No abstract

Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. We used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. We examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections, and determined the clincopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification/negative or amplification/equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18%) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in 5-50% of the tumor cells, was found in 11 cases (11%), all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low grade or equivocal HER2 amplification and equivocal (2 þ ) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification, and this effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. In conclusion, intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression. Modern Pathology (2012) 25, 938-948;

The incidence of EGFR mutations is variable according to histologic subtypes, gender, and smoking history. The mixed acinar and BAC and papillary and acinar subtypes, the presence of BAC (lepidic) or papillary components, EGFR, and TTF-1 protein expression can predict higher EGFR mutation in lung adenocarcinoma. However, intratumoral heterogeneity of EGFR mutation was not found. In addition, relatively high incidence of EGFR mutations in Korean men who smoked with adenocarcinoma histology suggests that these patients should not be left behind EGFR mutation test.

BackgroundThere has been an increase in the use of fine needle aspiration cytology (FNAC) for the diagnosis of parathyroid lesions (PLs). Differentiation between a thyroid lesion and a PL is not easy because of their similar features. We reviewed parathyroid aspirates in our institution and aimed to uncover trends in diagnostic criteria.MethodsWe selected 25 parathyroid aspirates (from 6 men and 19 women) confirmed surgically or immunohistochemically from 2006 to 2011.ResultsMajor architectural findings of PLs include scattered naked nuclei, loose clusters, a papillary pattern with a fibrovascular core, tight clusters, and a follicular pattern. These architectures were commonly admixed with one another. Cytological features included anisokaryosis, stippled chromatin, a well-defined cell border, and oxyphilic cytoplasm. Eighteen of the 25 patients were diagnosed with PL using FNAC. Seven patients had been misdiagnosed with atypical cells (n=2), benign follicular cells (n=2), adenomatous goiter (n=2) and metastatic carcinoma (n=1) in FNAC. Using clinicoradiologic data, the sensitivity of the cytological diagnosis was 86.7%. The cytological sensitivity decreased to 50% without this information.ConclusionsFNAC of PL is easily confused with thyroid lesions. A combination of cytological parameters and clinical data will be required to improve the diagnostic sensitivity of PLs.

The purposes of this study were to investigate the effects of fatigue location and age on changes in postural control induced by localized muscle fatigue, as well as the patterns of recovery post-fatigue. Groups of 16 younger (18-25 years) and 16 older (55-65 years) participants performed submaximal isotonic fatiguing exercises involving the unilateral ankle plantar flexors, knee extensors, and shoulder flexors, and bilateral lumbar extensors. Postural control was assessed during quiet upright stance, from center-of-pressure and center-of-mass time series obtained before and after the fatiguing exercises. Acute effects of fatigue differed between joints, with the most substantial effects evident at the lower back, followed by the ankle. Neither knee nor shoulder fatigue resulted in significant effects on postural control. Significant acute effects of fatigue were found only among the younger group. Recovery of postural control post-fatigue was influenced by age, being more rapid in the younger group, but not by fatigue location. Along with existing evidence, these results may facilitate the development of strategies to prevent occupational falls.

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Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers.

Primary apocrine sweat gland carcinoma (PASGC) is an extremely rare malignancy with a relatively favorable prognosis. PASGC is often suspected to be a benign disease during an initial clinical examination, which leads to inadequate initial treatment and extensive metastasis. Owing to the limited number of reports on PASGC, its diagnostic criteria and treatment guidelines have not yet been established. The only known curative therapy for localized PASGC is wide local excision. In the present report, we describe two cases of PASGC with locally aggressive disease that arose in the axilla and review the literature about its clinicopathological features, diagnosis, and treatment. Based on the findings of the current report, we suggest that a sentinel lymph node biopsy and adjuvant anti-estrogen therapy should be included in the management of PASGC.