevated LDH, elevated CRP, or metastases at ≥ 3 sites remains poor even in the modern molecular-targeted era. Novel treatment strategies are necessary to improve prognosis in these patients.

Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy.

Vascular endothelial growth factor (VEGF)-targeted therapies show significant antitumor effects for advanced clear cell renal cell carcinomas (CC-RCCs). Previous studies using VEGF inhibitors in mice models revealed that VEGF-dependent capillaries were characterized by the existence of endothelial fenestrations (EFs). In this study, we revealed that capillaries with abundant EFs did exist, particularly in CC-RCCs harboring VHL mutation. This finding was recapitulated in mice xenograft models, in which tumors from VHL null cells showed more abundant EFs compared to those from VHL wild-type cells. Importantly, treatment with bevacizumab resulted in a significant decrease of tumor size established from VHL null cells. Additionally, a significant reduction of EFs and microvessel density was observed in VHL null tumors. Indeed, xenograft from 786-O/mock (pRC3) cells developed four times more abundant EFs than that from 786-O/VHL (WT8). However, introduction of the constitutively active form of hypoxia-inducible factor (HIF)-2α to WT8 cells failed to either augment the number of EFs or restore the sensitivity to bevacizumab in mice xenograft, irrespective of the equivalent production of VEGF to 786-O/mock cells. These results indicated that HIF-2α independent factors also play significant roles in the development of abundant EFs. In fact, several angiogenesis-related genes including CCL2 were upregulated in 786-O cells in a HIF-2α independent manner. Treatment with CCL2 neutralizing antibody caused significant reduction of capillaries with EFs in 786-O xenograft, indicating that they were also sensitive to CCL2 inhibition as well as VEGF. Collectively, these results strongly indicated that capillaries with distinctive phenotype developed in VHL null CC-RCCs are potent targets for anti-angiogenic therapy.

[Outcome analysis of the urethral stent (Memotherm®)].

A number of patients with benign prostatic hyperplasia can not undergo surgical therapy because of advanced age, concomitant diseases, and other reasons. Since 1980, various types of urethral stents have been used for high-risk patients with benign prostatic hyperplasia. We report our experience with the use of urethral stents (Memotherm®). Between July 2002 and December 2010, we implanted urethral stents in 36 patients. The average follow-up period was 24.0 months. After stent implantation, 34 of the 36 patients were able to micturate. The average residual urine volume was 24.7 ml (0-250 ml), and the maximal urinary flow rate was 10.7 ml/s (3-24 ml/s). One stent had to be removed due to bladder tamponade, and one had to be exchanged due to dislocation. In 2 patients, a stone formed at the bladder end of the stent, and one of these patients underwent transurethral lithotripsy. Our results suggest that therapy with the Memotherm® urethral stent is a good option for patients suffering from urinary retention due to benign prostatic hyperplasia.

[A case of renal arteriovenous fistula complicated with pyelonephritis].

We report a case of renal arteriovenous fistula, which was found during treatment for pyelonephritis. A 61-year-old woman was referred to our hospital because of lumbar backache and infectious fever. The computed tomographic scan showed right hydronephrosis and perinephritis. We treated her conservatively for pyelonephritis, but 5 days later, the contrast-enhanced computed tomographic scan showed retroperitoneal hemorrhage. Renal angiography demonstrated an arteriovenous fistula in the central portion of the right kidney. Superselective transcatheter arterial embolization of the AVF was performed. Hemostasis was possible by embolization. She has not had any recurrence of renal arteriovenous fistula. To our knowledge, this is the 5th report of a rupture in the retroperitoneum of an arteriovenous fistula, and renal arteriovenous fistula with the pyelonephritis is very rare.

[A case of retroperitoneal well-differentiated liposarcoma with metaplastic bone formation].

A 43-year-old female was referred to our hospital from a local doctor. Her chief complaints were weight gain and abdominal fullness. Computed tomography and magnetic resonance imaging showed a huge tumor in the right retroperitoneal space, which adhered to the right kidney. It was resected with concomitant resection of the right kidney. It measured 30×15 cm and weighed 3.0 kg. Histological examination revealed well differentiated liposarcoma with metaplastic bone formation. She has survived 22 months since the operation with no evidence of recurrence. A retoroperitoneal liposarcoma with metaplastic bone formation is rare. Twenty cases have been reported in Japan including our case.

[Metastatic renal tumor originating from thyroid cancer: a case report].

A 82-year-old female was referred to our department for close examination and treatment of a right renal tumor incidentally found by computed tomography. Her past history included partial thyroidectomy for follicular thyroid carcinoma 20 years earlier. Enhanced computed tomography showed a hypervascular mass with a diameter of 3 cm at the lower pole of the right kidney. We carried out radical nephrectomy for diagnosis of renal cell carcinoma. Pathological findings revealed a metastatic renal tumor of follicular thyroid carcinoma. It is rare to find metastatic renal tumors arising from thyroid carcinoma in clinical practice. Thirty cases have been reported in the Japanese literature.

Management of urethral hemangiomas associated with Klippel-Trenaunay-Weber syndrome by endoscopic sclerotherapy.

Klippel-Trenaunay-Weber syndrome (KTS) is an unusual congenital anomaly characterized by cutaneous hemangiomas, varicosities and bony hypertrophy of the extremities. Herein the case is reported of a 24-year-old man with urethral bleeding from hemangiomas associated with KTS that were successfully managed by endoscopic sclerotherapy. A 23-G puncture needle was inserted into the bleeding vein to inject a 5% solution of monoethanolamine oleate (Oldamine), which is typically used for sclerotherapy of esophageal vasix. At a 4-month follow-up, the patient only had slightly bloodstained urethral discharge, and is doing well. This is the first case reporting endoscopic sclerotherapy for a KTS-associated urethral hemangioma.

Intermittent androgen deprivation therapy may prolong the duration of androgen dependence of well-differentiated prostate cancer.

We previously reported the results of a pilot study of intermittent androgen deprivation (IAD) therapy in which surveillance was performed when PSA level fell below 0.3 ng/ml and androgen deprivation was resumed when PSA level exceeded 2.0 ng/ml. In the present study, we compared the duration of androgen dependence in patients treated with IAD with that in patients with continuous androgen deprivation (CAD) therapy. Forty-six patients with clinically localized or metastatic prostate cancer, or biochemical recurrence after radical prostatectomy were treated with IAD from 1995 to 2003. Patients in or after the second cycle of IAD (30 patients) were evaluated for duration of androgen dependence. Patients whose serum PSA nadir became <0.3 ng/ml (33 patients) represented a control group of CAD. The overall 5-year biochemical progression-free rate was 58% and 89% in the IAD and CAD groups, respectively; there was no significant difference between the two groups (p=0.5). Subgroup analysis showed that, irrespective of metastasis, the 5-year biochemical progression-free survival rate in the IAD group was not significantly different from that in the CAD group. However, IAD offered significantly better results for well-differentiated prostate cancer, whereas CAD offered significantly better results for moderately or poorly differentiated prostate cancer. The results obtained from this retrospective and nonrandomized study suggested that IAD may be a feasible treatment for well-differentiated prostate cancer.

[Efficacy of intranasal desmopressin in the treatment of nocturia due to nocturnal polyuria].

Older adults often cite nocturia as one of the most bothersome lower urinary tract symptoms (LUTS). We investigated the efficacy and safety of intranasal desmopressin in the treatment of nocturia due to nocturnal polyuria on 12 patients (ten men, two women) ranging in age from 53 to 77 years (mean 67 years). All patients experienced more than two episodes of nocturia per night, and had a nocturnal urine volume greater than 35% of the daily voided volume, measured using a 3-day voiding diary with a frequency-volume chart. They began taking intranasal desmopressin (10 microg) at bedtime. When compared with the baseline data, the nocturnal urine volume, (928 +/- 307 versus 469 +/- 251 ml, p = 0.0007) and nocturnal frequency (4.8 +/- 2.0 versus 2.8 +/- 1.8, p = 0.0009) were significantly decreased. The daytime urine volume (1,008 +/- 458 versus 930 +/- 419 ml, p = 0.49) did not change significantly. The unine osmolarity (420 +/- 143 versus 598 +/- 158 mOsm/kg, p = 0.0065), and urine sodium levels (100 +/- 32 versus 140 +/- 60 mEq/l, p = 0.007) increased significantly, whereas the serum sodium levels (141 +/- 3 versus 135 +/- 7 mEq/l, p = 0.048) decreased significantly. Among the 12 patients, 5 (41.6%) patients reported side effects, including headache in 1, edema in 1 and hyponatremia in 3. The patient with edema discontinued medication, but the other 4 patients continued their medication and the side effects subsided. In conclusion, desmopressin is an effective treatment for adult patients complaining of nocturia due to nocturnal polyuria. One should be aware of the potential side effects including hyponatremia.

[Endoscopic treatment for severe encrusted ureteral stent left in place for 3 years].

A 52-year-old man had bilateral ureteral stents placed before treatment for ureteral and renal stones, but did not return for treatment and follow-up. Three years later, he complained of hematuria and vertigo. An abdominal X-ray revealed large renal and ureteral stones rising from and enveloping the stent. A bilateral percutaneous nephrostomy was placed. The right ureteral stent was easily removed with a cystoscope. The left ureteral stone was separated from the stent by ureteroscopic lithotripsy (TUL) and percutaneous nephroscopic lithotripsy (PNL). The left stent was torn off and difficult to remove because of encrustation. It was finally removed through an endoscopic procedure. Right PNL and extracorporeal shock wave lithotripsy (ESWL) were performed and all stones and stents were extracted. He was stone-free at 4 months.