Alexander C. Vlantis

Squamous cell carcinoma of the head and neck: diffusion-weighted MR imaging for prediction and monitoring of treatment response.

ObjectiveTo investigate the role of diffusion-weighted imaging (DWI) in predicting and monitoring chemoradiotherapy response in head and neck squamous cell carcinoma (HNSCC).MethodsDiffusion-weighted imaging was performed pre-treatment (n = 50), intra-treatment (n = 41) and post-treatment (n = 20). Apparent diffusion coefficient (ADC) values were correlated with locoregional failure (LF).ResultsLocoregional failure occurred in 20/50 (40%) patients. A significant correlation was found between LF and post-treatment ADC (p = 0.02) but not pre- or intra-treatment ADC. Serial change in ADC was even more significant (p = 0.00001), using a fall in ADC early (pre- to intra-treatment) or late (intra- to post-treatment) to indicate LF, achieved 100% specificity, 80% sensitivity and 90% accuracy.ConclusionsSingle ADC measurements pre- or intra-treatment did not predict response, but ADC post-treatment was a marker for LF. Serial change in ADC was an even stronger marker, when using an early or late treatment fall in ADC to identify LF.

Head and Neck Squamous Cell Carcinoma: Diagnostic Performance of Diffusion-weighted MR Imaging for the Prediction of Treatment Response

PURPOSE To determine the diagnostic performance of diffusion-weighted (DW) imaging for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS The study was approved by the local institutional ethics committee and conducted with informed written consent in patients with primary HNSCC treated with radiation therapy and chemotherapy. DW imaging of the primary tumor was performed before treatment in 37 patients and was repeated within 2 weeks of treatment in 30 patients. Histograms of apparent diffusion coefficients (ADCs) were analyzed, and mean ADC, kurtosis, skewness, and their respective percentage change were correlated for local failure and local control at 2 years by using the Student t test. Univariate and multivariate analyses of the ADC parameters, T stage, and tumor volume were performed by using logistic regression for prediction of local failure. RESULTS Local failure occurred in 16 of 37 (43%) patients and local control occurred in 21 of 37 (57%) patients. Pretreatment ADC parameters showed no correlation with local failure. There was significant intratreatment increase in mean ADC and a decrease in skewness and kurtosis (P < .001, P < .001, P = .024, respectively) for the whole group of patients when compared with those before treatment. During treatment, primary tumors showed a significantly lower increase in percentage change of mean ADC, higher skewness, and higher kurtosis for local failure than for local control (P = .016, .015, and .040, respectively). These ADC parameters also were significant for predicting local failure with use of univariate but not multivariate analysis. CONCLUSION Early intratreatment DW imaging has the potential to allow prediction of treatment response at the primary site in patients with HNSCC.

Regulation of cell growth by estrogen signaling and potential targets in thyroid cancer.

Thyroid cancer occurs three times more frequently in females than in males, and in females the incidence decreases after menopause. This gender difference suggests that the growth and progression of thyroid cancer may be influenced by female sex hormones, particularly estrogens. Experimental data have clearly demonstrated that estrogens can influence cancer cell growth. The action of estrogens on target sites is mediated through related but distinct estrogen receptors, designated estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), both of which are known to be expressed in thyroid cancer cells. The proliferation of thyroid cancer cells is promoted by an ERalpha agonist, whereas the proliferation is reduced by the enhanced expression of ERbeta or by an ERbeta agonist. When ERbeta is down-regulated, the proliferation of thyroid cells is significantly increased. Studies have shown that the expression of ERalpha in thyroid cancer cells is increased while the expression of ERbeta is either very low or absent. In conclusion, it appears that estrogens have opposite effects on the growth of thyroid cancer cells, depending on the balance between ERalpha and ERbeta in the cells. The modulation of ERalpha and ERbeta and the intervention of their pathways may open up new potential targets for the treatment of thyroid cancer.

Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor – ERK pathway

Abstract.  Objectives: Although thyroid cancer occurs much more frequently in females, the role of sex hormones in thyroid carcinogenesis is unknown. In this study, it has been investigated how 17β‐oestradiol (E2) influenced proliferation and growth of thyroid cancer cells. Materials and Methods: Cell proliferation and its related molecules were examined in thyroid papillary carcinoma cells (KAT5), follicular thyroid carcinoma cells (FRO) and anaplastic carcinoma cells (ARO). Levels of oestrogen receptor (ER) α and β were regulated by their agonists (PPT and DPN), antagonists and siRNA. Results: E2 promoted cell proliferation. Such an effect was positively related to ERα but negatively to ERβ; PPT enhanced cell proliferation while DPN inhibited it. PPT increased Bcl‐2 expression while DPN decreased it. DPN also elevated Bax expression. PPT elevated the level of phosphorylated extracellular signal‐regulated kinase 1/2 (pERK1/2), suggesting a positive role of ERK1/2 in E2‐induced cell proliferation. Knockdown of ERα significantly attenuated E2‐mediated Bcl‐2 and pERK1/2 expression. In contrast, knockdown of ERβ markedly enhanced them. Conclusions: Oestrogen stimulates proliferation of thyroid cancer cells, associated with increase in Bcl‐2 and decrease in Bax levels in an ERK1/2‐related pathway. Imbalance between ERα and ERβ may contribute to thyroid carcinogenesis.

Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of BCL-XL

PURPOSEOne of the features of thyroid carcinoma is its predilection for women of reproductive age relative to men. An increased risk has also been documented in women who have used estrogens for gynecologic reasons. The aim of this study was to explore the mechanism by which sex hormones contribute to the development of thyroid carcinoma, which is not well understood at present. MATERIALS AND METHODSIn this study, we investigated the effects of estradiol and testosterone on cell proliferation in a human thyroid papillary carcinoma cell line (KAT5) by MTT assay. We also studied the expression of estrogen receptors and the levels of anti-apoptotic Bcl-xL protein, pro-apoptotic Bax protein, and messenger RNA in the cells by Western blot and reverse transcriptase polymerase chain reaction analysis. RESULTSThe results showed that estradiol promotes cell proliferation when compared with cells treated with testosterone and untreated cells, and that the growth-promoting effect of estradiol was attenuated by tamoxifen. The expression of Bcl-xL was markedly increased in a dose-dependent manner, resulting in an elevated ratio of Bcl-xL to Bax. DISCUSSIONWe conclude that estradiol promotes KAT5 cell proliferation and that the underlying mechanism may be associated with up-regulation of Bcl-xL expression. The data provide insight into the molecular mechanism underlying the epidemiologic data that shows a two- to threefold increased prevalence of thyroid carcinoma in women relative to men. From the therapeutic point of view, the finding that estradiol enhances anti-apoptotic signaling pathways may be significant in the search for novel prevention and treatment strategies of thyroid carcinomas.

Heme oxygenase-1 protects against apoptosis induced by tumor necrosis factor-α and cycloheximide in papillary thyroid carcinoma cells

Heme oxygenase‐1 (HO‐1) plays a role in the resistance to apoptosis of several types of cells, but its role in the development of thyroid cancer is unknown. In this study, we investigated the regulation of HO‐1 in human papillary thyroid carcinoma cells (KAT5). The results show that HO‐1 is significantly induced by hemin and cadmium. In addition to inducing HO‐1, hemin and cadmium also cause a rise in the levels of p21, a cyclin‐dependent kinase inhibitor. Cells with increased levels of HO‐1 and p21 were more resistant to apoptotic stimuli than cells with normal levels. The cells resistant to apoptosis also displayed an increased arrest at the G0/G1 phase of the cell‐cycle. The induced levels of HO‐1 and p21 were significantly reduced by p38 mitogen‐activated protein kinase (p38 MAPK) and extracellular‐regulated kinase (ERK) inhibitors. More importantly, KAT5 cells regained their sensitivity to apoptotic stimuli after they were treated with these kinase inhibitors, indicating that p38 MAPK and ERK are required for the resistance to apoptosis conferred by HO‐1. Furthermore, we demonstrated that increased levels of HO‐1 and p21 expression are associated with an increase in the activity of NF‐kappaB and that inhibiting NF‐kappaB leads to a block in the induction of HO‐1 and p21. In summary, this study reveals that an increase in the level of HO‐1 markedly reduces the sensitivity of papillary thyroid carcinoma cells to apoptotic stimuli. The HO‐1 pathway of apoptosis resistance is associated with an increase in the levels of p21, involves a p38 MAPK and ERK‐mediated mechanism and can be suppressed by inhibiting NF‐kappaB.

The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas.

Oestrogen (E2) is known to promote the proliferation of thyroid papillary carcinoma cells (KAT5). However, the molecular mechanism responsible is not well understood. In the study reported herein, the localization of ER alpha (ERα) and beta (ERβ) in KAT5 and anaplastic carcinoma cells (FRO) was studied by immunofluorescence staining and by immunoblotting the proteins in subcellular fractions. Cell proliferation and apoptosis were also determined together with the expression of relevant proteins. The pattern of the subcellular localization of ERα and ERβ differed between papillary and anaplastic cancer. Upon E2 treatment, the level of ERα increased in the nuclei of papillary cancer cells but ERβ remained unchanged. The level of mitochondrial ERβ surpassed that of ERα in anaplastic cancer cells. The different locations of ERα and ERβ in KAT5 and FRO agreed with the finding that E2 promoted the proliferation of KAT5 but inhibited or did not affect that of FRO cells, and with the proposed functions of these two receptors. E2 inhibited the level of Bax in the mitochondria of papillary cancer, followed by a decrease of cytochrome c and/or apoptosis‐inducing factor (AIF) release from the mitochondria into the cytosol. However, in anaplastic cancer, E2 promoted the expression of Bax in the mitochondria and the release of cytochrome c and/or AIF from mitochondria into the cytosol. Our results may explain the differences in epidemiology and responses to anti‐tumour therapy between papillary and anaplastic cancer in terms of the subcellular localization of ER isoforms. In conclusion, the findings provide evidence to support the observation that E2 is an important factor in the development of thyroid cancer. The subcellular localization of ERα and ERβ may account for the different pathogenesis of thyroid papillary and anaplastic cancers. Copyright

Primary Nasopharyngeal Carcinoma: Diagnostic Accuracy of MR Imaging versus that of Endoscopy and Endoscopic Biopsy

PURPOSE To compare the accuracy of magnetic resonance (MR) imaging with that of the current clinical standard of endoscopy and endoscopic biopsy, to determine whether MR imaging depicts subclinical cancers missed at endoscopy and endoscopic biopsy, and to determine whether MR imaging can identify patients without nasopharyngeal carcinoma (NPC) who do not need to undergo invasive sampling biopsy. MATERIALS AND METHODS The study protocol was approved by the institutional review board; written informed consent was obtained from all patients. Patients suspected of having NPC underwent MR imaging, endoscopy, and endoscopic biopsy. Endoscopic biopsy targeted the suspected tumor or sampled the endoscopically normal nasopharynx. The final diagnosis was based on results of the endoscopic biopsy or on results of a repeat biopsy directed at the lesion detected at MR imaging. The sensitivity and specificity of the three investigations were compared by using the Fisher exact test. RESULTS NPC was present in 77 (31%) of 246 patients and absent in 169 (69%) patients. The combined sensitivity, specificity, and accuracy, respectively, were 100%, 93%, and 95% for MR imaging, 90%, 93%, and 92% for endoscopy, and 95%, 100%, and 98% for endoscopic biopsy. Benign disease was mistaken for NPC in 12 (7%) of 169 patients at MR imaging and in 11 (6%) patients at endoscopy. The sensitivity of MR imaging was significantly higher than that of endoscopy (P = .006) and was similar to that of endoscopic biopsy (P = .120). The specificity of MR imaging was similar to that of endoscopy (P = .120) and was significantly lower than that of endoscopic biopsy (P < .001). CONCLUSION MR imaging is an accurate test for the diagnosis of NPC. MR imaging depicts subclinical cancers missed at endoscopy and endoscopic biopsy and helps identify the majority of patients who do not have NPC and who therefore do not need to undergo invasive sampling biopsies.

Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells.

Abstract.The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.

Sensitivity and specificity of Epstein-Barr virus IgA titer in the diagnosis of nasopharyngeal carcinoma: A three-year institutional review

IgA antibody titers to the Epstein‐Barr virus (EBV) viral capsid antigen (EBV IgA‐VCA) and to the EBV early antigen (EBV IgA‐EA) are used to screen for nasopharyngeal carcinoma (NPC). This study evaluates the sensitivity and specificity of EBV IgA‐VCA and EBV IgA‐EA titers in screening patients for NPC and in those diagnosed with NPC at our institution.