A novel GJB2 mutation p.Asn54His in a patient with palmoplantar keratoderma, sensorineural hearing loss and knuckle pads

Mutations in the GJB2 gene encoding connexin26 are the major cause of autosomal-recessive or -dominant nonsyndromic congenital sensorineural hearing loss (SNHL) (Kelsell et al., 1997; Kenneson et al., 2002; refer to the connexin-deafness homepage at http://davinci.crg.es/deafness/). In addition, connexin26 mutations have been identified in autosomal-dominant syndromic congenital SNHL with palmoplantar keratoderma (PPK) (Maestrini et al., 1999; Richard et al., 2002, 2004; Brown et al., 2003; van Steensel et al., 2004; Arita et al., 2006). We have encountered a Japanese boy with PPK, knuckle pads and congenital SNHL and GJB2 mutation analysis revealed a novel mutation p.Asn54His

Fulvestrant with or without anti‐HER2 therapy in patients in a postmenopausal hormonal state and with ER‐positive HER2‐positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG‐C06)

Abstract Background The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)‐positive, human epidermal growth factor receptor 2 (HER2)‐positive advanced or metastatic breast cancer (AMBC) is unclear. Methods We analyzed the data from 94 patients with ER‐positive HER2‐positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER‐positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti‐HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first‐line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. Results The TTF was longer in the patients treated with F500 as first‐ or second‐line therapy (n = 20) than in those who received later‐line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti‐HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. Conclusions In patients with ER‐positive HER2‐positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first‐ or second‐line therapy. In patients who received chemotherapy‐free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut‐off for indicating clinical outcomes

A Novel N14Y Mutation in Connexin26 in Keratitis-Ichthyosis-Deafness Syndrome : Analyses of Altered Gap Junctional Communication and Molecular Structure of N Terminus of Mutated Connexin26

Connexins (Cxs) are transmembranous proteins that connect adjacent cells via channels known as gap junctions. The N-terminal 21 amino acids of Cx26 are located at the cytoplasmic side of the channel pore and are thought to be essential for the regulation of channel selectivity. We have found a novel mutation, N14Y, in the N-terminal domain of Cx26 in a case of keratitis-ichthyosis-deafness syndrome. Reduced gap junctional intercellular communication was observed in the patient’s keratinocytes by the dye transfer assay using scrape-loading methods. The effect of this mutation on molecular structure was investigated using synthetic N-terminal peptides from both wild-type and mutated Cx26. Two-dimensional (1)H nuclear magnetic resonance and circular dichroism measurements demonstrated that the secondary structures of these two model peptides are similar to each other. However, several novel nuclear Overhauser effect signals appeared in the N14Y mutant, and the secondary structure of the mutant peptide was more susceptible to induction of 2,2,2-trifluoroethanol than wild type. Thus, it is likely that the N14Y mutation induces a change in local structural flexibility of the N-terminal domain, which is important for exerting the activity of the channel function, resulting in impaired gap junctional intercellular communication

Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with post-menopausal estrogen receptor-positive advanced breast cancer: a sub-group analysis of the JBCRG-C06 Safari study

<p><b>Objective:</b> The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2−) cases.</p> <p><b>Methods:</b> The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (<i>n</i> = 960). Of these, 828 patients were HER2−.</p> <p><b>Results</b> Multivariate analysis showed that advanced age (≥65 years; <i>p</i> = .035), longer time (≥3 years) from ABC diagnosis to F500 use (<i>p</i> < .001), no prior chemotherapy (<i>p</i> < .001), and F500 treatment line (<i>p</i> < .001) were correlated with prolonged TTF (median = 5.39 months).</p> <p><b>Conclusions:</b> In ER+/HER2− patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.</p