Cisplatin-induced ototoxicity: the current state of ototoxicity monitoring in New Zealand.

Background: Many well-known pharmacologic agents have been shown to have toxic effects to the cochleo-vestibular system. Examples of such ototoxic agents include cisplatin and aminoglycoside antibiotics. Ototoxicity monitoring consists of a comprehensive pattern of audiological assessments designed to detect the onset of any hearing loss. Three main methods have emerged over the past decade, and include the basic audiological assessment, extended high frequency (EHF) audiometry, and otoacoustic emission (OAE) measurement. These measures can be used separately or in combination, depending on clinical purpose and patient considerations. It is suggested by the American Academy of Audiology Position Statement and Clinical Practice Guidelines: Ototoxicity Monitoring, that baseline testing be done in a fairly comprehensive manner, including pure-tone thresholds in both the conventional- and extended high frequency ranges, tympanometry, speech audiometry, and the testing of OAEs (AAA, 2009). Anecdotal evidence suggests that New Zealand Audiologists do not currently follow a national ototoxicity monitoring protocol. Therefore the main aim of this study was to explore the current status of ototoxicity monitoring within New Zealand. Hypothesis: It was hypothesized that hospital based Audiology departments across New Zealand each followed their own internal ototoxicity monitoring protocol based, to a large extent, on the guidelines proposed by the American Academy of Audiology and by the American Speech-Language-Hearing Association. Method: Through the use of a Telephone Interview Questionnaire, 16 charge Audiologists were interviewed to establish their current state of knowledge regarding ototoxicity monitoring at 16 out of 20 district health boards in New Zealand. Enquiries about the current systems and procedures in place at their departments together with any suggestions and recommendations to improve on these systems were made. Results: This study found that only 9 of the 16 DHBs interviewed currently follow an ototoxicity monitoring protocol. Furthermore, other than initially hypothesized the origin of the protocols followed by the remaining 7 departments were reported to have ranged from independently developed protocols to historically adopted protocols. One department implemented an adapted version of a protocol by Fausti et al. (Ear and Hearing 1999; 20(6):497-505). This diversity in origin however, does confirm our initial suspicion that no universal and standardized monitoring protocol is currently being followed by Audiologists working in the public health sector of New Zealand

Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits

Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein–protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype

Mitoxantrone/high-dose Ara-C and recombinant human GM-CSF in the treatment of refractory non-Hodgkin's lymphoma. A pilot study

Previous study has shown that the combination of mitoxantrone (Novantrone, NO) and Ara-C (AC) (NOAC) was active in refractory non-Hodgkin's lymphoma (NHL) but myelosuppression was dose-limiting. In a pilot study, we investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) after NOAC chemotherapy in patients with refractory NHL. NO was applied at a dosage of 10 mg/m2/day on days 2 and 3 and AC at 3 g/m2/12h on days 1 and 2. RhGM-CSF was administered at 250 ug/m2/day as a continuous i.v. infusion from day 6 until the neutrophils were greater than 3.0/nl for 3 consecutive days. Twenty-three patients from five of the nine participating centers were treated with NOAC chemotherapy plus rhGM-CSF, whereas 14 patients from the other four centers received chemotherapy alone. With rhGM-CSF, the median duration of severe neutropenia (less than 0.5/nl) after NOAC was 8 days versus a median of 13 days without rhGM-CSF (P = 0.0058), and that of thrombocytopenia (less than 20.0/nl), 3 days versus 7 days (P greater than 0.4, NS). The rates of infections and stomatitis were 25% and 17%, respectively, for patients treated with rhGM-CSF as compared to 53% (P = 0.0547, NS) and 60% (P = 0.0078), respectively, without rhGM-CSF. The following side effects were associated with the administration of rhGM-CSF: pleural and/or pericardial effusions in five patients, thrombosis in two patients, bone pain in two patients, and respiratory distress syndrome in one patient. A complete remission was achieved in nine of the 23 patients treated with NOAC plus rhGM-CSF, and in two of the 14 patients treated with chemotherapy alone. The median survival of patients treated with rhGM-CSF was not reached at 400 days and seemed to be longer than that of patients treated with chemotherapy alone (median, 109 days; P = 0.036). RhGM-CSF after chemotherapy can be applied safely to patients with NHL, shorten the period of severe cytopenia, reduce the rates of stomatitis, and did not seem to cause adverse effects on response