Shigenori Kakutani

Prognostic Factors for Renal Cell Carcinoma With Bone Metastasis: Who Are the Long-Term Survivors?

PURPOSE Renal cell carcinoma is sometimes associated with bone metastasis. Several risk factors have been reported but some are still controversial. Also, the significance of laboratory tests has not been fully examined for such cases. MATERIALS AND METHODS We collected data on 94 renal cell carcinoma cases with bone metastasis treated at 3 tertiary referral centers. Clinicopathological parameters and outcome data were analyzed to search for predictors of overall survival retrospectively. The log rank test and the Cox proportional hazard model were used for univariate and multivariate analyses, respectively. RESULTS There were 64 males with a median age of 63.9 years. Histological diagnosis showed clear cell renal cell carcinoma in 63 patients, nonclear cell renal cell carcinoma in 7 and unclassified cancer in 6. Sarcomatoid differentiation was found in 17 cases. Metastasis was detected synchronously in 37 patients or metachronously at a median interval of 33.1 months. Multivariate analysis identified sarcomatoid differentiation (p = 0.001), vertebral bone involvement (p = 0.003), extraosseous metastasis (p = 0.021), alkaline phosphatase increased to 1.5 times the upper limit of normal (p = 0.0003) and C-reactive protein increased to greater than 0.3 mg/dl (p = 0.018) as significant risk factors. Cases were classified into 3 groups based on the number of risk factors, including low risk-28 with 0 or 1 risk factor, intermediate risk-26 with 2 risk factors and high risk-40 with 3 to 5 risk factors. This grouping clearly separated survival among these groups (each p <0.001). It also confirmed the usefulness of the Memorial-Sloan Kettering Cancer Center classification system. CONCLUSIONS Our risk classification incorporating 5 risk factors enables accurate prediction of survival, which can be helpful to make clinical decisions in cases of renal cell carcinoma with bone metastasis.

A novel prognostic factor TRIM44 promotes cell proliferation and migration, and inhibits apoptosis in testicular germ cell tumor

Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto‐protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer‐specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer‐specific mortality (P = 0.046). Gain‐of‐function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44‐knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti‐apoptosis in TGCT.

Combination of docetaxel, ifosfamide and cisplatin (DIP) as a potential salvage chemotherapy for metastatic urothelial carcinoma

OBJECTIVE The aim of this study was to evaluate the efficacy and toxicity of the combination of docetaxel, ifosfamide and cisplatin as salvage chemotherapy after failure of standard cisplatin-based regimens for metastatic urothelial carcinoma. METHODS We prospectively administered docetaxel, ifosfamide and cisplatin chemotherapy to patients with metastatic urothelial carcinoma refractory to standard cisplatin-based regimens from 2003 to 2013. Patients who had received only adjuvant and/or neoadjuvant chemotherapy were excluded. Eligible patients received every 28 days docetaxel 60 mg/m(2) on Day 1, ifosfamide 1.0 g/m(2) on Days 2-6 and cisplatin 20 mg/m(2) on Days 2-6. The primary endpoints were progression-free survival and overall survival, calculated from the start of docetaxel, ifosfamide and cisplatin chemotherapy. Secondary endpoints included objective response and related toxicity. RESULTS Twenty-six cases received a median of 3.0 cycles of docetaxel, ifosfamide and cisplatin chemotherapy (interquartile range: 2-5), resulting in a median progression-free survival of 3 months (interquartile range: 2-9.5 months) and median overall survival of 8.5 months (interquartile range: 6.5-18.75 months), respectively. Of 26 patients, seven (27%) achieved major treatment responses, with one complete response (4%) and six partial responses (23%). Most of Grade 3/4 toxicities were hematologic events, including leukopenia (77%), anemia (54%) and thrombocytopenia (46%). No death from toxicity was observed. CONCLUSIONS Our results indicate that docetaxel, ifosfamide and cisplatin chemotherapy is a tolerable and moderately active regimen for metastatic urothelial carcinoma after failure of standard cisplatin-based regimens.

Radical Prostatectomy versus External Beam Radiotherapy for cT1-4N0M0 Prostate Cancer: Comparison of Patient Outcomes Including Mortality

Background Although radical prostatectomy (RP) and external beam radiotherapy (EBRT) have been considered as comparable treatments for localized prostate cancer (PC), it is controversial which treatment is better. The present study aimed to compare outcomes, including mortality, of RP and EBRT for localized PC. Methods We retrospectively analyzed 891 patients with cT1-4N0M0 PC who underwent either RP (n = 569) or EBRT (n = 322) with curative intent at our single institution between 2005 and 2012. Of the EBRT patients, 302 (93.8%) underwent intensity-modulated radiotherapy. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Related to these, other-cause mortality (OCM) was also calculated. Biochemical recurrence-free survival was assessed as a secondary endpoint. Cox proportional hazards model was used for multivariate analysis. Results Median follow-up durations were 53 and 45 months, and median ages were 66 and 70 years (P <0.0001), in the RP and EBRT groups, respectively. As a whole, significantly better prognoses of the RP group than the EBRT group were observed for both OS and CSS, although OCM was significantly higher in the EBRT group. There was no death from PC in men with low and intermediate D’Amico risks, except one with intermediate-risk in the EBRT group. In high-risk patients, significantly more patients died from PC in the EBRT group than the RP group. Multivariate analysis demonstrated the RP group to be an independent prognostic factor for better CSS. On the other hand, the EBRT group had a significantly longer biochemical recurrence-free survival than the RP group. Conclusions Mortality outcomes of both RP and EBRT were generally favorable in low and intermediate risk patients. Improvement of CSS in high risk patients was seen in patients receiving RP over those receiving EBRT.

Renal Cell Carcinoma with Intraluminal Spread of the Entire Upper Urinary Tract

We describe an unusual case of renal cell carcinoma (RCC) involving the entire upper urinary tract. A 51-year-old female was referred to us because of macroscopic hematuria. Computed tomography revealed a renal tumor filling renal pelvis and ureter, which turned to be a clear cell RCC after nephroureterectomy.

Salvage Combination Chemotherapy with Docetaxel, Ifosfamide and Cisplatin (DIP): Successful Treatment of a Case with Metastatic Testicular Immature Teratoma

We present a case of metastatic testicular immature teratoma that was successfully treated despite resistance to standard chemotherapy and unsuccessful salvage surgery. At first, BEP (bleomycin, etoposide and cisplatin) treatment was performed but failed. The patient underwent incomplete retroperitoneal lymph node dissection. He was then referred to us. By the time of the referral lung and mediastinal lymph node metastasis had appeared and para-aortic lymph node metastasis had grown larger. We administered the DIP (docetaxel, ifosfamide and cisplatin) regimen as a second line chemotherapy, which was effective with 82% reduction of para-aortic lymph nodes, 88% of mediastinal lymph nodes and 85% of lung metastasis. We performed para-aortic lymph node dissection followed by resection of lung metastasis and mediastinal lymph node dissection. The patient is now followed-up at the outpatient clinic without evidence of recurrent disease 3.5 years after the last surgery.

Drug review: Pazopanib

Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that primarily inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet endothelial growth factor receptor-α, and -β, and the stem-cell factor receptor c-kit. In preliminary experiments using angiogenesis models with mice and rabbits, pazopanib inhibited angiogenesis caused by combined vascular endothelial growth factor and basic fibroblast growth factor. Although pazopanib was developed as a therapeutic agent against various tumors, it is currently approved in many countries for advanced soft-tissue sarcoma and renal cell carcinoma. The importance of pazopanib has been acknowledged, with positive results demonstrated in large-scale clinical trials involving patients with soft-tissue sarcoma and renal cell carcinoma. However, adverse events such as liver dysfunction and hypertension are common, often necessitating treatment discontinuation. These adverse events are generally manageable, and from the perspective of health-related quality of life and cost-effectiveness, pazopanib provides an improvement in quality-adjusted life years and decreases the treatment cost compared with other alternatives. In this review, we present the results of clinical trials and discuss the pharmacological action of pazopanib, with the aim of evaluating its current state by examining various associated issues.

327. Oncolytic Virus Therapy Using Recombinant HSV-1 for Nonseminoma Germ Cell Tumors

Oncolytic herpes simplex viruses type 1 (HSV-1) have been shown promising for treating a variety of tumor. G47Δ is a third-generation oncolytic HSV-1 that has triple mutations in the gamma34.5, alpha47 and ICP6 genes, and the first recombinant HSV-1 tried clinically in Japan. Clinical trials using G47Δ are currently ongoing in patients with glioblastoma, olfactory neuroblastoma or castration resistant prostate cancer. Preclinical studies have shown that G47Δ is also effective in many other types of cancer including breast cancer, schwannoma, renal carcinoma, and urothelial carcinoma. The purpose of this study was to investigate whether oncolytic HSV-1 can also be applied for treating testicular cancer.Testicular cancer is relatively rare, accounting for approximately 1% of male neoplasms and comprising morphologically diverse group of tumors, 90-95% of which are germ cell tumors (GCTs). GCTs are broadly classified as seminoma and non-seminoma (NSGCT). With the increase in early diagnosis and the development of cisplatin-based chemotherapy, a long-term survival can be expected for most GCT patients even with the initial presence of metastases. However, a group of NSGCT patients show resistance to chemotherapy and the five-year survival rate of such group is less than 50%, so clearly a new therapeutic approach is necessary for those patients.In this study, two recombinant HSV-1 were used. T-01 and T-mfIL12 are oncolytic HSV-1 with an empty cassette or the CMV promoter-driven murine interleukin 12 gene inserted into the backbone of G47Δ. Human NSGCT cell lines NTERA-2, Tera-1 and ITO-II, and a mouse NSGCT cell line F9 were used for in vitro evaluation. NTERA-2 and F9 were susceptible to T-01 at an MOI of 0.1: The percentages of surviving cells were less than11% at day 3. Cytopathic activities of T-mfIL12 were comparable to T-01. Athymic mice bearing established subcutaneous NTERA-2 tumors and immunocompetent mice bearing established subcutaneous F9 tumors were used for in vivo evaluation. When inoculated intraneoplastically, T-01 (4 × 10^4, 2 × 10^5 or 1 × 10^6 pfu) caused a significant inhibition of tumor growth compared with mock even at the lowest dose in the NTERA-2 model. In the F9 model, T-mfIL12 (4 × 10^4 pfu) caused a significant inhibition of tumor growth compared with T-01. Moreover, the combination of T-01 (4 × 10^4 pfu) with cisplatin (0.05mg per mouse injected intraperitoneally) was more efficacious than T-01 alone or cisplatin alone in the NTERA-2 model.These data suggest that oncolytic virus therapy using recombinant HSV-1 might be a useful strategy for treating NSGCT.

Risk Factors for Clinical Metastasis in Men Undergoing Radical Prostatectomy and Immediate Adjuvant Androgen Deprivation Therapy

BACKGROUND Adjuvant androgen deprivation therapy (ADT) is a treatment option for prostate cancer (PC) patients after radical prostatectomy (RP). Although it can achieve a good progression-free survival rate, some patients still develop clinical metastasis. We here investigated risk factors of clinical metastasis in post- prostatectomy patients who received immediate adjuvant ADT. MATERIALS AND METHODS We identified 197 patients with non-metastatic PC who underwent RP at our institution between 2000 and 2012, followed by adjuvant ADT. The associations of various clinicopathologic factors with clinical metastasis (primary endpoint) and cancer-specific survival (secondary endpoint) were assessed. Multivariate analysis was conducted using a Cox proportional hazards model. Median follow-up was 87 months after RP. RESULTS Nine (4.6%) patients developed clinical metastasis and six (3.0%) died from PC. Eight of nine metastatic patients had a pathologic Gleason score (GS) 9 and developed bone metastasis, while the remaining one had pathologic GS 7 and developed metastasis only to para-aortic lymph nodes. On multivariate analyses, pathologic GS ≥9 and regional lymph node metastasis (pN1) were independent predictors of clinical metastasis and pathologic GS ≥9 was an independent predictor of cancer-specific death. CONCLUSIONS Pathologic GS ≥9 and pN1 were independent predictors of clinical metastasis in post-prostatectomy patients who received immediate adjuvant ADT. Furthermore, pathologic GS ≥9 was an indispensable condition for bone metastasis, which may imply that patients with GS ≤8 on adjuvant ADT are unlikely to develop bone metastasis.