Dharanipragada Kadambari

P-glycoprotein expression as a predictor of response to neoadjuvant chemotherapy in breast cancer.

BACKGROUND Chemoresistance is an important factor determining the response of tumor to neoadjuvant chemotherapy (NACT). P-glycoprotein (P-gp) expression-mediated drug efflux is one of the mechanisms responsible for multi-drug resistance. Our study was aimed to determine the role of P-gp expression as a predictor of response to NACT in locally advanced breast cancer (LABC) patients. MATERIALS AND METHODS P-gp expression was performed by real-time quantitative polymerase chain reaction [qRT-PCR] in 76 patients with LABC. Response to adriamycin-based regimen was assessed both clinically and with contrast enhanced computed tomography (CECT) scan before and after NACT. The significance of correlation between tumor and P-gp levels was determined with Chi-square test. RESULTS Twenty-one had high and 55 had low P-gp expression. On analyzing P-gp expression with response by World Health Organization (WHO) criteria, statistical significance was obtained (P = 0.038). Similarly, assessment of P-gp expression with response by Response Evaluation in Solid Tumors (RECIST) criteria in 48 patients showed statistical significance (P = 0.0005). CONCLUSION This study proves that P-gp expression is a determinant factor in predicting response to NACT. Finally, detection of P-gp expression status before initiation of chemotherapy can be used as a predictive marker for NACT response and will also aid in avoiding the toxic side effects of NACT in non-responders.

GENOTYPE, ALLELE AND HAPLOTYPE FREQUENCIES OF FOUR TCL1A GENE POLYMORPHISMS ASSOCIATED WITH MUSCULOSKELETAL TOXICITY IN THE SOUTH INDIAN DESCENT

Introduction: Decline in circulating estrogen levels causes lessening of bone mass accompanied with musculoskeletal pain, which is the primary cause of treatment discontinuation in patients taking aromatase inhibitors. Evidence from recent genome-wide association studies (GWAS) suggests that the genetic variability underlying TCL1A gene increases the risk of aromatase inhibitors (AIs) - induced musculoskeletal toxicity. Currently, no data is available on the frequency distribution of TCL1A gene polymorphisms in Indians. Methods: In this pilot study, we used TaqMan fluorescent probes to assess the genotypes of four TCL1A gene polymorphisms associated with musculoskeletal toxicity in 247 healthy homogenous South Indian subjects on real time thermocycler. Haplotype estimation and pairwise linkage disequilibrium (LD) analysis were executed by Haploview. Results: The incidence of polymorphic variant allele (G) frequencies of rs7158782, rs7159713, rs2369049 and rs11849538 were 22.1%, 23.5%, 18.2% and 22.9% in the study population, respectively. The polymorphisms were found to be in complete LD with each other. Four different haplotypes, each of which having a frequency of above 1% were inferred in South Indians using an expectation-maximization algorithm. Notably, three haplotypes were found to be population specific viz H4 A-A-A-G (1.2%) for South India, H5 G-G-A-C (1.3%) for JPT and H6 G-G-G-C (40.4%) for YRI. Further, H3 G-G-A-G (2.3-16.3%) haplotype occurs primarily in Asians and is virtually absent in Africans. Overall, the genetic variability and haplotype profile of South Indian population revealed significant inter-racial variability compared with HapMap data. Conclusion: This documentation contributes for further investigations on the pharmacogenetics of AIs in South Indians.

Imprint Cytology of Axillary Lymph Nodes in Breast Carcinoma Following Neoadjuvant Chemotherapy

OBJECTIVE To evaluate the efficacy of imprint cytology (IC) in detecting residual axillary metastasis following neoadjuvant chemotherapy (NACT) in order to check its feasibility on sentinel nodes in the posttherapy setting in patients with breast carcinoma STUDY DESIGN Thirty women on NACT for locally advanced breast cancer were subjected to total mastectomy with axillary node dissection. Routinely stained imprints from 172 resected nodes were studied to detect residual metastasis and therapy-induced changes, adopting a semiquantitative grading system for assessing the cell yield. Sensitivity and specificity tests were performed. The effect of cellularity in detecting malignancy was statistically determined by the McNemar test. RESULTS Of the 172 nodes, 58 (33.7%) and 64 (37.2%) were positive by IC and histopathologic examination, respectively. Sparse, moderate and high cell yield was observed in 27 (15.2%), 33 (19.4%) and 112 (66.4%) nodes, respectively. No statistically significant difference was found with respect to the cellularity of imprints. Sensitivity, specificity and diagnostic accuracy were 89.1%, 99.1% and 95.4%, respectively. The false positive and negative rates were 0.6% and 4.1%, respectively. The positive and negative predictive values were 98.3% and 93.9%, respectively. CONCLUSION IC is a sensitive, specific and accurate method of detecting axillary metastasis in patients with down-staged tumors following chemotherapy. The fact that therapy did not affect the cell yield on IC makes the technique very applicable for assessing the sentinel nodes following NACT.

Clinico-microbiological Profile of Septic Diabetic Foot with Special Reference to Anaerobic Infection

Introduction Diabetic foot infections are a major cause of non-traumatic amputations. The role of anaerobes in the prognosis of these infections is particularly unclear. This study was conducted with the aim of correlating microbiological profiles with clinical outcomes in these diabetic foot ulcer patients. Methodology This prospective observational study was done in a tertiary care centre in South India. All patients admitted with diabetic foot ulcers for two years were included in the study. Tissue biopsies were collected from the ulcer for aerobic and anaerobic cultures. The patients were grouped as those with aerobic infection alone (anaerobe negative) and those with mixed aerobic and anaerobic infections (anaerobe positive). Anaerobic culture was performed using the Robertson cooked meat (RCM) medium. The ulcer of the foot was described with respect to site, size, duration, history of previous amputation(s), and history of number and class of antibiotic intake prior to hospitalization. Clinical course and Wagner’s grades of the diabetic foot ulcers were compared for aerobic and anaerobic infections. Results A total of 104 patients were included in the study. There were no significant differences between the two groups with regards to duration of diabetes, random blood sugar (RBS) at the time of admission, compliance to drugs, and mode of blood sugar control and prior intake of antibiotics. Patients with anaerobic infections were found to have a higher incidence of fever in this study (38.1% vs. 14.5%; p = 0.0057), as compared to patients with aerobic infections. More than half of the patients in the anaerobic infection group presented with Wagner’s grade IV and above, as compared to the aerobic infection group (59.5% vs. 32.2%; p = 0.0059), which was statistically significant. Patients with anaerobic infections also had high numbers of major and minor amputations when compared to patients with aerobic infections. Conclusion Septic diabetic foot patients with fever at the time of admission and a high Wagner’s grade have a greater chance of harbouring anaerobic infections. Drugs for anaerobic coverage should be considered for wounds beyond Wagner’s grade III. Anaerobic infections resulted in increased risk of morbidity in diabetic foot ulcer patients but did not have any influence on mortality.