Publications by authors named "Noriaki Utsunomiya"

50 Publications

Robot-assisted partial nephrectomy via retroperitoneal approach in a patient with horseshoe kidney.

IJU Case Rep 2021 Jul 9;4(4):239-242. Epub 2021 May 9.

Department of Urology Kobe City Nishi-Kobe Medical Center Kobe Japan.

Introduction: Horseshoe kidney is a renal fusion anomaly often associated with ectopia, malformation, and vascular changes. Robot-assisted partial nephrectomy is selected for patients with T1a renal cell carcinoma; however, there are few reports of renal cell carcinoma in horseshoe kidney. We present a case of robot-assisted partial nephrectomy via a retroperitoneal approach in a patient with horseshoe kidney with a brief literature review.

Case Presentation: An 84-year-old woman presented with a 2-cm mass in horseshoe kidney. She underwent robot-assisted laparoscopic partial nephrectomy via a retroperitoneal approach.

Conclusion: The use of robot-assisted laparoscopic partial nephrectomy in patients with horseshoe kidney is very rare, and only four cases have been reported. Because of the unique anatomical structure, surgeons need to consider surgical strategy more carefully, considering tumor location, vascular anatomy, and past history of abdominal surgery.
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http://dx.doi.org/10.1002/iju5.12297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255279PMC
July 2021

[A Case of Ureteral Metastasis from Prostate Cancer].

Hinyokika Kiyo 2021 Apr;67(4):171-176

The Department of Urology, Kobe City Nishi-Kobe Medical Center.

Ureteral metastasis from prostate cancer is rare. The present case report describes an 83-year-old patient with distant metastasis of prostate cancer to the right ureter that caused hydronephrosis. Upon initial examination at our hospital, he presented with a high prostate-specific antigen (PSA) level of 10.0 ng/ml. He was diagnosed with prostate adenocarcinoma, with Gleason score of 10 (5+5) and clinical staging of cT2aN0M0. Intensity-modulated radiation therapy (IMRT) was performed after 1 year and 7 months of androgen depriation therapy. At 1 year and 4 months after IMRT, PSA increased to 3.068 ng/ml. Computed tomography scan revealed right hydronephrosis and thickening of the right ureter. We could not identify obvious malignant cells on ureteroscopic biopsy, and right nephroureterectomy was performed. Pathological examination revealed ureteral metastasis of prostate cancer. Six months after nephroureterectomy, PSA increased to 3.037 ng/ml. He was diagnosed with castration-resistant prostate cancer and has been treated with enzalutamide.
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http://dx.doi.org/10.14989/ActaUrolJap_67_4_171DOI Listing
April 2021

Detection of von Hippel-Lindau gene mutation in circulating cell-free DNA for clear cell renal cell carcinoma.

Cancer Sci 2021 May 19. Epub 2021 May 19.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.
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http://dx.doi.org/10.1111/cas.14972DOI Listing
May 2021

[Risk Factors for Recurrence in Patients with Pathological Lymph Node-Positive Prostate Cancer after Extended Lymph Node Dissection in Laparoscopic and Robotic-Assisted Radical Prostatectomy].

Hinyokika Kiyo 2021 Mar;67(3):83-90

The Department of Urology, Kobe City Medical Center General Hospital.

From April 2007 to April 2018, we performed lymph node dissection in 305 cases of laparoscopic radical prostatectomy and 202 cases of robot-assisted radical prostatectomy at our hospital, and there were 68 cases with positive lymph node metastasis (pN1). Of these 68 cases, we examined retrospectively 62 cases in which extended lymph node dissection (ELND) was performed. The median number of removed lymph nodes was 25 (interquartile range [IQR] ; 18-34) and the median number of metastatic lymph nodes was 1 (IQR ; 1-3). Postoperative prostate-specific antigen (PSA) recurrence was observed in 40 of the 62 patients. The median time to PSA recurrence was 24 months. After univariate analysis, PSA at initial diagnosis (iPSA) of 10 ng/ml or more, pathological Gleason score (pGS) of 8 or more, total number of lymph node metastases of 2 or more, and positive surgical margin (RM+) were found to be riskfactors of PSA recurrence. In multivariate analysis, iPSA of 10 ng/ml or more, pGS of 8 or more and RM+ were independent riskfactors of PSA recurrence (p<0.05). In the cases without riskfactors such as iPSA≥10, pGS≥8, and RM+, immediate postoperative adjuvant therapy may be avoided even with pN1.
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http://dx.doi.org/10.14989/ActaUrolJap_67_3_83DOI Listing
March 2021

Rapid recurrence of squamous cell carcinoma at a lymphocele after nephroureterectomy: A rare case report.

IJU Case Rep 2021 Mar 15;4(2):118-121. Epub 2021 Feb 15.

Department of Urology Kobe City Nishi-Kobe Medical Center Kobe Hyogo Japan.

Introduction: Lymphoceles are sometimes formed after pelvic lymph node dissection. However, recurrence at lymphoceles has not been reported previously. Here, we report a case of rapid prognosis of the recurrence at a lymphocele after nephroureterectomy.

Case Presentation: A 78-year-old man underwent retroperitoneoscopic radical nephroureterectomy with pelvic lymphadenectomy for left ureteral urothelial carcinoma. The histopathological diagnosis was high-grade invasive urothelial carcinoma with squamous differentiation. Follow-up computed tomography at 3 months postoperatively showed a lymphocele with a small solid component, in the left pelvic region. At 7 months postoperatively, he presented with severe fatigue, and computed tomography showed a solid tumor had replaced the lymphocele. Computed tomography-guided biopsy was performed and histopathological diagnosis was squamous cell carcinoma.

Conclusion: This report provides support for possible recurrence at the lymphocele after nephroureterectomy. If lymphocele occurs after surgery for malignant disease, it is recommended to follow up with the possibility of recurrence in the lymphatic cysts in mind.
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http://dx.doi.org/10.1002/iju5.12259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924088PMC
March 2021

[Clinical Course and Treatment of Acute Urinary Retention after Robot- Assisted Laparoscopic Radical Prostatectomy : A Single Institution Experience of 11 Cases].

Hinyokika Kiyo 2021 Jan;67(1):1-6

The Department of Urology, Kobe City Nishi-Kobe Medical Center.

Robot-assisted laparoscopic radical prostatectomy (RARP) is becoming the standard treatment procedure for localized prostate cancer. The main complications associated with RARP include urinary incontinence and sexual dysfunction. In addition, acute urinary retention (AUR) after urethral catheter removal is sometimes seen. Early catheter removal is a risk factor for AUR, and administration of alphablockers before catheter removal reduces the occurrence of AUR. However, the ideal management of AUR after RARP is not known. Here we report the clinical course and treatment after AUR. We performed 279 RARPs at our institution, and AUR developed in 11 cases. In all cases, urination status was improved after placement of a urinary catheter or intermittent catheterization. Later, urethral stricture was seen in 2 out of 11 cases. Ourstudy suggests that when AUR is observed afterRARP, catheterur ination should be initially performed. If urinary retention recurs, a urinary catheter should be placed with administration of alpha-blockers. The catheter is removed after about 3 days, and administration of analgesics is effective for reducing the pain on urination. If urination status is not improved, evaluation of the urethral stricture should be considered.
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http://dx.doi.org/10.14989/ActaUrolJap_67_1_1DOI Listing
January 2021

[Radical Nephroureterectomy in Octogenarians].

Hinyokika Kiyo 2020 Dec;66(12):421-426

The Department of Urology, Kobe City Nishi-Kobe Medical Center.

We compared the perioperative and oncological outcomes of radical nephroureterectomy for renal pelvic and ureteral cancer between octogenarians and younger patients. We examined 146 patients attending our hospital from January 2012 to December 2019. The octogenarian group included 48 patients and the control group (younger patients) 98 patients. The median body mass index (BMI) (21.2 vs 23.4 kg/m^2, p<0.001), American Society of Anesthesiologists (ASA) score (p=0.044), preoperative albumin concentration (p=0.04) and operation time (287 vs 314 min, p=0.029) differed significantly between the two groups. However, there were no significant differences in perioperative complications between the two groups. According to multivariable analysis of overall survival, pT3 or higher pathology was a significant indicator of poor prognosis in all patients. In the octogenarian group alone, perioperative transfusion was the only other factor significantly associated with prognosis, whereas anti-CD55 monoclonal antibody (RM1) was a significant factor in the control group. There were significant differences between the octogenarian and control groups with respect to overall survival in those with pT2 or below stage disease (60.2% vs 87.5%, p=0.049), but not to cancer-specific survival (≤pT2 : 73.5% vs 94.2%, p=0.202 ≥pT3 : 72.2% vs 63.8%, p=0. 87). Our findings indicate that nephroureterectomy is a safe and efficient procedure for selected octogenarian patients.
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http://dx.doi.org/10.14989/ActaUrolJap_66_12_421DOI Listing
December 2020

Black adrenal adenoma causing subclinical Cushing's syndrome complicated with pheochromocytoma.

IJU Case Rep 2021 Jan 3;4(1):56-58. Epub 2020 Dec 3.

Department of Urology Kobe City Nishi-Kobe Medical Center Kobe Japan.

Introduction: The development of adrenocortical adenoma and pheochromocytoma within the same adrenal gland is very rare. Furthermore, no reports have described coincident black adrenal adenoma and pheochromocytoma. We herein report a rare case of coincident black adrenal adenoma and pheochromocytoma in the same adrenal gland.

Case Presentation: A 71-year-old Japanese woman was hospitalized because a right adrenal tumor had been incidentally found by computed tomography. She was diagnosed with subclinical Cushing's syndrome and underwent laparoscopic right adrenalectomy. The tumor contained two adrenal nodules. The cut surface of the larger nodule was brownish-black on macroscopic examination. Pathological studies revealed coincident black adrenal adenoma and pheochromocytoma.

Conclusion: To the best of our knowledge, this is the first report of coincident black adrenal adenoma causing subclinical Cushing's syndrome and pheochromocytoma in the same adrenal gland. The mechanism of this rare scenario is unclear, and further study is necessary.
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http://dx.doi.org/10.1002/iju5.12240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784729PMC
January 2021

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

Cancer Med 2021 01 27;10(1):119-134. Epub 2020 Oct 27.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1002/cam4.3578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826464PMC
January 2021

Port-site incisional hernia from an 8-mm robotic trocar following robot-assisted radical cystectomy: Report of a rare case.

IJU Case Rep 2020 May 21;3(3):97-99. Epub 2020 Mar 21.

Department of Urology Kobe City Nishi-Kobe Medical Center Kobe Japan.

Introduction: Port-site incisional hernia is a rare but well-known complication following a laparoscopic procedure and it may cause severe adverse outcomes, such as intestinal necrosis. Here, we report a rare case of hernia that occurred from an 8-mm trocar after robot-assisted radical cystectomy.

Case Presentation: An 80-year-old woman was diagnosed with cT2bN1M0 bladder cancer. She underwent robot-assisted radical cystectomy. Nine days after surgery, she complained of severe abdominal pain. Computed tomography showed herniation of small intestine. Emergency explorative laparotomy revealed herniation of small intestine from an 8-mm trocar site. A section of the small bowel was necrotic and was resected.

Conclusion: It is debatable whether we should routinely close the fascia of an 8-mm trocar site. The patient was an elderly woman with multiple major abdominal surgery histories and hernia risk factors. For these patients, fascial closure of the 8-mm trocar site may be indicated.
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http://dx.doi.org/10.1002/iju5.12155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292067PMC
May 2020

Prognosis of patients with muscle invasive bladder cancer who are intolerable to receive any anti-cancer treatment.

Cancer Treat Res Commun 2020 15;24:100195. Epub 2020 Jul 15.

Department of Urology, Kobe City Nishi-Kobe Medical Center, 7-1 Kojidai, 5-chome Nishiku, Kobe 651-2273, Hyogo, Japan.

Background: The aim of this retrospective study was to evaluate the prognosis of patients who had been diagnosed with muscle invasive bladder cancer (MIBC) and did not receive anti-cancer treatment because of their physical characteristics.

Methods: Between January 2012 and October 2019, 96 patients were diagnosed with MIBC (cT2-4N0M0) in our institution. Of those, 64 patients had undergone radical cystectomy (RC), 6 had received palliative radiation therapy, and 26 had not received any anti-cancer treatment. We further evaluated the 26 patients who had received no anti-cancer treatment.

Results: The no anti-cancer treatment group were significantly older (91 vs. 75 years, p<0.001), comprised fewer men (42% vs. 72%, p=0.015), and had poorer performance status (PS) (mean 2.69 vs. 0.32, p<0.001) than the RC group. The follow periods were 9.5 months and 28.5 months, respectively. Median overall survival (OS) was 12 months in the no anti-cancer treatment group, whereas the median OS was not reached during the study period in the RC group. In univariate analysis, OS was significantly associated with estimated GFR (eGFR) less than 30 mL/min/1.73m (median OS, 10 vs 16 months, p = 0.044). Multivariate analysis demonstrated that eGFR was significantly associated with OS (hazards ratio 0.267 [95% CI 0.0858-0.8357]; p = 0.0023).

Conclusions: We evaluated the prognosis of patients with untreated MIBC. Their median OS was 12 months and eGFR was a significant prognostic factor. These findings may help in counseling patients about prognosis if no anti-cancer treatment is given.
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http://dx.doi.org/10.1016/j.ctarc.2020.100195DOI Listing
May 2021

[A Case of Isolated Peritoneal Metastasis from Prostate Cancer].

Hinyokika Kiyo 2019 May;65(5):175-179

The Department of Urology, Kobe City Nishi-Kobe Medical Center.

Peritoneal metastasis of prostate cancer is extremely rare, with only a few cases reported. A 78-yearold male patient was introduced to our hospital presenting with a prostate-specific antigen (PSA) level of 94.0 ng/ml at examination. He was diagnosed with poorly differentiated adenocarcinoma of the prostate, with a Gleasonscore of 9 (5+4) at cT3bN0M0. Intensity-modulated radiation therapy was performed after 6 months of combined-androgen blockade (CAB) therapy. Twenty-one months later, several lymph node metastases were observed. With the resumptionof CAB therapy, PSA levels dropped and the multiple lymph node metastasis disappeared ; however, peritoneal metastasis was observed after 43 months. We performed a laparoscopic biopsy and our diagnosis after pathological evaluation was metastasis of the prostate cancer. He was treated with Enzalutamide.
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http://dx.doi.org/10.14989/ActaUrolJap_65_5_175DOI Listing
May 2019

Primary small cell neuroendocrine carcinoma of adrenal gland.

Int Cancer Conf J 2019 Jul 27;8(3):122-125. Epub 2019 Mar 27.

1Department of Urology, Kobe City Nishi-Kobe Medical Center, 7-1 Kojidai, 5-chome Nishiku, Kobe, Hyogo 651-2273 Japan.

Neuroendocrine tumors are an extremely rare form of retroperitoneum tumor. A 79-year-old man presented with abdominal pain. Computed tomography and magnetic resonance imaging revealed a 51 × 36 mm mass in the left adrenal gland. Gastrofiberscopy, colonfiberscopy and positron emission tomography were performed and showed no lesions or other malignancies. Endocrine tests were normal. Two months later, the mass had grown to 68 × 52 mm. Suspecting a malignant tumor, we performed laparoscopic adrenalectomy. Histopathological diagnosis revealed the tumor was small cell neuroendocrine carcinoma. No other malignancies were revealed, so we diagnosed primary small cell neuroendocrine carcinoma of adrenal gland. To our knowledge, this is only the third report in English of primary small cell neuroendocrine carcinoma of the adrenal gland and the first report that is confined to the adrenal gland. Adrenal masses are often misdiagnosed as adenoma; however, we need to raise awareness of the potential for malignant adrenal tumors such as the rarer small cell neuroendocrine carcinoma.
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http://dx.doi.org/10.1007/s13691-019-00368-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545179PMC
July 2019

Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.

Sci Rep 2019 03 11;9(1):4030. Epub 2019 Mar 11.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

The therapeutic landscape of castration-resistant prostate cancer (CRPC) has rapidly expanded. There is a need to develop noninvasive biomarkers to guide treatment. We established a highly sensitive method for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma circulating cell-free DNA (cfDNA) and evaluated the AR statuses of patients with CRPC. AR amplification was detectable in VCaP cell line (AR amplified) genomic DNA (gDNA) diluted to 1.0% by digital PCR (dPCR). AR mutation were detectable in LNCaP cell line (AR T878A mutated) gDNA diluted to 0.1% and 1.0% by dPCR and target sequencing, respectively. Next, we analyzed AR status in cfDNA from 102 patients. AR amplification and mutations were detected in 47 and 25 patients, respectively. As a biomarker, AR aberrations in pretreatment cfDNA were associated with poor response to abiraterone, but not enzalutamide. In serial cfDNA analysis from 41 patients, most AR aberrations at baseline diminished with effective treatments, whereas in some patients with disease progression, AR amplification or mutations emerged. The analysis of AR in cfDNA is feasible and informative procedure for treating patients with CRPC. cfDNA may become a useful biomarker for precision medicine in CRPC.
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http://dx.doi.org/10.1038/s41598-019-40719-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411952PMC
March 2019

A family case with germline and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis.

J Clin Pathol 2018 Oct 30;71(10):936-943. Epub 2018 Jun 30.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Aim: We examined the genetic alterations in a mother and son with multiple eosinophilic chromophobe renal cell carcinomas (chRCCs) showing no other features.

Methods: Germline DNA and bilateral renal cell carcinoma DNA were genetically analysed by whole-exome sequencing. Candidate gene alterations in the first patient's germline were investigated in her child's germline and the chRCCs.

Results: We detected several germline gene alterations in the mother. Among the identified alterations, and mitochondrial DNA mutations were also confirmed in her son. Regarding somatic alterations in bilateral chRCCs, no common candidate gene alteration was found.

Conclusion: To the best of our knowledge, this is the first report of whole-exome sequencing revealing bilateral eosinophilic chRCCs associated with tuberous sclerosis complex in a family case without classical phenotype. These results suggest that germline and mitochondrial DNA gene mutations may be involved in the development of chRCCs in some cases.
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http://dx.doi.org/10.1136/jclinpath-2018-205211DOI Listing
October 2018

[Percutaneous Fibrin Glue Injection for Persistent Urinary Leakage after Partial Nephrectomy : A Case Report].

Hinyokika Kiyo 2017 Mar;63(3):107-110

The Department of Urology, Kobe City Medical Center General Hospital.

A 69-year-old man with left atrophic kidney was referred to our hospital because of a 5.7 cm solid mass in the lower pole of right kidney revealed by computed tomography for evaluation of aortic aneurysm. An open transperitoneal partial nephrectomy was performed, and final pathological diagnosis was clear cell carcinoma, grade 2, pT1b, pNx. One month postoperatively, a computed tomography revealed 16 cm retroperitoneal fluid collection which was diagnosed as urinoma due to urinary leakage from partial nephrectomy scar of the right lower calyx. Following percutaneous drainage of a 6 Fr Pigtail catheter, 6 Fr double-J ureteral stent and urethral catheter were placed, but the discharge through the percutaneous drain continued to be 700 to 1,000 ml/day. Forty-one days after drainage, two open-end catheters (5 Fr) were directed into the urinary fistula lumen through the percutaneous tract and 6 ml of fibrin glue was injected under fluoroscopic guidance. Four days later, another 2 ml of fibrin glue was injected because of a small amount of residual urinary leakage and percutaneous drainage catheter was removed. Thereafter, urinary leakage was completely cured and ureteral stent and urethral catheter were removed.
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http://dx.doi.org/10.14989/ActaUrolJap_63_3_107DOI Listing
March 2017

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

Cancer Med 2016 10 26;5(10):2920-2933. Epub 2016 Sep 26.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.
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http://dx.doi.org/10.1002/cam4.886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083746PMC
October 2016

[A Crossover Comparison Study on Lower Urinary Tract Symptoms with Overactive Bladder Secondary to Benign Prostatic Hyperplasia: Naftopidil versus Tamsulosin with Solifenacin].

Hinyokika Kiyo 2016 Jul;62(7):341-7

The Department of Urology, Hyogo Prefectural Tsukaguchi Hospita.

We compared the efficacy of naftopidil monotherapy with combination therapy using tamsulosin hydrochloride and solifenacin succinate in the treatment of lower urinary tract symptoms (LUTS) with overactive bladder (OAB) secondary to benign prostatic hyperplasia (BPH). Thirty one patients were enrolled in a randomized crossover study. Fourteen patients were initially prescribed naftopidil 75 mg (N) for 8 weeks, followed by tamsulosin 0.2 mg and solifenacin 5 mg (TS) for 8 weeks (group N) ; another 17 were initially prescribed TS, followed by N (group TS). The efficacy variables were the changes in international prostate symptom score (I-PSS), quality of life (QOL) score, overative bladder symptom score (OABSS), and post-void residual (PVR) urine volume. After the study, a questionnaire survey was carried out about the choice of treatment. After treatment with each agent, total I-PSS, storage symptom score, QOL score and OABSS except for the daytime frequency were significantly improved from baseline. PVR was significantly increased after TS treatment. There were no significant differences between the two treatments except for PVR. As a result of the questionnaire survey, 13 patients chose N and 17 chose TS. In conclusion, N monotherapy can be expected to have an equal effect in the treatment of LUTS with OAB secondary to BPH in comparison with TS combination therapy.
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http://dx.doi.org/10.14989/ActaUrolJap_62_7_341DOI Listing
July 2016

CLINICAL OUTCOMES OF EXTERNAL-BEAM RADIOTHERAPY COMBINED WITH NEOADJUVANT ANDROGEN DEPRIVATION THERAPY FOR HIGH-RISK PROSTATE CANCER.

Nihon Hinyokika Gakkai Zasshi 2016 ;107(3):162-169

Department of Urology, Kobe City Medical Center General Hospital.

(Purpose) We investigated the outcome of external-beam radiotherapy (EBRT) with neoadjuvant androgen deprivation therapy (NeoADT) for high-risk prostate cancer defined by National Comprehensive Cancer Network (NCCN) guideline. (Patients and method) From 2002 to 2013, 70 patients with high-risk prostate cancer (PSA ≥20 ng/ml or clinical T stage ≥T3a, Gleason score ≥8) were treated with NeoADT and EBRT. EBRT consisted of three-dimensional conformal or intensity modulated radiotherapy with or without whole-pelvic radiation. Biochemical failure was defined according to the Phoenix definition. Biochemical progression-free survival (bPFS) and overall survival (OS) were calculated by Kaplan-Meier method, and prognostic factors for bPFS were analyzed by using the Cox proportional hazard model. (Result) The median age and initial prostate-specific antigen (PSA) level were 72 years old and 25.2 ng/ml, respectively. 43 patients had PSA level ≥20 ng/ml, 51 patients had clinical stage ≥T3a, 27 patients had Gleason score ≥8. The number of risk factors patients possessed was 1 (RiskN-1) in 31 patients, 2 (RiskN-2) in 27 patients and 3 (RiskN-3) in 12 patients. Median EBRT dose and duration of Neo ADT were 74 Gy and13.0 months, respectively. Whole-pelvic radiation was administered in 7 patients. After median follow-up of 4.8 years, biochemical and clinical failure occurred in 23 and 2 patients, respectively. No patients died of cancer. Five-year/8-year bPFS and OS were 63%/54% and 100%/91%, respectively. In multivariate analysis, three high-risk factor of NCCN guideline (PSA, clinical stage, Gleason score) did not predict outcome after EBRT independently, but RiskN (-1 vs -2, 3, HR 35.35, 95%CI 2.51-498.05, p<0.01) and pre-EBRT PSA (continuous, hazard ratio 1.31, 95%CI 1.01-1.71, p<0.05) were the significant predictors of bPFS. Five-year/8-year bPFS in RiskN-1 group and RiskN-2 or -3 group were 89%/79% and 47%/39%, respectively. Grade 3/4 adverse events (CTCAE ver4.0-JCOG) occurred in 2 patients. (Conclusion) Median dose of 74 Gy EBRT with intermediate-term NeoADT was safe and beneficial for high-risk prostate cancer. The number of risk factors and pre-EBRT PSA level were the independent prognostic factors for biochemical progression-free survival.
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http://dx.doi.org/10.5980/jpnjurol.107.162DOI Listing
January 2016

[THE IMPACT OF LOWER URINARY TRACT SYMPTOMS ON GENERIC HEALTH-RELATED QUALITY OF LIFE IN MALE PATIENTS WITHOUT CO-MORBIDITY].

Nihon Hinyokika Gakkai Zasshi 2015 Jul;106(3):172-7

Purpose: We investigated the impact of lower urinary tract symptoms (LUTS) on generic health-related quality of life (HRQOL) in male patients without co-morbidity.

Patients And Method: From 2003 to 2011, a total 567 men who presented out urological department completed the questionnaires including International Prostate Symptom Score (IPSS), incontinence-frequency score (IFS) from the UCLA prostate cancer index, MOS 36-Item Short-Form Health Survey (SF-36). Among 230 patients with no coexisting morbidity, the relations between each LUTS score of IPSS indices and IFS and 8 domain scores of SF-36 were analyzed by Pearson's product-moment correlation and stepwise multiple regression analysis.

Result: Univariate analysis showed that the IFS had a significant correlation with all of 8 domain scores of SF-36, and also the IPSS item scores of urgency, nocturia and straining correlated significantly with multiple domain scores of SF-36. In multiple regression analysis, the proportionate contributions of LUTS to each SF-36 domain scores were low (R2 was 10% or less). Incontinence was considered as the most influential factor that had a negative impact on HRQOL in 7 SF-36 domains of physical functioning, role-physical, bodily pain, general health perception, vitality, social functioning and mental health. Additionally, nocturia, straining and urgency were significantly associated with deficit of HRQOL in 4 SF-36 domains (role-physical, general health perception, role-emotional, mental health), 2 domains (bodily pain, social functioning) and 1 domain (role-emotional) of SF-36, respectively. CONCLUSION; Among LUTS, incontinence, nocturia and straining were the most important symptoms in association with the negative impact on generic HRQOL measured by SF-36.
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http://dx.doi.org/10.5980/jpnjurol.106.172DOI Listing
July 2015

Decreased expression of lysophosphatidylcholine (16:0/OH) in high resolution imaging mass spectrometry independently predicts biochemical recurrence after surgical treatment for prostate cancer.

Prostate 2015 Dec 1;75(16):1821-30. Epub 2015 Sep 1.

Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Human prostate cancers are highly heterogeneous, indicating a need for various novel biomarkers to predict their prognosis. Lipid metabolism affects numerous cellular processes, including cell growth, proliferation, differentiation, and motility. Direct profiling of lipids in tissue using high-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry (HR-MALDI-IMS) may provide molecular details that supplement tissue morphology.

Methods: Prostate tissue samples were obtained from 31 patients, with localized prostate cancer who underwent radical prostatectomy. The samples were assessed by HR-MALDI-IMS in positive mode, with the molecules identified by tandem mass spectrometry (MS/MS). The effect of identified molecules on prostate specific antigen recurrence free survival after radical prostatectomy was determined by Cox regression analysis and by the Kaplan-Meier method.

Results: Thirteen molecules were found to be highly expressed in prostate tissue, with five being significantly lower in cancer tissue than in benign epithelium. MS/MS showed that these molecules were [lysophosphatidylcholine (LPC)(16:0/OH)+H](+), [LPC(16:0/OH)+Na](+), [LPC(16:0/OH)+K](+), [LPC(16:0/OH)+matrix+H](+), and [sphingomyelin (SM)(d18:1/16:0)+H](+). Reduced expression of LPC(16:0/OH) in cancer tissue was an independent predictor of biochemical recurrence after radical prostatectomy.

Conclusions: HR-MALDI-IMS showed that the expression of LPC(16:0/OH) and SM(d18:1/16:0) was lower in prostate cancer than in benign prostate epithelium. These differences in expression of phospholipids may predict prostate cancer aggressiveness, and provide new insights into lipid metabolism in prostate cancer.
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http://dx.doi.org/10.1002/pros.23088DOI Listing
December 2015

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

PLoS One 2015 26;10(6):e0130980. Epub 2015 Jun 26.

Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130980PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482605PMC
April 2016

[The safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) for treatment of metastatic renal cell carcinoma].

Hinyokika Kiyo 2014 May;60(5):209-14

The Department of Urology, Hyogo College Of Medicine.

We prospectively investigated the safety and efficacy of sunitinib using a modified regimen (2 weeks on/1 week off) in 24 patients (22 males, 2 females ; age range 39-86 years, median 64 years) with metastatic renal cell carcinoma (RCC). During the observation period (3-62 weeks, median 21 weeks), thrombocytopenia was seen in 13 (54.2%), leukopenia in 11 (45.8%), hand-foot syndrome in 5 (20.8%), hypertension in 4 (16.7%), and hypothyroidism in 3 (12.5%) patients, while grade 3 or higher adverse events were found in 4 (16.7%), 1 (4.2%), 1 (4.2%), 2 (8.3%), and 0 patients, respectively. Of the 21 patients evaluable for response, 5 (23. 8%) showed partial response, 8 (38.1%) stable disease, and 8 (38.1%) progressive disease. This new modified regimen may lead to a reduction in adverse events for treatment of patients with metastatic RCC as a substitute for the standard dosing regimen of sunitinib.
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May 2014

[Observational study on urinary status following HoLEP].

Hinyokika Kiyo 2014 Feb;60(2):57-60

The Department of Urology, Kobe City Medical Center General Hospital.

We assessed the safety, and postoperative urinary status of holmium laser enucleation of the prostate (HoLEP) for the treatment of benign prostatic hyperplasia (BPH). Of the initial 117 patients who underwent HoLEP from November 2004 to March 2011, 49 were followed up for two yearsor longer. These 49 patients were evaluated once preoperatively, and at the 3rd, 6th, 12th, 24th, 48th, and 60th month postoperatively using International Prostate Symptom Scores (I-PSS) total and sub-score, quality of life score (QOL), maximum flow rate (Qmax), and post-voiding residual urine volume (PVR). The median estimated transition zone and enucleated volume were 45. 1 and 47. 9 g, respectively. Evaluation scores showed significant improvementsthroughout the follow-up. I-PSS total scoresimproved from 21 points(before surgery) to 6 points(12 monthsafter surgery), QOL scoresimproved from 5 pointsto 2 points, Qmax improved from 6.8 ml/s to 17.4 ml/s, and PVR improved from 101 ml to 26 ml, respectively. Transient urinary incontinence was noted in 14 patients (28.5%). One case showed a Clavien grade 3 complication of postoperative bleeding. No blood transfusion or re-surgery for BPH was required. In conclusion, HoLEP proved to be a safe and effective therapy, with potential to become a new gold standard for treating BPH.
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February 2014

[Rechallenge of everolimus for metastatic renal cell carcinoma after recovery from grade 3 interstitial lung disease: a case report].

Hinyokika Kiyo 2014 Jan;60(1):25-8

The Department of Urology, Kobe City Medical Center General Hospital.

We report a case of the rechallenge of everolimus for metastatic renal cell carcinoma (RCC) after successful recovery from grade 3 interstitial lung disease (ILD). A 76-year-old man with metastatic RCC developed grade 3 ILD one month after the initiation of everolimus therapy (10 mg/day). ILD subsided in 4 months after the withdrawal of everolimus and treatment with corticosteroids. Half dose (5 mg/day) of everolimus was rechallenged for 9 months until another grade 3 ILD developed. Everolimus kept the disease under control for 13 months including the discontinuation period.
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January 2014

[Risk factors for recurrence in pT3aN0M0 renal cell carcinoma according to 2009 TNM classification].

Hinyokika Kiyo 2014 Jan;60(1):1-5

The Department of Urology, Kobe City Medical Center General Hospital.

The TNM classification of renal cell carcinoma was updated in 2009. In this new classification system, T3a consists of tumors with renal vein involvement and tumors with fat invasion. To assess risk factors for recurrence, we retrospectively reviewed 89 patients with pT3aN0M0 renal cell carcinoma who underwent radical or partial nephrectomy between 1992 and 2011. Analyzed risk factors for recurrence were age, gender, tumor size, grade, v factor, infiltrative growth (INF), adjuvant interferon, surgical technic (radical or partial), clinical T classification, renal vein thrombus, and pathological fat invasion. The median follow-up was 52.2 months. Five-year recurrence-free survival rate was 69.0%. Within the pT3a subcategory, the five-year recurrence-free survival was 76.7% in patients with fat invasion only, 42.9% in patients with renal vein thrombus only, and 28.6% in patients with the two concomitant features. On univariate analysis, tumor size, grade, INF, clinical T classification, and renal vein thrombus were significantly associated with recurrence. On multivariate analysis, INF (p = 0.023, HR 3.927) was an independent risk factor for recurrence. In pT3aN0M0 renal cell carcinoma, INF significantly affects recurrence, and patients with both fat invasion and renal vein thrombus have worst prognosis.
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January 2014

[Gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) in patients with metastatic urothelial cancer].

Hinyokika Kiyo 2013 Jan;59(1):1-6

The Department of Urology, Kobe City Medical Center General Hospital.

Twenty-four patients with metastatic urothelial carcinoma of bladder (11) and upper urinary tract (13) received gemcitabine 1,000 mg/m2 on days 1, 8, and 15, and cisplatin 70 mg/m2 (GC) or carboplatin area under the serum concentration-time curve (AUC) 5 (GCarbo) on day 2, every 28 days. One to 13 chemotherapy cycles (median number, 4) per patient were administered. Three patients (12.5%) achieved a complete response (CR) and 9 (37.5%) a partial response (PR). Six patients (25%) experienced no change (NC) and six patients (25%) progressive disease (PD). The overall response rate (CR+PR) of GC (57.9%) was greater than that of GCarbo (20%), but the difference was not statistically significant (p=0.13). At a median follow-up of 14.7 months, the median time to progression was 4.6 months (range, 0.9-34.7), and the median overall survival 12.3 months (range, 2.1-46.4). Grade 3 and 4 leukocytopenia occurred in 15 patients (53.6%) and grade 3 and 4 thrombocytopenia in 16 (57.1%). Gemcitabine could be administrated on both day 8 and day 15 only in 43 (34.7%) of the total 114 courses because of hematological toxicity. Gemcitabine chemotherapy combined with cisplatin or carboplatin is effective in the management of metastatic urothelial cancer. High hematological toxicity was observed and caused high omission rates of gemcitabine on day 8 and/or day 15.
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January 2013

[A case of Bellini collecting duct carcinoma with hypercalcemia in a young adult].

Hinyokika Kiyo 2012 Feb;58(2):83-6

The Department of Urology, Kobe City Medical Center General Hospital.

A 25-year-old man presented to a local clinic with right flank pain and gross hematuria. Computed tomography revealed the right renal tumor and he was referred to our hospital. Laparoscopic radical nephrectomy was performed and diagnosis of Bellini collecting duct carcinoma was made pathologically. Adjuvant therapy with interferon-α, followed by a gemcitabine and cisplatin-based regimen of chemotherapy was performed, but the disease progressed. Sunitinib was started 14 months after the operation. After one course of sunitinib, mental status was altered due to hypercalcemia (serum calcium level was 18.6 mg/dl and PTH-rP was 3.7 pmol/l). Level of consciousness recovered along with decreasing serum calcium level, but he died of multiple organ dysfunction 17 months after the operation. Autopsy showed liver, bone, lymph node, mediastinum and left adrenal tumor metastases.
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February 2012

[Granulocyte-colony-stimulating factor (G-CSF)-producing carcinoma of collecting ducts of Bellini: a case report].

Hinyokika Kiyo 2011 Nov;57(11):623-6

The Department of Urology, Kobe City Medical Center General Hospital.

We report a case of granulocyte-colony-stimulating factor (G-CSF)-producing carcinoma of collecting ducts of Bellini. A 62-year-old male was admitted to our hospital with the chief complaint of high grade fever,right flank pain and general malaise. The white blood cell count and serum G-CSF concentration were elevated to 20,100/ μ l and 140 pg/ml,respectively. Enhanced thoracoabdominal computed tomography (CT) showed a right renal malignant tumor without capsule,para-aortic lymph node metastases and lung metastases. CT-guided right renal biopsy was performed. The histological diagnosis was GCSF- producing carcinoma of collecting ducts of Bellini. The chemotherapy (gemcitabine and cisplatin) and the molecular target therapy (sunitinib) were administerd but the primary lesion and metastases was progressive and serum G-CSF concentration was elevated to 229 pg/ml. He died 3 months after diagnosis.
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November 2011
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