Management and outcomes of isolated axillary node recurrence in breast cancer

HYPOTHESIS: Management strategies affect the outcome of axillary recurrence in breast cancer. DESIGN: Population-based analysis. SETTING: Cancer agency breast cancer database. PATIENTS: Two hundred twenty women diagnosed with stage 0 through III breast cancer between 1989 and 2003 who subsequently developed an isolated axillary relapse. MAIN OUTCOME MEASURES: Overall survival rate and disease-free survival rate according to treatment strategy of the axillary recurrence. RESULTS: Among 19 789 women diagnosed with stage 0 through III breast cancer during the study era, 220 had an isolated axillary recurrence (Kaplan-Meier 5-year isolated axillary relapse rate, 1.0%). The median interval between primary breast cancer diagnosis and axillary recurrence was 2.2 years (range,1.8 months to 11.9 years). Median follow-up time after axillary recurrence was 5.4 years. Treatment for the axillary recurrence included lymph node biopsy (47.3%), complete axillary dissection (25.9%), axillary radiation (65.0%), chemotherapy (24.1%), and hormonal therapy (68.2%). The 5-year Kaplan-Meier overall survival rate estimate after axillary recurrence was 49.3% (95% confidence interval, 42.0-56.3). Median survival time from the isolated axillary recurrence was 4.9 years (range, 2.0 months to 15.1 years). Overall (P < .001) and disease-free (P = .006) survival times were highest in those treated with a combination of surgery and radiation. Other factors associated with improved overall survival rate were an interval from diagnosis to relapse greater than 2.5 years (P = .003), no initial axillary radiation (P < .001), asymptomatic presentation of the recurrence (P = .05), and subsequent systemic treatment (P = .02). CONCLUSIONS: The 5-year isolated axillary recurrence rate of women treated for breast cancer was 1.0%. Multimodality management at the time of recurrence, including axillary surgery, radiation, and systemic therapy, significantly improved overall and disease-free survival.     

Centrosome-targeting region of CG-NAP causes centrosome amplification by recruiting cyclin E-cdk2 complex

Centrosome duplication occurs once per cell cycle and is thought to be triggered by cyclin E-cdk2. However, it is largely unknown how the duplication is regulated. Here, we found that the expression of the centrosome-targeting region of CG-NAP (centrosome and Golgi-localized PKN-associated protein), which we designate as CG-NAP/D, increased the number of centrosomes in Chinese hamster ovary (CHO)-K1 cells. The amplified centrosomes co-localized with centrosome markers gamma-tubulin, centrin-2 and kendrin as well as endogenous CG-NAP. When CG-NAP/D was dislocated from centrosomes by deleting the centrosome-targeting domain or by fusing with a membrane-targeting sequence, centrosome amplification was suppressed. CG-NAP/D interacted with exogenously expressed cyclin E, which co-localized at centrosomes. The immunoprecipitates of CG-NAP/D exhibited histone H1 kinase activity, suggesting the co-immunoprecipitation of active cyclin-cdk complexes. Furthermore, centrosome fractions prepared from cells expressing CG-NAP/D contained increased amount of cdk2 compared with those from control cells. Centrosome amplification by CG-NAP/D was suppressed by co-expression of a mutant cyclin E unable to interact with cdk2. These results suggest that CG-NAP/D causes centrosome amplification by anchoring excess amount of cyclin E-cdk2 to centrosomes and, possibly, CG-NAP participates in centrosome duplication by recruiting cyclin E-cdk2 to centrosomes in normal cell cycle.     

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases

Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-β) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma.     

A case of meningoencephalitis associated with G1P[8] rotavirus infection in a Japanese child

We report the case of a 2-y, 11-month-old boy with G1P[8] rotavirus infection accompanied by acute meningoencephalitis. Substitutions in both the VP4 and VP7 genes were found in the identified strain. A commonly circulating G1P[8] rotavirus with such mutations might be associated with the pathogenesis of CNS complications, including meningoencephalitis.     

Engineering mucosal RNA interference in vivo.

Mucosal surfaces serve as a gateway to disease. Here, we demonstrate that RNA interference can be used to manipulate mucosal gene expression in vivo. Using a murine model, we show that direct application of liposome-complexed siRNA mediates gene-specific silencing in cervicovaginal and rectal mucosa. A single vaginal or rectal administration of siRNA targeting hematopoietic or somatic cell gene products reduced corresponding mRNA levels by up to 90%. Using a murine model of inflammatory bowel disease, we found that the rectal application of siRNA targeting TNF-alpha led to relative mucosal resistance to experimental colitis. Liposomal siRNA formulations proved nontoxic, did not elicit a nonspecific interferon response, and provide a means for genetic engineering of mucosal surfaces in vivo.     

Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study.

Tight junction associated proteins are key molecular components governing cellular adhesion, polarity and glandular differentiation. Tight junction proteins also play critical roles in cellular proliferation and neoplastic pathways via their functions as couplers of the extracellular milieu to intracellular signaling pathways and the cytoskeleton. Neoplastic cells frequently exhibit structural and functional deficiencies in the tight junction. The purpose of this study was to determine the pattern of expression and prognostic value of four tight junction associated proteins, claudin-1, claudin-4, occludin and ZO-1 in a cohort of TNM stage II colon cancer using tissue microarray technology. In this study, we retrospectively analyzed, resected and otherwise untreated paraffin embedded specimens from 129 consecutive patients with TNM stage II colonic carcinomas for claudin-1, claudin-4, occludin and ZO-1 protein expression by immunohistochemistry. Seventy-five, 58, 56 and 44% of the tumors exhibited normal to elevated expression levels (+2 and +3 immunopositivity) of claudin-1, claudin-4, occludin and ZO-1 respectively. Low expression levels of claudin-1 and ZO-1 were directly associated with higher tumor grade (P=0.05 and 0.03 respectively). Multivariate analysis indicated that lymphovascular invasion (P=0.01) and low levels of claudin-1 (P=0.0001) expression were independent predictors of recurrence and that reduced claudin-1 expression (P=0.0001) was associated with poor survival. This study is the first to comprehensively examine the expression of several tight junction associated proteins in colonic neoplasms and to correlate their expression with disease progression. Loss of claudin-1 expression proved to be a strong predictor of disease recurrence and poor patient survival in stage II colon cancer.