Arvind Krishnamurthy

Predictive markers of response to neoadjuvant chemotherapy in breast cancer

Several randomized prospective studies on breast cancer patients have proved the safety of neoadjuvant chemotherapy. These trials have also demonstrated that tumor down staging does indeed improve the eligibility for breast conservative surgery without increasing local recurrence rates with possibly an improved survival. However, complete pathologic remissions are noted in only 3-30% of patients. About 20% of patients do not benefit from different chemotherapy regimens currently in use and are thus subjected to toxic drugs. This often leads to progression of disease and thereby the surgeon may lose a window of opportunity to obtain durable locoregional control of disease. Identification of predictive markers associated with pathologic complete response can help to distinguish patients with high or low probability of a response to treatment so that an individualized treatment plan can be implemented. It could also streamline the development of new alternative regimens for those who are unlikely to benefit from existing drugs. It is expected that a combination of markers will be more informative than a single one. So far, several factors have been studied as predictors for response to cytotoxic treatment, viz., tumor size, hormone (estrogen and progesterone) receptor status, tumor type and differentiation, HER2/cerB-2, tumor proliferation Ki-67, apoptosis related genes p53, bcl-2 and BAX; certain subgroups of breast cancer, and the latest in this category is gene expression profiling. However, in terms of prediction of drug responsiveness, data reported are still very limited. This review aims to discuss the current relevant literature on the subject.

Lung Cancer Detection by Screening - Presenting Circulating miRNAs as a Promising Next Generation Biomarker Breakthrough

Lung cancer remains a major cause of morbidity and mortality worldwide, accounting for more deaths than any other cause. All the clinical practice guidelines recommended against routine screening for lung cancer have cited lack of robust evidence, at least until a few years back. However, the potential to screen lung cancers has received renewed interest due to superior performance of low dose CT (LD-CT) in detecting early stage cancers. The incremental costs and risks involved due to the invasive procedures in the screened population due to a high false positivity rate questions the use of LD-CT scan as a reliable community based screening tool. There is therefore an urgent need to find a less invasive and a more reliable biomarker that is crucial to increase the probability of early lung cancer detection. This can truly make a difference in lung cancer survival and at the same time be more cost and resource utilization effective. Sampling blood serum being minimally invasive, low risk and providing an easy to obtain biofluid, needs to be explored for potential biomarkers. This review discusses the use of circulatory miRNAs that have been able to discriminate lung cancer patients from disease free controls. Several studies conducted recently suggest that circulating miRNAs may have promising future applications for screening and early detection of lung cancer.

Early stage oral tongue cancer among non-tobacco users--an increasing trend observed in a South Indian patient population presenting at a single centre.

BACKGROUND Oral tongue squamous cell carcinoma (OTSCC) is the most common cancer diagnosed within the oral cavity worldwide. Many studies in India report OTSCC ranking among the top two most common subsites within the oral cavity. India is often labeled the oral cancer capital of the world. The incidence of tongue cancers in the population-based cancer registry (PBCR) of Chennai is showing an increasing trend. A majority of the oral cavity cancers (85%) in our cancer center present in advanced stages (III and IV). In contrast, early tongue cancers (stages I and II) constitute nearly 45% of all OTSCCs. AIM The aim of this study was to analyze the clinical profile and epidemiological trends in our early stage tongue cancer patients with an emphasis on tobacco and alcohol habits. MATERIALS AND METHODS This retrospective analysis was based on a prospectively collected database of 458 consecutive early stage OTSCC in-patients at a tertiary care oncology centre in Chennai between 1995 and 2008. RESULTS Our study suggests that the earlier trends have clearly changed whereby nearly half of our patients are now never-tobacco users. The findings of the study indicate that a majority of the patients were never alcohol users (86.4%) and nearly half of them were never tobacco users (49.3%), and they had the best survival outcomes. This increasing trend of OTSCC among non-tobacco users is in contrast to our earlier experience of tongue cancer more than five decades ago.The median age of patients in our study was 53.3 years; the male to female ratio was approximately 2:1. The median follow up for the 458 patients was 53 months. CONCLUSIONS Our study importantly as well as interestingly shows a conspicuous absence of association with the traditional risk factors, tobacco and alcohol.

Risk Stratification of Early Stage Oral Tongue Cancers Based on HPV Status and p16 Immunoexpression

BACKGROUND Recent epidemiological data have implicated human papilloma virus (HPV) infection in the pathogenesis of head and neck cancers, especially oropharyngeal cancers. Although, HPV has been detected in varied amounts in persons with oral dysplasia, leukoplakias and malignancies, its involvement in oral tongue carcinogenesis remains ambiguous. MATERIALS AND METHODS HPV DNA prevalence was assessed by PCR with formalin fixed paraffin embedded sections (n=167) of oral tongue squamous cell carcinoma patients and the physical status of the HPV16 DNA was assessed by qPCR. Immunohistochemistry was conducted for p16 evaluation. RESULTS We found the HPV prevalence in tongue cancers to be 51.2%, HPV 16 being present in 85.2% of the positive cases. A notable finding was a very poor concordance between HPV 16 DNA and p16 IHC findings (kappa<0.2). Further molecular classification of patients based on HPV16 DNA prevalence and p16 overexpression showed that patients with tumours showing p16 overexpression had increased hazard of death (HR=2.395; p=0.005) and disease recurrence (HR=2.581; p=0.002) irrespective of their HPV 16 DNA status. CONCLUSIONS Our study has brought out several key facets which can potentially redefine our understanding of tongue cancer tumorigenesis. It has emphatically shown p16 overexpression to be a single important prognostic variable in defining a high risk group and depicting a poorer prognosis, thus highlighting the need for its routine assessment in tongue cancers. Another significant finding was a very poor concordance between p16 expression and HPV infection suggesting that p16 expression should possibly not be used as a surrogate marker for HPV infection in tongue cancers. Interestingly, the prognostic significance of p16 overexpression is different from that reported in oropharyngeal cancers. The mechanism of HPV independent p16 over expression in oral tongue cancers is possibly a distinct entity and needs to be further studied.

The relevance of "Nonsmoking-associated lung cancer" in India: A single-centre experience

BACKGROUND Lung cancer remains a major cause of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. AIM The aim of this study was to analyze the clinical profile and the epidemiological trends in lung cancer patients from a single centre with an emphasis on the smoking practices. MATERIALS AND METHODS This is a retrospective analysis of prospectively collected data of 258 consecutive hospital in-patients with a proven diagnosis of lung cancer at a tertiary care oncology centre between 2003 and 2007. RESULTS The median age of patients in our study was 56 years; the male to female ratio was approximately 3.5:1. Non-small-cell lung cancer (NSCLC) was the predominant histology in 224 patients; the histology in the remaining 34 patients was small-cell carcinoma. Within NSCLC, the most common histology was adenocarcinoma followed by squamous cell carcinoma. One hundred and two patients were never-smokers as compared to 156 patients who were ever-smokers. Among the smokers, the majority of them were found to be cigarette smokers compared to 28.2% bidi smokers. There was a very significant correlation found with adenocarcinoma among nonsmokers, and with squamous cell carcinoma among the smokers compared to non-smokers. CONCLUSIONS Our study suggests that the epidemiology of lung cancer in India is possibly changing, with close to 40% of our lung cancer patients being nonsmokers. More importantly, our study reflects the global trend of rise in adenocarcinoma histology. These observations need to be substantiated in similar studies of larger magnitude, preferably population-based.

Chemoprevention of oral cancer: Green tea experience.

Oral cancer has a well characterized progression from premalignant oral epithelial changes to invasive cancer, making oral squamous cell carcinoma an optimal disease for chemoprevention interventions prior to malignant transformation. The primary goal of chemoprevention here is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Due to the extended duration of oral pathogenesis, its chemoprevention using natural products has been found promising due to their decreased dose and limited toxicity profiles. This review discusses with an emphasis on the clinical trials using green tea extract (GTE) in chemoprevention of oral premalignant lesions along with use of GTE as a chemopreventive agent in various other cancers as well. It is worthwhile to include green tea extract in an oral screening program for evaluating the premalignant lesions comparing the results between the treated and untreated group. Given the wide acceptance of green tea, its benefits may help in effective chemoprevention oral cancer.

Human papilloma virus in head and neck cancers-role and relevance in clinical management.

The biology and clinical behavior of Head and Neck Squamous Cell Carcinomas (HNSCCs) is very distinct within different subgroups due to the distinct molecular profiles for the HPV positive versus HPV negative tumors. HPV status is the most important independent prognostic variable in multivariate analysis taking into account all other prognostic factors like tumour stage, smoking status, age and performance status. The debate today is whether the intense therapy is too aggressive in this group of patients since they show a superior survival regardless of treatment strategies. A highly divergent prognosis and distinct biology of HPV positive and HPV negative HNSCCs underlines the fact that treating them as distinct diseases is the need of the hour. Infection with HPV is associated with less aggressive disease, better loco regional control and lower rates of second primary cancers. An important caveat that remains is the emergence of intermediate prognosis of HPV positive smokers and HPV negative non smokers. Though molecular biology has provided important data on the interaction of the HPV onco proteins with genes important in cell cycle control, also speculated to be involved in pathogenesis of HNSCC, more basic research is needed to describe the differential mechanisms of tumorigenesis among the HNSCCs that show presence and absence of HPV. This is clinically relevant to reduce morbidity without compromising tumour control in HPV positive patients and improving tumour control and co-morbid illness that could be pre-existing or treatment related in HPV negative patients. There may be a need for treatment intensification and incorporation of newer agents into induction chemotherapy protocols for the HPV negative patients and so HPV detection is important to aid in this selection. HPV tumour status is therefore more important than just providing the prognostic information in these classes of tumours. This article discusses the role and clinical relevance of HPV in HNSCCs.

Quick chip assay using locked nucleic acid modified epithelial cell adhesion molecule and nucleolin aptamers for the capture of circulating tumor cells

The role of circulating tumor cells (CTCs) in disease diagnosis, prognosis, monitoring of the therapeutic efficacy, and clinical decision making is immense and has attracted tremendous focus in the last decade. We designed and fabricated simple, flat channel microfluidic devices polydimethylsiloxane (PDMS based) functionalized with locked nucleic acid (LNA) modified aptamers (targeting epithelial cell adhesion molecule (EpCAM) and nucleolin expression) for quick and efficient capture of CTCs and cancer cells. With optimized flow rates (10 μl/min), it was revealed that the aptamer modified devices offered reusability for up to six times while retaining optimal capture efficiency (>90%) and specificity. High capture sensitivity (92%) and specificity (100%) was observed in whole blood samples spiked with Caco-2 cells (10-100 cells/ml). Analysis of blood samples obtained from 25 head and neck cancer patients on the EpCAM LNA aptamer functionalized chip revealed that an average count of 5 ± 3 CTCs/ml of blood were captured from 22/25 samples (88%). EpCAM intracellular domain (EpICD) immunohistochemistry on 9 oral squamous cell carcinomas showed the EpICD positivity in the tumor cells, confirming the EpCAM expression in CTCs from head and neck cancers. These microfluidic devices also maintained viability for in vitro culture and characterization. Use of LNA modified aptamers provided added benefits in terms of cost effectiveness due to increased reusability and sustainability of the devices. Our results present a robust, quick, and efficient CTC capture platform with the use of simple PDMS based devices that are easy to fabricate at low cost and have an immense potential in cancer diagnosis, prognosis, and therapeutic planning.

Adult soft-tissue sarcomas of the head and neck

BACKGROUND Head and neck sarcomas are relatively rare tumors, accounting for only about 2% of all head and neck malignancies and for 4 to 10% of all soft tissue sarcomas. The rarity and more over the heterogeneity of these tumors make rigorous study of their clinical behavior difficult. AIMS We analyzed our single center experience of adult soft tissue sarcomas of the head and neck. SETTINGS AND DESIGN Our study included 27 patients of adult soft-tissue sarcomas of the head and neck who presented to our center between January 1996 and December 2005. MATERIALS AND METHODS Patient characteristics, clinical features, treatment modalities, clinical course, and long-term outcomes and its determinants were analyzed. RESULTS Surgery in the form of wide excision aimed at achieving negative margins was the main modality of treatment and adjuvant radiation was used in selected patients. The five-year disease-free survival was 64.5% and overall survival (OS) was 68%. Of the multiple potential factors analyzed, univariate analysis showed grade, margin status, and adjuvant radiation to be the important prognostic factors for the survival. The multivariate analysis however only showed margin status and adjuvant radiation to be prognostic. CONCLUSIONS Surgery with negative margins is a key to long-term survival. Complete resection with adjuvant radiation in selected cases potentially decreases local recurrences and improves OS.

Microsurgical free flaps: Controversies in maxillofacial reconstruction

Reconstructive microsurgery for oral and maxillofacial (OMF) defects is considered as a niche specialty and is performed regularly only in a handful of centers. Till recently the pectoralis major myocutaneous flap (PMMC) was considered to be the benchmark for OMF reconstruction. This philosophy is changing fast with rapid advancement in reconstructive microsurgery. Due to improvement in instrumentation and the development of finer techniques of flap harvesting we can positively state that microsurgery has come of age. Better techniques, microscopes and micro instruments enable us to do things previously unimaginable. Supramicrosurgery and ultrathin flaps are a testimony to this. Years of innovation in reconstructive microsurgery have given us a reasonably good number of very excellent flaps. Tremendous work has been put into producing some exceptionally brilliant research articles, sometimes contradicting each other. This has led to the need for clarity in some areas in this field. This article will review some controversies in reconstructive microsurgery and analyze some of the most common microvascular free flaps (MFF) used in OMF reconstruction. It aims to buttress the fact that three flaps-the radial forearm free flap (RFFF), anterolateral thigh flap (ALT) and fibula are the ones most expedient in the surgeons arsenal, since they can cater to almost all sizeable defects we come across after ablative surgery in the OMF region. They can thus aptly be titled as the workhorses of OMF reconstruction with regard to free flaps.