A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic.

Differentiation is central to development, while dedifferentiation is central to cancer progression. Hence, a quantitative assessment of differentiation would be most useful. We propose an unbiased method to derive organ-specific differentiation indices from gene expression data and demonstrate its usefulness in thyroid cancer diagnosis. We derived a list of thyroid-specific genes by selecting automatically those genes that are expressed at higher level in the thyroid than in any other organ in a normal tissue's genome-wide gene expression compendium. The thyroid index of a tissue was defined as the median expression of these thyroid-specific genes in that tissue. As expected, the thyroid index was inversely correlated with meta-PCNA, a proliferation metagene, across a wide range of thyroid tumors. By contrast, the two indices were positively correlated in a time course of thyroid-stimulating hormone (TSH) activation of primary thyrocytes. Thus, the thyroid index captures biological information not integrated by proliferation rates. The differential diagnostic of follicular thyroid adenomas and follicular thyroid carcinoma is a notorious challenge for pathologists. The thyroid index discriminated them as accurately as did machine-learning classifiers trained on the genome-wide cancer data. Hence, although it was established exclusively from normal tissue data, the thyroid index integrates the relevant diagnostic information contained in tumoral transcriptomes. Similar results were obtained for the classification of the follicular vs classical variants of papillary thyroid cancers, that is, tumors dedifferentiating along a different route. The automated procedures demonstrated in the thyroid are applicable to other organs.

Intercellular adhesion molecule-1 (ICAM-1) is upregulated in aggressive papillary thyroid carcinoma.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is implicated in carcinogenesis. In this study we examined the expression of ICAM-1 in papillary thyroid cancer (PTC). We hypothesized that ICAM-1 correlates with indicators of tumor aggressiveness in PTC. METHODS: Thirty-five primary and metastatic PTCs, five follicular adenomas, five Hashimoto thyroiditis, five nodular hyperplasia, and eight normal thyroid tissue samples were analyzed for ICAM-1 gene expression using quantitative reverse-transcription polymerase chain reaction (RT-PCR). ICAM-1 gene expression was analyzed at protein level by immunohistochemistry (IHC) using a semiquantitative score. Gene expression and intensity levels were correlated with markers of tumor aggressiveness including BRAF V600E mutation, tumor size, extrathyroidal extension (ETE), angiolymphatic invasion, and lymph node metastasis. RESULTS: ICAM-1 gene expression was higher in PTC (p = 0.01) and lymph node metastases (p = 0.03) when compared with benign tumors and Hashimoto's. Furthermore, PTCs exhibiting BRAF V600E mutation (p = 0.01), ETE (p < 0.01), and lymph node metastasis (p = 0.02) were associated with higher ICAM-1 levels. Gene expression correlated with protein levels on IHC. Additionally, poorly differentiated thyroid carcinoma had a higher ICAM-1 intensity score compared with well-differentiated carcinoma (p = 0.03). CONCLUSIONS: ICAM-1 expression is upregulated in papillary thyroid carcinoma. Furthermore, ICAM-1 upregulation correlated with aggressive tumor features such as BRAF V600E mutation, ETE, and lymph node metastasis, suggesting that ICAM-1 plays a role in thyroid cancer progression.

Sinus surgery combined with antifungal therapy is effective in the treatment of invasive Aspergillus sinusitis in neutropenic patients with cancer.

BACKGROUND: Invasive Aspergillus sinusitis (IAS) is associated with high mortality and poor response to antifungal therapy in patients with hematologic malignancies (HM). PATIENTS AND METHODS: We identified 353 patients with invasive aspergillosis of whom 39 patients had IAS. Of the 39 patients, 13 underwent sinus surgery (SS) in addition to the antifungal therapy, and the remaining 26 control patients received antifungal therapy alone. Most patients with IAS had underlying leukemia (85%). Both groups had comparable clinical characteristics such as gender, age, underlying disease, neutropenia at the onset, persistent neutropenia, graft-vs-host-disease, and comparable antifungal therapy. RESULTS: Overall response was 7 (53.2%) in the SS group vs 5 (19.2%) in the control group (p = 0.06). Among the subgroup of patients with neutropenia at the onset of infection, the response rate in the SS group was significantly better than in the non-SS group (57% vs 11.8%, respectively; p = 0.028). CONCLUSION: In neutropenic patients with IAS and underlying HM, SS significantly improved the response to antifungal therapy. Additional studies are warranted.

A comparison of galactomannan-ELISA and a newly developed galactomannan-LATEX test in the serologic diagnosis of invasive aspergillosis in patients with hematologic malignancies.

We compared the sensitivity and specificity of galactomannan enzyme-linked immunosorbent assay (GM-ELISA) with that of a newly developed version of the commercially available latex agglutination test (GM-LATEX) in our patient population. Serum samples were collected from 144 healthy adult donors (controls); another 17 consecutive hematologic malignancy (HM) patients with probable or proven invasive aspergillosis (IA) were tested. Clinical, microbiological, and pathological data were obtained. The sensitivity of the GM-LATEX test was 53% per patient and 66% per sample and that of the GM-ELISA test was 41% per patient and 21% per sample. Both tests demonstrated a specificity of 99%. The GM-LATEX test demonstrated a superior sensitivity in terms of detecting galactomannan and thus may be useful in the diagnosis of IA in patients with HM.