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.

Transplantation of nonvascularized kidney tissue fragments into the rat liver with the aim of preserving renal function.

For research in regenerative medicine, not only the study of cellular pluripotency but also knowledge of the reorganization of tissue structure is crucial. However, the latter will probably be more difficult to acquire. When small fragments of kidney (approx. 1 x 1 mm) were implanted in the liver of syngeneic LEW rats, the tissue survived at least 2 weeks with retention of normal structure including glomeruli and tubules. In contrast, no kidney structure survived when transplanted to subcutaneous sites, omentum, or spleen. Molecules involved in renal tubular function, such as megalin and glut2 transporter protein, were detectable in the implanted tissue by immunohistochemistry, suggesting that the cells were biologically active. Survival of cortex, medulla, and calyx tissues was then compared. All three components were still detectable 8 weeks after transplantation but cortex and medulla were replaced by granuloma at 6 months. Only calyx tissue survived for up to 12 months after transplantation. There was no marked difference in tissue survival, either when the recipient liver was partially resected or when infantile donor kidney was implanted instead of adult kidney. The present method opens new avenues in the development of regenerative medicine (i.e., tissue transplantation) as an intermediate modus between organ transplantation and cell transplantation.

Standardization of ischemic hepatic failure in pigs as a model for bioartificial liver assessment.

PURPOSE: A standard protocol of ischemic liver failure in pigs was examined to establish a system for assessing the efficacy of a bioartificial liver, based on clinical practice. METHODS: The portal blood flow was extracorporeally bypassed into the cervical jugular vein, using a centrifugal blood pump. The portal vein and hepatic artery were then ligated. RESULTS: The maintenance protocol was established as follows: (1) the concentration of the inhaled anesthetic was decreased by 0.2% when the systolic blood pressure was <100 mmHg; (2) the volume of an infusion containing 5% glucose was increased to 10 ml/kg per hour when central venous pressure was <5 mmHg; (3) 20 ml of 50% glucose was injected intravenously when the blood glucose was <50 mg/dl; (4) 2000 units of heparin was injected intravenously when the activated clotting time was <150 s; (5) sodium bicarbonate was given when the blood pH was <7.3; (6) tidal volume was increased by 1 ml/kg when the pCO(2) was >80 mmHg; (7) oxygen was increased by 25% when the pO(2) was <100 mmHg. No vasopressors were used in the experiment. CONCLUSION: Our protocol reduced the operating time and minimized the risk of data deviation that can arise from variations in operating techniques and individual animal conditions. This experimental model is also easy to use as a bridge to transplantation.

Transplantation of amniotic epithelial cells into fetal rat liver by in utero manipulation.

It has been hoped that amniotic epithelial cells would be a gene carrier to neural and hepatic tissue, because of 1) the presence of neural and hepatic stem-like cells, 2) the ability to cryopreserve them, 3) long-term survival in the transplanted site, and 4) few ethical problems concerning procurement. But transplantation of a sufficient number of cells to adult tissue needs large-scale cell supply and may lead to vascular embolism. We attempted transplantation of amniotic epithelial cells into fetal liver, because 1) the fetal liver is at the proliferative stage, 2) the number of cells required is small, and 3) the fetal stage is advantageous for the induction of immunological tolerance. Amniotic epithelial cells from day 18.5-20.5 fetuses were transfected with adenoviral AdlacZ and harvested to inject into fetal rat liver of the syngeneic strain (day 18.5-20.5). The efficacy of cell transplantation into the liver increased in the order: intraplacental < intraumbilical vein < intrahepatic route. LacZ-transfected amniotic cells (1-8 x 10(5) cells), hepatocytes (5 x 10(5) cells), or AdlacZ vector solution (1.7 x 10(7) pfu) were injected through the uterine membrane into the liver. Transplanted cells formed a cellular mass and survived for up to 14 days after birth, whereas lacZ-transfected cells were rapidly decreased after the injection of AdlacZ vector or rat hepatocytes as a gene carrier so that the use of amniotic epithelial cells as a gene carrier will result in long-term expression of exogenous genes in the liver.