M. Krishnan Nair

Response of oral leukoplakias to the administration of vitamin A

Tobacco/betel nut chewers (Kerala, India) with well-developed oral leukoplakias were chosen for a short-term intervention trial of vitamin A therapy. Participants were randomly distributed into two groups, one receiving 200,000 IU vitamin A per week (0.14 mg/kg body wt/per day) for 6 months, and the other receiving placebo capsules. Their cancer-causing habit, which can be quantitated (an average of 13.1 betel quids/day, 26.1 min/quid), did not change during the trial period. The 6-month oral administration of vitamin A caused complete remission in 57.1% of participants, and a total suppression of the development of new leukoplakias in all chewers receiving vitamin A (n = 21), as compared to 3% and 21%, respectively, in the placebo group (n = 33). The results were substantiated by examining the histological and cytological changes on small biopsies which were taken at the onset and at the completion of the trial period. Over the 6-month period of vitamin A administration, the number of layers of spinous cells decreased in 85% of the participants, the loss of polarity of basal cells was reduced from 72.2% to 22.2% of chewers, subepidermal lymphocytic infiltration was greatly diminished from 66.7% to 5.5% of chewers, and nuclei with condensed chromatin disappeared from the epidermal layer (72.2% before to 0% at the end of the trial).

Germline BRCA1 mutation analysis in Indian breast/ovarian cancer families.

Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. To explore the contribution of BRCA1 mutations to hereditary breast cancer among Indian women, we examined the coding sequence of the BRCA1 gene in 14 breast cancer patients with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation sensitive gel electrophoresis (CSGE) followed by sequencing. Three mutations (21%) in the BRCA1 gene were identified. Two of them are novel mutations of which one is a missense mutation in exon 7 near the RING finger domain, while the other is a one base pair deletion in exon 11 which results in protein truncation. The third mutation, 185delAG, has been previously described in Ashkenazi Jewish families. To our knowledge this is the first report of a study of germline BRCA1 mutation analysis in familial breast cancer in India. Our data from 14 different families suggests a lower prevalence but definite involvement of germline mutations in the BRCA1 gene among Indian women with breast cancer and a family history of breast cancer.

DNA repair proficiency : a potential marker for identification of high risk members in breast cancer families

Breast cancer is the single largest cancer and causes the high rate of cancer mortality among women. A positive family history of breast cancer is recognized as one of the major risk factors for this disease. The present study evaluates bleomycin (BLM)-induced chromosome sensitivity analysis in breast cancer families which provides indirectly a measure of the DNA repair defect of each person. BLM sensitivity assay on cultured lymphocytes of 36 familial breast cancer patients, their 85 first or second degree female relatives, 36 sporadic breast cancer patients and 40 age- and sex-matched controls (without any family history of cancer) were carried out to measure interindividual variation in their DNA repair capacity through mutagen-induced chromosome sensitivity analysis. Fifty percent of familial breast cancer patients and seven unaffected relatives showed hypersensitivity. Compared to hyposensitive relatives these seven subjects may be considered as high risk individuals.

Overall survival from breast cancer in Kerala, India, in relation to menstrual, reproductive, and clinical factors

Background. Breast cancer accounts for one‐fourth of cancer cases seen in female patients in Kerala, India. Results of a retrospective analysis of breast cancer in Kerala are presented in this article.

Development of an immunological staging system to prognosticate disease course in malignant cervical neoplasia

A multiparameter analysis of immune function was done on patients with squamous cell carcinoma of the uterine cervix to look for any variable(s) that could be correlated with the clinical stage of the disease. Five immunological variables, viz., CD4+ lymphocytes, CD4/CD8 ratio, natural killer cells, concanavalin A-induced suppressor index, and circulating immune complexes, were found to consistently vary with tumor load. When these variables were subjected to a multiple regression and multivariate analysis, an equation for a diagnostic index curve was derived. Application of this equation led to an immunological staging system which could be used as an excellent prognostic indicator. The immunological staging system showed that patients classified into a particular clinical (FIGO) stage behaved in a heterogeneous way immunologically and that patients developing recurrent disease could easily be identified from those remaining disease free, even before treatment. Subsequent follow-up of these patients further confirmed this observation, with the recurrent disease group easily identifiable. These results point out the immense potential of such a staging system and the importance of immunological evaluation in the preliminary management of patients with malignant cervical neoplasia.

Interferon activation of latent natural killer cells and alteration in kinetics of target cell lysis: Clinical implications for oral precancerous lesions

Reduced natural killer cell activity was observed in patients with oral leukoplakia and submucous fibrosis compared with normal control subjects. However, the number of target binding lymphocytes was found to be normal in these precancers. Treatment of effector cells with interferon-alpha resulted in highly elevated active killer cell activity, although no change was observed in target binding lymphocyte counts. This finding could imply that precytotoxic cells that are activated by interferon exist in peripheral blood or that direct recruitment of a new cell population takes place. In addition, altered target lysis kinetics was observed, with interferon-activated killer cells demonstrating a tremendous lytic activation that is completed so quickly that a statistical kinetic analysis could not be accurately done. Because natural killer cell activity is an important effector system in immunosurveillance against tumors, its modulation with interferon may be an exciting clinical possibility in the control of malignant transformation or oral precancers.

Interleukin 2 and Alpha Interferon Induced in Vitro Modulation of Spontaneous Cell Mediated Cytotoxicity in Patients with Cancer of the Uterine Cervix Undergoing Radiotherapy

In vitro modulation of spontaneous cell mediated cytotoxicity by interferon and interleukin 2 was carried out using peripheral blood lymphocytes from patients with cancer of the uterine cervix before and at different intervals after commencement of radiation treatment. A total of 150 patients with various stages of the disease were included and cytotoxicity was measured using the single cell cytotoxic assay. These results indicate a beneficial effect in vitro of interleukin 2 and interferon in augmenting spontaneous cell mediated cytotoxicity, a possibly vital antitumour immune mechanism in patients with relatively early cervix cancer. Natural killer cell, lymphokine activated killer cell and interferon activated killer cell activity was depressed immediately following radiotherapy. The activity of these cell types later on increased above pretreatment levels in patients with stages I, IIA and IIB. A similar rebound above pretreatment levels was not observed in patients with stages III and IV.

Evaluation of salvage surgery in heavily irradiated cancer of the buccal mucosa

This report describes the authors experience with salvage surgery in 78 patients with carcinoma of the buccal mucosa who failed after high‐dose radical radiation therapy at Regional Cancer Centre, Trivandrum, India. Forty‐four patients (56%) required a hemimandibulectomy for adequate tumor clearance. Fifty‐four patients (69%) required a primary reconstructive procedure for wound closure. Follow‐up periods ranged from 28 months to 63 months (median follow‐up, 41 months). Thirteen patients (17%) developed nonfatal postoperative complications. Thirty‐one patients recurred after surgery, five of whom were again salvaged by further surgery. Overall, the recurrence rate was 36%. Most of the recurrences (26/31) were at the primary site. The overall 5‐year actuarial disease‐free survival after salvage surgery was 59.7%. T stage of the recurrent tumor and its skin infiltration emerged as factors which significantly influenced disease‐free survival (P < 0.05).

Nonrandom karyotype abnormalities in 36 multiple myeloma patients.

G-banded analysis performed on pretreated bone marrow samples of 36 multiple myeloma patients allowed the identification of clonal chromosome abnormalities. Abnormalities consisting of trisomies, monosomies, translocations, deletions, and marker chromosomes apparently followed a nonrandom pattern. The chromosomes involved in the production of abnormal karyotypes were numbers 1,2,3,11,12,14,17, and 18. Even though no specific chromosome pattern has been identified, the involvement of chromosomes 1, 3, and 14 was found to be more frequent. Many of the chromosomes and chromosomal breakpoints involved in these abnormalities correspond to the location of identified oncogenes or tumor suppressor genes. Hence, it is presumed that these chromosome abnormalities may be playing an important role in the genesis of multiple myeloma by altering the structure or function of oncogenes or tumor suppressor genes.

Lymphocyte subset distribution after radiation therapy for cancer of the uterine cervix. Possible prognostic implications and correlation with disease course

An analysis of lymphocyte subpopulations was done in patients with cancer of the uterine cervix before and at different intervals after the commencement of radiation therapy. A common feature was a duration of T‐cell and B‐cell lymphopenia after therapy. The findings relating to the T‐cell subsets were interesting. Although the CD4/CD8 ratio remained unchanged in Stages I/IIA for 24 months after treatment, patients with Stages IIB and III showed a lowering of the ratio immediately after treatment. Distinctive patterns of lymphocyte subset distribution were seen in a comparison between patients who were disease‐free and those with recurrent disease. The CD4+ cell counts and CD4/CD8 ratio differed between the two groups, with consistent lowered values during the follow‐up associated with recurrent disease. This study demonstrates the effects of radiation therapy in altering lymphocyte subset distribution, resulting in characteristic patterns which could be used as clinical and prognostic indicators.