Connie G. Chiu

Diagnostic utility of galectin-3 in thyroid cancer.

Galectin-3 (Gal-3), which has received significant recent attention for its utility as a diagnostic marker for thyroid cancer, represents the most well-studied molecular candidate for thyroid cancer diagnosis. Gal-3 is a protein that binds to beta-galactosidase residues on cell surface glycoproteins and has also been identified in the cytoplasmic and nuclear compartment. This marker has been implicated in regulation of normal cellular proliferation and apoptosis, as well as malignant transformation and the metastasis of cancer cells. We here present a mechanistic review of Gal-3 and its role in cancer development and progression. Gal-3 expression studies in thyroid tissue and cytologic tumor specimens and their methodological considerations are also discussed in this article. Despite great variance in their methodology, the majority of immunohistochemical studies found that Gal-3 was differentially expressed in thyroid carcinoma compared with benign and normal thyroid specimens, suggesting that Gal-3 is a good diagnostic marker for thyroid cancer. Recent studies have also demonstrated improved methodological reliability. On the other hand, Gal-3 genomic expression studies have shown inconsistent results for diagnostic utility and are not recommended. Overall, the development of Gal-3 as a diagnostic marker for thyroid cancer represents a promising avenue for future study, and its clinical application could significantly reduce the number of diagnostic thyroid operations performed for cases of indeterminant fine needle aspiration biopsy cytology, and thus positively impact the current management of thyroid nodular disease.

HER-3 overexpression is prognostic of reduced breast cancer survival: a study of 4046 patients.

Introduction:Advances in molecular biology have led to the identification of potential markers of prognostic and therapeutic importance in human cancers. HER-2 testing and targeted therapy now represents a critical cornerstone in the management of breast cancer. The objectives of the current study were to determine the frequency and prognostic significance of HER-3 over-expression and HER-4 over-expression by invasive breast cancer. Methods:Tissue microarrays were constructed using clinically annotated formalin-fixed and paraffin-embedded tumor samples from 4046 patients diagnosed with invasive breast carcinoma with a median 12.5 years of follow-up. Type 1 growth factor receptor family members HER-1, HER-2, HER-3, and HER-4 expression levels were determined by immunohistochemistry, and HER-2 status was further resolved by fluorescent in-situ hybridization. The study cohort was randomly divided and analyzed as a core data set and a validation data set. Results:HER-3 over-expression was identified in 10.0% of tumors and was a significant marker of reduced patient breast cancer-specific survival on univariate analysis (P = 1.32 × 10−5). Furthermore, in tumors with normal expression levels of HER-1 and HER-2, the overexpression of HER-3 had a significant negative prognostic effect on disease-specific survival (HR: 1.541, 95% CI: 1.166–2.036, P = 2.37 × 10−3) independent of patient age at diagnosis, Estrogen receptor status, tumor grade, tumor size, nodal status, and the presence of lymphatic or vascular invasion by cancer. HER-4 overexpression was identified in 78.2% of breast cancers and was not a significant marker of patient survival (P = 0.214). Results of all statistical tests were positively confirmed in the validation data set analysis. Conclusions:HER-3 status is an important prognostic marker of disease-specific survival in patients with invasive breast cancer. Accordingly, evaluation of the HER-3 expression level may identify a subset of patients with a poor disease prognosis, and who could undergo further evaluation for the efficacy of HER-3 targeted anticancer agents.

Biomarker panel diagnosis of thyroid cancer: a critical review

The accurate preoperative diagnosis of thyroid cancer continues to be a significant challenge for those individuals who present with nodular thyroid disease, particularly for tumors with indeterminate cytomorphological features by fine-needle aspiration biopsy. In an effort to develop improved diagnostic tools, a number of studies have investigated the discriminatory potential of many different RNA and protein molecules. However, no individual thyroid cancer biomarker has been found with sufficient sensitivity and specificity. Therefore, research focus has shifted to panels of multiple markers with the hope of improved performance and robustness. A panel comprised of GAL3, CK19 and HBME1 is by far the most studied to date and offers some improvement over individual marker performance alone. However, relatively few marker panels have been studied and their performances and application as diagnostic tests have not been consistently reported. We present a comprehensive review of molecular marker panel studies for thyroid tumors and current issues and challenges. In the future, studies evaluating larger numbers of biomarkers in large patient cohorts are required for the development and validation of a clinically applicable test.

Autocrine motility factor receptor: a clinical review

The ability to target and alter the metastatic activity of cancer cells is a key avenue for cancer therapeutics. While local tumor control is often achieved through surgical resection, patient morbidity and mortality is dependent upon the control of regional and distant spread of disease. Autocrine motility factor receptor (AMFR) is an internalizing cell surface receptor that also exhibits ubiquitin E3 ligase activity in the endoplasmic reticulum. Stimulation of AMFR by its ligand (autocrine motility factor/phosphoglucose isomerase) alters cellular adhesion, proliferation, motility, and apoptosis. Increased AMFR expression has been reported in numerous human cancer types. Review of these studies suggests that AMFR upregulation is significantly correlated with more advanced tumor stage and decreased survival for cancer of the lung, esophagus, stomach, colon, rectum, liver and skin. AMFR has also served as an independent predictor of poor disease prognosis in these tumor types. Significant associations between AMFR expression and other clinicopathologic parameters implicated in disease progression have also been reported. Further characterization of AMFR in human cancer and the development of an understanding of the molecular regulation of this protein is critical for its future role as a target for anticancer agents.

Hemithyroidectomy is the preferred initial operative approach for an indeterminate fine needle aspiration biopsy diagnosis

BACKGROUND Fine needle aspiration biopsy represents the critical initial diagnostic test used for evaluation of thyroid nodules. Our objectives were to determine the cytological distribution, the utility of clinicopathologic characteristics for predicting malignancy and the true proportion of cancer among individuals who presented with indeterminate cytology and had undergone thyroid surgery for suspicion of cancer. METHODS We retrospectively reviewed 1040 consecutive primary thyroid operations carried out over an 8-year period at a tertiary care endocrine referral centre. Follicular neoplasm (FN), Hürthle cell neoplasm (HN), neoplasms suspicious for but not diagnostic of papillary carcinoma (IP) and neoplasms with cellular atypia (IA) were reviewed. RESULTS In all, 380 individuals presented with cytologically indeterminate thyroid nodules. Of these, 252 (66%) patients had FN, 47 (12%) HN, 44 (12%) IP, 26 (7%) IA and 11 (4%) had mixed diagnoses. Biopsied lesions were found to be malignant on pathological evaluation in 102 (27%) patients: 49 (19%) with FN, 11 (23%) HN, 28 (64%) IP and 9 (35%) with IA. Hemithyroidectomy was adequate definitive treatment in 196 of 225 (87%) patients with FN and 39 of 42 (93%) with HN. Significant associations with a cancer diagnosis were identified for smaller tumour size in patients with FN (p = 0.004) and right thyroid lobe location in patients with IP (p = 0.012), although these factors were nonsignificant in the corrected analyses for multiple comparisons. CONCLUSION In a review of the experience at a Canadian centre, 4 operations were carried out to identify each cancer, and hemithyroidectomy was the optimal initial and definitive surgical approach for most patients.

HAART slows progression to anal cancer in HIV-infected MSM.

Objective:Antiretrovirals do not prevent anal intraepithelial neoplasia. However, the influence of antiretrovirals in the natural history of invasive anal cancer is less clear. The objective is to investigate the impact of antiretrovirals in the time to the development of anal cancer in HIV-positive MSM. Design:A retrospective analysis of cases of anal cancer in a cohort of HIV-positive MSM receiving antiretrovirals between 1988 and 2008. Methods:Time from first CD4+ cell count or HIV RNA viral load test to anal cancer diagnosis was analysed using Cox regression and Kaplan–Meier curves. Anal cancer cases treated in the era prior to HAART (<1996) were compared with those treated later (1996–2008). Results:Anal cancer cases (n = 37) were compared with a cohort of 1654 HIV-positive MSM on antiretrovirals. Antiretrovirals were started in the pre-HAART era by 70% of cancer cases, and median CD4+ cell count nadir was 70 cells/&mgr;l (10–130). Time to development of anal cancer was shorter for cases treated during the pre-HAART era [adjusted hazard ratio (AHR) 3.04, 95% confidence interval (95% CI) 1.48–6.24, P = 0.002], with a CD4+ cell count nadir less than 100 cells/&mgr;l (AHR 2.21, 95% CI 1.06–4.62, P = 0.035) and longer duration of CD4+ cell count less than 100 cells/&mgr;l (AHR 1.33, 95% CI 1.11–1.58, P = 0.002). Conclusion:Results show that severe immunosuppression and starting therapy pre-HAART are associated with an increased risk of anal cancer. HIV-positive MSM initiating antiretrovirals during the HAART era (1996–2008) had a longer time to the development of anal cancer than those treated pre-HAART. Our results suggest that early use of HAART may delay progression to anal cancer.

Beta-catenin expression is prognostic of improved non–small cell lung cancer survival

INTRODUCTION The objectives of this study were to determine the frequency and prognostic significance of beta-catenin expression in a cohort of non-small cell lung cancer (NSCLC) patients. METHODS Tissue microarrays were constructed using clinically annotated formalin-fixed paraffin-embedded tumor samples from individuals diagnosed with NSCLC who underwent surgical resection with curative intent and had beta-catenin expression status determined by immunohistochemistry. RESULTS Negative beta-catenin expression was seen in 28% (103/370) of NSCLC cases and was prognostic of a reduced overall patient survival (P = .008) and also was significantly correlated with the presence of lymphatic invasion (P = .015). In multivariate analysis, the loss of beta-catenin expression retained independent prognostic significance and showed an adjusted hazard ratio of 3.18 (confidence interval, 1.46-6.91, P = .004) for reduced patient survival when adjusting for the presence of lymphatic invasion, tumor grade, nodal status, and tumor stage. CONCLUSIONS Beta-catenin represents an important prognostic marker in individuals diagnosed with surgically resectable NSCLC.

Gender differences in thyroid cancer: a critical review

It has long been known that the incidence of thyroid cancer in women is significantly higher than that in men. The objective of this article is to review gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy. Although more common in women, thyroid cancer typically presents at a more advanced stage and with a worse disease prognosis in men. Clinical evidence on the impact of estrogen and other sex hormones on thyroid cancer has remained inconclusive, although numerous experimental studies have suggested that these hormones and their receptors may play a role in tumorigenesis and tumor progression. Studies of thyroid cancer cell lines suggest that an imbalance between the two estrogen receptor (ER) isoforms, α and β, may be responsible for the cell proliferation seen with estrogen treatment. Expression studies on thyroid tumors indicate that they express ER and possibly progesterone receptors and androgen receptors, but there is conflicting evidence as to whether or not there is a difference in receptor status between thyroid cancers, benign thyroid lesions and normal thyroid tissue. There have been few studies evaluating the ERα/ERβ profiles in thyroid tumors and normal thyroid tissue. Our understanding of the underlying basis for sex differences in thyroid cancer has improved over the last few decades, but the relationship between gender and thyroid cancer risk has remained elusive. Areas for future research include ERα/ERβ profiling of normal and neoplastic thyroid tissue, association between ER status and tumor dedifferentiation, and evaluation of the signaling pathways by which estrogen and other sex steroids exert their effects on thyroid cancer cells. Sex steroid receptors, and then downstream signaling pathways, represent promising future therapeutic targets for thyroid cancer treatment, and further study is required.

Cancer incidence among HIV-positive women in British Columbia, Canada: Heightened risk of virus-related malignancies

We used population‐based data to identify incident cancer cases and correlates of cancer among women living with HIV/AIDS in British Columbia (BC), Canada between 1994 and 2008.

Overview of cancer incidence and mortality among people living with HIV/AIDS in British Columbia, Canada: Implications for HAART use and NADM development

BackgroundThe objective of this study is to evaluate the incidence of non-AIDS defining malignancies (NADMs) among people living with HIV/AIDS (PLWHA) in British Columbia, focusing on clinical correlates, highly active antiretroviral therapy (HAART) use, and survival, in order to elucidate mechanisms for NADM development.MethodsA retrospective population based analysis was carried out for individuals with HIV/AIDS that began their treatment between 1996 and 2008.ResultsThere were 145 (2.95%) NADMs and 123 (2.50%) AIDS defining malignancies (ADMs) identified in 4918 PLWHA in the study population. NADMs were represented by a range of cancer types including, most commonly, lung cancer, followed by anal, breast, head/neck, prostate, liver, rectal, and renal cancers. PLWHA had a SIR of 2.05 (CI:1.73, 2.41) for the development of NADMs compared to individuals without an HIV/AIDS diagnosis in the general population. Independent factors significantly associated with a NADM were: male gender, older age, lower CD4 cell counts, previous NADM, absence of HAART (non-HAART versus HAART) and treatment during the early-HAART era (before 2000 versus after 2000).ConclusionsNADMs represent an important source of morbidity for PLWHA. Use of HAART with its associated improvement in immune-restoration, and tailored targeted cancer screening interventions, may be beneficial and improve outcomes in this unique patient population.