Terutaka Noda

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

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.

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

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.

Silencing of ECHDC1 inhibits growth of gemcitabine‑resistant bladder cancer cells

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 ECHDC1 reduced ECHDC1 expression and significantly inhibited the proliferation of UMUC3GR cells. Furthermore, silencing of ECHDC1 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.

A case report of living kidney transplantation using ectopic pelvic kidney harvested by reduced port laparoscopic donor nephrectomy

A 28-year-old woman was diagnosed as having an ectopic kidney in adolescence. She desired to donate her ectopic kidney to her mother, who was diagnosed as having renal failure. The ectopic kidney was located behind the sigmoid colon with 3 renal arteries and 3 renal veins. Laparoscopic donor nephrectomy was performed by reduced port surgery using the GelPOINT access platforms at a midline incision below the umbilicus with 1 accessory port. A thin artery of the donated kidney was ligated. An artery of the upper pole was anastomosed to the internal iliac artery, and a second artery was anastomosed directly to the inferior epigastric artery. Three veins were anastomosed to the external iliac vein: 1 anastomosed directly, 1 interposed by saphenous vein graft, and 1 interposed by harvested ovarian vein. To our knowledge, this is the first successful case of transplantation using an ectopic pelvic kidney by reduced port laparoscopic donor nephrectomy.

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

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.

PD4-07 PREOPERATIVE FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY ON THE DIAGNOSIS IN UPPER URINARY TRACT CANCER

INTRODUCTION AND OBJECTIVES: Fluorodeoxygulcose positron emission tomography/computed tomography (FDG-PET/CT) is becoming useful for diagnosis, staging and prognosis in many cancers. In contrary, the use in urological oncology has been slower to develop because the radiotracer is excreted into the urine. Then, to assess the ability of preoperative FDG-PET/CT to detect upper urinary tract cancers (UUTC), compared with pathological examinations of tissues obtained by ureteroscopic biopsy or split cytologic analysis of urines obtained following retrograde pyelography. METHODS: Clinicopathological records of patients who were examined by FDG-PET/CT were retrospectively reviewed. Sixty-four patients (66 lesions) with clinically suspected UUTC, who were diagnosed by ureteroscopy or nephroureterectomy or partial ureterectomy at our institution from September 2010 to September 2014, were included. The patient cohort consisted of 51 men and 13 women, with a median age of 73 (range 54e92) years. RESULTS: 66 lesions were histologically diagnosed as 59 urothelial carcinomas and 1 clear cell carcinoma and 6 benign lesions. Only 22% of 58 lesions with UUTC had positive voided urine cytology and 45% of 47 lesions had positive split urine cytology. In addition, only 53 % of 15 lesions with UUTC had positive endoscopic biopsy. However, 83% of 60 lesions with UUTC had positive FDG-PET/CT examination. The positive predictive value was 93%. The sensitivities of <pT2 and pT2 were 82% and 83%, respectively, and the sensitivities of G1, G2, and G3 tumors were 100%, 86%, and 82%, respectively. There were no correlations between the sensitivity in FDG-PET/CT and tumor stage or tumor grade. Mean SUVmax was 3.0 and 10.0 in benign lesions and UUTC, respectively. The difference was statistically significant (p1⁄40.027). The ROC analysis showed that a SUVmax cut-off value to discriminate UUTC was 5.6. The sensitivity and the specificity were 76% and 80%, respectively. An area under the curve was 0.800 (Fig). CONCLUSIONS: FDG-PET/CT was effective to detect UUTC. Furthermore, SUVmax had a role of supplementary index. FDG-PET/ CT may be able to replace of endoscopic biopsy depending on the patients. Source of Funding: none