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N K Shukla

Publications and source records attributed to N K Shukla.

At least 37 records · Page 2Linked to original sources
PubMed2001

Co-expression of colligin and collagen in oral submucous fibrosis: plausible role in pathogenesis.

The high incidence of oral submucous fibrosis (OSF), a potentially malignant condition of the oral cavity, in the Indian subcontinent is causally associated with commonly prevailing habit of chewing areca nut and tobacco. Knowledge of molecular alterations in OSF is meagre. OSF is characterised by progressive accumulation of collagen fibres in lamina propria and oral submucosa. Colligin/HSP47 is a 47KDa stress protein which acts as a chaperone for collagen. We hypothesized that since colligin plays a vital role in folding and assembling collagen it may be involved in the pathogenesis of OSF. The present study was undertaken in tobacco and areca nut chewing Indian OSF patients to investigate the correlation, if any, between the expression of colligin and collagen type I proteins in OSF lesions. Immunohistochemical analysis showed overexpression of colligin and collagen type I proteins in 16/23 (70%) and 15/23 (65%) of OSF cases, respectively. The hallmark of the study was the significant association between the increased expression of type I collagen and its chaperone, colligin, in OSF lesions (P=0.0494). The data suggest that the increased levels of colligin in OSF may contribute to the deposition of collagen and consequent increased fibrosis in the oral submucosa in OSF lesions.

Adolescent↗
PubMed2001

Attitudes and treatment outcome of breast conservation therapy for stage I & II breast cancer using peroperative iridium-192 implant boost to the tumour bed.

Breast conservation therapy for early breast cancer is an established but grossly under-utilized treatment option in India for various reasons. Breast conservation therapy was offered to 200 suitable breast cancer patients between June 1993 and June 1998. Fifty-one patients (25%) opted for breast conservation and the remaining preferred mastectomy. In patients agreeing to conservation therapy, surgery was performed first along with peroperative implantation of iridium-192 to deliver a boost. Whole breast irradiation of 45 Gy was delivered 3-4 weeks after the boost. Cosmesis was assessed at the end of 6 months from completion of therapy. The main reason for refusal of breast conservation therapy was fear of recurrence in the remaining breast (60%). There were no locoregional failures in our study at a median follow up of 42 months; one patient experienced a systemic relapse. Cosmesis was good to excellent in 80% of patients. Breast conservation therapy using peroperative iridium-192 implant provides excellent locoregional disease control and cosmesis. The results of our study indicate that patient preference for mastectomy is an important reason for the under-utilization of breast conservation therapy in India.

Adult↗
PubMed2001

Carcinoma breast metastatic to the hand and the foot.

Metastases to the peripheral bones of the extremities are rare. Such lesions are often diagnosed as inflammatory or infective in nature. We present a report of a case of simultaneous involvement of the peripheral bones of the extremities--the talus and the thumb of the left hand--with a brief review of pathophysiology and management.

Adult↗
PubMed2001

Persistent Mullerian duct syndrome presenting with bilateral intra-abdominal gonadal tumours and obstructive uropathy.

Persistent Mullerian duct syndrome is a rare, autosomal recessive intersex disorder characterized by the presence of completely developed Mullerian duct derivatives in an otherwise normally virilized male with a 46, XY karyotype. We discuss a rare presentation of this disorder, bilateral gonadal tumours with obstructive uropathy, and its management, together with a review of the literature.

Abdominal Neoplasms↗
PubMed2001

Interstitial brachytherapy with or without external beam irradiation in head and neck cancer: Institute Rotary Cancer Hospital experience.

Iridium-192 interstitial brachytherapy is practiced infrequently in developing countries, even where head and neck cancer is a major neoplasm and the technique could provide good results. This report from India is presented as an audit to validate the benefit of brachytherapy. One hundred and six head and neck cancer patients were treated by interstitial brachytherapy alone (n = 29) or combined with external irradiation (n = 77). The oral cavity and the oropharynx together constituted 82% of the sites of implanted tumours; 75% were T(1-2)N0 status. Brachytherapy was carried out using afterloaded plastic catheters and the Paris dose prescription system was followed. External cobalt-60 beam portals covered the primary and the neck. The median duration of follow-up was 22 months. The median dose of brachytherapy used alone was 60 Gy. With combined treatment, the median external radiotherapy and brachytherapy doses were 50 Gy and 25 Gy respectively. The median brachytherapy dose rate was 0.5 Gy/h. Primary and nodal recurrences were recorded in 41/106 (38.7%) and 18/106 (17.0%) patients at median intervals of 15 and 13 months respectively. Implant site failure was more common after combined treatment than with brachytherapy alone (42.8% versus 27.5%), but it did not reach statistical significance in this analysis (P = 0.15). Kaplan-Meier actuarial 5-year estimates showed 52% and 87% disease-free and overall survivals. Iridium-192 interstitial implants in suitably selected head and neck cancer patients can improve the radiotherapeutic results, with the promise of organ conservation in 50%. In India, the practice should be established in more radiotherapy centres and could be utilized in 10,000-25,000 head and neck cancer patients annually.

Adult↗
PubMed2001

Prognostic impact of Ets-1 overexpression in betel and tobacco related oral cancer.

In oral squamous cell carcinoma (SCC), the presence of lymph node metastasis is one of the most important prognostic factors, correlating locoregional spread, recurrence, distant metastasis and survival. However, the biological factors implicated and the mechanisms underlying these events are not completely elucidated. We reported Ets-1 expression in oral SCC and proposed that it may serve as a plausible marker of invasive potential and lymph node metastasis. Herein, we investigate the prognostic significance of Ets-1 expression in oral cancer. One hundred oral SCCs assessed for Ets-1 expression showed significant association with tumor stage (P = .027), lymph node involvement (P < 10(-6)) and distant organ metastasis (P = .007). The transcription factor Ets-1 regulates the expression of several genes involved in extracellular matrix remodeling that may account for its association with lymph node and distant organ metastasis. Kaplan-Meier survival analysis entailed significant association of Ets-1 expression in oral SCCs with reduced disease free survival (P = .0041), suggesting its utility as a prognosticator for oral cancer. In conclusion, these findings underscore the role of Ets-1 in oral tumor invasion and metastasis and may thus account for its association with diminished disease free survival.

Areca↗
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

Frequent alterations in the expression of tumor suppressor genes p16INK4A and pRb in esophageal squamous cell carcinoma in the Indian population.

PURPOSE: Alterations in the cell cycle regulatory p16INK4a/Cyclin D1/pRb pathway play a pivotal role in tumorigenesis. Knowledge of alterations in the tumor suppressor protein pRb and its negative regulator, p16CDKN2/MTS1/INK4a in esophageal squamous cell carcinoma (ESCC) from the Indian subcontinent is meager. To gain insight into the mechanisms underlying tumorigenesis and to search for diagnostic molecular markers for ESCC, we analyzed the expression of p16INK4a and pRb in ESCCs in the Indian population. METHODS: Immunohistochemical analysis of pRb and p16INK4a proteins was carried out in paraffin-embedded sections from 61 surgically resected ESCCs and matched normal tissues, and the results correlated with clinicopathological parameters using chi square and Fisher's exact tests. Dual immunohistochemical analysis has been carried out to demonstrate the concomitant loss of expression of p16INK4a and pRb. RESULTS: Fifty-nine of 61 (97%) cases showed aberration(s) in either or both of these proteins confirming their critical role in esophageal tumorigenesis. Loss of pRb was observed in 51 of the 61 (84%) and loss of p16INK4a was observed in 35 of 61 (57%) cases. Loss of pRb showed significant association with dedifferentiation of the tumor (P = 0.004). p16-/pRb-, and p16+/pRb- phenotypes were significantly associated with nodal metastasis (P = 0.017 and 0.027, respectively), while p16-/pRb+ phenotype was associated with dedifferentiation of the tumor (P = 0.012). CONCLUSION: pRb/p16INK4a pathway plays a critical role in esophageal tumorigenesis in the Indian population. The dual hits (concomitant loss) of pRb and p16INK4a expression suggest that these two components are not mutually exclusive, and can both be altered in a significant proportion of primary ESCCs serving as putative diagnostic markers for esophageal cancer. However, the impact of dual hit on tumor behavior and disease prognosis remains to be determined.

Adult↗
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↗
PubMed2000

Nutritional risk factors in esophageal cancer.

OBJECTIVE: The present case-control study was undertaken with the objective to study the nutritional risk factors associated with esophageal cancer. METHODOLOGY: One hundred and fifty diagnosed esophageal cancer patients and an equal number of healthy individuals constituted the patient and control groups, respectively. Dietary consumption pattern during the preceding 20 years prior to the diagnosis of esophageal cancer was assessed utilising the standard food frequency questionnaire method. Information on alcohol consumption, smoking habits, chewing of betel leaf with tobacco was also collected. RESULTS: Multivariate analysis revealed that the risk of esophageal cancer was 7.81 times (p < 0.01) higher with daily consumption of alcohol. The risk increased to 3.16 times (p < 0.01) with the daily habit of chewing of betel leaf with tobacco. Nearly a two fold risk was observed when the consumption of "other vegetables" was less than four times per week. A 1.95 times (p < 0.01) increase in risk was observed with the daily habit of bidi smoking. CONCLUSION: Cancers in general are multifactorial in origin, and several environmental interactions are possible. It is not easy to quantify the contribution of diet to cancer risk. However, the results of the present study suggested that nutritional factors do play a role.

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

Mitoxantrone, mitomycin-C, methotrexate combination chemotherapy with radiotherapy and/or surgery in stage III (T4B, NO-2, M0) breast cancer.

Results of primary surgery with or without locoregional radiotherapy (LRRT) are poor in stage III (T4b, NO-2, M0) breast cancer. Combination of mitoxantrone, mitomycin-c and methotrexate (MMM) has been reported to be as efficacious as doxorubicin based protocols with advantages of reduced nausea, vomiting, alopecia and cardiotoxicity. We tested MMM chemotherapy with LRRT and surgery in locally advanced breast cancer (LABC) with a view to assess response, survival, breast conservation, cost and toxicity. Fifty two previously untreated patients were given Mitoxantrone: 8 mg/m sq by infusion on days 1 and 21, Mitomycin-C: 8 mg/m sq by infusion on day 1 and Methotrexate: 35 mg/m sq i.v. on days 1 and 21. Cycles were repeated every 42 days. After 3 cycles LRRT was given if lump reduced to less than 2 cms. Otherwise patients were subjected to modified radical mastectomy (MRM) or radical mastectomy (RM). Following this 3 more cycles of chemotherapy were given. Patients with soft tissue, skin or heavy nodal involvement also received LRRT. Tamoxifen 20 mg daily was prescribed at the end of chemotherapy to postmenopausal patients. Complete/partial responses were seen in 5 and 26 patients, respectively after chemotherapy giving an overall response of 59.5%. Twenty four patients each had LRRT and MRM/RM. Responses could be significantly enhanced by LRRT/and or surgery. Nineteen out of 25 relapses were at distant sites. Breast conservation was achieved in 24/52 (46%) patients. Three year disease free and overall survival was 54% and 65%, respectively. There was 1 toxic death. Severe prolonged myelosuppresion was seen in those who also received LRRT. Mucositis, alopecia, nausea and vomiting were minor problems. Overall, combination was less expensive than doxorubicin based protocols.

Adult↗