Unusual Clinical Manifestations of Thyroid Carcinoma.

Thyroid cancer is considered the most common endocrine malignancy, with the most frequent presentation of differentiated thyroid cancer being a neck swelling or an incidental finding of a thyroid nodule on imaging. In this case series, we describe three cases of thyroid cancer with unusual clinical manifestations. The first case describes a patient who underwent parathyroidectomy for primary hyperparathyroidism and was found to have papillary thyroid cancer on a cervical lymph node biopsy. While this may be coincidental, the literature raises the question of whether there may be an association. The second case describes a patient who presents with a suspicious thyroid nodule and was subsequently diagnosed with follicular thyroid cancer on biopsy. This raises the question of performing thyroidectomy early in patients with a suspicious thyroid nodule but a false negative biopsy. The third case describes a patient with a scalp lesion found to have poorly differentiated thyroid carcinoma, a rare presentation of this form of cancer.

Early versus late intravenous insulin administration in critically ill patients.

OBJECTIVE: To investigate whether timing of intensive insulin therapy (IIT) after intensive care unit (ICU) admission influences outcome. DESIGN AND SETTING: Single-center prospective cohort study in the 14-bed medical ICU of a 1,171-bed tertiary teaching hospital. PATIENTS: The study included 127 patients started on ITT within 48 h of ICU admission (early group) and 51 started on ITT thereafter (late group); the groups did not differ in age, gender, race, BMI, APACHE III, ICU steroid use, admission diagnosis, or underlying comorbidities. MEASUREMENTS AND RESULTS: The early group had more ventilator-free days in the first 28 days after ICU admission (median 12 days, IQR 0-24, vs. 1 day, 0-11), shorter ICU stay (6 days, IQR 3-11, vs. 11 days, vs. 7-17), shorter hospital stay (15 days, IQR 9-30, vs. 25 days, 13-43), lower ICU mortality (OR 0.48), and lower hospital mortality (OR 0.27). On multivariate analysis, early therapy was still associated with decreased hospital mortality (ORadj 0.29). The strength and direction of association favoring early IIT was consistent after propensity score modeling regardless of method used for analysis. CONCLUSIONS: Early IIT was associated with better outcomes. Our results raise questions about the assumption that delayed administration of IIT has the same benefit as early therapy. A randomized study is needed to determine the optimal timing of therapy.

CD133+ anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies. Its rapid onset and resistance to conventional therapeutics contribute to a mean survival of six months after diagnosis and make the identification of thyroid-cancer-initiating cells increasingly important. METHODOLOGY/PRINCIPAL FINDINGS: In prior studies of ATC cell lines, CD133(+) cells exhibited stem-cell-like features such as high proliferation, self-renewal and colony-forming ability in vitro. Here we show that transplantation of CD133(+) cells, but not CD133(-) cells, into immunodeficient NOD/SCID mice is sufficient to induce growth of tumors in vivo. We also describe how the proportion of ATC cells that are CD133(+) increases dramatically over three months of culture, from 7% to more than 80% of the total. This CD133(+) cell pool can be further separated by flow cytometry into two distinct populations: CD133(+/high) and CD133(+/low). Although both subsets are capable of long-term tumorigenesis, the rapidly proliferating CD133(+/high) cells are by far the most efficient. They also express high levels of the stem cell antigen Oct4 and the receptor for thyroid stimulating hormone, TSHR. Treating ATC cells with TSH causes a three-fold increase in the numbers of CD133(+) cells and elicits a dose-dependent up-regulation of the expression of TSHR and Oct4 in these cells. More importantly, immunohistochemical analysis of tissue specimens from ATC patients indicates that CD133 is highly expressed on tumor cells but not on neighboring normal thyroid cells. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first report indicating that CD133(+) ATC cells are solely responsible for tumor growth in immunodeficient mice. Our data also give a unique insight into the regulation of CD133 by TSH. These highly tumorigenic CD133(+) cells and the activated TSH signaling pathway may be useful targets for future ATC therapies.

Replication and/or separation of some human telomeres is delayed beyond S-phase in pre-senescent cells.

Cultured primary human cells, which lack telomerase, enter a state of replicative senescence after a characteristic number of population doublings. During this process telomeres shorten to a critical length of approximately 5-7 kb. The mechanistic relationship between advanced cell passage, cellular senescence and telomeric function has yet to be fully elucidated. In the study described here, we investigated the relationship between changes in telomeric replication timing and/or sister chromatid separation at telomeric regions and advanced cell passage. Using fluorescence in situ hybridization, we analyzed the appearance of double hybridization signals (doublets), which indicate that the region of interest has replicated and the replicated products have separated sufficiently to be resolved as two distinct signals. The results showed that the replication and separation of several telomeric regions occurs during the second half of S-phase and that a delay in replication and/or separation of sister chromatids at these regions occurs in pre-senescent human fibroblasts. Surprisingly, in a significant percentage of pre-senescent cells, several telomeric regions did not hybridize as doublets even in metaphase chromosomes. This delay was not associated with extensive changes in methylation levels at subtelomeric regions and was circumvented in human fibroblasts expressing ectopic telomerase. We propose that incomplete replication and/or separation of telomeric regions in metaphase may be associated with proliferative arrest of senescent cells. This cell growth arrest may result from the activation of a mitotic checkpoint, or from chromosomal instability consequent to progression in the cell cycle despite failure to replicate and/or separate these regions completely.