Kunio Ono

UV RESONANCE RAMAN SCATTERING FROM METAL-COORDINATING HISTIDINE RESIDUES IN CU, ZN-SUPEROXIDE DISMUTASE

Metal-binding modes of histidine residues in Cu,Zn-superoxide dismutase (Cu,Zn-SOD) were investigated by UV resonance Raman spectroscopy. The metal-bridging imidazolate (Im-) ring of His61 gives prominent Raman bands at ca. 1565, 1335, 1285, 1260, 1050 and 980 cm-1. On the other hand, the imidazole ring of other histidines gives a Raman band at ca. 1395 or 1355 cm-1 when it is ligated to a metal ion via the Nτ or Nπ atom, respectively, and the other nitrogen atom is deuterated (ImD). These Raman marker bands together with the previously established correlation between the C4=C5 stretching wavenumber and metal-coordination site for non-deuterated imidazole (ImH) were used to investigate the metal-binding modes of histidine residues in the reduced and inhibitor-bound states of Cu,Zn-SOD. Upon reduction of the enzyme, the Raman bands of the metal-bridging Im- ring disappear. Concomitantly, a new band appears at 1590 cm-1, which is assignable to the C4=C5 stretch of an ImH ring coordinating to a metal ion via the Nπ atom. These Raman spectral changes provide direct evidence that the Cu—Nτ linkage of His61 is broken upon reduction and the Nτ atom is protonated in the reduced state. The binding of a competitive inhibitor (CN-) produces wavenumber downshifts of Raman bands arising from vibrations of the Nτ—C5=C4 moiety of the His61 Im- ring, indicating a structural modification of His61 by the inhibitor binding.

Case of carcinosarcoma of urinary bladder obtained a pathologically complete response by neoadjuvant chemoradiotherapy.

Abstract:  Carcinosarcoma of the bladder is an unusual malignancy characterized by an intimate admixture of malignant epithelial elements (carcinoma) and malignant soft tissue elements (sarcoma). To our knowledge, almost 80 cases have been reported, usually as case reports or small series. Patient with carcinosarcoma usually present with a high stage malignancy. Cystectomy or transurethral resection is the preferred treatment, often followed by radiation therapy, although prognosis is very bad. We herein report a case of carcinosarcoma of bladder obtained pathologically complete response by neoadjuvant chemoradiotherapy. She now shows no evidence of disease 30 months after the operation. To our knowledge, it is the first case where urinary bladder carcinosarcoma obtained a pathologically complete response by chemoradiotherapy.

Gemcitabine plus carboplatin; and gemcitabine, docetaxel, and carboplatin combined chemotherapy regimens in patients with metastatic urothelial carcinoma previously treated with a platinum-based regimen: preliminary report

BackgroundThe aim of this study was to evaluate the efficacy and safety of two combined chemotherapy regimens in the treatment of previously treated metastatic urothelial carcinoma: gemcitabine plus carboplatin (GC), and gemcitabine, docetaxel, and carboplatin (GDC).MethodsSixteen patients with metastatic urothelial cancer, previously treated with a platinum-based regimen, were studied. GC (gemcitabine 750 mg/m2, on days 1, 8, and 15; carboplatin 200 mg/m2, on day 2) was administered every 28 days to 15 patients. GDC (gemcitabine 750 mg/m2, on days 1 and 8; docetaxel 50 mg/m2, on day 1; carboplatin 200 mg/m2 on day 1) was administered every 21 days to 9 patients. Eight of the 9 GDC-treated patients had earlier been treated with GC and had become refractory.ResultsWith the GC therapy, 7 of the 15 treated patients (47%; 95% confidence interval, 21%–73%) showed an objective response, with 3 achieving a clinical complete response (CR) and 4 a partial response (PR). With the GDC therapy, 6 of the 9 treated patients (67%; 95% confidence interval, 29%–92%) showed an objective response, with 1 achieving CR and 5, PR. Five of the 8 (63%) GC-refractory patients responded to GDC therapy. The median duration of response was 4 months (range, 2–10+ months) on GC therapy, and 3 months (range, 3–5 months) on GDC therapy. Toxicities associated with GC were less than those with GDC.ConclusionGC was effective for refractory metastatic urothelial cancer, and GDC was effective for GC-refractory cancer.

Vibrational analysis of the imidazolate ring

Abstract IR and Raman spectra have been investigated for imidazolate and 4-methylimidazolate including five and three deuterated analogs, respectively. Assignment of the observed IR and Raman bands has been made on the basis of isotopic frequency shifts, Raman polarization properties, and normal coordinate calculations. The calculated normal frequencies are in good agreement with experimental ones: the average error below 1600 cm −1 is 4.5 cm −1 for 104 in-plane vibrations and 3.8 cm −1 for 43 out-of-plane vibrations. The calculated vibrational modes are useful in analyzing the Raman bands of histidine residues in proteins.

Complete regression of bone metastases on super bone scan, by low-dose cisplatin, UFT, diethylstilbestrol diphosphate, and dexamethasone in a patient with hormone-refractory prostate cancer

Abstract. Many types of chemotherapy are now being attempted all over the world for hormone-refractory prostate cancer (HRPC) patients, and prostate-specific antigen (PSA) reduction in almost half of the treated patients has been reported. However, only a few studies have reported the response of bone metastasis. The authors report a patient with HRPC who obtained complete regression of bone metastases on super bone scan by biochemical modulation (BM), dexamethasone, and endocrine therapy.

Trans-urethral whole layer core biopsy for detection of residual tumor after neoadjuvant therapy in invasive bladder cancer

The most essential information necessary for the treatment of bladder cancer is to know its exact staging. We have developed a percutaneous whole layer core biopsy (PC-WLCB) of the bladder tumor and applied it successfully since April 1985 for the staging and evaluation of neoadjuvant therapy in locally invasive bladder cancer. We report here a modified method, the trans-urethral WLCB (TU-WLCB) and present its clinical results. Methods: A 20 F. rigid nephroscope was introduced trans-urethrally and an 18 gauge, 350mm-long biopsy needle or newly developed 450mm-long biopsy needle was advanced to the tumor through the nephroscope. Biopsy was performed under trans-abdominal ultrasound guidance. Results: Specimens of all 20 TU-WLCB cases included the muscle layer and adipose tissue, and demonstrated small focus of residual cancers after neoadjuvant therapy. Serious complications were not observed so far. Conclusion: TU-WLCB may prove to be a reliable method to stage and evaluate neoadjuvant therapy for invasive bladder cancer.

Diagnosis and treatment of pelvic lymph node metastasis in bladder cancer

Background and Methods : Bipedal lymphography and percutaneous fine needle aspiration biopsy (FNAB) of pelvic lymph node was done in 200 patients with bladder cancer.

Treatment sequence in castration-resistant prostate cancer: A retrospective study in the new anti-androgen era

In recent years, abiraterone acetate (AA) and enzalutamide (EZL) have become available for the treatment of cancer. Prior clinical trials have demonstrated the benefits of these agents in males with castration-resistant prostate cancer (CRPC). The optimal sequencing of available therapies in the context of efficacy and known cross-resistance remains uncertain. Based on the mechanisms of action and accessible clinical data, AA and EZL may be indicated for the early stages of prostate cancer. Until clinical trials are conducted to determine the best treatment sequence, individualized therapy is required for each patient based on the clinicopathological characteristics. In the present study, 46 sequential patients (median age: 77, range 59-89; median serum PSA level: 56 ng/ml, range 1.5-3,211) with CRPC treated with EZL (160 mg/day) were retrospectively analyzed between June 2014 and July 2015 at the following institutions: Yamagata Prefectural Central Hospital (Yamagata, Japan); Yamagata Tokushukai Hospital (Yamagata, Japan); Ishinomaki Red Cross Hospital (Ishinomaki, Japan); Kan-etsu Hospital (Tsurugashima, Japan); Niigata Cancer Center Hospital (Niigata, Japan); Sakado Central Hospital (Sakado, Japan). A total of 18 patients were pre-treated with Docetaxel (DOC) and 28 patients were DOC-naïve. Once EZL therapy was initiated, increases in prostate specific antigen (PSA) levels were observed in 3/18 patients (17%) pre-treated with DOC and in 6/20 (30%) who were DOC-naïve. In total, 8/28 DOC-naïve patients were treated with AA without EZL. An increase in the PSA level was observed in only 1/8 (12%) cases following AA treatment in the DOC-naïve group. It was demonstrated that AA had a better efficacy in DOC-naïve patients. The efficacy of EZL was limited in AA-pre-treated patients following DOC administration.

Updated recommendation on molecular-targeted therapy for metastatic renal cell cancer

Molecular-targeted therapy was recommended for the systemic therapy of renal cell cancer (RCC) in the RCC guidelines, but these guidelines do not address the order of administration of the multiple presently available agents. There are several aspects that remain unknown regarding the optimal administration order and combination of molecular-targeted drugs. Until the optimal treatment sequence is determined by clinical trials, treatment individualization is required for each patient based on patient and disease characteristics. We herein investigate 12 cases of RCC patients who received axitinib. Axitinib was used as the first-line drug in 4 cases, second-line in 5 cases, third-line in 1 case and as a fourth-line drug in 2 cases. Partial response (PR) was observed in 4 cases (30%) and stable disease in 4 cases (30%) during axitinib treatment, with an overall response rate of 60%. The duration of PR ranged from 6 to 19 months. Based on our cases, axitinib exhibited reasonable therapeutic efficacy as first- as well as second-line treatment. However, more cases are required to draw firm conclusions.

895 ROLE FOR PULMONARY METASTASECTOMY WITH A CURATIVE INTENT IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA

INTRODUCTION AND OBJECTIVES: Recent studies showed therapeutic benefit from lymphadenectomy in advanced stage urothelial carcinoma of the upper urinary tract (UCUUT). However, there is still a lack of prospective studies and standardization of the extent of lymphadenectomy. We conducted this multi-institutional prospective study to further examine the role of lymphadenectomy in UCUUT. METHODS: From January 2005, we performed lymphadenectomy in 82 patients at the time of radical nephroureterectomy for curative purposes as a prospective study in both institutes. These lymphadenectomies were performed in all patients except those with severe co-morbidity by exactly following the anatomical template determined from the mapping study (Pros-CompLND). These results were compared with those from 203 patients who underwent curative surgery except for Pros-CompLND in Tokyo Womenufs Medical University. We classified these patients into three groups: the patients in whom all regional sites were dissected before 2005 (Retro-CompLND), those in whom lymphadenectomy did not include all regional sites (IncompLND), and those without lymphadenectomy (No-LND). This study protocol was approved by the institutional review board of each institute. RESULTS: Mean follow-up period was 26.8 19.3 months in 82 Pros-CompLND patients, 99.7 62.4 months in 40 Retro-CompLND, 73.4 64.5 months in 45 IncompLND, and 48.5 49.1 months in 118 No-LND patients. The number of lymph nodes was significantly higher in Pros-CompLND (14.5 6.6) than in Retro-CompLND (8.5 5.6) and IncompLND (4.6 2.8) (p 0.001). We examined cancer-specific survival (CSS) in the non-metastatic patients with pT2 or higher. In 121 patients with renal pelvic cancer, 3-year CSS was 87.9% in ProsCompLND, 90.8% in Retro-CompLND, 68.9% in IncompLND, and 64.7% in No-LND. CSS of Pros-CompLND and Retro-CompLND was significantly better than that of No-LND (p 0.04, p 0.01). In contrast, CSS of 69 patients with ureteral cancer was not significantly different between Pros-CompLND, Retro-CompLND, and No-LND. CONCLUSIONS: This multi-institutional study further supports the therapeutic role of template-based lymphadenectomy in patients with advanced stage renal pelvic cancer. Source of Funding: None