Monitoring of neoadjuvant chemotherapy using multiparametric, <Superscript>23</Superscript>Na sodium MR,and multimodality (PET/CT/MRI) imaging in locally advanced breast cancer

We prospectively investigated using advanced magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) to identify radiological biomarkers for treatment response in patients receiving preoperative systemic therapy (PST) for locally advanced breast cancer. Patients with a stage II or III breast cancer receiving PST were selected and underwent positron emission tomography (PET), magnetic resonance imaging (MRI), and breast biopsies at baseline and after the first cycle of PST (days 7–8) during the full course of treatment. PET/CT was acquired after injection of 2-deoxy-2-[18F]-fluoro-d-glucose (¹⁸FDG, 0.22 mCi/kg) and quantified with standardized uptake value assessment (SUV). Diagnostic breast MRI and sodium (²³Na) was acquired at 1.5 T. Total tissue sodium concentration (TSC), response criteria in solid tumors (RECIST), and volumes were quantified. Treatment response was determined by pathological assessment at surgery. Immunohistochemistry values of the proliferative index (Ki-67) were performed on biopsy specimens. Six of nineteen eligible women (43 ± 11 years) who received PST underwent radiological imaging of ¹⁸FDG-PET/CT and MRI for at least two cycles of treatment. Five patients had a pathological partial response (pPR) and one had pathological non-response (pNR). TSC decreased 21% in responders with increases in the non-responder (P = 0.03). Greater reduction in SUV was observed in responders (38%) compared to the non-responder (22%; P = 0.03). MRI volumes decreased after cycle 1 by 42% (responders) and 35% (non-responder; P = 0.11). Proliferation index Ki-67 declined in responders in the first cycle (median = 47%, range = 29–20%), but increased (4%) in the non-responder. Significant decreases in TSC, SUV, and Ki-67 were observed in responders with increases in TSC and Ki-67 in non-responders. Our results demonstrate the feasibility of using multi-modality proton, ²³Na MRI, and PET/CT metrics as radiological biomarkers for monitoring response to PST in patients with operable breast cancer.     

A breast cancer cell microarray (CMA) as a rapid method to characterize candidate biomarkers

Tissue microarrays (TMAs) have become an invaluable tool in cancer research to evaluate expression and subcellular localization of proteins in cells and tissues. As the catalogs of candidate biomarkers and therapeutic targets become more extensive, there is a need to characterize and validate these targets and biomarkers in cell lines as a primary biological system in research laboratories. Thus, cell microarrays (CMAs) are useful as a high-throughput screening tool. Here, we constructed a CMA containing 32 publicly available immortalized breast cell lines with the goal of creating a method to rapidly screen for antigens of interest in breast cancer research in a relatively easy, rapid and cost-effective manner. As proof of concept, we performed immunocytochemical staining of the HER2 receptor, as the status of this protein is relevant to breast cancer and has previously been reported for these cell lines. We observed a complete concordance of our staining with the published status of HER2 in these cell lines. In addition, we examined the expression of CD44, epithelial markers EpCAM and E-cadherin and tyrosine phosphoproteins. The labeling of these proteins correlates with the known biology of the cell lines. Our results demonstrate the utility of our method to screen for potential biomarkers and therapeutic targets in breast cancer and we suggest that CMAs be used as a general approach in breast cancer research.     

Selective inhibition of fatty acid synthase for lung cancer treatment.

PURPOSE: Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. However, in vitro use of previous generations of FAS inhibitors has been limited by severe, but reversible, anorexia in treated animals, which is thought to be related to a parallel stimulation of fatty acid oxidation by these agents. This study investigated pharmacologic inhibition of FAS using C93, a rationally designed molecule that inhibits FAS activity without affecting fatty acid oxidation in preclinical models of lung cancer. EXPERIMENTAL DESIGN: Activity of C93 on FAS and fatty acid oxidation was evaluated in cultured non-small cell lung cancer (NSCLC) cells. Antineoplastic activity of the compound, given orally or by i.p. injection, was evaluated in s.c. and orthotopic NSCLC xenografts. RESULTS: Our experiments confirm that C93 effectively inhibits FAS without stimulating fatty acid oxidation in lung cancer cells. More importantly, C93 significantly inhibits the growth of both s.c. and orthotopic xenograft tumors from human NSCLC cell lines without causing anorexia and weight loss in the treated animals. CONCLUSIONS: We conclude that inhibition of FAS can be achieved without parallel stimulation of fatty acid oxidation and that inhibition of tumor growth in vivo can be achieved without anorexia and weight loss. Thus, this therapeutic strategy holds promise for clinical treatment of cancers, including non-small cell lung cancer, the leading cause of cancer mortality in the United States and Europe.     

Elastase in gingival crevicular fluid from smokers and non-smokers with chronic inflammatory periodontal disease

OBJECTIVE: To compare elastase concentrations in gingival crevicular fluid (GCF) from individual sites of smokers and non-smokers.
MATERIALS AND METHODS: Twelve pairs of smokers and non-smokers with untreated, moderate to advanced chronic inflammatory periodontal disease were matched for gender, age, ethnicity and the clinical and radio-graphic extent of disease. Durapore filter strip samples were collected over 30 s from two mesiopalatal sites on upper left posterior teeth. Samples were analysed for: I) polymorphonuclear neutrophil leucocyte (PMNL) cell counts; 2) PMNL elastase-αI-antitrypsin complex in the GCF supernatant by ELISA; and 3) functional elastase, free or bound to α2-macroglobulin, estimated from activity against N-tert-butoxycarbonyI-alanyl-prolyl-nor-valylg-chlorothiobenzyl ester in supernatant and lysates of GCF PMNLs.
RESULTS: There were no differences in disease parameters between groups except that bleeding on probing was less extensive in smokers (P< 0.001). Cell counts and elastase content of crevicular PMNLs showed no differences between groups. Lower concentrations of elastase were found in GCF supernatants from smokers than non-smokers. This difference was observed for functional elastase (mean [s.d.] = 30.21 [17.60] against 73.77 [75.26] ng μI^-1, P <0.05) and elastase complexed with αl-antitrypsin (8.97 [6.54] ng μl^-1 against 25.71 [22.07] ng μI^-1, P < 0.001).
CONCLUSIONS: Smokers have lower elastase concentrations in GCF than non-smokers. Further investigation is required to elucidate the underlying cause and its relationship with periodontal disease.     

Beneficial Cardiac Effects of Caloric Restriction Are Lost with Age in a Murine Model of Obesity

Obesity is associated with increased diastolic stiffness and myocardial steatosis and dysfunction. The impact of aging on the protective effects of caloric restriction (CR) is not clear. We studied 2-month (younger) and 6–7-month (older)-old ob/ob mice and age-matched C57BL/6J controls (WT). Ob/ob mice were assigned to diet ad libitum or CR for 4 weeks. We performed echocardiograms, myocardial triglyceride assays, Oil Red O staining, and measured free fatty acids, superoxide, NOS activity, ceramide levels, and Western blots. In younger mice, CR restored diastolic function, reversed myocardial steatosis, and upregulated Akt phosphorylation. None of these changes was observed in the older mice; however, CR decreased oxidative stress and normalized NOS activity in these animals. Interestingly, myocardial steatosis was not associated with increased ceramide, but CR altered the composition of ceramides. In this model of obesity, aging attenuates the benefits of CR on myocardial structure and function.     

Mycobacterial disease associated with aplastic anaemia

Haematological changes associated with infectious disease are relatively common but true aplastic anaemia secondary to infection is rare. We describe a patient wit disseminated Mycobacterium avium-intracellulare infection and who had a histologically proven remission of his aplastic anemia accompanying antimycobacterial therapy. We also review the literature on the haematological changes associated with mycobacterial infections and other infectious causes of aplastic anaemia.