BACKGROUND: Parotid gland metastasis in breast cancer is extremely rare, and only 14 cases have been reported between 1982 and 2010. CASE REPORT: A 67-year-old female patient was diagnosed with invasive lobular carcinoma of the left breast. Although clinical staging was T1N3M1 (stage IV), the tumor experienced a complete response to chemotherapy. We therefore performed a mastectomy followed by radiotherapy, and continued administration of trastuzumab. However, 11 months later, the patient complained of a swelling in the left parotid gland. Histology following a partial parotidectomy revealed a parotid gland metastasis from the breast. CONCLUSION: Treatment with capecitabine in addition to trastuzumab, which is one of the strategies applied in HER2-positive breast cancer, was effective in our patient. Analysis of the 14 cases of parotid gland metastasis from the breast reported between 1982 and 2010 revealed that the metastasis may occur not by direct lymphatic but by hematogenous spread.

Although etiological studies have shown genetic disorders to be a common cause of congenital/early-onset sensorineural hearing loss, there have been no detailed multicenter studies based on genetic testing. In the present report, 264 Japanese patients with bilateral sensorineural hearing loss from 33 ENT departments nationwide participated. For these patients, we first applied the Invader assay for screening 47 known mutations of 13 known deafness genes, followed by direct sequencing as necessary. A total of 78 (29.5%) subjects had at least one deafness gene mutation. Mutations were more frequently found in the patients with congenital or early-onset hearing loss, i.e., in those with an awareness age of 0-6 years, mutations were significantly higher (41.8%) than in patients with an older age of awareness (16.0%). Among the 13 genes, mutations in GJB2 and SLC26A4 were mainly found in congenital or early-onset patients, in contrast with mitochondrial mutations (12S rRNA m.1555A>G, tRNA(Leu(UUR)) m.3243A>G), which were predominantly found in older-onset patients. The present method of simultaneous screening of multiple deafness mutations by Invader assay followed by direct sequencing will enable us to detect deafness mutations in an efficient and practical manner for clinical use.

Mutations in the GJB2 gene (connexin 26) are the major cause of autosomal recessive non-syndromic hearing impairment in many populations. In contrast to the volume of information regarding the involvement of GJB2 mutations in hearing impairment in populations of European ancestry, less is known regarding other ethnic groups. In this study, we analyzed the GJB2 gene for mutations in 1227 hearing-impaired Japanese individuals. This revealed a unique spectrum of GJB2 mutations, different from that found in the Caucasian population. The most frequent mutation in Japanese, 235delC, has never been reported in Caucasians. To investigate a possible founder effect for the 235delC mutation, we analyzed single nucleotide polymorphisms in the vicinity of the GJB2 gene. Results were consistent with inheritance of the 235delC mutation from a common ancestor. The results of this study have important implications for genetic diagnostic testing for deafness in the Japanese population.

Molecular diagnosis makes a substantial contribution to precise diagnosis, subclassification, prognosis, and selection of therapy. Mutations in the PDS (SLC26A4) gene are known to be responsible for both Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct, and the molecular confirmation of the PDS gene has become important in the diagnosis of these conditions. In the present study, PDS mutation analysis confirmed that PDS mutations were present and significantly responsible in 90% of Pendred families, and in 78.1% of families with nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Furthermore, variable phenotypic expression by the same combination of mutations indicated that these two conditions are part of a continuous category of disease. Interestingly, the PDS mutation spectrum in Japanese, including the seven novel mutations revealed by this study, is very different from that found in Caucasians. Of the novel mutations detected, 53% were the H723R mutation, suggesting a possible founder effect. Ethnic background is therefore presumably important and should be noted when genetic testing is being performed. The PDS gene mutation spectrum in Japanese may be representative of those in Eastern Asian populations and its elucidation is expected to facilitate the molecular diagnosis of a variety of diseases.European Journal of Human Genetics (2003) 11, 916-922. doi:10.1038/sj.ejhg.5201073 Published online 24 September 2003

Through cDNA microarray analysis of gene expression in human cochlea and vestibule, we detected strong expression of mu-crystallin (CRYM; also known as "NADP-regulated thyroid hormone-binding protein") only in these inner-ear tissues. In a subsequent search for mutations of CRYM, among 192 patients with nonsyndromic deafness, we identified two mutations at the C-terminus; one was a de novo change (X315Y) in a patient with unaffected parents, and the other was a missense mutation (K314T) that segregated dominantly in the proband's family. When the mutated proteins were expressed in COS-7 cells, their subcellular localizations were different from that of the normal protein: the X315Y mutant showed vacuolated distribution in the cytoplasm, and the K314T mutant localized in perinuclear areas, whereas normal protein was distributed homogeneously in the cytoplasm. Aberrant intracellular localization of the mutated proteins might cause dysfunction of the CRYM product and result in hearing impairment. In situ hybridization analysis using mouse tissues indicated its expression in the lateral region of the spiral ligament and the fibrocytes of the spiral limbus, implying its possible involvement in the potassium-ion recycling system. Our results strongly implicate CRYM in normal auditory function and identify it as one of the genes that can be responsible for nonsyndromic deafness.

The COCH gene is the only gene identified in man that causes autosomal dominantly inherited hearing loss associated with vestibular dysfunction. The condition is rare and only five mutations have been reported worldwide. All affected families showed a similar progressive hearing loss and vestibular dysfunction. Since Meniere's disease-like symptoms have also been described in some families, it was suggested that COCH mutations might be present in some patients diagnosed with Meniere's disease. In this study, using a Japanese population, we performed a COCH mutation analysis in 23 patients from independent families with autosomal dominant hearing impairment, four of whom reported vestibular symptoms, and also in 20 Meniere's patients. While a new point mutation, A119 T, was found in a patient with autosomal dominant hearing loss and vestibular symptoms, no mutations were found in the Meniere's patients. Like all other previously identified COCH mutations, the mutation identified here is a missense mutation located in the FCH domain of the protein. The current mutation is located in close spatial proximity to W117, in which a mutation (W117R) had previously been associated with autosomal dominant hearing loss. Model building suggests that, like the W117R mutation, the A119 T mutation does not affect the structural integrity of the FCH domain, but may interfere with the interaction with a yet unknown binding partner. We conclude that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominantly inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction, or sporadic Meniere's disease.

Mutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.

To examine the frequency of the 961delT mitochondrial point mutation, considered to be associated with aminoglycoside-induced hearing loss, restriction fragment length polymorphism (RFLP) analysis was performed in (1) 334 unrelated sensorineural hearing loss (SNHL) patients and (2) 56 patients with aminoglycoside antibiotic injection history. Approximately 2% of the SNHL patients had the 961delT mutation, raising the possibility of a relatively high prevalence of this mutation among hearing impaired populations. However, the following findings cast doubt on whether this mutation is truly associated with hearing loss:(1) a similar frequency found in the control subjects,(2) hearing loss that was not segregated within the families,(3) rates of heteroplasmy and aging that were not correlated with the severity of hearing loss, and (4) a low prevalence among the aminoglycoside-induced hearing loss patients (1/56=1.8%). The present analysis did not agree with the concept that the 961delT mutation causes aminoglycoside-induced hearing loss.

Despite progress in identification of deafness genes, clinical application has lagged due to the genetic heterogeneity of deafness. We designed and tested a comprehensive and simple diagnostic strategy to simultaneously detect deafness gene mutations based on a mutation/gene database followed by Invader assay screening of 41 known mutations of nine known deafness genes. Three hundred thirty-eight Japanese patients with congenital or childhood-onset (up to age 10) bilateral sensorineural hearing loss participated in this study. A total of 100 (29.6%) subjects had at least one mutation in GJB2, SLC26A4, and/or the mitochondrial 12S rRNA, indicating that these are the three major causative genes in Japanese deafness patients. The present study demonstrated that the Invader assay has excellent sensitivity and accuracy, and its application to deafness mutation screening will greatly improve medical management and facilitate extensive genetic counseling for hearing impairment.

We report three possibly disease-causing point mutations in one of the inner-ear-specific genes, KIAA1199. We identified an R187C mutation in one family, an R187H mutation in two unrelated families, and an H783Y mutation in one sporadic case of nonsyndromic hearing loss. In situ hybridization indicated that the murine homolog of KIAA1199 mRNA is expressed specifically in Deiters' cells in the organ of Corti at postnatal day zero (P n) P0 before the onset of hearing, but expression in those cells disappears by day P7. The signal of KIAA1199 was also observed in fibrocytes of the spiral ligament and the spiral limbus through to P21, when the murine cochlea matures. Thus, the gene product may be involved in uptake of potassium ions or trophic factors with a particular role in auditory development. Although the R187C and R187H mutations did not appear to affect subcellular localization of the gene product in vitro, the H783Y mutation did present an unusual cytoplasmic distribution pattern that could underlie the molecular mechanism of hearing impairment. Our data bring attention to a novel candidate for hearing loss and indicate that screening of mutations in inner-ear-specific genes is likely to be an efficient approach to finding genetic elements responsible for deafness.

Discovery of deafness genes has progressed but clinical application lags because of the genetic heterogeneity. To establish clinical application strategy, we reviewed the frequency and spectrum of mutations found in Japanese hearing loss patients and compared them to those in populations of European ancestry. Screening revealed that in Japanese, mutations in GJB2, SLC26A4, and CDH23, and the mitochondrial 12S rRNA are the major causes of hearing loss. Also, mutations in KCNQ4, TECTA, COCH, WFS1, CRYM, COL9A3, and KIAA1199 were found in independent autosomal dominant families. Interestingly, spectrums of GJB2, SLC26A4, and CDH23 mutations in Japanese were quite different from those in Europeans. Simultaneous screening of multiple deafness mutations based on the mutation spectrum of a corresponding population using an Invader panel revealed that approximately 30% of subjects could be diagnosed. This assay will enable us to detect deafness mutations in an efficient and practical manner in the clinical platform. We conclude that specific racial populations may have unique deafness gene epidemiologies; therefore, ethnic background should be considered when genetic testing is performed. Simultaneous examination of multiple mutations based on a population's spectrum may be appropriate and effective for detecting deafness genes, facilitating precise clinical diagnosis, appropriate counseling, and proper management.

PURPOSE: To assess the efficacy of (1)H MR spectroscopy (MRS) to evaluate early responses to neoadjuvant chemotherapy in breast cancer patients, as compared to that of the standardized uptake value (SUV) in (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). MATERIALS AND METHODS: This retrospective study included seven patients with breast cancer who had both single-voxel (1)H MRS and PET/computed tomography (CT) acquired before, during, and after neoadjuvant chemotherapy. RESULTS: The averages of the Choline (Cho) integral value and peak SUV before chemotherapy were 2.5 (range, 1.2-5.3) and 7.5 (range, 1.9-19), respectively. Three cases became negative for both Cho and peak SUV after two cycles of chemotherapy, and one patient became negative before surgery. In the remaining three patients, the curves of both values paralleled the time course of chemotherapy treatment. The difference between Cho and peak SUV before, during, and after chemotherapy was r = 0.65 (P = 0.12), r = 0.80 (P = 0.03), and r = 0.99 (P < 0.001), respectively. The reduction rate (RR) of both values after chemotherapy was also correlated (r = 0.84, P = 0.02). CONCLUSION: A change in the Cho integral value is well correlated with that of peak SUV in the time course of neoadjuvant chemotherapy; thus, breast (1)H MRS is thought to be an alternative to sequential (18)F-FDG PET. J. Magn. Reson. Imaging 2008;28:420-427.(c) 2008 Wiley-Liss, Inc.