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Biomedical subjects

N K Shukla

Publications and source records attributed to N K Shukla.

At least 19 recordsLinked to original sources
PubMed2000

Circulating p53 antibodies, p53 gene mutational profile and product accumulation in esophageal squamous-cell carcinoma in India.

Esophageal cancer (EC) in the Indian population presents in advanced stages with poor prognosis and warrants the identification of a non-invasive marker for early detection and better prognostic assessment. We have previously reported high prevalence of p53 protein accumulation in esophageal squamous-cell carcinomas (ESCCs). The present study was designed to determine (i) if esophageal cancer patients elicit a humoral immune response to intra-tumoral p53 protein accumulation and (ii) their relationship with p53 gene mutations. The goal was to compare the cellular events, p53 protein accumulation and gene mutations with the presence of serum anti-p53 antibodies (p53-Abs) and to assess the utility of serological p53-Ab analysis as a surrogate marker for p53 alterations in esophageal cancer. A high prevalence of circulating p53-Abs was observed in 36 of 60 (60%) ESCC patients. In a subset of 44 ESCCs, exons 5-9 of the p53 gene were examined for mutations by PCR and direct sequencing of PCR products. Mutational data have been correlated with p53-Abs and p53 protein accumulation in ESCCs. Circulating p53-Abs in ESCC patients were significantly associated with intra-tumoral p53 protein accumulation (p=0.0005). A strong correlation observed between humoral immune response against p53 protein, missense gene mutations and protein accumulation warrants the application of serological p53-Abs as a non-invasive surrogate marker in screening high-risk populations for early detection of malignancy.

Adult↗
PubMed2000

Novel polymorphism in p21(waf1/cip1) cyclin dependent kinase inhibitor gene: association with human esophageal cancer.

p21(waf1/cip1), an important regulator of the cell cycle, binds to PCNA and acts as a mediator of the growth suppressing and apoptosis promoting functions of p53. We report a hitherto unobserved polymorphism in the carboxy terminal domain (codon 149) of p21(waf1/cip1) gene, the domain encoding the PCNA binding motif. The codon 149 polymorphism (GAT-->GGT) was observed in 42 of 50 (84%) esophageal squamous cell carcinomas (ESCCs) and eight of 50 (16%) normal individuals. The resultant amino acid substitution from aspartate to glycine may have vital implication in PCNA mediated cell cycle regulation by p21(waf1/cip1). The second polymorphism at codon 31, involving a C-->A transversion at nucleotide 168 (AGC-->AGA) changing the amino acid from serine to arginine, was observed in 2/50 (4%) ESCCs at a relatively lower frequency in the Indian population than that reported in the West. No significant association was observed between p21(wap1/cip1) polymorphism at codon 149 and p21(wap1/cip1) protein expression in ESCC in this cohort of patients. Interestingly, the frequency of p21(wap1/cip1) variants (codon 149) in ESCCs (18 of 19 cases) with wild-type p53 was significantly higher than in tumors with p53 mutations, suggesting that this polymorphism affects the p53 pathway and may play an important role in esophageal tumorigenesis. Analysis of p21(waf1/cip1) expression in relation to p53 gene and protein status revealed its induction by p53-dependent as well as independent pathways in esophageal tumorigenesis.

Carcinoma, Squamous Cell↗
PubMed2000

Modified radical mastectomy using harmonic scalpel.

BACKGROUND AND OBJECTIVES: Modified radical mastectomy (MRM) remains the most commonly performed surgery for breast cancer today. Conventional surgery using scalpel and electrocautery is associated with moderate blood loss and morbidity in the form of haematoma, flap necrosis, prolonged axillary drainage, and seroma. This study was performed to evaluate the feasibility of using ultrasonic energy (harmonic scalpel) for MRM and to standardise the operative technique of harmonic scalpel MRM using various available accessories of the harmonic scalpel. METHODS: Fourteen patients suffering from carcinoma breast planned for MRM were included in the study. RESULTS: The learning curve of harmonic scalpel MRM was short. Harmonic scalpel is a multifunctional instrument and the whole operative procedure could be accomplished with the currently available accessories. No sutures or electrocautery were used. The mean blood loss was 57.5 ml and the mean operative time was 117 min. There were no hematomas or flap necroses, whereas one patient developed seroma. The mean postoperative drainage volume was 430 ml. CONCLUSIONS: In comparison to the historical data of conventional mastectomy, there seems to be a reduction in the blood loss and drainage volume using harmonic scalpel. Results of our study show that modified radical mastectomy using the harmonic scalpel is feasible and the learning curve is short, however, further studies are needed to assess the impact on morbidity.

Breast Neoplasms↗
PubMed2000

Lipid peroxidation, free radical production and antioxidant status in breast cancer.

Reactive oxygen metabolites (ROMs), including superoxide anion (O2*-), hydrogen peroxide (H2O2) and hydroxyl radical (*OH), play an important role in carcinogenesis. There are some primary antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) which protect against cellular and molecular damage caused by the ROMs. We conducted the present study to determine the rate of O2*- and H2O2 production, and concentration of malondialdehyde (MDA), as an index of lipid peroxidation, along with the SOD, GPx and CAT activities in 54 breast cancer (BC) patients. Forty-two age- and sex-matched patients with minor surgical problems, who had no history of any neoplastic or breast disorders, were taken as controls. The rate of O2*- production was significantly higher (p < 0.001) in BC patients than controls, irrespective of clinical stages and menopausal status. Similarly, H2O2 production was significantly higher in BC patients, especially in stage III and postmenopausal groups, as compared to the respective controls. MDA concentration was also observed significantly elevated in stage II (p < 0.001), stage III (p < 0.01), postmenopausal (p < 0.005), and premenopausal (p < 0.02) group as compared to their corresponding controls. SOD and GPx activities were found significantly raised in all the groups (p < 0.001), except the GPx activity was found a smaller alteration in stage IV (p < 0.02). On the contrary, CAT activity was found significantly depressed in all the study groups. The maximum depression was observed in stage II (-61.8%). Lower CAT activity in our study may be the effect of higher production of ROMs, particularly O2*- and *OH. SOD and GPx, however, were less effected by these higher ROMs production. The results of our study have shown a higher ROMs production and decreased CAT activity, which support the oxidative stress hypothesis in carcinogenesis. The relatively higher SOD and GPx may be due to the response of increased ROMs production in the blood. However, the higher SOD and GPx activities may be inadequate to detoxify high levels of H2O2 into H2O leading to the formation of the most dangerous *OH radical followed by MDA. Therefore, administration of CAT may be helpful in the management of BC patients. However, further elaborate clinical studies are required to evaluate the role of such antioxidant enzymes in BC management.

Adult↗
PubMed1999

P-glycoprotein is positively correlated with p53 in human oral pre-malignant and malignant lesions and is associated with poor prognosis.

P-glycoprotein (Pgp) encoded by the MDR1 gene, a predictor of chemoresistance, may also serve as a prognosticator of clinical outcome in cancer patients. The mutant tumour-suppressor p53 protein has been shown to activate the MDR1 promoter, whereas the wild-type p53 represses this activity in cultured cells. We have described the differential expression of Pgp and p53 proteins in betel- and tobacco-related oral tumorigenesis in the Indian population. Herein, Pgp expression was analysed in relation to p53 protein accumulation in pre-malignant and malignant oral lesions by immunohistochemical and flow-cytometric analyses. The relationship between Pgp and p53 protein accumulation and clinicopathological parameters as well as prognosis was determined. Expression of Pgp was observed in 81% of oral squamous cell carcinomas (SCCs) and 71% of pre-malignant lesions. Sixty-five of 75 p53-positive oral SCCs and 21/24 p53-positive pre-malignant lesions showed expression of Pgp. Significant correlation between Pgp and p53 expression was found not only in oral SCCs but also in pre-malignant lesions. Co-expression of Pgp and p53 proteins was indicative of poor prognosis. Follow-up studies of 35 patients showed that 7 of 10 oral SCCs with accumulation of Pgp and p53 proteins also exhibited shorter disease-free survival (recurrence/metastases). Our findings provide clinical evidence for a significant association between Pgp and p53 protein expression in oral tumorigenesis and may account for the aggressive nature of the tumour and poor prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Ets-1: a plausible marker of invasive potential and lymph node metastasis in human oral squamous cell carcinomas.

The proto-oncogene Ets-1 is a transcription factor known to regulate the expression of a number of genes involved in extracellular matrix remodelling. It has been postulated to play a role in angiogenesis, cell migration, and regulation of tumour invasion. In betel and tobacco-related oral tumourigenesis, oral squamous cell carcinomas (SCCs) having a poor prognosis often exhibit extensive local disease with spread into regional lymph nodes. At present, no tumour marker is available to predict the metastatic potential of oral carcinomas. To elucidate the involvement of Ets-1 in human oral tumourigenesis, 60 cases of oral SCC, 30 potentially malignant lesions, and 30 samples of normal oral mucosa were examined by immunohistochemistry and the findings corroborated with immunoblotting. The relationship of Ets-1 expression with the degree of differentiation, lymph node metastasis, and tumour stage was determined in oral SCCs. Ets-1 was not detected in the normal oral epithelium. Among the 60 cases of oral SCC, 35 cases (58 per cent) showed positive staining for the Ets-1 protein in tumour cells. In potentially malignant lesions, 14 of 30 cases (47 per cent) showed Ets-1 immunopositivity. Ets-1 expression correlated significantly with tumour stage ( p=0.01) and lymph node metastasis ( p=0.005). The presence of Ets-1 mRNA in oral SCCs was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). These findings suggest that overexpression of Ets-1 in potentially malignant lesions may be related to angiogenesis and its expression in oral SCCs may be one of the factors involved in tumour progression and lymph node metastasis.

Biomarkers, Tumor↗
PubMed1998

Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status.

p21waf1/cip1 protein, an inhibitor of cyclin dependent kinases, is a critical downstream target in the p53-specific pathway of growth control, and can also be induced by p53 independent pathways in relation to terminal differentiation. p21waf1 is also a putative tumour suppressor. Hence, we sought to determine whether this protein is abnormally expressed during betel- and tobacco-related oral oncogenesis. The aim was to determine whether a correlation exists between the expression profile of p21 and clinicopathological parameters of the patients, as well as with their p53 status. Immunohistochemical analysis showed that the expression of p21 protein in premalignant lesions was consistently elevated in the superficial, differentiated cells of the epithelium, while overexpression of the p53 tumour suppressor gene was observed in the basal proliferating layers of the epithelium. Our study demonstrated that p21 overexpression is associated with differentiation in proliferating dysplasias and squamous cell carcinomas (SCCs). The expression of p21 and p53 proteins was observed in 11/25 premalignant lesions. In 7 of these 11 cases, a heterogenous pattern of expression of p21 and p53 was observed. Four of these 11 premalignant and 30/51 malignant lesions showed concordant expression of both p21 and p53 proteins. The discordant p21 +/p53- phenotype was observed in 4/25 premalignant lesions and 5/51 oral SCCs. The p21-/p53+ phenotype was observed in 5/25 premalignant lesions and 7/51 oral SCCs. These results suggest that induction of p21 occurs by both p53 dependent and independent mechanisms during oral tumorigenesis.

Adult↗
PubMed1998

pRb and p16 protein alterations in human oral tumorigenesis.

Cyclin dependent kinase inhibitor 2/multiple tumour suppressor gene 1 (CDKN2/MTS1) and retinoblastoma (Rb) tumour suppressor genes play important roles in the regulation of the cell cycle. The protein products of these genes p16INK4 (p16) and pRb, respectively, like p53 protein inhibit progression from G1 to S phase. p16 exerts its function through inhibition of CDK4-mediated phosphorylation of pRb. The pRb/p16 pathway is a critical target for molecular aberration at the G1-S checkpoint in a wide range of primary human tumours. The expression of p16 and pRb proteins was analyzed by immunohistochemistry in 35 cases of oral squamous cell carcinomas (SCCs), 22 cases of premalignant oral lesions and 30 normal oral tissues. Lack of pRb expression was observed in 23/35 (66%) oral SCCs and 14/22 (64%) premalignant lesions. Lack of p16 expression was observed in 22/35 (63%) oral SCCs and 13/22 (59%) premalignant lesions. Weak p16 and pRb immunoreactivities were observed in normal oral mucosal epithelium. The status of p16 and pRb was correlated with clinicopathological characteristics of the patients. Alteration in p16 expression showed significant correlation with tumour staging and progression (P = 0.024). Alteration in pRb/p16 expression correlated with heavy consumption of betel and tobacco. Our results suggest that alterations in the p16/pRb pathway are early events in oral tumorigenesis and may be involved in the development of betel- and tobacco-related oral malignancies.

Adult↗
PubMed1998

Circulating p53 antibodies as early markers of oral cancer: correlation with p53 alterations.

p53 aberrations are early events in the pathogenesis of betel- and tobacco-related oral malignancies. Accumulation of p53 protein in oral lesions may elicit a humoral immune response against p53 protein in these patients. p53 antibodies (Abs) were analyzed in 183 sera obtained from patients with premalignant or malignant oral lesions and normal individuals by enzyme-linked immunoassay using recombinant p53 protein as antigen. These results were correlated with accumulation of p53 protein in patients' matched oral tissue specimens. Circulating p53 Abs were observed in 24 of 70 (34%) cancer patients and 15 of 50 (30%) patients with premalignant oral lesions. p53 Abs showed a significant association with increase in tumor size and dedifferentiation of tumors, factors indicative of poor prognosis. Expression of p53 protein was analyzed in 43 matched oral lesions (18 premalignant and 25 malignant cases). All the p53-seropositive patients (7 leukoplakia and 11 squamous cell carcinoma) showed elevated levels of p53 protein in matched oral lesions. However, the total number of patients seropositive for p53 Abs was lesser than that of patients exhibiting p53 protein accumulation in oral lesions. Four of the 63 normal healthy individuals who were heavy consumers of tobacco (smoking/chewing) and betel were found to be positive for p53 Abs. Detection of circulating p53 Abs in patients with premalignant oral lesions suggests that humoral immune response against p53 protein is an early event in oral oncogenesis and may be a surrogate marker for both p53 alteration and preclinical cancer.

Adult↗
PubMed1998

Stromal sarcoma of the breast: a case report.

Malignant mesenchymal tumours of the breast are rare neoplasms. Their incidence varies from 1%-3% of all malignant breast tumours (1). Stromal sarcoma of the breast is an extremely uncommon tumour (2). We present a rare case of advanced stromal sarcoma of the breast successfully managed with radical surgery and radiotherapy.

Adult↗
PubMed1997

Evaluation of P-glycoprotein expression in human oral oncogenesis: correlation with clinicopathological features.

To determine whether the multidrug-resistance-gene product phospho-glycoprotein (P-gp) is implicated in progression of oral tumours and/or drug resistance, the expression of P-gp was examined in different stages of oral oncogenesis using monoclonal antibody C-219. Cryosections from normal (41 cases), dysplastic lesions (32 cases), untreated primary SCCs (50 cases) and recurrent tumours (31 cases) were used for immunostaining, and the results were corroborated by immunoblotting. Chi-square test for trend analysis showed a significant increase in P-gp immunopositivity across the normal, leukoplakia, primary oral SCC and recurrent SCC groups (p < 0.01). Expression of P-gp in dysplastic lesions showed significant association with severity of dysplasia, the level of P-gp protein being higher in severe and moderate dysplasia. Among the primary tumours, significant correlation was observed between P-gp positivity as well as level of P-gp expression and tumour stage. The recurrent tumours showed significant increase in P-gp expression as compared with untreated primary oral tumours. We conclude that differential expression of P-gp may be an index of the disease prognosis in oral-cancer patients in the context of the Indian population.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Differential expression of multidrug resistance gene product, P-glycoprotein, in normal, dysplastic and malignant oral mucosa in India.

Multidrug resistance (MDR) in human cancer is often associated with over-expression of the mdr-1 gene, which encodes a 170-kDa transmembrane protein, termed P-glycoprotein (P-gp). We evaluated the immunoreactivity of P-gp in oral tissues at different stages of tumorigenesis in the Indian population by flow cytometry, using the MRK-16 monoclonal antibody, which recognizes an external epitope of P-gp. The expression of P-gp was studied in human oral normal tissues (12 cases), dysplastic lesions (13 cases), primary untreated squamous-cell carcinomas (12 cases) and recurrent tumors (18 cases). Quantitative flow-cytometric analysis of P-gp expression showed a significant increase in P-gp levels in untreated primary oral tumors (p < 0.01) and in dysplastic lesions (p < 0.05) as compared with normal oral tissues. A marked significant increase in P-gp expression was observed in recurrent oral carcinomas as compared with normal oral tissues (p < 0.001) and dysplastic lesions (p < 0.01). Among recurrent tumors, a significant increase in the level of P-gp was observed in T4-stage tumors as compared with T3-stage tumors (p < 0.01). We conclude that P-gp is differentially expressed during oral tumorigenesis, and may be an indicator of the biological behavior of oral malignancies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Short stay surgery for breast cancer: an audit of an experience in a regional cancer centre in northern India.

At the Institute Rotary Cancer Hospital, AIIMS, New Delhi, 246 patients of breast cancer were operated on from June 1993 to June 1996; 82 suitable patients were discharged within 48 h (short stay surgery, SSS) after surgery and 164 were discharged after 48 h (conventional stay surgery, CSS). After discharge, patients of both groups were followed in the outpatient clinic until the removal of sutures and drains. There was no mortality or readmission for a complication in either group. Mean post-operative hospital stay was 1.5 days in the SSS group, and 3.3 days in the CSS group. There was no statistically significant difference in the incidence of post-operative complications like wound infection (4.8% vs 4.2%), flap necrosis (6% vs 5.4%), seroma (14% vs 19%), and the average number of hospital visits (3.42 vs 3.2) in SSS and CSS groups, respectively. Patient acceptance of early discharge was good except in the day care group. The study supports the safety and feasibility of short stay surgery for breast cancer in certain circumstances for properly selected patients.

Adult↗
PubMed1997

Glutathione S-transferase pi expression in matched human normal and malignant oral mucosa.

Over-expression of glutathione S-transferase pi (GST-pi) class isozyme is often associated with malignant transformation and/or drug resistance. To determine whether GST-pi is implicated in betel and tobacco related oral carcinogenesis and/or drug resistance, its expression was studied in oral untreated primary squamous cell carcinomas (SCCs), recurrent tumours and matched normal oral tissues by immunohistochemical and immunoblotting techniques. The GST-pi expression in primary tumours predominantly varied from mild to moderate levels and no significant difference in its expression was observed in the matched normal tissue surrounding these lesions. Mild to moderate levels of GST-pi expression in the oral mucosa of consumers of betel and tobacco observed in the matched normal tissues may support the physiological role of this detoxification enzyme in the metabolism of xenobiotics and elimination of toxic constituents of tobacco. The hallmark of the study is the significant increase in GST-pi expression in recurrent oral SCCs, compared to the matched normal tissues, as well as primary oral tumours, suggesting its potential role as an indicator of prolonged exposure to carcinogens, or prognosis of the disease.

Adolescent↗
PubMed1996

Male breast cancer: a retrospective study from a regional cancer center in northern India.

Over a 7-year period from 1987 to 1993, 41 male breast cancer patients were seen in the breast cancer clinic of the Institute Rotary Cancer Hospital (IRCH) at the All India Institute of Medical Sciences (AIIMS). Their mean age was 54.2 years; and duration of symptoms ranged from 1 to 84 months with a mean of 15.1 months. Breast lump was the commonest presenting symptom. Fine needle aspiration cytology (FNAC) was the commonest diagnostic procedure. The TNM stage distribution was stage I, 5; stage II, 13; stage III, 17; and stage IV, 6. Radical mastectomy (25/36) was the commonest surgical procedure. Locoregional radiotherapy was given in 15 patients. Thirty patients received systemic adjuvant therapy (chemotherapy or tamoxifen, or a combination of the two). Local or distant recurrence occurred in 8 patients (8/31, 28.3%). Actuarial overall and disease-free survival was 100% and 80.1% at 2 years and 91.7% and 66.7% at 4 years, respectively. On univariate analysis, axillary lymph node status and age were found to affect disease-free survival significantly. Advanced stage of disease at presentation is common in Indian patients and will continue to influence treatment policies. Neoadjuvant chemotherapy needs to be evaluated for locally advanced tumors to improve outcome. Multicentric studies are necessary to define the relative roles of tamoxifen and chemotherapy for adjuvant treatment.

Adult↗
PubMed1996

Role of transabdominal pelvic ultrasound and computed tomography in the detection of bladder involvement in advanced cancer of the cervix.

The imaging data of 125 advanced cancer cervix patients attending the Institute Rotary Cancer Hospital between June 1992 and June 1994 was reviewed. The aim of the study was to assess the role of transabdominal pelvic ultrasound (TAPUS) and computed tomography (CT) in the detection of bladder involvement. TAPUS was performed in 65 patients (group I) and CT in 60 patients (group II). With respect to clinical stage, both groups were comparable. Cystoscopy was performed in all patients and the findings were taken as the gold standard for comparison of imaging data. The sensitivity, specificity and accuracy of TAPUS were 65, 94 and 75%, respectively, while those for CT were 80, 92 and 85%, respectively. Results of the present study reveal that the accuracy of TAPUS is comparable to the accuracy of other imaging modalities in the detection of bladder involvement in cervical cancer and that it should be used more frequently in developing countries that deal with a large number of cervical cancer patients in view of its easy availability, low cost and absence of exposure to radiation.

Adult↗
PubMed1995

Multicentric liposarcoma: report of two cases.

We present herein two unusual cases of multicentric liposarcoma which highlight the problems associated with the management of this disease entity. When the surgeon is confronted with multicentric liposarcomas, it is necessary to define whether they are secondary tumors or independently arising multicentric liposarcomas, since the latter situation merits a more aggressive approach. Guidelines for this differentiation are suggested in the discussion following the case reports. Surgery, which is often multiple, remains the mainstay of treatment, although adjuvant chemotherapy and radiotherapy are also usually required.

Abdominal Neoplasms↗