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RA JIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA ANNEXURE – II Proforma for Registration of Subjects for Dissertation 1 Name and Address of Dr. Nandini Mohan. C., the Candidate Postgraduate Student, Dept. of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre, Bangalore – 560 076. 2 Name of the Institution AECS Maaruti College of Dental Sciences and Research Centre. 3 Course of Study and Master of Dental Surgery Subject 4 Oral and Maxillofacial Pathology. Date of Admission to June 2013 the Course 5 Title of the Topic Expression of Human Chorionic Gonadotropin-β in serum and tissue sections of preoperative oral squamous cell carcinoma patients. 6. Brief resume of intended work: Head and neck cancer is the sixth most common type of cancer in the world. Histopathologically, Squamous Cell Carcinoma (SCC) is by far the most frequent histological type of this disease. After curative treatment, about 50% of the patients develop a recurrence and 80% of the relapses occur within the first 2 years of follow up. About 50% of the patients with SCC of head and neck die from cancer with no significant improvement during recent decades1. In the management of patients with SCC of head and neck, treatment decisions are still based on the TNM classification system, although T and N status do not reliably predict the clinical outcome in individual cases. Thus, effective treatment planning would be enhanced by identification of prognostic indicators that would reflect the biological behavior of a tumor. The identification of a reliable circulating tumor marker therefore has great potential. Although new potential prognostic markers are continuously being introduced and evaluated in SCC of head and neck, so far none has influenced standard treatment1. Human Chorionic Gonadotropin (hCG) is a hormone belonging to the glycoprotein family. It is initially secreted by the pre-implantation embryo and subsequently by trophoblasts. It is responsible for rescue of the corpus luteum, thereby sustaining progesterone secretion until placental progesterone synthesis commences. hCG is a heterodimeric molecule consisting of an α-subunit noncovalently associated with a hormone specific β-subunit. The α-subunit is common to hCG, Luteinising hormone, Follicle stimulating hormone and Thyroid stimulating hormone and contains 92 amino acids. The β-subunit of hCG confers biological specificity and contains 145 amino acids2. hCG is normally produced in significant amounts only during pregnancy. It is also ectopically made by trophoblastic as well as non-trophoblastic(colon, prostate, bladder, breast and lung) carcinomas3. β-hCG has therefore been proposed as a cancer marker of broad utility. In general, hCG and/or subunit synthesis is seen in poorly differentiated tumors. hCG expression is prominent in metastatic cancers and is associated with poor prognosis4. Survival time of patients with hCG expressing cervical, pancreatic and colorectal cancers has been reported to be statistically shorter than those with hCG negative neoplasms. In bladder cancer as well, the serum level of hCG is considered a prognostic indicator of disease. The presence of hCG has been linked to chemo- and radio- resistance and the molecule has been shown to increase invasiveness1. Thus evaluation of β-hCG levels in patients with SCC of oral cavity has significant diagnostic and prognostic value. 6.1 Need for the Study: The aim of this study is to observe the expression of hCG-β in serum by ELISA and its immunohistochemical expression in tissue sections of patients with oral squamous cell carcinoma preoperatively and to quantify and compare the same. 6.2 Review of Literature: Iles R K et al (1990) studied the expression of hCG-β by non-trophoblastic, nonendocrine, normal and malignant epithelial cells. They examined 83 different cell lines derived mainly from common epithelial tumours. 32 of the cell lines were found to secrete hCG like material into their culture media. Partial immunochemical characterization showed that of these only choriocarcinoma and fetal tissue cell lines produced intact hCG and α-subunit. The remaining 28 hCG expressing epithelial cell lines, which are of mucosal origin, only secreted free β-subunit. Expression of free hCG-β by non trophoblastic non endocrine cells would appear to be especially characteristic of mucosal epithelia from the genitourinary and oral/respiratory tracts. It may also show squamous cell-like properties. Marcillac I et al (1992) studied free hCG-β subunit in serum of patients with gonadal neoplasms and nongonadal neoplasms and concluded that detection of free hCG-β subunit in serum of nonpregnant subjects was highly diagnostic of malignancy in general and specifically defines a subgroup of aggressive nongonadal malignancies. Sheaff M T et al (1996) studied the importance of immunohistological detection of hCGβ in localized prostatic adenocarcinoma with regard to prognosis and clinical applications. They studied 80 cases of clinically localized adenocarcinoma of prostate and found that hCG-β was detected in 12 cases. 9 of these patients were found to have metastases at follow up and 11 were dead within 18 months. They thus concluded that the demonstration of hCG-β in prostatic adenocarcinoma identifies a group of patients with poor prognosis, irrespective of histological grade. This information is extremely valuable in the subsequent clinical management of such patients. Johan Hedstrom et al (1999) studied the concentration of free hCG-β subunit in serum as a prognostic marker for squamous cell carcinoma of oral cavity and oropharynx. They studied 59 cases of squamous cell carcinoma of oral cavity and oropharynx preoperatively. Elevated preoperative hCG-β levels were observed in 8 patients and these patients showed shorter recurrence free survival than those with normal hCG-β levels. Risk for recurrent disease in patients with preoperatively elevated hCG-β was 3.6 folds more than that of patients with normal hCG-β levels. Bhalang et al (1999) conducted an immunohistochemical study of the expression of hCG-β in Oral Squamous Cell Carcinomas (OSCC) in comparison with oral fibromas. hCG-β immunoreactivity was identified in 29 of 45 cases of oscc. hCG-β immunoreactivity could not be demonstrated in any of the oral fibromas. hCG-β staining was positive in 5 of 15 cases of well differentiated OSCC, in 12 of 15 cases of moderately differentiated OSCC, and 12 of 15 cases of moderately to poorly differentiated OSCC, thus concluding that the presence of hCG-β positive tumor cells appears potentially to reflect a malignant behavior of OSCC. Hotakainen K et al (2003) studied expression of free hCG-β subunit in Renal Cell Carcinoma (RCC) both in serum and tumor specimens. The prognostic value of hCG-β in serum and tissue and its association with usual clinicopathological variables were analysed. They concluded that serum concentration of hCG-β is an independent prognostic variable in RCC and its tissue expression is not significantly associated with prognosis. 6.3 Objectives of the Study: 1) To observe the level of hCG-β in serum of patients with oral squamous cell carcinoma and normal volunteers. 2) To evaluate the degree of expression of hCG-β in tumor specimens of oral squamous cell carcinoma immunohistochemically and to correlate with grades of oral squamous cell carcinomas. 3) To correlate serum hCG-β levels and its expression in tumor specimens of different grades of oral squamous cell carcinomas. 7 .Materials and Methods: 7.1 Source of Data: Patients with oral squamous cell carcinoma reported to the Department of Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Hrudayalaya, Bangalore. 7.2 Method of collection of data 7.2.1 Sample Size: 60 preoperative patients with oral squamous cell carcinoma. 20 volunteers. 7.2.2 Study Material: Serum of patients with oral squamous cell carcinoma. Serum of volunteers. Formalin-fixed paraffin-embedded blocks of the tumor specimen of the same patients. ELISA kit. IHC kit. 7.2.3 Study Method: hCG-β levels will be evaluated in the serum of patients with oral squamous cell carcinoma using ELISA kit. Tumor specimen from the same patients will be stained with IHC kit using mouse anti-hCG-β antibody. In each case expression and quantification of hCG-β will be performed in both serum and tumour specimens. Serum hCG-β levels of patients will be compared with volunteers. The data collected will be subjected to appropriate statistical analysis. 7.2.4 Study Design: Cross sectional study 7.3 Inclusion Criteria: 1. Preoperative Oral Squamous Cell Carcinoma patients. 7.4 Exclusion Criteria: 1. Oral Squamous Cell Carcinoma patients undergoing treatment. 2. Oral Squamous Cell Carcinoma patients with history of treatment. 3. Patients with any other carcinomas. 7.5 Does the study require any investigation or interventions to be conducted on patients or other humans or animals? If so, please describe briefly. Yes. 5ml of blood sample and biopsy specimen will be collected from the patients with oral squamous cell carcinoma and 5ml of blood sample will be collected from the volunteers after obtaining informed consent from them. 7.6 Has ethical clearance been obtained from your institution for this study? Yes. The study would be conducted in the department of Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Hrudayalaya, Bangalore and permission has been obtained from the internal review board and the ethical committee of the institute 8 List of References: 1) Hedstrom J, Grenman R, Ramsay H, Finne P, Lundin J, Haglund C et al. Concentration of free hCG-β subunit in serum as a prognostic marker for squamous cell carcinoma of the oral cavity and oropharynx. International Journal of Cancer 1999 Oct 22; 84(5): p.525-528. 2) Kanokporn B, Abdel H.K, Dale A. Miles. Immunohistochemical study of the expression of hCG-β in oral squamous cell carcinoma. American Cancer Society 1999 Feb15; 85 (4): p.757-762 3) IlesR K, Purkis P E, Whitehead P C, Oliver R T D, Leigh I , Chard T. Expression of β-hCG by non-trophoblastic non-endocrine ‘normal’ and malignant epithelial cells. Br. J. Cancer 1990; 61: p.663-6. 4) Sheaff M T, Martin J E, Badenoch D F, Baithun S I. β-hCG as a prognostic marker in adenocarcinoma of the prostate. J. Clin Pathol 1996; 49: p.329-332 5) Marcillac I, Troalen F, Bidart J.. Free hCG-β subunit in gonadal and nongonadal neoplasms. Cancer Res 1992; 52: p.3901-07 6) Hotakainen K, Ljungberg B, Haglund C, Nordling S, Paju A and Stenman U.Expression of free β subunit of hCG in renal cell carcinoma: Prognostic study on tissue and serum. Int J Cancer 2003; 104: p.631-635. 7) Alfthan H, Haglund C, Dabek J, and Sntenman U. Concentrations of Human Choriogonadotropin, Its β-subunit, and the core fragment of the β-subunit in serum and urine of men and nonpregnant women. Clinicalchemistry1992; 38:10. 8) Cole L, Kardana A, Ying F, Birken S. The biological and clinical significance of nicks in Human Chorionic Gonadotropin and its free β- subunit. The Yale Journal of Biology and Medicime 1991;64:627-637 9. Signature of the Candidate: 10. Remarks of the Guide: 11. Name and Designation of the Guide/s: 11.1. Guide : Dr. PUSHPALATHA MAHESH PROFESSOR Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre, Bangalore – 560 076 11.2. Signature: 11.3. Co-Guide (if any): 11.4. Signature: 11.5. Head of the Dept.: DR. P.SHARADA, PROFESSOR & HEAD, Department of Oral and Maxillofacial Pathology, AECS Maaruti College of Dental Sciences and Research Centre, Bangalore – 560 076 11.6. Signature: 12. Remarks of the Chairman and Principal: 12.1. Signature: PATIENT CONSENT FORM Name: Age : Sex: Address : Biopsy obtained from (site): I hereby give my consent to the Department of Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Hrudayalaya, Bangalore to use my blood sample and the biopsy specimen (Incisional/Excisional) for research purpose. Signature of the patient RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA MASTER OF DENTAL SURGERY (MDS) ORAL AND MAXILLOFACIAL PATHOLOGY 2013 A.E.C.S MAARUTI COLLEGE OF DENTAL SCEINCES & RESEARCH CENTRE, BANGALORE – 560 076