Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.     

c-KIT expression in columnar cell lesions of the breast accompanied by benign and malignant breast diseases

Columnar cell lesions (CCLs) of the breast are reported with increasing frequency. However, the significance of these lesions and the treatment approach to these lesions are still unknown. The aim of the present study was to evaluate c-KIT expression in CCLs accompanying benign and malignant breast diseases. A total of 65 patients (18 benign breast diseases, 8 ductal carcinomas in situ (DCI), and 39 invasive carcinomas) were included in the study. c-KIT was strongly expressed in normal breast epithelium (staining intensity; SI: 3 +/- 0.0), whereas a heterogeneous and cytoplasmic staining pattern was observed in CCLs accompanying both benign and malignant diseases. c-KIT expression was decreased, with increasing atypia in CCLs (SI in CCLs with/without atypia; 1.45 +/- 0.52/no case, 1.25 +/- 0.50/1.38 +/- 0.52, 0.77 +/- 0.73/1.21 +/- 0.42 accompanying benign breast disease, DCI and invasive carcinoma, respectively). c-KIT expression was detected in 10.4% of invasive carcinomas. No significant association between c-KIT expression and the histologic grade and nodal status of tumor was noted. As there is a reduction in c-KIT expression with malignant transformation of breast epithelium, c-KIT is believed to play a role in breast carcinogenesis. Furthermore, similar c-KIT expression patterns in CCLs accompanying malignant breast diseases suggest that at least some CCLs could reflect a premalignant status of breast carcinoma. However, the significance of c-KIT expression in CCLs and its relationship to breast carcinogenesis should be evaluated in follow up studies investigating larger series.     

Telbivudine: a new nucleoside analogue for the treatment of chronic hepatitis B

Telbivudine, β-L-2′-deoxythymidine (LdT), is a new β-L-nucleoside analogue with potent inhibitory activity against the hepatitis B virus. In invitro studies and animal models, telbivudine has demonstrated potent and specific antiviral activity against hepatitis B. Additionally, in preclinical animal toxicology studies, telbivudine showed no adverse side effects or adverse effects on mitochondrial function. The promising results of the early invitro and animal telbivudine studies prompted the development and initiation of Phase I andII human clinical trials. The Phase I clinical study demonstrated that end-of-treatment virological response rates were better for telbivudine recipients at multiple dosing levels as compared with placebo patients. The subsequent Phase IIb human clinical study demonstrated superior antiviral efficacy of telbivudine, significantly better ALT normalisation and better hepatitis B e-antigen loss as compared with lamivudine. Telbivudine was well tolerated with no identified safety issues. Virological breakthrough with telbivudine was significantly lower than with lamivudine.     

4-Vinylcyclohexene diepoxide (VCD) inhibits mammary epithelial differentiation and induces fibroadenoma formation in female Sprague Dawley rats

4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that targets ovarian follicles and accelerates ovarian failure in rodents, was used to test the effect of early-onset reproductive senescence on mammary fibroadenoma formation. One-month female Sprague Dawley rats were dosed with VCD (80 mg/kg or 160 mg/kg) and monitored for 22 months for persistent estrus and tumor development. Only high-dose VCD treatment accelerated the onset of persistent estrus relative to controls. However, both doses of VCD accelerated mammary tumor onset by 5 months, increasing incidence to 84% (vs. 38% in controls). Tumor development was independent of time in persistent estrus, 17β-estradiol, androstenedione and prolactin. Delay in VCD administration until after completion of mammary epithelial differentiation (3 months) did not alter tumor formation despite acceleration of ovarian senescence. VCD administration to 1-month rats acutely decreased mammary alveolar bud number and expression of β-casein, suggesting that VCD's tumorigenic effect requires exposure during mammary epithelial differentiation.     

干细胞因子及其受体c-KIT对羊驼毛囊黑色素细胞增殖与分化的影响及其机制

目的 探讨SCF/c-KIT信号通路对羊驼毛囊黑色素细胞分化、增殖和定位的作用及羊驼丰富毛色性状形成的细胞学机制。 方法 选取8只成年雄性羊驼（4只有色被毛,4只白色被毛）,采用免疫组织化学方法研究SCF和c-KIT受体在羊驼皮肤组织中的表达定位;采用实时定量PCR方法分析SCF和c-KIT基因在羊驼皮肤组织中的表达水平。 结果 SCF和c-KIT受体在不同毛色皮肤组织中均有表达,但在不同被毛颜色羊驼皮肤组织中的表达量和表达部位存在差异;ΔΔCt法统计分析SCF和c-KIT基因在不同颜色被毛羊驼皮肤组织中的表达情况显示,SCF基因在有色被毛皮肤组织中的相对表达量是白色被毛皮肤组织的2.41倍,而c-KIT基因在有色被毛皮肤组织中的相对表达量是白色被毛组织的1.20倍。 结论 SCF/c-KIT信号通路参与调节黑色素细胞在皮肤组织中的增殖、分化;成熟黑色素细胞的数量及其在毛囊组织中的分布位置决定羊驼被毛颜色的形成;SCF信号调节不同分化程度黑色素细胞在毛囊组织中的分布。     

Vascular characterization of clear cell sarcoma of the kidney in a child: a case report and review

Clear cell sarcoma of the kidney (CCSK) is uncommon pediatric renal tumor and can present a significant therapeutic challenge in those patients whose tumors spread beyond the kidney. Thus, identifying potential novel targets for treatment may be clinically important. Clear cell sarcoma of the kidney is characterized by a unique vascular pattern, in which nests of tumor cells are separated by regularly-spaced, fine fibrovascular septa. This distinctive histopathology raises the possibility that understanding the factors which drive angiogenesis in CCSK tumors may suggest new therapeutic targets. Here, we describe a case of CCSK and present immunohistochemical studies of its vasculature.     

Simultaneously occurring chronic myelogenous leukemia and gastrointestinal stromal tumors treated with imatinib

Imatinib mesylate (imatinib, STI571, Gleevec; Novartis Pharma) is an orally administered competitive inhibitor of BCR-ABL tyrosine kinase that has demonstrated significant efficacy in chronic myelogenous leukemia (CML). Imatinib is also a potent inhibitor of the receptor-type KIT tyrosine kinase with demonstrated benefits in KIT-expressing gastrointestinal stromal tumors (GISTs). This article presents the case of a patient with simultaneous occurrence of CML and GIST who was treated with the single agent imatinib. To our knowledge, this is the first report of simultaneous occurrence of these two malignancies and of the efficacy of imatinib in concurrent treatment of both neoplasms in a single patient.     

胃肠间质瘤诊治进展

胃肠间质瘤(GIST)发生的关键因素是c-KIT原癌基因和血小板衍生生长因子受体α(PDGFRα)的突变。GIST确诊要根据病理学和免疫组化结果。手术切除仍然是局限性GIST的主要治疗手段。酪氨酸激酶抑制剂伊马替尼是治疗转移和复发GIST的一线药物。但随着伊马替尼治疗时间的延长,绝大多数GIST患者会对伊马替尼产生耐药性。而多靶点酪氨酸激酶抑制剂的问世已经成为耐药和不能耐受伊马替尼治疗的GIST患者的二线用药。     

C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu

The proto-oncogene c-KIT (CD117) is highly expressed in normal breast epithelium and is decreased in invasive breast cancer. In this study, we analyzed the protein expression and the mutational status of c-KIT in ductal carcinoma in situ (DCIS) of the breast and correlated these findings with nuclear grade, architectural pattern, and expression of HER-2, estrogen receptor (ER)-alpha, and progesterone receptor (PR). C-KIT, HER-2, ER, and PR expression were analyzed immunohistochemically in 106 cases of paraffin-embedded DCIS (85 pure DCIS and 21 DCIS with concurrent carcinoma). Direct sequencing of exons 9 and 11 of the c-KIT gene was performed to analyze the hot spot mutational regions in representative cases. C-KIT expression was found in 55 (52.8%) of all DCIS, correlating with high nuclear grade (P < .0001), comedonecrosis (P < .0001), and solid growth pattern (P = .001). Furthermore, c-KIT expression was strongly associated with HER-2 positivity (P < .0001) and was significantly lower in ER- or PR-positive cases (P = .001 and P = .006, respectively). C-KIT expression alone or co-expression with HER-2 in pure DCIS did not differ significantly from DCIS with invasive component (P = .09). Mutational analysis in 6 c-KIT-positive DCIS revealed no activating mutations in exons 9 or 11. Our findings suggest that the expression of c-KIT protein might define a subset of poorly differentiated, HER-2-positive DCIS with decreased expression of steroid hormone receptors, comedonecrosis, and a solid growth pattern. The implications of c-KIT and HER-2 co-expression for breast carcinogenesis should be further evaluated.