Ketoconazole for the Treatment of Docetaxel-Naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Systematic Review

Objective:This systematic review aimed to determine the efficacy of ketoconazole in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods:A literature search was performed on four databases of PubMed, Google Scholar, Cochrane Database of Systematic Reviews, and Directory of Open Access Journals (DOAJ). The initial search resulted in 602 articles, which were progressively eliminated based on duplication, irrelevancy, and unsuitable methodology. A total of seventeen articles were included in the final analysis, including four randomized controlled trials, nine retrospective cohorts, and four prospective cohorts, with a total population of 1,095 patients. A 200-400 mg, tid dose of ketoconazole was used in these studies along with corticoid replacement therapy with hydrocortisone, 20-30 mg in the morning and 10-20 mg in the evening, or prednisone, 5 mg, bid. Results:Based on our findings, 8 out of 17 studies reported PSA decrease of >50% in approximately half of the population, with a more significant PSA response at 400 mg ketoconazole dosage, and the average progression-free survival (PFS) of 2.6-14.5 months, or time to progression of 3.2-6.7 months. Conclusion:Ketoconazole with corticosteroid could be an effective alternative for the treatment of mCRPC with a satisfactory PSA response and disease progression.Key Words: Ketoconazole, Corticosteroid, mCRPC, PSA, PFS, Response     

Reducing dynamin 2 expression rescues X-linked centronuclear myopathy

Centronuclear myopathies (CNM) are congenital disorders associated with muscle weakness and abnormally located nuclei in skeletal muscle. An autosomal dominant form of CNM results from mutations in the gene encoding dynamin 2 (DNM2), and loss-of-function mutations in the gene encoding myotubularin (MTM1) result in X-linked CNM (XLCNM, also called myotubular myopathy), which promotes severe neonatal hypotonia and early death. Currently, no effective treatments exist for XLCNM. Here, we found increased DNM2 levels in XLCNM patients and a mouse model of XLCNM (Mtm1^–/y). Generation of Mtm1^–/y mice that were heterozygous for Dnm2 revealed that reduction of DNM2 in XLCNM mice restored life span, whole-body strength, and diaphragm function and increased muscle strength. Additionally, classic CNM-associated histological features, including fiber atrophy and nuclei mispositioning, were absent or reduced. Ultrastructural analysis revealed improvement of sarcomere organization and triad structures. Skeletal muscle–specific decrease of Dnm2 during embryogenesis or in young mice after disease onset revealed that the rescue associated with downregulation of Dnm2 is cell autonomous and is able to stop and potentially revert XLCNM progression. These data indicate that MTM1 and DNM2 regulate muscle organization and force through a common pathway. Furthermore, despite DNM2 being a key mechanoenzyme, its reduction is beneficial for XLCNM and represents a potential therapeutic approach for patients.     

Antioxidant Activity and Cytotoxicity of the Traditional Indonesian Medicine Tahongai (Kleinhovia hospita L.) Extract

We investigated the leaves of Kleinhovia hospita, a plant which has been traditionally used in Indonesia as phytotherapy to cure liver disease, to describe antioxidant materials from plant sources. K. hospita leaves were extracted with methanol and further partitioned into n-hexane, diethyl ether, and ethyl acetate. The antioxidant activity of each fraction and the residue was assessed using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and their cytotoxicity on HepG2 liver cancer cells was determined by a MTT assay. The K. hospita leaf methanol extract showed strong antioxidant activity (96%) compared with vitamin C (98%) by the DPPH method and the measured activity from the subsequent extracts of the methanol extract were 48.9% for n-hexane, 74.0% for diethyl ether, 84.3% for ethyl acetate, and 77.1% for the residue. The MTT assay showed the cytotoxicity of the methanol extract on HepG2 cells at 14%, 76%, and 80% at concentrations of 50μg/mL, 87.5μg/mL, and 125μg/mL, respectively. Leaf extracts of the medicinal plant K. hospita showed potent antioxidant activity and moderate cytotoxicity on HepG2 liver cancer cells.     

Foreign body removal with fine-nosed forceps and assistance of image intensification

Foreign body removal has been developed as a routine radiology department service. Techniques, indications and hazards are described.     

Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF

Increased platinum-DNA adduct removal has been shown by several DNA repair assays to be associated with cisplatin resistance in the A2780/C-series human ovarian cancer model system. In the present study, we provide further evidence that the resistance phenotype of these cell lines is due, in part, to enhanced nucleotide excision repair (NER). Cisplatin resistance was found to be associated with increased UV resistance. Northern blot analysis revealed that increased expression of ERCC1 was also associated with cisplatin resistance in this panel. Several other NER genes were found to be constitutively overexpressed in the most resistant cell line, C200, as compared with the parental A2780 cells. A plasmid substrate containing a site-specific cisplatin adduct was used to measure the nucleotide excision activity of cell extracts prepared from cisplatin-sensitive and -resistant cells. Using this in vitro assay, extracts prepared from C200 cells exhibited approximately 3-fold more activity than extracts prepared from A2780 cells, similar to the difference in UV sensitivity. Complementation of A2780 extracts with ERCC1-XPF protein resulted in approximately 2-fold increased activity, but had little effect on excision in C200 extracts. Overall, these results support a role for the ERCC1-XPF endonuclease as a determinant of increased NER in this cisplatin resistance model.