Publications by authors named "Tadahiko Kikugawa"

32 Publications

Predictors of Hypotension after Adrenalectomy for Pheochromocytoma.

Acta Med Okayama 2021 Jun;75(3):345-349

Department of Urology, Graduate School of Medicine, Ehime University.

The management of blood pressure is a significant concern for surgeons and anesthesiologists performing adrenalectomy for pheochromocytoma. We evaluated clinical factors in pheochromocytoma patients to identify the predictors of postoperative hypotension. The medical records of patients who underwent adrenalectomy for pheochromocytoma between 2001 and 2017 were retrospectively reviewed and clinical and biochemical data were evaluated. Of 29 patients, 13 patients needed catecholamine support in the perisurgical period while 16 patients did not. There were significant differences in median age, tumor size, and blood pressure drop (maxmin) between the 2 groups (68 vs 53 years old, p=0.045; 50 vs 32 mm diameter, p=0.022; 110 vs 71 mmHg, p=0.015 respectively). In univariate logistic analysis, age > 65.5 years, tumor size > 34.5 mm, urine metanephrine > 0.205 mg/day and urine normetanephrine > 0.665 mg/day were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urine metanephrine and urine normetanephrine levels were correlated with postoperative hypotension. These predictors may help in the safe perioperative management of pheochromocytoma patients treated with adrenalectomy.
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http://dx.doi.org/10.18926/AMO/62229DOI Listing
June 2021

Venous reconstruction using a Y-shaped saphenous vein in kidney transplantation: A report of three cases.

IJU Case Rep 2021 May 16;4(3):146-149. Epub 2021 Feb 16.

Department of Urology Ehime University Graduate School of Medicine Toon Ehime Japan.

Introduction: Transplantation, especially, of the right kidney may be difficult to properly choose the main drainage vein due to abundance of renal veins with the thin wall and the small diameter. Therefore, we report three cases, wherein anastomosis-related complications may be avoided by using a reconstructed Y-shaped major saphenous vein graft.

Case Presentation: The first case was a case of congestion when anastomosed with a trifurcated renal vein which ligated branch. The second case was a case of donated kidney with three renal veins, which were all short, small, and thin-walled. The third case was a case of donated kidney with four renal veins. Two of them were unused, though the other two veins were short and thin-walled with equal diameters. In all of three cases, renal veins were anastomosed with Y-shaped saphenous vein graft.

Conclusion: Y-shaped saphenous vein graft is possibly effective for such reconstructions as it may prevent anastomosis-related complications.
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http://dx.doi.org/10.1002/iju5.12266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088897PMC
May 2021

A low RENAL Nephrometry Score can avoid the need for the intraoperative insertion of a ureteral catheter in robot-assisted partial nephrectomy.

World J Surg Oncol 2021 Feb 4;19(1):40. Epub 2021 Feb 4.

Department of Urology, Ehime University Graduate school of Medicine, Shitsukawa, Toon, Matsuyama, Ehime, 791-0295, Japan.

Background: Intraoperative urinary collecting system entry (CSE) in robot-assisted partial nephrectomy (RAPN) may cause postoperative urinary leakage and extend the hospitalization. Therefore, identifying and firmly closing the entry sites are important for preventing postoperative urine leakage. In RAPN cases expected to require CSE, we insert a ureteral catheter and inject dye into the renal pelvis to identify the entry sites. We retrospectively analyzed the factors associated with intraoperative CSE in RAPN and explored the indications of intraoperative ureteral catheter indwelling in RAPN.

Methods: Of 104 Japanese patients who underwent RAPN at our institution from August 2016 to March 2020, 101 were analyzed. The patients were classified into CSE and non-CSE groups. The patients' background characteristics, RENAL Nephrometry Score (RNS), and surgical outcomes were analyzed.

Results: Intraoperative CSE was observed in 41 patients (41%). The CSE group had a significantly longer operative time, console time, ischemic time, and hospital stay than the non-CSE group. In a multivariable analysis, the N-score (odds ratio [OR] = 3.9, P < 0.05) and RNS total score excluding the L-score (OR = 3.1, P < 0.05) were associated with CSE. In a logistic regression analysis, CSE showed a moderate correlation with the RNS total score excluding the L-score (AUC 0.848, cut-off 5, sensitivity 0.83, specificity 0.73).

Conclusion: A ureteral catheter should not be placed in patients with an RNS total score (excluding the L-score) of ≤ 4.
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http://dx.doi.org/10.1186/s12957-021-02146-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863492PMC
February 2021

DNA maintenance methylation enzyme Dnmt1 in satellite cells is essential for muscle regeneration.

Biochem Biophys Res Commun 2021 01 10;534:79-85. Epub 2020 Dec 10.

Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon Ehime, 791-0295, Japan; Department of Pathophysiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon Ehime, 791-0295, Japan; Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Shitsukawa, Toon Ehime, 791-0295, Japan. Electronic address:

Epigenetic transcriptional regulation is essential for the differentiation of various types of cells, including skeletal muscle cells. DNA methyltransferase 1 (Dnmt1) is responsible for maintenance of DNA methylation patterns via cell division. Here, we investigated the relationship between Dnmt1 and skeletal muscle regeneration. We found that Dnmt1 is upregulated in muscles during regeneration. To assess the role of Dnmt1 in satellite cells during regeneration, we performed conditional knockout (cKO) of Dnmt1 specifically in skeletal muscle satellite cells using Pax7 mice and Dnmt1 flox mice. Muscle weight and the cross-sectional area after injury were significantly lower in Dnmt1 cKO mice than in control mice. RNA sequencing analysis revealed upregulation of genes involved in cell adhesion and apoptosis in satellite cells from cKO mice. Moreover, satellite cells cultured from cKO mice exhibited a reduced number of cells. These results suggest that Dnmt1 is an essential factor for muscle regeneration and is involved in positive regulation of satellite cell number.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.116DOI Listing
January 2021

SPOP is essential for DNA-protein cross-link repair in prostate cancer cells: SPOP-dependent removal of topoisomerase 2A from the topoisomerase 2A-DNA cleavage complex.

Mol Biol Cell 2020 03 22;31(6):478-490. Epub 2020 Jan 22.

Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.

SPOP, speckle-type POZ protein is a substrate adaptor protein of the Cullin-3/RING ubiquitin E3 complex. The gene is the most commonly point mutated in human primary prostate cancers, but the pathological contribution of the SPOP mutations remains unclear. In this study, we investigated several known factors that are critical in the DNA--protein cross-link repair process. The depletion of SPOP or overexpression of a prostate cancer-associated SPOP mutant, F133V, in androgen receptor-positive prostate cancer cells increased the amount of topoisomerase 2A (TOP2A) in the nuclei together with the increased amount of γH2AX, an indication of DNA breaks. Tyrosyl-DNA phosphodiesterases (TDPs) and an endo/exonuclease MRE11 are enzymes that liberate TOP2A from the TOP2A-DNA cleavage complex, and thus is essential for the completion of the DNA repair process. We found that the amount of TDP1 and TDP2 was decreased in SPOP-depleted cells, and that of TDP2 and MRE11 was decreased in F133V-overexpressing cells. These results suggest that the F133V mutant exerts dominant-negative and gain-of-function effects in down-regulation of TDP2 and MRE11, respectively. We conclude that SPOP is involved in the DNA-protein cross-link repair process through the elimination of TOP2A from the TOP2A cleavage complex, which may contribute to the genome stability.
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http://dx.doi.org/10.1091/mbc.E19-08-0456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185892PMC
March 2020

Feasibility of Laparoscopic Radical Cystectomy in Elderly Patients: A Comparative Analysis of Clinical Outcomes in a Single Institution.

Acta Med Okayama 2019 Oct;73(5):417-418

Department of Urology, Ehime University Medical School, Toon City, Ehime 791-0245, Japan.

Laparoscopic radical cystectomy (LRC) is a standard surgical treatment for muscle-invasive bladder cancer and high-risk non-muscle-invasive bladder cancer. LRC is a less invasive modality than conventional open surgery. Therefore, even elderly patients with invasive bladder cancer may be candidates for LRC. In this study, a comparative analysis of perioperative/oncological outcomes between elderly patients and younger patients who underwent LRC was performed to assess the feasibility of LRC in elderly patients. Sixty-eight consecutive patients who underwent LRC between October 2013 and March 2018 were enrolled and stratified into those younger than 75 years (n=37) and those ≥ 75 years old (n=31). The median follow-up period was 28.2 months. The preoperative and operative parameters and complications were similar in both groups. The 2-year overall survival (OS) was 64.4% in the younger vs. 76.4% in the elderly group (p=0.053), cancer-specific survival (CSS) was 79.3% vs. 81.7% (p=0.187), and recurrence-free survival (RFS) was 58.2% vs. 75.7% (p=0.174), respectively. No significant differences were observed in OS, CSS, or RFS between the groups. No significant differences were found between the groups with respect to peri-surgical/oncological outcomes. We conclude that LRC is feasible in elderly patients.
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http://dx.doi.org/10.18926/AMO/57371DOI Listing
October 2019

GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer.

Int J Cancer 2020 03 22;146(5):1369-1382. Epub 2019 Jul 22.

Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Japan.

The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.
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http://dx.doi.org/10.1002/ijc.32554DOI Listing
March 2020

New classification of hydronephrosis on 18F-FDG-PET/CT predicts post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma.

Jpn J Clin Oncol 2018 Nov;48(11):1022-1027

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Objectives: To evaluate the value of a classification of hydronephrosis on 18F-flurodeoxyglucose (FDG)-PET/CT in predicting post-operative renal function and pathological outcomes among patients with upper urinary tract urothelial carcinoma.

Methods: We retrospectively reviewed 71 patients treated with nephroureterectomy (NU) for upper urinary tract urothelial carcinoma after FDG-PET/CT between 2010 and 2016. Eight patients treated with ureteral stent or nephrostomy at the time of FDG-PET/CT were excluded. We classified hydronephrosis based on renal excretion of FDG as follows: Type 0, no hydronephrosis; Type 1, hydronephrosis with FDG excretion; and Type 2, hydronephrosis without FDG excretion. eGFR was recorded before pre-operataive FDG-PET/CT examination and after nephroureterectomy.

Results: Thirty-three patients (52%) had hydronephrosis, classified as Type 1 in 19 patients (30%) and Type 2 in 14 (22%). Type 2 hydronephrosis was associated with ureteral cancer and severe hydronephrosis on CT. Median changes in eGFR before and after nephroureterectomy in patients classified as Type 0, 1 and 2 were -23.9, -18.8 and 2.0 ml/min/1.73 m2, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of change in eGFR (P = 0.001). Rates of muscle-invasive upper urinary tract urothelial carcinoma among Type 0, 1 and 2 patients were 37, 42 and 86%, respectively. On multivariate analysis, Type 2 hydronephrosis was a significant predictor of muscle-invasive upper urinary tract urothelial carcinoma (P = 0.032, OR 6.491).

Conclusions: This classification of hydronephrosis from FDG-PET/CT is simple and useful for predicting post-operative renal function and muscle-invasive disease in patients with upper urinary tract urothelial carcinoma, especially with ureteral cancer. This classification can help in deciding eligibility for lymphadenectomy or perioperative cisplatin-based chemotherapy.
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http://dx.doi.org/10.1093/jjco/hyy135DOI Listing
November 2018

Silencing of inhibits growth of gemcitabine-resistant bladder cancer cells.

Oncol Lett 2018 Jan 26;15(1):522-527. Epub 2017 Oct 26.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

Combined gemcitabine and cisplatin (GC) treatment is a first line chemotherapy for bladder cancer. However, acquired resistance to GC has been a major problem. To address the mechanism of gemcitabine resistance, and to identify potential biomarkers or target proteins for its therapy, we aimed to identify candidate proteins associated with gemcitabine resistance using proteomic analysis. We established gemcitabine-resistant human bladder cancer cell lines (UMUC3GR and HT1376GR) from gemcitabine-sensitive human bladder cancer cell lines (UMUC3 and HT1376). We compared the protein expression of parental and gemcitabine-resistant cell lines using isobaric tags for relative and absolute quantification (iTRAQ) and liquid chromatography tandem mass spectrometry. Among the identified proteins, ethylmalonyl-CoA decarboxylase (ECHDC1) expression was significantly increased in both of the gemcitabine-resistant cell lines compared to the respective parental cell lines. Silencing of reduced ECHDC1 expression and significantly inhibited the proliferation of UMUC3GR cells. Furthermore, silencing of induced upregulation of p27, which is critical for cell cycle arrest in the G1 phase, and induced G1 arrest. In conclusion, ECHDC1 expression is increased in gemcitabine-resistant bladder cancer cells, and is involved in their cell growth. ECHDC1, which is a metabolite proofreading enzyme, may be a novel potential target for gemcitabine-resistant bladder cancer therapy.
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http://dx.doi.org/10.3892/ol.2017.7269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769416PMC
January 2018

Role of robot-assisted radical prostatectomy in locally advanced prostate cancer.

Int J Urol 2018 01 13;25(1):30-35. Epub 2017 Sep 13.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Locally advanced prostate cancer is regarded as a very high-risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot-assisted radical prostatectomy is currently carried out even in high-risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot-assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot-assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer.
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http://dx.doi.org/10.1111/iju.13441DOI Listing
January 2018

Primary adrenal leiomyosarcoma with lymph node metastasis: a case report.

World J Surg Oncol 2016 Jul 2;14(1):176. Epub 2016 Jul 2.

Department of Urology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan.

Background: Leiomyosarcomas typically originate in smooth muscle cell. Leiomyosarcoma potentially arising from the adrenal gland is an extremely rare mesenchymal tumors associated with delayed diagnosis and poor prognosis.

Case Presentation: A 34-year-old man visited our department complaining of right hypochondriac pain. Computed tomography demonstrated a solid mass measuring 5.2 cm in diameter above the right kidney, corresponding to the right adrenal gland, and a lymph node mass, which appeared to have invaded the IVC wall. Right adrenalectomy and lymphadenectomy were performed. A microscopic examination revealed primary adrenal leiomyosarcoma with lymph node metastasis. No adjuvant therapy was performed, and the patient remains recurrence-free at 10 months postoperatively.

Conclusions: We experienced a very rare case of primary adrenal leiomyosarcoma. Aggressive surgical resection including vascular reconstruction may be associated with improved survival.
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http://dx.doi.org/10.1186/s12957-016-0936-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930559PMC
July 2016

Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer.

Chemotherapy 2016 4;61(1):23-31. Epub 2015 Nov 4.

Aim: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone.

Methods: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014.

Results: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis.

Conclusion: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients.
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http://dx.doi.org/10.1159/000440942DOI Listing
August 2016

Circulating Cytokine Levels in Patients with Prostate Cancer: Effects of Neoadjuvant Hormonal Therapy and External-beam Radiotherapy.

Anticancer Res 2015 Jun;35(6):3379-83

Department of Urology, Houshasen-Daiichi Hospital, Ehime, Japan.

Aim: The aim of the study was to better characterize the temporal induction of inflammatory cytokines in the serum of patients with prostate cancer (PCa) treated with radiotherapy and to ascertain the influence of hormonal therapy upon those expressions.

Patients And Methods: Between May 2007 and December 2009, 30 patients with localized PCa were treated with 3-dimensional conformal external-beam radiotherapy. Fifteen patients had received neoadjuvant hormonal therapy using a leuteinizing hormone-releasing hormone (LH-RH) analog for six months prior to radiotherapy. The cytokine levels were collectively measured using a multiplex assay system.

Results: Seventeen cytokines were at detectable levels throughout the blood sampling times before and during radiotherapy. Hormonal therapy for six months significantly decreased the serum levels of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). The levels of epidermal growth factor (EGF), granulocyte-colony stimulating factor (G-CSF), and interferon-gamma (IFNγ) significantly increased during radiotherapy. Most cytokine levels, except for eotaxin, G-CSF, growth-related oncogene (GRO), transforming growth factor-beta (TGFβ)-1 and TGFβ2, significantly increased during radiotherapy compared to the levels observed before radiotherapy.

Conclusion: The present study revealed the influence of hormonal, and of radiation therapy on the proinflammatory cytokine levels in the sera of patients with PCa. In addition, neoadjuvant hormonal therapy amplified the radiation-induced alteration of serum cytokines. Further studies to characterize the mechanism underlying a radiation- or hormone-induced inflammatory state are, therefore, necessary.
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June 2015

Fluorodeoxyglucose positron emission tomography/computed tomography for diagnosis of upper urinary tract urothelial carcinoma.

Int J Clin Oncol 2015 Oct 21;20(5):1042-7. Epub 2015 Mar 21.

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.

Background: The purpose of this study was to assess the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to detect upper urinary tract urothelial carcinomas (UTUC) compared with pathological examination of tissues obtained by ureteroscopic biopsy and split cytologic analysis of urine obtained after retrograde pyelography.

Methods: Clinicopathological records of patients at our institution were retrospectively reviewed. Fifty patients with clinically suspected UTUC, who were histologically diagnosed by nephroureterectomy, partial ureterectomy, or endoscopic biopsy, were included. The patient cohort included 42 men and 8 women, with a median age of 73 (range 54-92) years.

Results: Only 27 % of 49 patients with UTUC had positive voided urine cytology, and 33 % of 40 patients had positive split urine cytology. In addition, 40 % of 10 patients had a positive endoscopic biopsy. However, 83 % of 48 patients with UTUC had positive results from FDG-PET/CT examination. The positive predictive value of FDG-PET/CT was 95 %. There were no correlations between sensitivity and tumor stage or tumor grade. Sensitivity of FDG-PET/CT for patients with and without diabetes mellitus was 60 and 89 %, respectively.

Conclusions: These preliminary results from a small number of patients revealed that FDG-PET/CT enabled effective detection of UTUC.
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http://dx.doi.org/10.1007/s10147-015-0817-4DOI Listing
October 2015

Long‑term exposure to leptin enhances the growth of prostate cancer cells.

Int J Oncol 2015 Apr 23;46(4):1535-42. Epub 2015 Jan 23.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791‑0295, Japan.

Obesity correlates with an increased risk of developing prostate cancer (PCa) and leptin plays an important role in PCa progression. Since leptin is produced by adipocytes, the serum leptin level is higher in obese than in non-obese individuals. However, the effects of leptin remain controversial and unclear. The aim of the present study was to investigate the effect of leptin on PCa cell aggressiveness. Three human PCa cell lines (LNCaP, DU145 and PC-3) were treated with recombinant leptin for 28 days. Cell proliferation, migration, and invasion were estimated using the WST assay, a wound-healing assay, and a BD Matrigel invasion assay, respectively. The mechanism underlying the proliferative effect of leptin was investigated by cell transfections with small interfering RNA (siRNA) against the leptin receptor (ObR) or forkhead box O1 (FOXO1), and by immunocytochemistry. Long-term exposure of PCa cells to leptin enhanced their proliferation, migration and invasion. Leptin increased ObR expression and enhanced Akt phosphorylation constitutively. Leptin also increased the phosphorylation of FOXO1 via PI3K signaling and FOXO1 gene silencing enhanced PCa cell proliferation. Leptin induced the translocation of FOXO1 from the nucleus to the cytoplasm. Furthermore, the PI3K inhibitor, LY294002 suppressed this translocation. These results suggested that leptin regulated the subcellular localization of FOXO1 and induced Akt phosphorylation. Additionally, we revealed that leptin increased the expression of cyclin D1 and decreased the expression of p21 protein. In conclusion, long-term exposure to leptin increased the cell proliferation, migration, and invasion of PCa cells through inactivation of FOXO1. This inactivation resulted from exclusion of FOXO1 from the nucleus and its restriction to the cytoplasm through PI3K/Akt signaling. Our findings contribute to an understanding of the association between obesity and PCa aggressiveness.
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http://dx.doi.org/10.3892/ijo.2015.2845DOI Listing
April 2015

[Clinicopathologic characteristics and prognosis of patients with adrenocortical carcinoma].

Nihon Hinyokika Gakkai Zasshi 2014 Jul;105(3):79-84

Purpose: Adrenocortical carcinoma (ACC) is a rare condition associated with poor prognosis. This study aimed to evaluate the clinicopathologic characteristics and prognosis of 7 patients with ACC.

Patients And Methods: The clinicopathologic characteristics, treatment, and survival of 7 patients with pathologically confirmed ACC treated at our institution between January 2002 and December 2012 were retrospectively examined.

Results: The study cohort comprised 4 male and 3 female patients (median age at diagnosis, 63 years [range, 36-71 years]). The median tumor size was 7.0 cm (range, 4.0-13.0 cm), and the median follow-up duration was 22 months (range, 9-107 months). One patient had stage I ACC, 4 had stage III, and 2 showed metastasis. The patient with stage I disease underwent laparoscopic adrenorectomy and those with stage III disease underwent adrenorectomy with the excision of adjacent organs. Four of these 5 patients are alive without recurrence at a median of 55 months (range, 22-107 months) after surgery. Of the 2 patients with metastases, 1 received combined chemotherapy with etoposide, adriamycin, and cisplatin plus mitotane without surgical resection but died 19 months later, and the other, with a solitary lung metastasis, underwent adrenorectomy and metastatectomy followed by adjuvant treatment with mitotane and is alive without recurrence at 9 months after treatment. The 3-year cause-specific survival rate was 56%.

Conclusions: Patients with advanced-stage tumors showed long-term survival with complete tumor resection at diagnosis; hence, this seems to be most beneficial treatment option for patients with ACC.
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http://dx.doi.org/10.5980/jpnjurol.105.79DOI Listing
July 2014

Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer.

Chemotherapy 2013 25;59(6):402-6. Epub 2014 Jun 25.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Japan.

Background: To improve the prognosis of patients with urachal cancer and establish an effective chemotherapeutic regimen for distant metastases.

Methods: We conducted a retrospective study to evaluate the efficacy and safety of a modified combination of 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) therapy in patients with metastatic urachal cancer.

Results: Five patients were treated with mFOLFOX6. Their median age was 65 years (range 41-80). The median follow-up time was 42 months (range 18-46). Two of the 5 patients (40%) showed an objective response: 1 achieved a clinically complete response and 1 a partial response. The grade 3/4 toxicity associated with this regimen was primarily neutropenia, but febrile neutropenia was not observed. Oxaliplatin treatment was discontinued because of a grade 2 allergic reaction in 1 patient. Grade 2 peripheral sensory neuropathy caused by oxaliplatin was observed in 2 patients, and the OPTIMOX (stop and go) approach had to be adopted.

Conclusions: mFOLFOX6 appears to be effective for the treatment of metastatic urachal cancer.
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http://dx.doi.org/10.1159/000362400DOI Listing
May 2015

Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells.

Oncol Lett 2014 Mar 19;7(3):674-678. Epub 2013 Dec 19.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

Cisplatin is currently the most effective anti-tumor agent available against bladder cancer. To clarify the mechanism underlying cisplatin resistance in bladder cancer, the present study examined the role of the aldo-keto reductase family 1 member C2 (AKR1C2) protein on chemoresistance using a human bladder cancer cell line. The function of AKR1C2 in chemoresistance was studied using the human HT1376 bladder cancer cell line and the cisplatin-resistant HT1376-CisR subline. AKR1C2 was expressed in HT1376-CisR cells, but not in the parental cells. The effect of small interfering (si) RNAs and an inhibitor targeting AKR1C2 was examined to determine whether cisplatin sensitivity can be rescued by blocking AKR1C2 expression or function. Silencing of AKR1C2 mRNA or inhibition of AKR1C2 by 5β-cholanic acid resulted in a decrease in the survival of cells following cisplatin exposure. Intracellular accumulation of reactive oxygen species (ROS) was determined using a 2,7-dichlorodihydrofluorescein diacetate (HDCFDA) fluorescent probe. Cisplatin exposure increased the level of intracellular ROS in HT1376 cells in a dose-dependent manner. The ROS levels in HT1376-CisR cells were significantly lower than those in HT1376 cells and knockdown of AKR1C2 mRNA significantly restored ROS levels. Cisplatin exposure did not increase intracellular ROS in HT1376-CisR cells, although the level of intracellular ROS increased in HT1376 cells following cisplatin exposure. Silencing of AKR1C2 mRNA restored the ROS increase response to cisplatin and menadione as an oxidative stressor in HT1376-CisR cells. Menadione has the function of an oxidative stressor. The silencing of AKR1C2 mRNA restored the increased ROS response to cisplatin and menadione in HT1376-CisR cells. These results indicate that induction of AKR1C2 in human bladder cancer cells aids in the development of cisplatin resistance through antioxidative effects. The results of this study indicate that AKR1C2 may be an effective molecular target for restoring cisplatin resistance.
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http://dx.doi.org/10.3892/ol.2013.1768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919892PMC
March 2014

Combined chemotherapy with gemcitabine and carboplatin for metastatic urothelial carcinomas in patients with high renal insufficiency.

Int J Clin Oncol 2013 Oct 31;18(5):910-5. Epub 2012 Aug 31.

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan,

Background: This was a retrospective study to evaluate the activity and toxicity of a combined chemotherapeutic regimen of gemcitabine and carboplatin (GCa) in patients with metastatic urothelial carcinomas (UCs) with special regard to patients with highly impaired renal function.

Methods: Eleven patients whose creatinine clearance was 30 ml/min or under and who had been diagnosed with metastatic UC were treated with GCa. The patient cohort comprised 4 males and 7 females, with a median age of 74 (range 67-84) years. The median follow-up was 19 (range 1-58) months.

Results: Five of the 11 patients (45%) showed an objective response, with 2 achieving a clinically complete response and 3 a partial response with GCa. The grade 3/4 toxicity of the regimen was primarily hematological, including anemia (55%), neutropenia (45%), and thrombocytopenia (45%). Four patients (36%) could not complete the treatment in total. Grade 3 pneumonitis was found in one patient, and the treatment was terminated. Grade 4 febrile neutropenia occurred in the patient on hemodialysis, and the patient was forced to discontinue the chemotherapy. Another 2 patients also called off the treatment due to a pulmonary adverse event and an elevation of serum creatinine, respectively.

Conclusions: GCa appears to be effective for the treatment of metastatic UCs in patients with impaired renal function, but it is necessary to pay attention to the occurrence of severe adverse events.
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http://dx.doi.org/10.1007/s10147-012-0466-9DOI Listing
October 2013

Adseverin: a novel cisplatin-resistant marker in the human bladder cancer cell line HT1376 identified by quantitative proteomic analysis.

Mol Oncol 2012 Jun 4;6(3):311-22. Epub 2012 Jan 4.

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan.

Cisplatin is currently the most effective antitumor agent available against bladder cancer. However, a majority of patients eventually relapse with cisplatin-resistant disease. Chemoresistance thus remains a major obstacle in bladder cancer therapy. To clarify the molecular mechanisms underlying cisplatin resistance in bladder cancer, we established a cisplatin-resistant subline from the human bladder cancer cell line HT1376 (HT1376-CisR), and conducted large-scale analyses of the expressed proteins using two-dimensional (2D) gel electrophoresis coupled with mass spectrometry (MS). Comparative proteomic analysis of HT1376 and HT1376-CisR cells revealed 36 differentially expressed proteins, wherein 21 proteins were upregulated and 15 were downregulated in HT1376-CisR cells. Among the differentially regulated proteins, adseverin (SCIN), a calcium-dependent actin-binding protein, was overexpressed (4-fold upregulation) in HT1376-CisR, with the increase being more prominent in the mitochondrial fraction than in the cytosol fraction. SCIN mRNA knockdown significantly reduced cell proliferation with mitochondria-mediated apoptosis in HT1376-CisR cells. Immunoprecipitation analysis revealed voltage-dependent anion channels (VDACs) to be bound to SCIN in the mitochondrial fraction. Our results suggest that the VDAC-SCIN interaction may inhibit mitochondria-mediated apoptosis in cisplatin-resistant cells. Targeting the VDAC-SCIN interaction may offer a new therapeutic strategy for cisplatin-resistant bladder cancer.
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http://dx.doi.org/10.1016/j.molonc.2011.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528333PMC
June 2012

Potential of histone deacetylase inhibitors for bladder cancer treatment.

Expert Rev Anticancer Ther 2011 Jun;11(6):959-65

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.

Bladder cancer incidence increases with age, presumably reflecting a cumulative exposure to carcinogens and ever-increasing life expectancy. While aberrant protein expression due to DNA mutations is an essential step during oncogenesis, one recent interest has been the role of epigenetic changes in regulating bladder tumor development. Because aberrant histone acetylation has been linked to malignant diseases in several cases, histone deacetylase inhibitors have great potential as new anticancer drugs owing to their ability to modulate transcription and induce differentiation and apoptosis. We herein review the current knowledge on epigenetic issues in bladder cancer, particularly regarding histone acetylation, and discuss its implications for understanding the molecular basis and treatment of this disease.
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http://dx.doi.org/10.1586/era.10.230DOI Listing
June 2011

[Low-dose docetaxel in combination with dexamethasone for hormone-refractory prostate cancer].

Nihon Hinyokika Gakkai Zasshi 2011 Jan;102(1):23-7

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime.

Purpose: Efficacy and tolerability of docetaxel-based chemotherapy against hormone-refractory prostate cancer (HRPC) has been shown lately. The objective of this study was to evaluate retrospectively the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone.

Patients And Methods: Sixteen patients, with a median age of 69.5 years (range 54-85 years), diagnosed with HRPC were administered a treatment regimen consisting of docetaxel (60-80 mg/body or 50 mg/m2) once every 3 or 4 weeks and dexamethasone 1 mg daily at our institution between November, 2004 and March, 2010.

Results: The patients received a median of 11.5 cycles of treatment (range, 2-35 cycles). Eleven of 16 patients (68.8%) had a > or = 50% decrease in serum prostate-specific antigen. The median progression-free survival and overall survival times were 7.1 and 20.3 months, respectively. Grade 3 neutropenia occurred only in 2 patients. Infective endocarditis, gastrointestinal or cerebral hemorrhage, and compressive fracture were occurred in each patient.

Conclusions: The combination of low-dose docetaxel every 3-4 weeks and dexamethasone daily was effective and well tolerated in patients with HRPC. However, it is necessary to pay continuous attention to side effects due to the frequent presence of comorbid diseases particularly in the elderly.
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http://dx.doi.org/10.5980/jpnjurol.102.23DOI Listing
January 2011

Combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas in patients 80 years of age and over.

Anticancer Res 2010 Sep;30(9):3839-43

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

Background: This retrospective study aimed to determine the efficacy and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) for the treatment of metastatic urothelial carcinomas (UCs) in patients 80 years of age and over.

Patients And Methods: Twelve patients who were at least 80 years old and had been diagnosed with metastatic UC were treated with GC. The patient cohort consisted of 9 men and 3 women, with a median age of 83 (range 80-84) years. The median follow-up was 54 (range 14-80) months.

Results: Five out of the 12 patients (42%) showed an objective response, with two achieving a clinically complete response and three a partial response with GC. The median time to progression was 6 months, and the median overall survival was 14 months. The grade 3 and 4 toxicities of the regimen were primarily hematological, including anemia (33%), neutropenia (58%), and thrombocytopenia (50%). No grade 3 or 4 non-hematological toxicities were found.

Conclusion: GC appears to be an effective and well-tolerated regimen for the treatment of metastatic UCs in very old patients.
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September 2010

[Case report: simultaneous bilateral testicular tumors with different cell types].

Nihon Hinyokika Gakkai Zasshi 2010 Mar;101(3):574-8

Department of Urology, Ehime University Graduate School of Medicine, Tohon-city, Ehime.

A 29-year-old man was admitted to our hospital due to bilateral testicular tumors. The bilateral testicular tumors were palpated and visualized by ultrasound and magnetic resonance imaging (right 8 cm, left 6 cm in diameter). Bilateral high orchiectomies were performed after frozen storage of the sperm. Pathological examination revealed seminoma and immature teratoma in the right testis and seminoma in the left testis. Three months later, computed tomography (CT) showed multiple metastatic lung nodules. In addition, positron emission tomography (PET)-CT examination revealed peri-caval lymph node metastasis together with the lung metastases. Lung metastases disappeared, but the lymph node metastasis reduced and remained after 3 courses of combination chemotherapy with bleomycin, etoposide and cisplatin. PET-CT examination revealed that no uptake of FDG was seen in the lung and lymph nodes. Retroperitoneal lymph node dissection was performed. No viable tumor cells were histologically present in the excited lymph nodes. The postoperative course was good and uneventful at 10 months under androgen replacement therapy without disease recurrences.
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http://dx.doi.org/10.5980/jpnjurol.101.574DOI Listing
March 2010

Long-term results of combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas.

Int J Clin Oncol 2010 Aug 26;15(4):369-75. Epub 2010 Mar 26.

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

Background: This retrospective study aimed to determine the long-term effects and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) in the treatment of metastatic urothelial carcinomas (UCs).

Methods: Seventy-one patients with metastatic UC were treated with GC (gemcitabine 1000 mg/m(2) on days 1, 8, and 15 and cisplatin 70 mg/m(2) on day 2 every 28 days). The patients were divided into 3 groups: patients who had not undergone prior chemotherapy (group 1), patients who relapsed more than 6 months after being treated with the prior cisplatin-based regimen (group 2), and patients in whom the prior cisplatin-based regimen demonstrated no effect (group 3). The median follow-up was 42 months.

Results: In group 1, 20 of the 32 patients (63%) showed an objective response, with 6 achieving a clinically complete response (CR) and 14 a partial response (PR) with GC. Ten of 32 patients (31%) and 1 of 7 patients (14%) showed objective responses in groups 2 and 3, respectively. Patients in group 2 who had previously been treated with regimens other than GC showed a better objective response (58%) than those with GC (15%). The median time to progression in group 1 was 6 months, and the median overall survival was 14 months. In all, the nonhematological toxicities associated with GC were quite mild. Grade 3-4 toxicity was primarily hematological, including anemia (19%), neutropenia (36%), and thrombocytopenia (42%).

Conclusions: GC is therefore considered to be a highly effective and well-tolerated regimen with moderate toxicity for the treatment of metastatic UCs.
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http://dx.doi.org/10.1007/s10147-010-0069-2DOI Listing
August 2010

Inhibition of bladder tumour growth by histone deacetylase inhibitor.

BJU Int 2010 Apr 13;105(8):1181-6. Epub 2009 Aug 13.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Objective: To examine the expression profile of histone deacetylase (HDAC)-1 and explore its potential role in the development of bladder cancer, using valproic acid (VPA), a HDAC inhibitor, which reduces tumour growth and metastasis formation in animal models.

Materials And Methods: The study comprised clinical samples from patients with urinary bladder cancer, mouse urinary bladder tissue specimens, and two human urinary bladder cancer cell lines (HT-1376 and 5637). HDAC1 mRNA and protein expression were examined using real-time reverse transcription-polymerase chain reaction and immunohistochemical methods. Female C3H/He mice were given VPA (0, 250, 500 and 750 mg/kg body weight, intraperitoneal, every day) from the start or 4 weeks after 0.05%N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) treatment, and were humanely killed and sampled at 8 and 12 weeks.

Results: A significantly higher level of HDAC1 mRNA was expressed in human urinary bladder cancer specimens. The immunohistochemical study showed that HDAC1 was expressed in the cytoplasm and nucleus in the specimens. BBN treatment increased HDAC1 mRNA expression in the urinary bladder. VPA administration seemed to delay the incidences of BBN-induced mouse urinary bladder tumour, possibly through p21(WAF1) protein expression.

Conclusion: These results indicate that HDAC might be an effective molecular target for cancer therapy.
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http://dx.doi.org/10.1111/j.1464-410X.2009.08795.xDOI Listing
April 2010

A signaling network in phenylephrine-induced benign prostatic hyperplasia.

Endocrinology 2009 Aug 14;150(8):3576-83. Epub 2009 May 14.

Departments of Surgery andBiological Chemistry and Molecular Pharmacology, Harvard Medical School, The Urological Diseases Research Center, Children's Hospital, Boston, Massachusetts 02115, USA.

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology characterized by prostatic enlargement and coinciding with distinctive alterations in tissue histomorphology. To identify the molecular mechanisms underlying the development of BPH, we conducted a DNA microarray study using a previously described animal model in which chronic alpha(1)-adrenergic stimulation by repeated administration of phenylephrine evokes histomorphological changes in the rat prostate that resemble human BPH. Bioinformatic tools were applied to microarray data obtained from prostate tissue to construct a network model of potentially relevant signal transduction pathways. Significant involvement of inflammatory pathways was demonstrable, including evidence for activation of a TGF-beta signaling cascade. The heterodimeric protein clusterin (apolipoprotein J) was also identified as a prominent node in the network. Responsiveness of TGF-beta signaling and clusterin gene and protein expression were confirmed independently of the microarray data, verifying some components of the model. This is the first attempt to develop a comprehensive molecular network for histological BPH induced by adrenergic activation. The study also implicated clusterin as a novel biochemical target for therapy.
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http://dx.doi.org/10.1210/en.2008-1782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717887PMC
August 2009

Androgens upregulate aquaporin 9 expression in the prostate.

Int J Urol 2008 Oct 20;15(10):936-41. Epub 2008 Aug 20.

Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Objectives: Aquaporins (AQP) function as selective pores allowing water, glycerol and other small solutes to pass through the cell membrane. We previously reported that AQP are expressed in the prostates of both humans and rats. The present study investigated the androgen-dependent expression of AQP9 in the prostate in vivo and in vitro.

Methods: Rat ventral prostate tissue specimens and a normal human prostatic epithelial cell line (PNT2) were used. AQP9 messenger ribonucleic acid (mRNA) and protein expression were examined using real-time polymerase chain reaction, Western blotting and immunohistochemical methods. Androgen modulation was achieved by surgical castration, treatment with testosterone propionate (5 microg/g bodyweight) or bicalutamide (20 microg/g bodyweight), and the ribonucleic acid interference (RNAi) method of the androgen receptor (AR). The synthetic small interfering RNA was transfected into PNT2 at a concentration of 10 nM, and the RNAi effect was evaluated using a Western blotting analysis.

Results: AQP9 mRNA and protein were expressed in the rat prostate. Surgical castration or bicalutamide treatment significantly decreased their expression. In addition, the treatment with testosterone propionate after castration restored the expression to the level of the controls. An RNAi experiment in PNT2 also decreased the expression.

Conclusions: AQP9 expression in the prostate is controlled by androgens.
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http://dx.doi.org/10.1111/j.1442-2042.2008.02130.xDOI Listing
October 2008

Expression of aquaporin 3 in the human prostate.

Int J Urol 2007 Dec;14(12):1088-92; discussion 1092

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

Objective: Aquaporins (AQPs) function as selective pores allowing water, glycerol and other small solutes to pass through the cell membrane. The present study investigated the expression and localization of AQP3 in the human prostate.

Methods: Three human prostate cancer cell lines (DU-145, LNCaP and PC-3) and one normal human prostate cell line (PNT1A) were used in this study. Clinical materials from patients with prostate cancer were also used. AQP3 mRNA and protein expression were examined using reverse transcription-polymerase chain reaction and immunohistochemical methods.

Results: Aquaporin 3 mRNA was expressed in normal and cancerous prostate cells. Moreover, the expression of AQP3 mRNA was seen in both normal and cancerous epithelia of human prostate tissues, but not in the mesenchyme. In the normal epithelia of the prostate, localization was limited to cell membranes, particularly the basolateral membranes. However, the expression of AQP3 protein in the cancer epithelia was not observed on the cell membranes.

Conclusion: The results suggest that water-channel protein may be involved in the preservation of cellular character in the human prostate and prostate cancer is associated with an alteration of water-transporting mechanisms. Changes in the localization of AQP3 in cancer cells may result from tumorigenesis.
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http://dx.doi.org/10.1111/j.1442-2042.2007.01901.xDOI Listing
December 2007

Gemcitabine and cisplatin for advanced urothelial carcinomas: the Ehime University Hospital experience.

Int J Clin Oncol 2007 Aug 20;12(4):279-83. Epub 2007 Aug 20.

Department of Urology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, 791-0295, Japan.

Background: The aim of this study was to evaluate the efficacy and safety of a combined chemotherapy regimen, gemcitabine and cisplatin (GC), in the treatment of advanced urothelial carcinomas.

Methods: Fifty-five patients with advanced urothelial cancer were treated with GC (gemcitabine 1000 mg/m(2) on days 1, 8, and 15; cisplatin 70 mg/m(2) on day 2) every 28 days. The median follow-up was 30 months (range, 3 to 57 months).

Results: With the GC therapy, 35 of the 55 patients (63.6%) showed an objective response, with 7 (12.7%) achieving a clinical complete response (CR) and 28 (50.9%), a partial response (PR). GC therapy had a better impact on metastases in the lung and lymph nodes than on metastases in the liver and bone. Lung and lymph nodes showed objective responses of 64.7% and 65.8%, respectively. Eight of the 20 patients (40.0%) who had previously been treated with other regimens showed an objective response, with 1 achieving a CR and 7 achieving a PR. In the 47 patients with metastasis, the median time to progression was 7.0 months (range, 2 to 49 months), and the median overall survival was 12.0 months (range, 3 to 49 months). The 2-year survival rate was 80.0% in the CR group, while it was 55.1% in the PR group and 10.0% in the progressive disease (PD) group. The toxicities associated with GC, particularly mucositis, anorexia, and alopecia, were quite mild. Grade 3-4 toxicity was primarily hematological, including anemia (27.3%), neutropenia (32.7%), and thrombocytopenia (43.6%).

Conclusion: GC is considered to be a highly effective and well-tolerated regimen for the treatment of advanced urothelial carcinomas, with moderate toxicity.
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http://dx.doi.org/10.1007/s10147-007-0678-6DOI Listing
August 2007
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