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.

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.

[Examination of prostate biopsy among Japanese with less than 4.0 ng/ml prostate specific antigen--usefulness of free/total PSA ratio].

The low specificity of the prostate specific antigen (PSA) test is considered to be a problem when PSA measurement alone is performed to detect cancer. Therefore, we examined a method to decrease the number of unnecessary biopsies while maintaining the power of the test by using PSA, PSA free/total ratio (PSAf/t), and digital rectal examination (DRE). The subjects were 232 patients with PSA levels of 4.0 ng/ml or less who underwent biopsy for prostate cancer. An endorectal ultrasound perineal biopsy was conducted, and the average biopsy core number was 21. Cancer was detected in 37 of the 232 subjects. Receiver operating characteristic curves of PSA and PSAf/t were subsequently determined. Although the area under the curve (AUC) was 0.56 for PSA alone, the AUC increased to 0.75 when the factor of positive data in DRE was taken into account. Although the AUC was 0.62 for PSAf/t alone, when the factor of positive data in DRE was added as for PSA, the AUC increased to 0.79. In addition, as a result of examining the combination of PSA, PSAf/t and DRE, the condition of the biopsy for prostate cancer in the cases with PSA of 4.0 ng/ml was determined as follows: PSA should be 3.1 ng/ml or more and PSAf/t 27% or less, or the result of DRE should be positive. Based on these criteria, the sensitivity, specificity and detection rate of cancer increased to 0.919, 0.436 and 23.2%, respectively. We consider that this approach will be useful.

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

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.

[Small cell carcinoma of the prostate: a case report].

A 79-year-old man was admitted to our department with a chief complaint of urinary incontinence. The prostate was enlarged (145 cc), although the serum level of prostate specific antigen (PSA) was within the normal range (1.09 ng/ml). Digital rectal examination showed an enlarged, irregular prostate with stony hardness. We performed a prostate biopsy and histological examinations indicated poorly differentiated adenocarcinoma with a Gleason score of 5+5=10. A computed tomographic (CT) scan revealed a prostatic tumor invading the bladder, seminal vesicle and rectum. He was diagnosed with a stage T4N1M0 adenocarcinoma of the prostate. He was started-on hormonal therapy, but died one month from the start of treatment. Histological and immunohistological examinations were repeated; suggesting small cell neuroendocrine carcinoma of the prostate.

A novel "reverse screening" to identify refolding additives for activin-A.

A general approach for refolding recombinant proteins from inclusion bodies (IBs) is to screen conditions, that facilitate a conversion of unfolded to folded structure and minimize a conversion of unfolded to misfolded and aggregated structures. In this simplified model, such conditions may be those that stabilize the native protein and/or reduce aggregation. In this paper, a novel screening approach, termed reverse screening, was developed using a native activin. Activin-A, a member of transforming growth factor beta superfamily, is a homodimeric protein with nine disulfide bonds. We examined partial unfolding process of native activin-A dissolved in a buffer containing moderate concentrations of denaturant and reducing reagent (i.e., 1.5 M urea and 0.2 mM dithiothreitol). The recovery of the protein was followed by reverse-phase high performance chromatography analysis. Without additives, activin-A showed about 60% loss of the protein due to aggregation after 12-h incubation in the above condition. We then tested various additives for their effects on the recovery after partial unfolding. One of these additives, sodium taurodeoxycholate (TDCA), greatly increased recovery and suppressed aggregation of the protein. These additives were then tested for refolding activin-A from IBs. TDCA among others is proved to be a highly effective refolding additive. These results strongly suggest that reverse screening using native proteins, if available, may be another approach to discovering effective refolding additives.

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.

BACKGROUND: The 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). METHODS: Sixteen patients with metastatic urothelial cancer, previously treated with a platinum-based regimen, were studied. GC (gemcitabine 750 mg/m(2), on days 1, 8, and 15; carboplatin 200 mg/m(2), on day 2) was administered every 28 days to 15 patients. GDC (gemcitabine 750 mg/m(2), on days 1 and 8; docetaxel 50 mg/m(2), on day 1; carboplatin 200 mg/m(2) 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. RESULTS: With 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. CONCLUSION: GC was effective for refractory metastatic urothelial cancer, and GDC was effective for GC-refractory cancer. The 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).

[A case of renal cell carcinoma with lymph node metastasis keeping remission for five years by adjuvant immunotherapy with ubenimex].

We report herein the long-term remission of a woman following postoperative ubenimex therapy. A 46-year-old woman with a tumor in the left kidney and a swollen para-aortic lymph node was referred to our department for surgery. Preoperative computed tomography revealed a stage IV renal cell carcinoma. Since her right kidney naturally ruptured after hospitalization, the patient underwent bilateral kidney and partial paraaortic lymph node dissection. Histopathological tests revealed that the tumor was T3, N2, M0, mixed type. As the residual lymph node was swollen at 4 months after the operation, treatment with ubenimex was started. Five years after the operation, no new lymph node metastases were recognized under continuous treatment with ubenimex. Single administration of ubenimex appears to be effective for cases of renal cell carcinoma with lymph node metastasis to maintain good patient QOL because of its few side effects.

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.

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.

[Low-dose cisplatin and UFT for hormone refractory prostate cancer].

OBJECTIVES: Biochemical modulation (BM) was initially used to enhance the effect of 5-fluorouracil (5-FU) by modulating its pharmacological action with the addition of other drugs. BM with low-dose cisplatin and 5-FU or UFT has been examined in cases of advanced gastric or pancreas cancer and 30 to 40% response rates have been reported. In the present study, the effect of BM on hormone refractory prostate cancer (HRPC) patients was examined. METHODS: BM consisting of 5 mg/body of cisplatin 3 times per week and 300-450 mg of UFT/day was given to 30 HRPC patients (median and range of age: 66 and 52-72, respectively). The ECOG performance status was 0 to 1. Gleason score was 7 in 8 patients, 8 in 10 patients and 9 in 12 patients, respectively. The metastatic site was bone in 29 patients (extent of disease on bone scan [EOD] grade 1: 10, 2: 10, 3: 8, 4: 1), lymph node in 8 and liver in 1. RESULTS: Among the 29 patients assessable for bone metastasis, 5 (17%) obtained marked improvement on bone scan. One was EOD grade 4 (super bone scan) and 4 were EOD grade 1-3. Eight (28%) were stable and 16 (55%) progressed on bone scan. Among 8 patients with lymph node metastasis, 4 (50%) showed partial response and 4 (50%) progression. One patient with liver metastasis showed complete response. Fourteen (47%) out of 30 patients showed a PSA decline of 50% or greater. Their median response duration was 8 months (range; 2 to 44 months). Among the 25 patients assessable for bone pain, 7 (28%) improved, 12 (48%) remained stable and 6 (24%) progressed. A side effect of Grade II anemia was seen in one patient. CONCLUSION: BM is effective in almost half of hormone refractory prostate cancer patients.

Crystal structure of microbial transglutaminase from Streptoverticillium mobaraense.

The crystal structure of a microbial transglutaminase from Streptoverticillium mobaraense has been determined at 2.4 A resolution. The protein folds into a plate-like shape, and has one deep cleft at the edge of the molecule. Its overall structure is completely different from that of the factor XIII-like transglutaminase, which possesses a cysteine protease-like catalytic triad. The catalytic residue, Cys(64), exists at the bottom of the cleft. Asp(255) resides at the position nearest to Cys(64) and is also adjacent to His(274). Interestingly, Cys(64), Asp(255), and His(274) superimpose well on the catalytic triad "Cys-His-Asp" of the factor XIII-like transglutaminase, in this order. The secondary structure frameworks around these residues are also similar to each other. These results imply that both transglutaminases are related by convergent evolution; however, the microbial transglutaminase has developed a novel catalytic mechanism specialized for the cross-linking reaction. The structure accounts well for the catalytic mechanism, in which Asp(255) is considered to be enzymatically essential, as well as for the causes of the higher reaction rate, the broader substrate specificity, and the lower deamidation activity of this enzyme.