Application of magnetic-resonance-spectroscopy- based metabolomics to the fine-needle aspiration diagnosis of papillary thyroid carcinoma.

OBJECTIVE: This study explores the potential use of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary diagnostic technique for papillary thyroid carcinoma in thyroid fine-needle aspiration biopsies. The method has already been shown to be effective in the classification of various other nonthyroid cancers. STUDY DESIGN: Twenty-six samples (13 paired cytologic and histologic samples) from patients being evaluated for thyroid abnormalities at the Massachusetts General Hospital were spectroscopically analyzed, and included: papillary thyroid carcinomas (n = 4), follicular adenomas (n = 4), and normal thyroid samples (n = 5). Metabolic profiles were statistically generated based on the spectroscopy results, which were then correlated with the final cytologic and histologic diagnoses from the same samples to determine the diagnostic capacity of the profiles. RESULTS: Principal component analysis of the tissue samples revealed statistically significant correlations among principal components and various cytologic and histologic features. Canonical score 1, calculated with principal components in correlation with analyzed pathologies, revealed the ability of the metabolic profile to differentiate all three examined histologic tissue groups (ANOVA, p < 0.0001). Applying coefficients of principal components and canonical scores obtained with tissue samples directly onto spectral results of cytology samples, the calculated canonical score 1 also revealed similar trends among the three fine-needle aspiration biopsy groups. In particular, the papillary thyroid carcinoma group exhibited significant differences from both the adenomatous and normal cytology groups (p < 0.0170). CONCLUSIONS: The results indicate the potential of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary marker for papillary thyroid carcinoma in fine-needle aspiration biopsy specimens.

Metabolomic imaging for human prostate cancer detection.

As current radiological approaches cannot accurately localize prostate cancer in vivo, biopsies are conducted at random within prostates for patients at risk for prostate cancer, leading to high false-negative rates. Metabolomic imaging can map cancer-specific biomolecular profile values onto anatomical structures to direct biopsy. In this preliminary study, we evaluated five whole prostates removed during prostatectomy from biopsy-proven cancer patients on a 7-tesla human whole-body magnetic resonance scanner. Localized, multi-cross-sectional, multivoxel magnetic resonance spectra were used to construct a malignancy index based on prostate cancer metabolomic profiles obtained from previous intact tissue analyses with a 14-tesla spectrometer. This calculated malignancy index is linearly correlated with lesion size and demonstrates a 93 to 97% overall accuracy for detecting the presence of prostate cancer lesions, suggesting the potential clinical utility of this approach.

Assessing prostate cancer growth with mRNA of spermine metabolic enzymes.

Statistical data from prostate cancer (PCa) clinics indicates that a large patient population discovered by annual prostate specific antigen (PSA) screening may have a latent form of the disease. However, current medical tests cannot differentiate slow from fast growing PCa, resulting in many unnecessary radical treatments and morbidities. It is thus necessary to find new screening tests that enable us to differentiate between fast- and slow-growing tumors. Inspired by the reported functions of spermine in carcinogenesis, we analyzed spermine and mRNA expression levels of rate-limiting enzymes in the spermine metabolic pathway for nine cases of PCa with accurately defined PSA velocity (Vpsa). Using MR spectroscopy, histopathology, laser-capture microdissection and real-time PCR techniques, we analyzed relationships between changes in spermine levels, mRNA expression levels of spermine anabolic and catabolic enzymes and human prostate cancer growth rates represented by serum Vpsa. The expression levels of spermine anabolic enzymes: ornithine decarboxylase (ODC1) and S-adenosylmethionine decarboxylase (AMD1) in benign epithelia surrounding cancer glands was logarithmically reduced with the increase of Vpsa (ODC1, p < 0.016; AMD1, p < 0.048), and antizyme (OAZ1) expression in cancer cells was increased with the increase of Vpsa (p < 0.001). Finally, we observed an inverse correlation between ODC1 and OAZ1 (p < 0.019) measured in cancer cells. These correlations may function to evaluate the aggressiveness of human prostate cancer, and assist patients and clinicians to select appropriate treatment strategies based on biological activities of individual tumors.

A systems biology approach to understanding cis-regulatory module function.

The genomic instructions used to regulate development are encoded within a set of functional DNA elements called cis-regulatory modules (CRMs). These elements determine the precise patterns of temporal and spatial gene expression. Here we summarize recent progress made towards cataloguing and characterizing the complete repertoire of CRMs. We describe CRMs as genomic information processing devices containing clusters of transcription factor binding sites and we position CRMs as nodes within large gene regulatory networks. We define CRM architecture and describe how these genomic elements process the information they encode to their target genes. Furthermore, we present an overview describing high-throughput techniques to identify CRMs genome wide and experimental methodologies to validate their function on a large scale. This review emphasizes the advantages and power of a systems biology approach which integrates computational and experimental technologies to further our understanding of CRM function.

Metabolomic characterization of human rectal adenocarcinoma with intact tissue magnetic resonance spectroscopy.

PURPOSE: This study was designed to test whether metabolic characterization of intact, unaltered human rectal adenocarcinoma specimens is possible using the high-resolution magic angle spinning proton (1H) magnetic resonance spectroscopy technique. METHODS: The study included 23 specimens from five patients referred for ultrasonographic staging of suspected rectal cancer. Multiple biopsies of macroscopically malignant rectal tumors and benign rectal mucosa were obtained from each patient for a total of 14 malignant and 9 benign samples. Unaltered tissue samples were spectroscopically analyzed. Metabolic profiles were established from the spectroscopy data and correlated with histopathologic findings. RESULTS: Metabolomic profiles represented by principle components of metabolites measured from spectra differentiated between malignant and benign samples and correlated with the volume percent of cancer (P = 0.0065 and P = 0.02, respectively) and benign epithelium (P = 0.0051 and P = 0.0255, respectively), and with volume percent of stroma, and inflammation. CONCLUSIONS: Magnetic resonance spectroscopy of rectal biopsies has the ability to metabolically characterize samples and differentiate between pathological features of interest. Future studies should determine its utility in in vivo applications for non-invasive pathologic evaluations of suspicious rectal lesions.

NMR-based metabolomics approach to target biomarkers for human prostate cancer.

In the era of genomics and proteomics, metabolomics offers a unique way to probe the underlying biochemistry of malignant transformations. In the context of oncological metabolomics, the study of the global variation of metabolites involved in the development and progression of cancers, few existing techniques offer as much potential to discover biomarkers as nuclear magnetic resonance techniques. The most fundamental magnetic resonance methodologies with regard to human prostate cancer are magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging. Recent in vivo explorations have examined crucial metabolites that may indicate cancerous lesions and have the potential to direct treatment; while ex vivo studies of prostatic fluids and tissues have defined novel diagnostic parameters and indicated that magnetic resonance methodologies will be paramount in future prostate cancer management.

Evaluation of Tissue Metabolites with High Resolution Magic Angle Spinning MR Spectroscopy Human Prostate Samples After Three-Year Storage at -80 degrees C.

Accurate interpretation and correlation of tissue spectroscopy with pathological conditions requires disease-specific tissue metabolite databases; however, specimens for research are often kept in frozen storage for various lengths of time. Whether such frozen storage results in alterations to the measured metabolites is a critical but largely unknown issue. In this study, human prostate tissues from specimens that had been stored at -80 degrees C for 32 months were analyzed with high resolution magic angle spinning (HRMAS) magnetic resonance (MR) spectroscopy, and compared with the initial measurements of the adjacent specimens from the same cases when snap frozen in the operation room and kept frozen for less than 24 hours. Results of the current study indicate that that the storage-induced metabolite alterations are below the limits that tissue MR spectroscopy can discriminate. Furthermore, quantitative pathology evaluations suggest the observed alterations in metabolite profiles measured from the adjacent specimens of the same prostates may be accounted for by tissue pathological heterogeneities and are not a result of storage conditions. Hence, these results indicate that long-term frozen storage of prostate specimens can be quantitatively analyzed by HRMAS MR spectroscopy without concerns regarding significant metabolic degradation or alteration.