Masahiro Nozawa

Bacillus Calmette–Guérin Perfusion Therapy for the Treatment of Transitional Cell Carcinoma in situ of the Upper Urinary Tract

Objectives: The aim of this study is to evaluate the efficacy and safety of intrarenal bacillus Calmette–Guérin (BCG) instillation as a treatment for transitional cell carcinoma in situ (CIS) of the upper urinary tract.Methods: Diagnostic criteria of upper urinary tract CIS were (1) positive urinary cytology, (2) negative multiple random biopsy of the bladder and prostatic urethra, (3) negative radiographic findings in the upper urinary tract and (4) two serial positive cytologies in selective ipsilateral urine sampling from the pyeloureteral system. Eleven patients diagnosed as having upper urinary tract CIS were enrolled in this study. Thus, 11 renal units were treated with BCG instillation. After placing a 6–french Double–J stent, BCG (80 mg) in 40 ml saline was instilled into the bladder weekly, 6 times in total as one course.Results: At the end of one course, 9 cases showed negative urinary cytology. Among these 9 cases, 2 showed recurrence in the upper urinary tract after 4 months and 8 months of disease–free interval, respectively. These 2 cases have received an additional course of BCG instillation, but the urinary cytology did not normalize. Mean recurrence–free time was 19.6 months. Of the other 7 cases who responded to the first course of instillation, 6 cases were alive with no evidence of the disease. The remaining patient died of rectal cancer with no evidence of transitional cell carcinoma (TCC). Of the 2 cases who showed positive urinary cytology even after the first course, 1 underwent nephroureterectomy. The other case was diagnosed as having malignant lymphoma 3 months after the end of this instillation therapy, and he died of malignant lymphoma. As side effects, 8 cases (72.7%) showed bladder irritability, and 4 presented fever higher than 38°C. However, no patient needed antitubercular treatment.Conclusion: As for the short–term response, BCG instillation for the treatment of upper urinary tract CIS is considered to be effective and safe. Longer follow–up and further experience with this treatment are required.

A Phase 2 Randomized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone Alone in Chemotherapy-naive Castration-resistant Prostate Cancer

BACKGROUND It is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years. OBJECTIVE To evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS A phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1mg/d) or to dexamethasone (1mg/d) alone. A maximum of four HLA-matched peptides (each 3mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis. RESULTS AND LIMITATIONS Overall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p=0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p=0.00084). The relatively small number of patients enrolled is the major limitation of the study. CONCLUSIONS PPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings. PATIENT SUMMARY We compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines. TRIAL REGISTRATION UMIN-CTR: 000000959.

Sorafenib rechallenge in patients with metastatic renal cell carcinoma

Study Type – Therapy (case series)

Oral Combination of Cyclophosphamide, Uracil plus Tegafur and Estramustine for Hormone-Refractory Prostate Cancer

Objective: To evaluate the clinical usefulness of an oral combination of cyclophosphamide, uracil plus tegafur (UFT) and estramustine in the treatment of patients with hormone-refractory prostate cancer (HRPC). Methods: Twenty-one patients were treated with oral administration of cyclophosphamide (100 mg/day), UFT (400 mg/day) and estramustine phosphate (560 mg/day). The median age of the patients was 70 years. Twelve patients had symptomatic bone metastasis, 6 had asymptomatic bone metastasis, 5 had lymph node metastasis, while 2 had only biochemical progression evaluated by prostate-specific antigen (PSA). Results: Twelve (57%) out of 21 patients showed a PSA decline of 50% or greater. The median response duration was 7 months (range 2–15 months). Among the 20 patients assessable for bone pain, 2 (10%) improved, 12 (60%) remained stable and 6 (30%) progressed. Among the 10 patients assessable for bone metastasis, 1 (10%) improved, 5 (50%) were stable and 4 (40%) progressed on bone scan. Among 3 patients assessable for measurable disease (lymph node metastasis), 2 (67%) showed partial response and 1 (33%) progression. Most toxicities were mild. Conclusions: The combination of cyclophosphamide, UFT and estramustine is an active and well-tolerated regimen for HRPC. To evaluate the survival benefit, further randomized studies are required.

Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma

Background:It is well known that renal cell carcinoma (RCC) represents one of the most immune-responsive cancers. Although the lack of defined antigens in RCC has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of RCC for more than 30 years.Methods:To evaluate the safety of the vascular endothelial growth factor receptor 1 (VEGFR1) peptide vaccination and its clinical outcomes, data from 18 metastatic RCC (mRCC) patients treated with VEGFR1 vaccine were collected. Toxicity assessments were performed. Clinical outcomes included assessment using CT scanning, magnetic resonance imaging or X-ray examination in accordance with the WHO Response Evaluation Criteria in Solid Tumors.Results:No patient showed any toxicities of grade 3 or greater. Of the 18 patients, 2 patients showed a partial response during treatment. Stable disease for more than 5 months was observed in eight patients with a median duration of 16.5 months (4–32 months). At the time of the analysis in this study, six patients were alive with a median follow-up of 30 months (26–36 months).Conclusion:These results suggest that VEGFR1 peptide vaccine is safe and is recommended for further trials for patients with mRCC.

ANGIOGENESIS INHIBITOR TNP-470 INHIBITS GROWTH AND METASTASIS OF A HORMONE-INDEPENDENT RAT PROSTATIC CARCINOMA CELL LINE

PURPOSE Inhibitory effects of TNP-470, a synthetic analogue of the antibiotic fumagillin secreted by Aspergillus fumigatus, were studied with respect to growth and lung metastasis of the hormone-independent rat prostatic carcinoma cell line AT6.3. MATERIALS AND METHODS Rat prostatic carcinoma AT6.3 cells were implanted in nude mice subcutaneously. Antimetastatic and growth-inhibitory effects of TNP-470 in vivo were examined 3 weeks after inoculation of AT6.3 cells. Direct growth-inhibitory effect was examined by MTT assay in vitro. RESULTS TNP-470 inhibited the growth of AT6.3 cells in vitro. Subcutaneously injected TNP-470 markedly reduced numbers and individual size of lung metastases from AT6.3 cells inoculated percutaneously or intravenously into male BALB/c-nu/nu mice. CONCLUSION This agent, which acts as an angiogenesis inhibitor, may prove to be clinically useful in preventing metastasis of hormone-independent prostatic cancer.

Utility of immunohistochemical detection of prostate‐specific Ets for the diagnosis of benign and malignant prostatic epithelial lesions

Background : Human prostate‐specific Ets (hPSE) belongs to the Ets family. It regulates the proliferation, differentiation, and development of prostate epithelial cells. A recent study showed that hPSE can be detected in normal glands but not in cell lines established from prostate cancer (PCA), suggesting a translational disorder of hPSE from mRNA to protein in PCA. Immunohistochemical detection of hPSE could therefore be another method of differential diagnosis of PCA from other proliferative conditions in the prostate.

Adverse Event Profile and Dose Modification of Everolimus for Advanced Renal Cell Carcinoma in Real-world Japanese Clinical Practice

OBJECTIVE The aim of the study was to assess the safety and efficacy of everolimus therapy for advanced renal cell carcinoma in Japanese patients receiving real-world care. METHODS Patients who had been treated with everolimus for advanced renal cell carcinoma at 39 Japanese medical centers between January 2010 and November 2011 were retrospectively investigated to assess adverse events and the time to treatment failure. RESULTS A total of 180 patients were identified. Their median age was 65 years (range 23-93). The median time to treatment failure was 2.9 months (95% confidence interval 2.4-3.4). The median time to treatment failure was significantly longer in patients with dose modification (4.2 months; 95% confidence interval 3.4-5.0) than in patients without dose modification (1.7 months; 95% confidence interval 1.0-2.3; P < 0.01) after experiencing adverse events. Stomatitis (44%) was the most frequent adverse event, followed by thrombocytopenia (31%), anemia (22%), interstitial pneumonia (22%) and hyperglycemia (17%). Interstitial pneumonia was the most frequent cause of discontinuation in patients who discontinued everolimus due to intolerability regardless of the dose modification status. None of the patients with dose modification of everolimus discontinued everolimus due to thrombocytopenia or leukopenia. CONCLUSIONS The adverse event profile of everolimus may differ between Japanese and Caucasian patients. Dose modification of everolimus might be associated with longer treatment duration in patients with advanced renal cell carcinoma. Further studies are required to clarify this association. Interstitial pneumonia may be difficult to overcome by dose modification.

Xanthoma of the Bladder

We report a case of xanthoma of the bladder incidentally discovered during transurethral ureteral lithotripsy for a right ureteral stone and histopathologically diagnosed by cold cup biopsy. Xanthoma, a disorder of the lipid metabolism without tumorous or inflammatory changes, is rare in the bladder with only 7 cases reported previously. Interestingly, 5 of these 7 cases were reported in the Japanese literature, as were cases of xanthogranulomatous cystitis. We have no explanation for this occurrence. Xanthoma, caused by macrophages with the ability to phagocytose, is a benign lesion. It is necessary to continue careful followup by cystoscopy to determine if xanthoma increases or decreases in size.

INFLAMMATORY PSEUDOTUMOR OF THE URETER

A 54-year-old man presented with a 5-month history of left back pain and no urological problems. Physical examination was unremarkable. The results of laboratory tests were within normal limits, urinalysis was normal and urine cytology was negative. The left kidney was not visualized on excretory urography. Computerized tomography (CT) revealed a heterogeneous 3 em. mass in the upper part of the left ureter and left hydronephrosis with thin parenchyma Diagnosis was ureteral cancer and consequently total left nephroureterectomy was performed. There were no postoperative complications and the patient was discharged from the hospital 23 days after surgery. Followup with excretory urography and CT revealed no recurrence for 7 months. The 4 x 3 x 3 cm. resected mass was rubbery firm with a yellowish-white cut surface and it surrounded the upper part of the left ureter. Macroscopic inspection of the cut surface revealed no obvious lesion on the ureteral mucosa. On microscopy the mass was not encapsulated and it was located