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Detection of residual tumor cells in the circulation can provide prognostic as well as therapeutic information and help in identifying patients at high risk for developing metastases. Maspin and mammaglobin are two molecules that are specifically associated with breast cancer. We looked for mammaglobin and maspin transcripts in the peripheral blood of patients with breast cancer and evaluated their utility as a marker of the response to therapy. Maspin and mammaglobin transcripts were analyzed in 85 breast-cancer patients by nested RT-PCR, prior to and after treatment. Before therapy, 10 patients were found positive for mammaglobin and 20 patients were positive for maspin. In four patients, both transcripts were detected. Immediately following treatment, only one patient was still positive for mammaglobin while maspin transcripts persisted in three patients. Disease progression was observed mainly in patients in whom maspin transcripts were not detectable. Molecular detection of circulating tumor cells during therapy based on analysis for mammaglobin and maspin transcripts is an easy and practical method that can be applied to follow-up patients. We suggest that detection of mammaglobin mRNA is useful to determine the effect of therapy while maspin transcripts may indicate more aggressive disease.
Genet Mol Res 2010
PMID:Mammaglobin and maspin transcripts in blood may reflect disease progression and the effect of therapy in breast cancer. 2009 39

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.
Mol Cancer Ther 2010 Apr
PMID:Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma. 2037 14

Glioblastoma multiforme (GBM) is one of the most malignant human tumors, with a uniformly poor outcome. One obstacle in curing malignant brain tumors is the limitation of conventional light microscopy in detecting microscopic residual tumor in biopsy samples from the perimeter of the surgically resected tumor. We further refined the identification of GBM tumor tissue at the sub-cellular level, utilising the technique of Synchrotron, sourced mid-infrared (mid-IR) spectromicroscopy. Paired, thin (5 microm) cryosections of snap-frozen human GBM tumor samples removed at elective surgery were mounted on glass slides (hematoxylin and eosin-stained tissue section) and calcium fluoride (CaF2) windows (unstained tissue section for transmission spectromicroscopy), respectively. Concordance of tumor bearing areas identified in the stained section with the unstained IR tissue section was confirmed by the pathologist of the study. Compared with molecular signatures obtained from normal control brain tissue, unique spectroscopic patterns were detected in GBM tumor samples from 6 patients. The identifying features of GBM were: i) high protein-to-lipid ratios (amide I+II/CH2 symmetric stretch; amide I+II/CH2+CH3 symmetric and asymmetric stretch), and ii) considerable enhancement of the intensities of characteristic peaks at 2,957 and 2,871 cm(-1) representing CH3 asymmetric and symmetric stretch, respectively. Spectral data sets were subjected to Ward's algorithm for assignment to similar groups, and then subjected to hierarchical cluster analysis (HCA) by means of false color digital maps. False color images of 5 clusters obtained by HCA identified dominant clusters corresponding to tumor tissue. Corroboration of these findings in a larger number of GBM may allow for more precise identification of these and other types of brain tumors.
Int J Mol Med 2010 Jul
PMID:Biomolecular diagnosis of human glioblastoma multiforme using Synchrotron mid-infrared spectromicroscopy. 2051 16

Determination of NPM1 mutation status has become essential for the molecular classification of acute myeloid leukemias (AML). Methods with high clinical sensitivity and specificity adapted to the molecular laboratory workflow are required for the diagnosis, prognosis, and monitoring of AML with normal karyotype. We report here the development and evaluation of a novel, streamlined, RNA-based assay for the rapid multiplex detection of common NPM1 mutations in a 96-well assay format. Using synthetic transcripts and total RNA from leukemic cell lines, we show that the assay can specifically detect NPM1 wild-type and mutants A, B, D, or J transcripts in the same reaction. Dilution experiments indicate an assay dynamic range >4 log units with an analytical sensitivity of approximately 0.01%. Evaluation of 69 clinical specimens at initial diagnosis resulted in 100% agreement with reference methods. Of patients with AML with normal karyotype, 53% carried one of four different mutations. The assay was also combined with other laboratory-developed tests to simultaneously detect NPM1 mutant transcripts and fusion transcripts resulting from t(8;21) or inv(16) in a single reaction well. Overall, these results show that the assay is a versatile and specific tool for the screening of NPM1 mutations in patients with AML. Its high analytical sensitivity further suggests potential utility for the monitoring of residual disease in AML with normal karyotype.
J Mol Diagn 2010 Sep
PMID:Performance and clinical evaluation of a sensitive multiplex assay for the rapid detection of common NPM1 mutations. 2061 61

Bone marrow hypoplasia and pancytopenia are among the most undesirable sequelae of chemotherapy for the treatment of cancer. We recently showed that hyaluronan (HA) facilitates hematopoietic recovery in tumor-free animals receiving chemotherapeutic agents. However, following a chemotherapeutic regimen in tumor-bearing animals, it is possible that residual tumor cells might respond to systemic injections of HA. Thus, in this study, we investigated the effect of HA on the regrowth of residual tumor cells following chemotherapy. As a model, we used the HCT-8 human colon carcinoma cell line, which expresses the HA receptor CD44, binds exogenous HA, and is susceptible to a chemotherapy protocol containing irinotecan and 5-fluorouracil in a human/mouse xenograft model. HCT-8 cells were implanted in severe combined immunodeficient mice, followed by irinotecan/5-fluorouracil treatment. After three rounds of chemotherapy, residual tumors were allowed to regrow in the presence or absence of HA. The dynamics of tumor regrowth in the group treated with HA was slower compared with the control group. By week 5 after tumor implantation, the difference in the size of regrown tumors was statistically significant and correlated with lower proliferation and higher apoptosis in HA-treated tumors as compared with controls. This finding provides evidence that HA treatment does not stimulate but delays the growth of residual cancer cells, which is an important parameter in establishing whether the use of HA can enhance current chemotherapeutic strategies.
Mol Cancer Ther 2010 Nov
PMID:Hyaluronan inhibits postchemotherapy tumor regrowth in a colon carcinoma xenograft model. 2083 54

Molecular biology tests can quantify extremely low levels of cancer cells, provided that a genetic marker for the cancer is known. Acute lymphoblastic leukemia (ALL) exhibits many genetic abnormalities, but most are uncommon or technically difficult to use as markers for sensitive quantification. We therefore use the leukemia clone's rearranged immunoglobulin heavy-chain (IgH) gene as a clonal marker (1,2). A very sensitive, quantitative polymerase chain reaction (PCR) test with "clone-specific" primers can be developed for 60-70% of B-lineage ALLs (see Fig. 1 ). Fig. 1. Strategy for quantifying residual disease.
Methods Mol Med 2001
PMID:Quantifying residual leukemia by "clone-specific" polymerase chain reaction. 2131 7

In initial staging of head and neck cancers, the addition of FDG PET to conventional imaging improves the accuracy for cervical nodal metastases. The sensitivity of FDG PET is, however, limited in nodes <1 cm and in completely necrotic nodes. In the posttherapy setting, PET scans obtained at least 10 weeks after radiotherapy have an excellent predictive value to rule out residual disease. Due to the limited positive predictive value of FDG PET after radiation therapy, a positive PET scan needs to be confirmed before management decisions are made.
Methods Mol Biol 2011
PMID:FDG PET imaging of head and neck cancers. 2133 26

The introduction of PET(-CT) has brought about a major paradigm shift in the management of thyroid carcinoma, especially from the diagnostic standpoint. From the viewpoint of patient management, the areas where it has made significant impact include the following: (1) the detection of disease focus in patients with differentiated thyroid carcinoma with elevated Tg levels and negative radioiodine scan. When localized disease is identified with F-18 FDG-PET-CT, surgery or focused radiotherapy could be utilized to eradicate the tumor; (2) the localization of disease in patients of MTC with elevated serum calcitonin levels; (3) the detection of unsuspected focal F-18 FDG uptake in the thyroid in patients undergoing whole body F-18 FDG PET for a different indication. This would prompt a workup to rule out thyroid carcinoma. The use of I-124 is evolving at this time and has been of great promise with regard to (a) its better efficacy of lesion detection and (b) the ability to provide lesion-specific dosimetry. In addition, F-18 FDG PET appears to be of potential value in patients with thyroid lymphoma in making the initial diagnosis, monitoring therapeutic response, and assessing for residual disease and/or recurrence.
Methods Mol Biol 2011
PMID:PET and PET/CT in the management of thyroid cancer. 2133 36

The most important prognostic parameters for gynecologic malignancies are tumor stage, residual tumor after surgical treatment, histological subtype, and degree of malignancy (1-2). However, these factors present an incomplete picture of the tumor biology. Therefore, investigation of other prognostic factors is of special clinical relevance, particularly in view of the unexpectedly progressive course of the disease and frequent relapses in some cases.
Methods Mol Med 2001
PMID:ELISA-Based Quantification of p105 (c-erbB-2, HER2/neu) in Serum of Ovarian Carcinoma. 2134 Jul 63

The deregulation of the balance between proliferation and programmed cell death is considered one of the most important features of malignant tumors. The search for new markers, which may reflect the tumor progress and response to various therapy regimens, has recently focused on alterations of genes involved in regulation of programmed cell death and apoptosis. The bcl-2-family is a still growing family of genes, which play a major role in regulation of cell suicide, acting either as inhibitors (e.g., bcl-2, bcl-xl, mcl-1) or promoters (e.g., bcl-xs, bax, bak, bad) of apoptosis (1-3). The chromosomal translocation t(14;18), leading to overexpression of the Bcl-2 protein was first described in human B-cell lymphoma (4). Later on, Bcl-2-overexpression without chromosomal translocations was also detected in various epithelial tumors (5-12). It has been suggested that Bcl-2 as the major inhibitor of apoptosis plays a role in tumor development and progress by prolonging the survival of malignant cells. Unexpectedly, expression of Bcl-2 has been shown to be connected with parameters of favorable prognosis and prolonged survival in nonsmall-cell lung cancer (6), breast (7-9), and, recently, in ovarian cancer (10-12). Bax-expression, in contrast, was associated with an unfavorable outcome, as well as negative histopathological features in breast (13) and ovarian cancer (12). Moreover, the association of Bax-expression with predictors of poor clinical outcome was strongly connected with concomitant downregulation of Bcl-2-expression (12,13). The unexpected effect of Bcl-2- and Bax-expression on prognosis of ovarian cancer patients is underlined by the survival curves of patients. Especially, patients with exclusively Bax-positive tumors had a statistically significantly reduced survival as compared to patients with exclusively Bcl-2-positive tumors (12). This difference could be observed for patients with tumors of different stage and grade, as well as for patients with no evidence of disease or residual tumor after primary surgery (12). One explanation for these observations is that the apoptosis inhibiting or promoting effect of these homologous proteins depends partly on protein-protein interactions. Bax, for example, the main antagonist of Bcl-2, heterodimerizes with Bcl-2 or Bcl-Xl and homodimerizes with itself (1-3). The ratio of Bax-heterodimers to Bax-homodimers seems to be the critical determinant for regulating cell death (2,3). In cells in which 80% of Bax is found in homodimers, an apoptotic signal results in cell death (2,3), suggesting a crucial role of the Bax/Bcl-2 balance for the regulation of proliferation or cell suicide.
Methods Mol Med 2001
PMID:Differential Expression of Apoptosis-Associated Genes bax and bcl-2 in Ovarian Cancer. 2134 Aug 31


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