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Sam M Wiseman

Publications and source records attributed to Sam M Wiseman.

At least 19 recordsLinked to original sources
PubMed2006

Anaplastic thyroid carcinoma: expression profile of targets for therapy offers new insights for disease treatment.

BACKGROUND: Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment. METHODS: Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984-2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, beta-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin. RESULTS: A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0-100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: beta-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%). CONCLUSIONS: Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.

Aged↗
PubMed2006

Meta-analysis and meta-review of thyroid cancer gene expression profiling studies identifies important diagnostic biomarkers.

PURPOSE: An estimated 4% to 7% of the population will develop a clinically significant thyroid nodule during their lifetime. In many cases, preoperative diagnoses by needle biopsy are inconclusive. Thus, there is a clear need for improved diagnostic tests to distinguish malignant from benign thyroid tumors. The recent development of high-throughput molecular analytic techniques should allow the rapid evaluation of new diagnostic markers. However, researchers are faced with an overwhelming number of potential markers from numerous thyroid cancer expression profiling studies. MATERIALS AND METHODS: To address this challenge, we have carried out a comprehensive meta-review of thyroid cancer biomarkers from 21 published studies. A gene ranking system that considers the number of comparisons in agreement, total number of samples, average fold-change and direction of change was devised. RESULTS: We have observed that genes are consistently reported by multiple studies at a highly significant rate (P < .05). Comparison with a meta-analysis of studies reprocessed from raw data showed strong concordance with our method. CONCLUSION: Our approach represents a useful method for identifying consistent gene expression markers when raw data are unavailable. A review of the top 12 candidates revealed well known thyroid cancer markers such as MET, TFF3, SERPINA1, TIMP1, FN1, and TPO as well as relatively novel or uncharacterized genes such as TGFA, QPCT, CRABP1, FCGBP, EPS8 and PROS1. These candidates should help to develop a panel of markers with sufficient sensitivity and specificity for the diagnosis of thyroid tumors in a clinical setting.

Biomarkers, Tumor↗
PubMed2006

Genomic profiles of colorectal cancers differ based on patient smoking status.

Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-beta signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-beta RII mutations were more common among nonsmokers.

Adult↗
PubMed2006

Normocalcemic parathyroid carcinoma: an unusual clinical presentation.

BACKGROUND: Parathyroid carcinoma is a rare cause of primary hyperparathyroidism and may be associated with significant disease related morbidity and mortality. Preoperative diagnosis remains a challenge, which may jeopardize appropriate and successful patient treatment. CASE PRESENTATION: We report a case of parathyroid carcinoma diagnosed in a 60-year-old woman that presented with a tender nodule located at the left lower thyroid pole and had been present for several years. Ultrasound examination revealed a 2.7 x 1.6 x 2.7 cm mass within the lower left lobe of the thyroid with cystic and solid areas. Lab measurement of the intact PTH level revealed it to be three times the upper limit of normal and the serum calcium level was within normal limits. A left thyroid lobectomy and isthmusectomy was carried out. Histopathological evaluation was diagnostic for a parathyroid carcinoma. At greater than two years of follow-up, the patient has had no evidence of disease recurrence and her serum PTH and calcium levels have remained within normal. CONCLUSION: Parathyroid carcinoma is a rare endocrine tumor which must be considered in the differential diagnosis of a nodular thyroid mass. En bloc resection remains the treatment of choice for this malignancy. Disease prognosis is influenced by the extent of the initial resection, the presence of metastases, and adequate long-term follow-up.

Journal Article↗
PubMed2006

Hemithyroidectomy: the optimal initial surgical approach for individuals undergoing surgery for a cytological diagnosis of follicular neoplasm.

BACKGROUND: The primary objective of this study was to determine the true proportion and optimal surgical approach for individuals undergoing thyroid operation for a suspicion of cancer based on a fine-needle aspiration biopsy diagnosis of a follicular neoplasm (FN). A secondary objective of this study was to determine whether patient characteristics could assist the clinician in predicting malignancy in this FN patient cohort. METHODS: A retrospective chart, pathology, and cytology review of 370 consecutive primary thyroid operations was performed over a 4-year period at a tertiary care referral center. Clinical patient data were evaluated as an adjunct for predicting malignancy in the FN patient cohort. Univariate and multivariate analyses were used to investigate the association and the predictability. RESULTS: A total of 80 (22%) of the 370 patients underwent hemithyroidectomy to rule out cancer based on clinical presentation with a fine-needle aspiration biopsy diagnosis of FN. Fifteen (19%) of the FN cases were diagnosed as cancer by histological analysis (4 follicular carcinomas and 11 papillary carcinomas). Hemithyroidectomy was considered adequate treatment for 77 patients (96%). No patient characteristic significantly predicted the presence of cancer by either univariate or multivariate analysis. CONCLUSIONS: Overall, in the FN patient population, five hemithyroidectomies were performed to identify each cancer, and no further operation was required in 96% of patients. New diagnostic tools are needed to reduce the number of operations performed for benign pathology in patients with nodular thyroid disease and a needle biopsy diagnosis of FN.

Adenocarcinoma, Follicular↗
PubMed2006

Genomic instability in invasive breast carcinoma measured by inter-Simple Sequence Repeat PCR.

We have measured genomic instability in invasive breast carcinomas and assessed the relationship of genomic instability to known tumor prognostic factors. DNAs from tumors and adjacent normal tissue of 18 breast cancer patients were subjected to inter-Simple Sequence Repeat (inter-SSR) PCR for quantitation of tumor genomic instability. Associations between genomic instability level and known breast cancer prognostic factors were evaluated using the Pearson Product Moment Correlation, the Kruskal-Wallis test of independent samples and the Mann-Whitney non-parametric test. Genomic instability was detected by inter-SSR PCR in over 90% of the breast tumors. The mean instability index was 3.08% (0-7.59%), approximately the same mean value observed in studies of colorectal and thyroid carcinomas. Significantly higher levels of instability were associated with tumors exhibiting necrosis. Genomic instability as measured is detected in the majority of breast cancers at levels comparable to other tumor types. Hypoxia, such as that observed in necrotic regions of tumors, has been associated with elevated genomic damage. We hypothesize that the higher levels of genomic instability detected in necrotic tumors is a consequence of hypoxia-associated DNA damage.

Adult↗
PubMed2006

Derangement of the E-cadherin/catenin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid cancer arises, or transforms, from pre-existing differentiated thyroid cancer. E-cadherin functions as a cell-cell adhesion molecule that complexes with catenin proteins for function. The objective of this study was to evaluate the change in E-cadherin/beta-catenin expression in the transformation of differentiated to anaplastic thyroid carcinoma. METHODS: A tissue microarray was constructed from 12 anaplastic thyroid tumors and their adjacent associated differentiated foci. Immunohistochemistry was used to evaluate tumor expression of E-cadherin and beta-catenin. RESULTS: There was decreased expression of E-cadherin and beta-catenin by the anaplastic tumors when compared with the differentiated thyroid tumors from which they evolved. The expression of E-cadherin and beta-catenin was 92% and 67%, respectively, by the differentiated thyroid carcinoma, and 17% and 50%, respectively, by the anaplastic tumors. CONCLUSIONS: This report shows that derangement of the E-cadherin/catenin complex is associated with the transformation of differentiated into anaplastic thyroid carcinoma.

Aged↗
PubMed2005

Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival.

BACKGROUND: The clinical significance of coexpression of type 1 growth factor receptor (T1GFR) family members remains largely unknown. The objective of the current study was to determine the frequency and the possible prognostic effect of coexpression of HER-1, HER-2, HER-3, and HER-4 by breast carcinoma. METHODS: Tissue microarrays were constructed using clinically annotated formalin-fixed, paraffin-embedded tumor samples from 242 patients with invasive breast carcinomas with a median 15-year follow-up. The levels of TIGFR family members (HER-1-HER-4) were measured by immunohistochemistry. K-means clustering algorithm, as well as univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) survival analyses were applied to the data set. RESULTS: Using univariate analysis, expression of HER-1, HER-2, and HER-3, but not HER-4, was significantly associated with decreased patient disease-specific survival (P < 0.05). Kaplan-Meier survival analysis showed that coexpression of >/= 2 of HER-1, HER-2, and HER-3 in any combination was associated with reduced patient disease-specific survival compared with single marker expression or no expression (35% vs. 65% vs. 78% 10-year survival rates, P = 0.001). Using multivariate analysis, expression of >/= 2 of HER-1, HER-2, and HER-3 was independent of lymph node status and tumor size. CONCLUSIONS: In a cohort of patients with breast carcinoma, the authors observed T1GFR family member coexpression (HER-1, HER-2, and HER-3) to have a negative synergistic effect on patient outcome, independent of tumor size or lymph node status. Thus, coexpression of T1GFR family members identified a subset of patients with a poor disease prognosis who may potentially benefit from therapy simultaneously targeting several T1GFR family members.

Biomarkers, Tumor↗
PubMed2005

Selective unilateral parathyroid exploration: an effective treatment for primary hyperparathyroidism.

BACKGROUND: Unilateral neck exploration (UNE) is a well-recognized approach in the treatment of primary hyperparathyroidism (PHP). The objective of this study was to review the success of an approach involving UNE guided by preoperative sestamibi (SM) scanning. METHODS: All data were gathered by retrospective chart review. All patients undergoing surgery for the treatment of primary hyperparathyroidism at a tertiary referral center over a 3-year period were included in the study cohort. RESULTS: Fifty-two of 80 patients (65%) had an SM scan consistent with a solitary adenoma and were eligible for a UNE, with 57.5% (46/80) undergoing a UNE. Seventy-seven of 80 (96.3%) patients were normocalcemic after initial neck exploration. UNE was curative in 50 of 52 (96.2%) UNE eligible patients and required less operative time than bilateral neck exploration (mean, 60 versus 87 minutes). CONCLUSION: Selective unilateral neck exploration, guided by preoperative SM scanning, is an effective surgical approach for the management of primary hyperparathyroidism.

Adenoma↗
PubMed2005

Advanced soft palate cancer: the clinical importance of the parapharyngeal space.

OBJECTIVE: To identify the incidence of parapharyngeal space (PPS) recurrences and how they impact survival in advanced-stage soft-palate carcinoma patients. STUDY DESIGN AND SETTING: One hundred thirty-seven patients' charts were reviewed from 1971 to 1996. Inclusion criteria were patients who received a per-oral resection, discontinuous neck dissection, and postoperative adjuvant radiation therapy; 15 patients met criteria for inclusion. The incidence of PPS recurrences, regional failure, and survival were endpoints that were analyzed. RESULTS: There were no local failures in our study. Regional failures excluding the PPS (levels I-V) were 27%, and 40% occurred within the PPS. Cervical adenopathy was associated with 83% of the PPS recurrences. Median survival for PPS recurrences was 26 months, compared with 67 months for levels I-V recurrences (n = ns). CONCLUSIONS: The incidence of PPS recurrences is substantial in advanced-stage soft-palate cancer. PPS recurrences negatively impact survival; without effective salvage techniques for these recurrences or effective adjuvant therapy, poor patient outcomes can be expected.

Adult↗
PubMed2004

Upregulation of the tissue inhibitor of metalloproteinase-1 protein is associated with progression of human non-small-cell lung cancer.

PURPOSE: Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been shown that TIMP-1 may be a multifunctional protein. Little is known about the role of TIMP-1 in progression and metastasis of human lung cancer (tumor inhibiting or tumor promoting), although studies using a variety of techniques have analyzed the expression of TIMP-1 mRNA and/or protein in human cancers. PATIENTS AND METHODS: We examined the expression of TIMP-1 protein by immunohistochemistry in patients (n = 160) with primary respectable (stage I to IIIA) non-small-cell lung cancer (NSCLC). RESULTS: Twenty-seven percent of the tumors (43 of 160) demonstrated elevated expression of this protein. We demonstrate that overexpression of TIMP-1 protein is associated with an adverse outcome. In addition, disease stage, patient's age, and performance status were all significantly related to survival. In multivariate analyses, patients with high TIMP-1 expression had a 90% increased risk of death when compared with those with low expression (relative risk, 1.92; 95% CI, 1.19 to 3.09; P =.008). TIMP-1 expression did not correlate with expression of MMP-2 and MMP-9. CONCLUSION: These results suggest that TIMP-1, independent of its inhibiting activity of MMPs, may have other function(s) critical for NSCLCs. The significance of our results is two-fold. The adverse outcome in patients with overexpression of TIMP-1 indicates its potential prognostic value in NSCLC. Thus, TIMP-1 overexpression may serve to help identify patients with particularly aggressive disease for adjuvant treatments. In addition, the TIMP-1 molecule may represent a novel therapeutic target for treatment of some NSCLCs.

Adult↗
PubMed2004

The role of genomic instability in the pathogenesis of squamous cell carcinoma of the head and neck.

Measurements of genomic instability, or identification of genes responsible for instability, may potentially be used as molecular markers to predict disease course and response to therapy. Other possible applications include use of genomic instability measurements, or genes, as tools to screen for primary or recurrent disease. Methodologies for detection of genetic mutations in saliva, blood, and sputum have already been described[61,62]. Brennan et al [63] have described a molecular technique for analyzing histopathologically negative margins and lymph nodes for the presence of p53 gene mutation. This study showed that a positive molecular margin significantly predicted disease recurrence. The recognition that HNSCC is a genetically heterogeneous disease represents a major step toward developing an understanding of its underlying genetic basis. To develop an insight into this genetically heterogeneous disease, investigators must not only focus their efforts on specific head and neck disease sites. Laser-capture microdissection represents a powerful tool for isolating very specific cell populations from tumors [64]. Leethanakul et al[65] performed laser-capture microdissection on oral cavity SCC to construct stage-specific cDNA libraries. Sequencing of 96 clones from each of the six libraries constructed suggested the existence of 132 novel genes, which may play a role in the pathogenesis of HNSCC. The current literature suggests that many individuals diagnosed withHNSCC are genetically predisposed to developing malignancy because of some inherent deficiency of their capacity to maintain their genome in the presence of environmental stressors. Head and neck cancers are highly heterogeneous tumors and exhibit a wide variety of forms of genomic instability. Thus, genomic instability may be viewed as a fundamental force driving head and neck tumorigenesis and evolution. Future study of the specific genetic mechanisms that underlie genomic instability in the HNSCCpatient population is needed. It is only through study of this fundamental force that drives the development of these tumors that clinicians may gain the insight required to develop new diagnostic and therapeutic modalities to benefit the HNSCC patient population as a whole.

Carcinoma, Squamous Cell↗
PubMed2004

Neck dissection: current concepts and future directions.

For individuals diagnosed with head and neck cancer, neck dissection may be performed for therapy or disease staging. The classification of neck dissection and the definition of precise anatomic landmarks have allowed for this operation, and its many variations, to become standardized world-wide. SLNBX shows promise in its ability to accurately stage NO head and neck cancer and may allow patients with no micro metastatic disease to avoid neck dissection. Before this technique becomes adopted into routine clinical practice, however, it must first be prospectively scrutinized in large patient populations. Regardless of the future role of SLNBX in the management of head and neck cancer, currently it is only through a complete understanding of the clinical, theoretic, and technical aspects of neck dis-section that surgeons may benefit individual patients and the head and neck cancer patient population as a whole.

Carcinoma, Squamous Cell↗
PubMed2004

Parathyroid carcinoma: a multicenter review of clinicopathologic features and treatment outcomes.

We conducted a retrospective study of 13 patients with parathyroid carcinoma to assess their clinical characteristics and surgical outcomes. Study parameters included patient demographics, survival, treatment response, and recurrence. We found that all patients who had undergone local tumor excision developed a recurrence, compared with only 33% of those available for follow-up after en bloc tumor resection. Based on these findings, we recommend en bloc tumor resection as the initial treatment of choice for patients diagnosed with parathyroid carcinoma.

Adult↗
PubMed2003

Anaplastic thyroid cancer evolved from papillary carcinoma: demonstration of anaplastic transformation by means of the inter-simple sequence repeat polymerase chain reaction.

BACKGROUND: In thyroid tumors, the coexistence of well- and poorly differentiated tumor types has led to the hypothesis that poorly differentiated thyroid tumors develop from well-differentiated thyroid tumors. By evaluating the genomic instability of histologically distinct but coexisting tumor foci, this study aimed to develop an improved understanding of thyroid tumorigenesis and tumor evolution. DESIGN: Laser capture microdissection (LCM) was carried out on archival formalin-fixed, paraffin-embedded sections from a tumor containing foci of classic papillary thyroid cancer and anaplastic thyroid cancer. DNA was extracted from each microdissected tumor focus. In addition, cryopreserved bulk normal and neoplastic thyroid tissue underwent DNA extraction. All DNA samples were subsequently evaluated for genomic instability by means of inter-simple sequence repeat polymerase chain reaction. RESULTS: The LCM DNA from each archival paraffin-embedded tumor focus demonstrated unique patterns of banding as compared with the cryopreserved tumor and normal tissue DNA. Thus, intratumoral variability in genomic instability was observed. Comparison of inter-simple sequence repeat polymerase chain reaction patterns of LCM DNA from adjacent foci of papillary and anaplastic tumors showed conserved genome alterations. CONCLUSIONS: At the genome level, thyroid tumors may be highly heterogeneous. The intratumoral histologic heterogeneity observed in thyroid neoplasms reflects genetically heterogeneous underlying tumor cell populations that are demonstrated by the observed differences in their rates and extents of genomic instability. The conserved genomic alterations in the microdissected papillary and anaplastic foci suggest intratumoral evolution, with transformation of a preexisting papillary tumor to anaplastic carcinoma.

Aged↗
PubMed2003

Anaplastic transformation of thyroid cancer: review of clinical, pathologic, and molecular evidence provides new insights into disease biology and future therapy.

BACKGROUND: Anaplastic thyroid cancer ranks among the most lethal of all human malignancies. Its rarity and rapidly fatal course have made it a difficult cancer to both study and treat. Unfortunately, there has been little progress in the management and control of this malignancy. Anaplastic transformation, or the intratumoral evolution of anaplastic carcinoma from pre-existing differentiated thyroid cancer, has become a well-accepted process, despite a limited understanding of its underlying mechanisms. METHODS: It is through review of the literature that an understanding of the aggressive disease biology can be developed. The aim of this review is to evaluate the relevant clinical, pathologic, and molecular studies to develop an insight into the mechanisms that underlie the intratumoral molecular evolution of anaplastic thyroid carcinoma. RESULTS/CONCLUSION: It is based on an understanding of this process that effective treatments for this aggressive malignancy are currently being developed.

Carcinoma↗
PubMed2003

Papillary thyroid cancer: high inter-(simple sequence repeat) genomic instability in a typically indolent cancer.

OBJECTIVES: The object of this study is to measure genomic instability in papillary thyroid cancer and correlate these measurements with known clinical prognosticators such as patient age, tumor size, histologic subtype, and three commonly used thyroid risk assessment indices. A secondary objective of this study was to use the measurements of genomic instability to estimate the number of mutational events present in the papillary thyroid cancer genome. METHODS: Inter-simple sequence repeat polymerase chain reaction (ISSR-PCR) is a rapid and reproducible technique for quantitation of genomic instability, or the degree of genome alteration, in solid tumors. This includes quantitation of amplifications, deletions, translocations, and insertions. Twenty-eight papillary carcinomas were evaluated by ISSR-PCR. RESULTS: Evaluation of 28 papillary carcinomas by ISSR-PCR demonstrated a wide range of genomic instability. Of the panel of clinicopathologic factors examined, only patient age was significantly associated with genomic instability. The mean genomic instability index value was greatest in the youngest age group, which was significantly different from the median value measured in the oldest age group (3.7, 2.5, respectively, p =.05). The mean value in the intermediate age group fell between the younger and older groups (3.1). By use of ISSR-PCR, we have calculated 15,000 individual genomic events as having occurred in each papillary tumor cell. CONCLUSIONS: Despite its generally indolent biologic behavior, papillary thyroid cancer exhibits a high degree of genomic instability comparable to that seen in colorectal cancer. These results suggest that elevated genomic instability, as measured by ISSR-PCR, may not be sufficient to enable thyroid tumor progression to less indolent disease and that this process is severely constrained by some additional essential factor such as the differentiated state of the tissue or the need to bring into play an additional form of genomic destabilization.

Adolescent↗