Yutaka Yanagihara

Inhibition of bladder tumour growth by histone deacetylase inhibitor

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.

A Signaling Network in Phenylephrine-Induced Benign Prostatic Hyperplasia

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.

Modified FOLFOX6 Chemotherapy in Patients with Metastatic Urachal Cancer

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.

Widespread metastases from sarcomatoid renal cell carcinoma detected by 18F-FDG positron emission tomography/computed tomography

We present a case of sarcomatoid renal cell carcinoma (RCC). Although preoperative computed tomography (CT) scans demonstrated small lung and pleural nodules and mediastinal lymphadenopathy, these findings were not conclusive for metastases. Whole-body fluorine-18 fluorodeoxyglucose positron emission tomography and CT (FDG-PET/CT) performed 15 days after right nephrectomy showed intense FDG uptake in the aforementioned lesions (lung and pleural nodules, mediastinal lymph nodes). Unexpectedly, focal increased FDG uptake was found in the right infraspinatus muscle. FDG-PET/CT was considered useful for evaluating distant metastases and thus portending the aggressive nature of sarcomatoid RCC.

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

BackgroundThe 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.MethodsFifty-five patients with advanced urothelial cancer were treated with GC (gemcitabine 1000 mg/m2 on days 1, 8, and 15; cisplatin 70 mg/m2 on day 2) every 28 days. The median follow-up was 30 months (range, 3 to 57 months).ResultsWith 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%).ConclusionGC is considered to be a highly effective and well-tolerated regimen for the treatment of advanced urothelial carcinomas, with moderate toxicity.

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.

Spontaneous regression of metastatic renal cancer after short‐term treatment with sunitinib

We herein report a case of metastatic renal cancer regression after stopping treatment with sunitinib. The 61-year-old female patient was diagnosed with metastatic bone tumors in the 12th thoracic vertebral arch, right 9th rib and left shelf in November 2008. She also had a left renal tumor and multiple liver metastases. She underwent radiation therapy of the 12th thoracic vertebral arch for pain control. A left radical nephrectomy was carried out in December 2008. Pathological examination showed clear cell carcinoma, G2 > G3 and microscopic infiltrating type-b. After the operation, obvious disease progression was shown in each metastatic region. She was treated with sunitinib (50 mg/ day) starting in January 2009. On day 11, it was discontinued as a result of G4 thrombocytopenia and G3 digestive symptoms. G2 vaginal bleeding occurred, and continued while the platelet count was suppressed. Although she was re-treated with sunitinib (25 mg/day) starting in February 2009, it was stopped again as a result of G3 thrombocytopenia on day 21. Thereafter, best supportive care was adopted. After leaving Ehime University Hospital, Toon, Japan, her lumbago was progressive, and G3 diarrhea and G3 fatigue occurred. Furthermore, a laboratory examination showed pancytopenia. She was again hospitalized and leukocyte reduction-red cell concentrate was transfused several times. Although esophagogastroduodenoscopy showed reflux esophagitis, this was improved by conservative therapies. At the time of her discharge (April 2009), computed tomography (CT; Fig. 1a–d) showed disease progression in all metastatic lesions compared with January 2009. She had pain from the bone metastases, and was weak as a result of an eating disorder. She was treated with narcotic analgesics. A repeat CT showed disease regression, particularly in the liver and 9th rib metastases, and stable disease in other bone metastases (Fig. 1e–h, July 2010). Her general fatigue gradually resolved after stopping sunitinib. Her pain also resolved. We have continued palliative analgesic treatment with non-steroidal anti-inflammatory drugs. She has been treated without any medicines that might affect cancer regression during her clinical history. Cases of spontaneous regression of cancer were first collected in the form of a monograph. Spontaneous regression of cancer is defined as the complete or partial disappearance of a malignant tumor in the absence of therapy. In the case of renal cell carcinoma (RCC), spontaneous regression has most frequently followed nephrectomy. In the present case, the regression might also be an effect of the sunitinib, despite the brief administration, or a phenomenon caused by the cessation of sunitinib. Discontinuation of pro-angiogenic

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

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.

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