Biomedical subjects

Jeremy Freeman

Publications and source records attributed to Jeremy Freeman.

9 recordsLinked to original sources

PubMed2006

Hürthle cell tumors: applying molecular markers to define a new management algorithm.

OBJECTIVE: To design a new management algorithm for all Hürthle cell tumors and variants based on histopathologic findings and the ret/PTC molecular marker. DESIGN: A retrospective medical record review. SETTING: A large tertiary care teaching center. PATIENTS: Forty-five consecutive cases of Hürthle cell carcinoma were gathered from a database of 661 patients with well-differentiated epithelial thyroid cancers compiled over 22 years. Data collected included patient information, tumor information, and treatment factors. MAIN OUTCOME MEASURES: Outcome parameters included tumor and treatment variables, which were analyzed statistically using the chi(2) and t tests. Disease-free survival and disease-specific survival analyses were performed using Kaplan-Meier analysis. RESULTS: A female-male ratio of 3:1 was found, with a median patient age of 57 years. Twenty-three patients had American Joint Commission on Cancer stage II disease. Treatment factors had no significant effect on disease recurrence or survival. More than half of the patients had histologically proved regional metastases. Vascular invasion significantly diminished disease-specific survival and disease-free interval. CONCLUSIONS: We found a high incidence of Hürthle cell carcinoma with cervical metastasis. On the basis of findings of this study and our previous clinical and molecular findings, we propose a treatment algorithm that combines histologic examination and molecular assays for the ret/PTC gene rearrangements specific to papillary thyroid carcinoma. After permanent section analysis demonstrating Hürthle cell metaplasia, the algorithm mandates completion thyroidectomy in patients with ret/PTC-positive Hürthle cell tumors and clinical observation for ret/PTC-negative Hürthle cell adenomas. We recommend more aggressive treatment of ret/PTC-positive Hürthle cell lesions (or Hürthle cell papillary thyroid cancer), because of the higher incidence of regional metastatic disease.

Adenoma, Oxyphilic↗

PubMed2006

Young patients with oral squamous cell carcinoma: study of the involvement of GSTP1 and deregulation of the Fanconi anemia genes.

OBJECTIVE: To investigate whether oral squamous cell carcinomas (OSCCs) from young (</=40 years) and older (>/=60 years) patients have differential expression levels of GSTP1, FANCA, FANCC, FANCD2, and FANCG. DESIGN: Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemical analysis were used to assess gene and protein expression, respectively. SETTING: This study was performed in a research institute within a hospital setting. PATIENTS: Our study group consisted of 104 patients (42 young and 62 older). We collected RNA from 32 OSCC samples (10 young and 22 older patients) for gene expression analysis. Seventy-seven OSCC samples (37 from young and 40 from older patients) were used for protein expression analysis. Five patients were studied in both analyses. RESULTS: Lower expression of GSTP1 (P = .04) and FANCA (P = .01) was observed in the tumors of young compared with older patients. We also detected lower expression of GSTP1 in the tumors of young patients compared with their nondysplastic mucosa (P = .01). FANCA was underexpressed in nondysplastic mucosa of young compared with older patients (P = .01). GSTP1 protein showed negative or low expression in 41% (n = 15 of 37) of young vs 5% (n = 2 of 40) of older patient tumors (P = .001). FANCG protein expression was absent or low in 81% (n = 30 of 37) of young compared with 36% (n = 15 of 40) of older patient tumors (P<.001). CONCLUSIONS: Differences in expression levels of GSTP1, FANCA, and FANCG in OSCC of young and older patients suggest that different mechanisms may be involved in tumor development through defective carcinogen metabolism and/or DNA repair capabilities. GSTP1 plays a key role in detoxification; therefore, underexpression of this gene in tumors of young patients may cause deficient detoxification that could lead to an increased susceptibility to the development of oral carcinoma.

Adult↗

PubMed2005

Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model.

The molecular mechanisms underlying salivary gland tumorigenesis remain unclear. In order to identify genetic changes that occur during the development of invasive adenocarcinoma from normal salivary gland, we used the Smgb-Tag transgenic mouse model. This transgene induces the progressive development of dysplasia to invasive adenocarcinoma in the submandibular salivary gland. Gene expression patterns from 20 submandibular glands (two normal, nine dysplasia and nine adenocarcinoma samples) were assessed using a mouse 15 K cDNA array. Unsupervised hierarchical clustering was used to group gene expression based on 157 differentially expressed genes distinguishing between dysplasias and adenocarcinomas. Further analysis identified 25 significantly overexpressed and 28 underexpressed cDNA sequences in adenocarcinoma as compared to dysplasia. Differential expression of five genes (Lcn2, Ptn, Cd24a, Mapk6 and Rnps1) was validated by quantitative real-time RT-PCR in a total of 48 mouse salivary gland tissues (seven histologically normal, 13 dysplasias and 28 adenocarcinomas), including the 20 samples analyzed by cDNA arrays. Immunohistochemical analysis was used to validate the expression of Ptn and Cd24a at the protein level in a subset of 16 mouse salivary glands (four normal, five dysplasia and seven adenocarcinoma samples), as well as in 23 human submandibular gland tumors (16 pleomorphic adenomas, three adenoid cystic carcinomas, one acinic cell carcinoma, one adenocarcinoma NOS, one myoepithelial and one mucoepidermoid carcinoma). We thus demonstrated that the Smgb-Tag transgenic mouse model is a useful tool for the identification of genes that are deregulated in salivary gland adenocarcinomas. Our data suggest that Ptn and Cd24a may be genetic markers associated with salivary gland tumorigenesis and/or progression.

Adenocarcinoma↗

PubMed2005

Parathyroid hormone as a predictor of hypocalcemia after thyroidectomy.

OBJECTIVES: The aims of this study are to ascertain whether parathyroid hormone (PTH) assay before total/completion thyroidectomy followed by levels immediately thereafter in the recovery room and the morning after surgery are a reliable predictor of hypocalcemia at our institution. In addition, to determine the feasibility of early discharge home from hospital after total thyroidectomy on the basis of postoperative PTH levels. STUDY DESIGN: Prospective clinical study. METHODS: Two hundred one patients undergoing total thyroidectomy at our institution were enrolled in the study. Preoperative levels of PTH, serum calcium, ionized calcium, and albumin were drawn. In the postoperative phase, the same biochemical markers were taken in the recovery room within 1 hour of the procedure and at a standard time the morning after the procedure. Discharge planning took place as per existing standards. RESULTS: Two hundred and one patients were reviewed. PTH levels below 1.1 pmol/L within 1 hour of completion or total thyroidectomy were predictive of risk for developing hypocalcemia, requiring calcium replacement therapy. PTH levels above 1.6 pmol/L were predictive of patients who would remain normocalcemic. Patients who fell in between these two values require further monitoring with conventional calcium levels. CONCLUSIONS: At our institution, PTH assays drawn postoperatively are predictive of patients who are at risk for developing hypocalcemia. Early identification of at-risk patients will facilitate prompt calcium replacement therapy and potential safe early discharge from hospital.

Biomarkers↗

PubMed2004

Molecular classification of oral cancer by cDNA microarrays identifies overexpressed genes correlated with nodal metastasis.

Our purpose was to classify OSCCs based on their gene expression profiles, to identify differentially expressed genes in these cancers and to correlate genetic deregulation with clinical and histopathologic data and patient outcome. After conducting proof-of-principle experiments utilizing 6 HNSCC cell lines, the gene expression profiles of 20 OSCCs were determined using cDNA microarrays containing 19,200 sequences and the BTSVQ method of data analysis. We identified 2 sample clusters that correlated with the T3-T4 category of disease (p = 0.035) and nodal metastasis (p = 0.035). BTSVQ analysis identified a subset of 23 differentially expressed genes with the lowest QE scores in the cluster containing more advanced-stage tumors. Expression of 6 of these differentially expressed genes was validated by quantitative real-time RT-PCR. Statistical analysis of quantitative real-time RT-PCR data was performed and, after Bonferroni correction, CLDN1 overexpression was significantly correlated with the cluster containing more advanced-stage tumors (p = 0.007). Despite the clinical heterogeneity of OSCC, molecular subtyping by cDNA microarray analysis identified distinct patterns of gene expression associated with relevant clinical parameters. Application of this methodology represents an advance in the classification of oral cavity tumors and may ultimately aid in the development of more tailored therapies for oral carcinoma.

Adult↗

PubMed2003

Preoperative radiotherapy for adult head and neck soft tissue sarcoma: assessment of wound complication rates and cancer outcome in a prospective series.

Combination surgery and radiotherapy (RT) is frequently used in soft tissue sarcoma (STS). Because lower doses and smaller irradiation volumes are possible in preoperative RT (pre-op RT), this approach can be especially valuable in anatomic settings where critical organs are in close proximity to the RT target area. A recent multicenter phase III trial (SR.2 trial of the National Cancer Institute of Canada Clinical Trials Group) comparing pre-op RT against post-op RT for extremity STS has shown significantly higher major wound complication rates (35%) with pre-op RT. We postulated that wound complication rates may be less frequent in the head and neck with better vascularity and wider use of secondary wound reconstruction. Using a prospective database, we identified 40 consecutive patients with head and neck STS treated with pre-op RT (50 Gy) and subsequent (4 to 6 weeks later) resection between 1/89 and 8/99 in a single institution setting. Major wound complications (MWC) were classified by the identical criteria used in the SR.2 trial. Intracranial extension was evident in 5 patients, whereas 50% of the patients had large tumors (> 5 cm). Deep tumor was present in 34 (85%), and 6 (15%) were superficial to fascia. In this series, 31 patients (77.5%) had secondary reconstruction of the acquired soft tissue deficit. The actuarial 2-year local relapse-free rate was 80%, and the metastatic relapse-free rate was 85%. Major wound complications occurred in 8 of 40 patients (20%) within 120 days of surgery according to the SR.2 criteria: secondary wound surgery (3), readmission or prolonged hospital admission for wound care (2), deep packing (0), prolonged dressing changes (2), and invasive procedure for wound care (1). The latter was a minor wound management problem (a single outpatient drainage of a seroma) for the combined rate of 8/20 or 20%. Our findings show that (1) pre-op RT in head and neck STS is associated with lower rates of major wound complications compared to extremity cases; (2) pre-op RT provides high rates of local control in an adverse group of cases of adult head and neck STS; (3) the choice of scheduling of RT should be based on anatomic issues with emphasis on the trade-offs between RT doses and volumes versus wound morbidity for individual patients. This is especially important when tumor may be adjacent to critical head and neck structures which may be protected from the high-dose RT area.

Adolescent↗

PubMed2003

Expression of p53 in inverted papilloma and malignancy associated with inverted papilloma.

OBJECTIVE: To determine the association of p53 protein in malignant cases of inverted papilloma compared with cases of benign inverted papilloma of the sinonasal tract. DESIGN: Case-control study of archived pathologic material. SETTING: Tertiary care hospital. METHODS: Archived pathologic material of cases of malignancy associated with inverted papilloma and controls of benign inverted papilloma were obtained from Mount Sinai Hospital. These were subjected to immunohistochemistry for p53. Clinical correlation was obtained by retrospective chart review. MAIN OUTCOME MEASURES: Staining of pathologic specimens for p53 and survival or recurrence. RESULTS: Four of the five cases of malignancy associated with inverted papilloma demonstrated overexpression of p53. None of the benign cases of inverted papilloma demonstrated overexpression. Only two of the five patients with malignancy associated with inverted papilloma were alive at 2 years. CONCLUSIONS: Overexpression of p53 may serve as a marker for malignant transformation of inverted papilloma.

Case-Control Studies↗

PubMed2002

Hürthle cell tumors: using molecular techniques to define a novel classification system.

BACKGROUND: Since ret/PTC gene rearrangements are specific to papillary thyroid carcinoma (PTC), the diagnosis of Hürthle cell PTC (HCPTC) has recently been expanded to include a subset of Hürthle cell tumors (HCTs) that may lack both papillary architecture and/or classic nuclear features but that harbor a ret/PTC gene rearrangement. We hypothesize that such HCPTCs behave in a fashion analogous to other papillary carcinomas, while Hürthle cell carcinomas (HCCs) behave similarly to follicular carcinomas. EDUCATIONAL OBJECTIVES: At the conclusion of this article, participants should be able to discuss HCTs and to identify HCPTCS using molecular techniques. METHODS: A retrospective chart review was carried out on 56 patients with HCTs. All pathological specimens were analyzed for ret/PTC gene rearrangements. Hürthle cell adenoma (HCA) was defined as an HCT that did not exhibit capsular and/or vascular invasion and that lacked a ret/PTC gene rearrangement when evaluated by immunohistochemical and reverse transcription polymerase chain reaction analysis. An HCC was defined as an HCT with capsular and/or vascular invasion that lacked a ret/PTC gene rearrangement, and an HCPTC was defined as any HCT that harbored a ret/PTC gene rearrangement. RESULTS: The subclassification of the 56 HCTs was as follows: 21 HCAs, 15 HCCs, and 20 HCPTCs. No patients with HCA or HCC were ret/PTC positive. Five of the 6 patients with definite lymph node metastasis were in the HCPTC group, demonstrating that molecular analysis helps to explain biological behavior. CONCLUSIONS: Hürthle cell neoplasms can now be classified using histopathological as well as molecular criteria. It appears that the new subclassification of malignant HCTs into follicular (HCC) and papillary (HCPTC) variants identifies 2 distinct biological groups.

Adenoma, Oxyphilic↗

PubMed2002

Genetic events in the evolution of thyroid cancer.

OBJECTIVE: To delineate the evolution of thyroid cancer using the Volgelstein model of cancer evolution and to demonstrate the genetic "hits" in the development of undifferentiated cancer from normal thyroid cells. METHOD: Immunohistochemical and molecular biologic techniques were used to delineate the prevalence of (1) the ras oncogene, (2) p53, and (3) the ret/PTC oncogene in the development of differentiated thyroid cancer from normal cells and hyperplasia. The evolution of differentiated thyroid cancer to the dedifferentiated or anaplastic type was also investigated. The methodology used was standard immunohistochemical staining techniques as well as polymerase chain reaction technology for the elucidation of these various oncogenes and tumour suppressor genes. RESULTS: We have demonstrated that there is a high preponderance of ras and ret/PTC oncogenes in the evolution of thyroid cancer. Further along the continuum, p53 has been demonstrated to be prevalent in the development of dedifferentiated thyroid cancer (i.e., tall cell and insular variety as well as anaplastic cancer). CONCLUSION: Several genetic hits have been demonstrated to be prevalent in the evolution of thyroid cancer. These are preliminary oncogenic maps, and further work in this area will help to establish a definite biologic pattern in the development of this malignancy.

Carcinoma, Papillary↗