Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

Objective: The aim of this study was to correlate the apparent diffusion coefficient (ADC) value of breast cancer with prognostic factors. Methods: 335 patients with invasive ductal carcinoma not otherwise specified (IDC NOS) and ductal carcinoma in situ (DCIS) who underwent breast MRI with diffusionweighted imaging were included in this study. ADC of breast cancer was calculated using two b factors (0 and 1000 s mm -2 ). Mean ADCs of IDC NOS and DCIS were compared and evaluated. Among cases of IDC NOS, mean ADCs were compared with lymph node status, size and immunochemical prognostic factors using Student's t-test. ADC was also correlated with histological grade using the Kruskal-Wallis test. Results: Mean ADC of IDC NOS was significantly lower than that of DCIS (p,0.001). However, the mean ADC of histological grade of IDC NOS was not significantly different (p50.564). Mean ADC of oestrogen receptor (ER)-positive or progesterone receptor (PR)-positive cancer was significantly lower than that of ER-negative or PRnegative cancer (p50.003 vs p50.032). Mean ADC of Ki-67 index-positive cancer was significantly lower than that of Ki-67 index-negative cancer (p50.028). Mean ADC values of cancers with increased microvascular density (MVD) were significantly lower than those of cancer with no MVD increase (p50.009). No correlations were observed between mean ADC value and human growth factor receptor 2 expression, tumour size and lymph node metastasis. Conclusion: Low ADC value was correlated with positive expression of ER, PR, increased Ki-67 index, and increased MVD of breast cancer. Breast MRI is an established supplemental technique to mammography and ultrasonography for evaluation of suspicious breast lesions. Diffusion-weighted MRI (DWI) has recently been integrated into the standard breast MRI for discrimination of benign and malignant breast lesions obtained with dynamic contrast-enhanced MRI [1][2][3][4][5][6][7][8][9][10][11][12][13]. DWI is a non-invasive technique that represents the biological character of the mainly Brownian movement of protons in bulk water molecules in vivo. Apparent diffusion coefficient (ADC) values are quantified by measurement of mean diffusivity along three orthogonal directions, which are affected by cellularity of the tissue, fluid viscosity, membrane permeability and blood flow [7,[9][10][11]. Microstructural characteristics, including water diffusion and blood microcirculations in capillary networks, were associated with ADC value. Decreased movement of molecules in highly cellular tissue showed correlation with a low ADC value [3,4]. Several studies of DWI of the breast have reported significantly lower ADC values in malignant tumours, compared with benign breast lesions and normal tissue [1-3, 5-11, 14]. Classic prognostic markers, including tumour size and grade, and lymph node status in patients with breast cancer, and molecular markers, including oestrogen receptor (ER), progesterone receptor (PR), Ki-67 index, human growth factor receptor 2 (HER2) protein and angiogenic mo...

Purpose: Mutations in the SLC26A4 gene are second only to GJB2 mutations as a currently identifiable genetic cause of sensorineural hearing loss. In most areas of China, genetic testing for sensorineural hearing loss is unavailable because of limited knowledge of the mutation spectrum. Although SLC26A4 c.919-2AϾG (IVS7-2AϾG) is a common mutation among some Asian populations, the mutation prevalence among various ethnic groups within China has not been studied. Methods: DNA specimens from 3271 subjects with moderate to profound sensorineural hearing loss from 27 regions of China were genotyped for the c.919-2AϾG mutation by polymerase chain reaction/restriction-fragment-length polymorphism. Normal hearing controls from Han (n ϭ 185) and Uigur (n ϭ 152) populations were also tested. Results: Overall, 408 subjects with sensorineural hearing loss (12.5%) carried at least one c.919-2AϾG allele, with 158 (4.8%) homozygotes and 250 (7.6%) heterozygotes. Within the subpopulations examined, the rate varies from 0% to 12.2% for c.919-2AϾG homozygotes and from 0% to 17.6% for heterozygotes. Based on this cohort, Chinese subjects with sensorineural hearing loss seem to have a relatively

CONFLICTS OF INTERESTSSC has received research support and clinical trial support (funding to institution) from Daiichi-Sankyo, Novartis, Sanofi, Paige.ai, and Lilly. SC has received consulting honoraria from Novartis, Sanofi, and Lilly. JDC is a current member of the Scientific Advisory Board of OpenEye Scientific Software and a consultant to Foresite Laboratories. NSG is a founder, science advisory board member (SAB) and equity