Sudhir Nair

Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer

BACKGROUND Whether patients with early-stage oral cancers should be treated with elective neck dissection at the time of the primary surgery or with therapeutic neck dissection after nodal relapse has been a matter of debate. METHODS In this prospective, randomized, controlled trial, we evaluated the effect on survival of elective node dissection (ipsilateral neck dissection at the time of the primary surgery) versus therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse) in patients with lateralized stage T1 or T2 oral squamous-cell carcinomas. Primary and secondary end points were overall survival and disease-free survival, respectively. RESULTS Between 2004 and 2014, a total of 596 patients were enrolled. As prespecified by the data and safety monitoring committee, this report summarizes results for the first 500 patients (245 in the elective-surgery group and 255 in the therapeutic-surgery group), with a median follow-up of 39 months. There were 81 recurrences and 50 deaths in the elective-surgery group and 146 recurrences and 79 deaths in the therapeutic-surgery group. At 3 years, elective node dissection resulted in an improved rate of overall survival (80.0%; 95% confidence interval [CI], 74.1 to 85.8), as compared with therapeutic dissection (67.5%; 95% CI, 61.0 to 73.9), for a hazard ratio for death of 0.64 in the elective-surgery group (95% CI, 0.45 to 0.92; P=0.01 by the log-rank test). At that time, patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5% vs. 45.9%, P<0.001). Elective node dissection was superior in most subgroups without significant interactions. Rates of adverse events were 6.6% and 3.6% in the elective-surgery group and the therapeutic-surgery group, respectively. CONCLUSIONS Among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease-free survival than did therapeutic neck dissection. (Funded by the Tata Memorial Centre; ClinicalTrials.gov number, NCT00193765.).

Head and neck cancers in developing countries.

Head and neck cancers are the most common cancers in developing countries, especially in Southeast Asia. Head and neck cancers are more common in males compared to females. This is mainly attributed to tobacco, areca nut, alcohol, etc. Oral cancers are most common amongst all head and neck squamous cell cancers (HNSCC). HNSCC in the developing world differ from those in the Western world in terms of age, site of disease, etiology, and molecular biology. Poverty, illiteracy, advanced stage at presentation, lack of access to health care, and poor treatment infrastructure pose a major challenge in management of these cancers. The annual GDP (gross domestic product) spent on health care is very low in developing countries compared to the developed countries. Cancer treatment leads to a significant financial burden on the cancer patients and their families. Several health programs have been implemented to curb this rising burden of disease. The main aims of these health programs are to increase awareness among people regarding tobacco and to improve access to health care facilities, early diagnosis, treatment, and palliative care.

UVR Exposure Sensitizes Keratinocytes to DNA Adduct Formation

UV radiation (UVR) and exposure to tobacco smoke, a source of polycyclic aromatic hydrocarbons (PAH), have been linked to skin carcinogenesis. UVR-mediated activation of the aryl hydrocarbon receptor (AhR) stimulates the transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAH to genotoxic metabolites. We determined whether UVR exposure sensitized human keratinocytes to PAH-induced DNA adduct formation. UVR exposure induced CYP1A1 and CYP1B1 in HaCaT cells, an effect that was mimicked by photooxidized tryptophan (aTRP) and FICZ, a component of aTRP. UVR exposure or pretreatment with aTRP or FICZ also sensitized cells to benzo(a)pyrene (B[a]P)-induced DNA adduct formation. αNF, an AhR antagonist, suppressed UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1 and inhibited B[a]P-induced DNA adduct formation. Treatment with 17-AAG, an Hsp90 inhibitor, caused a marked decrease in levels of AhR; inhibited UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1; and blocked the sensitization of HaCaT cells to B[a]P-induced DNA adduct formation. FICZ has been suggested to be a physiologic ligand of the AhR that may have systemic effects. Hence, studies of FICZ were also carried out in MSK-Leuk1 cells, a model of oral leukoplakia. Pretreatment with α-naphthoflavone or 17-AAG blocked FICZ-mediated induction of CYP1A1 and CYP1B1, and suppressed the increased B[a]P-induced DNA adduct formation. Collectively, these results suggest that sunlight may activate AhR signaling and thereby sensitize cells to PAH-mediated DNA adduct formation. Antagonists of AhR signaling may have a role in the chemoprevention of photocarcinogenesis.

Oral squamous cell carcinoma arising in background of oral submucous fibrosis: a clinicopathologically distinct disease

Oral cancer is the most common cancer in Indian males and is the third most common cancer in Indian females. Tobacco, alcohol, areca nut, and human papillomavirus (HPV) are the common etiologic factors. Each of these agents follows a unique model of carcinogenesis that leads to a certain distinct presentation and behavior. For example, HPV is strongly associated with oropharyngeal cancers in younger age and is known to have a better outcome and specific histopathologic characteristics. A high incidence of oral submucous fibrosis (OSMF) is linked to areca nut (group 1 human carcinogen) chewing in the Indian subcontinent.

Predictors of prognosis for squamous cell carcinoma of oral tongue.

Certain tumor‐related factors like thickness increases the risk of nodal metastasis and may affect survival in patients with oral tongue cancers. The objective of this study is to identify those tumor‐related prognostic predictors that can potentially influence decision for adjuvant radiotherapy.

UV radiation inhibits 15-hydroxyprostaglandin dehydrogenase levels in human skin: evidence of transcriptional suppression.

Elevated levels of prostaglandins (PG) have been detected in the skin following UV radiation (UVR). PGs play an important role in mediating both the acute and the chronic consequences of UVR exposure. UVR-mediated induction of cyclooxygenase-2 (COX-2) contributes to increased PG synthesis. In theory, reduced catabolism might also contribute to increased PG levels. 15-Hydroxyprostaglandin deyhdrogenase (15-PGDH), a tumor suppressor gene, plays a major role in PG catabolism. In this study, we investigated whether UVR exposure suppressed 15-PGDH while inducing COX-2 in keratinocytes and in human skin. UVR exposure caused dose-dependent induction of COX-2, suppression of 15-PGDH, and increased prostaglandin E2 (PGE2) production in HaCaT cells. Exposure to UVR suppressed the transcription of 15-PGDH, resulting in reduced 15-PGDH mRNA, protein, and enzyme activities. UVR exposure induced Slug, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Slug blocked UVR-mediated downregulation of 15-PGDH. The effects of UVR were also evaluated in the EpiDerm skin model, a three-dimensional model of human epidermis. Here too, COX-2 levels were induced and 15-PGDH levels suppressed following UVR exposure. Next, the effects of UVR were evaluated in human subjects. UVR treatment induced COX-2 while suppressing 15-PGDH mRNA in the skin of 9 of 10 subjects. Collectively, these data suggest that reduced expression of 15-PGDH contributes to the elevated levels of PGs found in the skin following UVR exposure. Possibly, agents that prevent UVR-mediated downregulation of 15-PGDH will affect the acute or the long-term consequences of UVR exposure, including nonmelanoma skin cancer. Cancer Prev Res; 3(9); 1104–11. ©2010 AACR.

Delay in seeking specialized care for oral cancers: Experience from a tertiary cancer center

OBJECTIVE Advanced oral cancers are a challenge for treatment, as they require complex procedures for excision and reconstruction. Despite being occurring at a visible site and can be detected easily, many patients present in advanced stages with large tumors. Timely intervention is important in improving survival and quality of life in these patients. The aim of the present study was to find out the causes of delay in seeking specialist care in advanced oral cancer patients. MATERIALS AND METHODS A prospective questionnaire based study was done on 201 consecutive advanced oral squamous cancer patients who underwent surgery at our hospital. All patients had either cancer of gingivobuccal complex (GBC) or tongue and had tumors of size more than 4 cm (T3/T4) and were treatment naοve at presentation. RESULTS Even though most patients observed abnormal lesions in their mouth, majority delayed the decision to visit a physician early. A significant percentage of patients (50%) also reported a delayed diagnosis by the primary care physician before being referred to a tertiary care center for definitive treatment. The average total duration from symptoms to treatment was 7 months. CONCLUSION The main reasons of this delay in receiving treatment were due to patients themselves (primary delay) or due to time taken by the primary physician to diagnose the condition (secondary delay). Oral self-examination can be helpful in detecting oral cancers early.

Prospective study of ultrasound-guided fine-needle aspiration cytology and sentinel node biopsy in the staging of clinically negative T1 and T2 oral cancer.

The purpose of this study was to compare sentinel node biopsy (SNB) and ultrasound‐guided fine‐needle aspiration cytology (FNAC) for preoperative evaluation of the N0 neck in T1 to T2 oral cavity squamous cell carcinoma (SCC).

Utility of frozen section in assessment of margins and neck node metastases in patients undergoing surgery for carcinoma of the tongue.

OBJECTIVE The aims of this study are to evaluate the impact of frozen section in achieving adequate surgical margin and to study the accuracy of frozen section in detection of occult metastases. MATERIALS AND METHODS This was a retrospective review of prospectively collected data of 877 patients with squamous cell carcinoma of the tongue who underwent surgery and intra-operative frozen section at our center from January 2007 to June 2010. RESULTS Frozen section was found to have very high accuracy in assessment of margin as well nodal status. On frozen section, 2% of our patients had positive margins and 21% had close margins. Most of these underwent intra-operative revision and at final pathology, 1.2% patients had positive margins and 11% were close. Of the 651 supraomohyoid neck dissections performed, one third were found to have occult metastases on frozen section. Of those reported positive on frozen section, 68% got additional removal of level 4 ± 5. Interestingly, 11% of these additionally removed nodes harbored metastases at final pathology. However, 7% of the patients were wrongly declared negative on frozen section. Tumor thickness was predictor of margin positivity as well as occult metastases. Tumor volume did not correlate with occult metastases or margin status. CONCLUSIONS Frozen section nearly halves the rates of positive margin and close margins which certainly translates into clinical benefits. The incidence of 11% positive nodes in the frozen section guided removal of lower levels is an important finding in our study that questions the ability of supraomohyoid neck dissection to completely eradicate the nodal burden in such patients.

Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer

Background Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC). Patients and Methods We analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays. Results We show, unlike TCGA HNSCC data set, NOTCH1 harbors significantly lower frequency of inactivating mutations (4%); is somatically amplified; and, overexpressed in 31% and 37% of early stage TSCC patients, respectively. HNSCC cell lines over expressing NOTCH1, when plated in the absence of attachment, are enriched in stem cell markers and form spheroids. Furthermore, we show that inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in TSCC. Clinically, Notch pathway activation is higher in tumors of non-smokers compared to smokers (50% Vs 18%, respectively, P=0.026) and is also associated with greater nodal positivity compared to its non-activation (93% Vs 64%, respectively, P=0.029). Conclusion We anticipate that these results could form the basis for therapeutic targeting of NOTCH1 in tongue cancer.