Naveen Hedne

Meta-Analyses of Microarray Datasets Identifies ANO1 and FADD as Prognostic Markers of Head and Neck Cancer.

The head and neck squamous cell carcinoma (HNSCC) transcriptome has been profiled extensively, nevertheless, identifying biomarkers that are clinically relevant and thereby with translational benefit, has been a major challenge. The objective of this study was to use a meta-analysis based approach to catalog candidate biomarkers with high potential for clinical application in HNSCC. Data from publically available microarray series (N = 20) profiled using Agilent (4X44K G4112F) and Affymetrix (HGU133A, U133A_2, U133Plus 2) platforms was downloaded and analyzed in a platform/chip-specific manner (GeneSpring software v12.5, Agilent, USA). Principal Component Analysis (PCA) and clustering analysis was carried out iteratively for segregating outliers; 140 normal and 277 tumor samples from 15 series were included in the final analysis. The analyses identified 181 differentially expressed, concordant and statistically significant genes; STRING analysis revealed interactions between 122 of them, with two major gene clusters connected by multiple nodes (MYC, FOS and HSPA4). Validation in the HNSCC-specific database (N = 528) in The Cancer Genome Atlas (TCGA) identified a panel (ECT2, ANO1, TP63, FADD, EXT1, NCBP2) that was altered in 30% of the samples. Validation in treatment naïve (Group I; N = 12) and post treatment (Group II; N = 12) patients identified 8 genes significantly associated with the disease (Area under curve>0.6). Correlation with recurrence/re-recurrence showed ANO1 had highest efficacy (sensitivity: 0.8, specificity: 0.6) to predict failure in Group I. UBE2V2, PLAC8, FADD and TTK showed high sensitivity (1.00) in Group I while UBE2V2 and CRYM were highly sensitive (>0.8) in predicting re-recurrence in Group II. Further, TCGA analysis showed that ANO1 and FADD, located at 11q13, were co-expressed at transcript level and significantly associated with overall and disease-free survival (p<0.05). The meta-analysis approach adopted in this study has identified candidate markers correlated with disease outcome in HNSCC; further validation in a larger cohort of patients will establish their clinical relevance.

Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition

Chemoresistance leading to disease relapse is one of the major challenges to improve outcome in head and neck cancers. Cancer Stem Cells (CSCs) are increasingly being implicated in chemotherapy resistance, this study investigates the correlation between CSC behavior and acquired drug resistance in in vitro cell line models. Cell lines resistant to Cisplatin (Cal‐27 CisR, Hep‐2 CisR) and 5FU (Cal‐27 5FUR) with high Resistance Indices (RI) were generated (RI ≥ 3) by short‐term treatment of head and neck squamous cell carcinoma (HNSCC) cell lines with chemotherapeutic drugs (Cisplatin, Docetaxel, 5FU), using a dose‐incremental strategy. The cell lines (Cal‐27 DoxR, Hep‐2 DoxR, Hep‐2 5FUR) that showed low RI, nevertheless had a high cross resistance to Cisplatin/5FU (P < 0.05). Cal‐27 CisR and DoxR showed 12–14% enrichment of CD44+ cells, while CisR/5FUR showed 4–6% increase in ALDH1A1+ cells as compared to parental cells (P < 0.05). Increased expression of stem cell markers (CD44, CD133, NOTCH1, ALDH1A1, OCT4, SOX2) in these cell lines, correlated with enhanced spheroid/colony formation, migratory potential, and increased in vivo tumor burden (P < 0.05). Inhibition of ALDH1A1 in Cal‐27 CisR led to down regulation of the CSC markers, reduction in migratory, self‐renewal and tumorigenic potential (P < 0.05) accompanied by an induction of sensitivity to Cisplatin (P < 0.05). Further, ex vivo treatment of explants (n = 4) from HNSCC patients with the inhibitor (NCT‐501) in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment (P = 0.001). This study hence suggests an ALDH1A1‐driven, CSC‐mediated mechanism in acquired drug resistance of HNSCC, which may have therapeutic implications.

Selective Neck Dissection Is Effective in N1/N2 Nodal Stage Oral Cavity Squamous Cell Carcinoma

PURPOSE Although the efficacy of selective neck dissection (SND) in the management of a node-negative neck is established, its utility in the management of node-positive disease remains controversial. The objective of this study was to evaluate the oncologic safety of SND in the management of N1/N2 oral cavity squamous cell carcinoma. MATERIALS AND METHODS From a prospectively collected electronic database of patients with oral cavity cancer, a retrospective analysis was conducted of patients with nonrecurrent, clinical, and/or pathologic N1/N2 oral cavity squamous cell carcinoma who underwent SND of levels I to III/IV. The patients were stratified into 2 groups: clinical N0 but pathologic N1/N2 (cN0-pN1/N2) and clinical N1/N2 (cN1/N2). The primary outcome variable of the study was the ipsilateral regional recurrence rate. Categorical data were analyzed by the 2-sided Fisher exact test, and 3-year Kaplan-Meier ipsilateral regional control rate, regional recurrence-free survival, disease-free survival, and overall survival were estimated. RESULTS Forty-nine patients constituted the study sample, with 37 patients in the cN1/N2 group and 12 patients in the cN0-pN1/N2 group. During the follow-up period of 3 years, 2 patients (∼4%) developed ipsilateral neck recurrence, and these patients were in the cN1/N2 group. The 3-year Kaplan-Meier ipsilateral regional control rate was 95%. CONCLUSIONS SND may produce a satisfactory ipsilateral regional control rate in patients with early-stage node-positive oral squamous cell carcinoma. A prospective, randomized clinical trial comparing SND with modified radical neck dissection may be required for a categorical conclusion of these findings.

The Jugaad Technique for Jaw Reconstruction: Denture Based Inverse Planning

AimThe aim of this clinical paper is to introduce a technique to plan for functional maxillofacial reconstructions.Materials and MethodsPreoperative dental casts were made of the patient and mock surgery performed on the casts. A fibula analogue was then placed in an ideal functional reconstruction position. New dentures were fabricated on the fibula analogue and drill holes for the placement of implants were placed through the denture. This denture formed as a guide to position the fibula transplant during surgery.ResultsThis technique was useful in producing functional and rehabilitative outcomes in cases of both maxillary and mandibular reconstructive surgeries.ConclusionThe Jugaad technique—denture based inverse planning—is a cost effective method for planning and executing maxillofacial reconstructions using mock surgery on casts and interim dentures.

Orbital floor reconstruction with free flaps after maxillectomy.

Background The purpose of this study is to evaluate the outcome of orbital floor reconstruction with free flaps after maxillectomy. Methods This was a retrospective analysis of 34 consecutive patients who underwent maxillectomy with orbital floor removal for malignancies, reconstructed with free flaps. A cross-sectional survey to assess the functional and esthetic outcome was done in 28 patients who were alive and disease-free, with a minimum of 6 months of follow-up. Results Twenty-six patients had bony reconstruction, and eight had soft tissue reconstruction. Free fibula flap was the commonest flap used (n = 14). Visual acuity was normal in 86%. Eye movements were normal in 92%. Abnormal globe position resulted in nine patients. Esthetic satisfaction was good in 19 patients (68%). Though there was no statistically significant difference in outcome of visual acuity, eye movement, and patient esthetic satisfaction between patients with bony and soft tissue reconstruction, more patients without bony reconstruction had abnormal globe position (p = 0.040). Conclusion Free tissue transfer has improved the results of orbital floor reconstruction after total maxillectomy, preserving the eye. Good functional and esthetic outcome was achieved. Though our study favors a bony orbital reconstruction, a larger study with adequate power and equal distribution of patients among the groups would be needed to determine this. Free fibula flap remains the commonest choice when a bony reconstruction is contemplated.

Versatility of Adipofascial Anterolateral Thigh Flap for Reconstruction of Maxillary Defects with Infratemporal Fossa Extension

Tumors arising from the posterior hard palate or posterolateral maxilla may extend to involve the infratemporal fossa (ITF). Resection of these tumors results in infrastructural maxillectomy with ITF defects. In this study, we describe the use of an adipofascial anterolateral thigh flap (ALT) specifically for such defects. This case series includes four patients who underwent an infrastructure maxillectomy with ITF clearance and the resultant defects were reconstructed using adipofascial anterolateral thigh flaps. The complications as well as the functional outcomes were assessed. This study included patients with lesions involving the hard palate, posterolateral part of maxilla with extension into the ITF. The mean flap dimension was 150 cm2 (range, 120–180 cm2). All flaps were harvested based on a single perforator. The flap was used to obliterate the ITF defect and also to achieve oroantral separation. All flaps mucosalized well within 6 weeks. All patients were on oral diet and had adequate mouth opening. There were no donor-site complications. Adipofascial ALT is an excellent choice for infrastructural maxillectomy defects with ITF extension. The intraoral part got mucosalized well and provided a smooth and taut surface. A large adipofascial tissue flap helps obliterate the ITF, thus minimizing complications.

Efficacy of Per Oral Access in the Surgical Management of T2/T3 Oral Cavity Squamous Cell Carcinoma

Objective Transcutaneous “access” procedures still continue to be widely employed for surgical management of medium-sized (T2, T3) oral cavity tumors in spite of the almost 4-cm mouth opening available to the surgeon to access the oral cavity. We undertook a retrospective study to objectively evaluate “per oral access” in managing these tumors with regard to the ability to achieve a clear surgical margin and enable reconstruction of resultant defect. Study Design Case series with chart review. Setting Tertiary academic hospital. Subjects and Methods Seventy-nine consecutive patients of oral squamous cell carcinoma excised by per oral approach were analyzed. Multiple patient- and tumor-related factors known to influence status of surgical margins were analyzed. The overall frequency of clear, close, and involved margins was noted, as well as 5-year local control rate. The method of reconstruction employed was evaluated. Results The close/involved margins were more frequent with larger tumors and tumors exhibiting perineural infiltration, but none were statistically significant (P > .12). The overall frequency of clear, close, and involved margins was 81%, 11%, and 8%, respectively. Tongue and buccal mucosa sites constituted approximately 85% of the cases and had an 85% clear margin rate. Five-year local control rate was 70.35%. Fifty-three free flaps reconstruction were undertaken without any additional “access” procedure. Conclusion Our results demonstrate ability to obtain comparable tumor clearance rates employing per oral access, without compromising ability to perform optimal reconstruction. We suggest per oral access should be the access of choice for medium-sized oral cavity tumors, and additional access procedures should only be considered if the initial access proves inadequate.

Reconstruction of Cheek Defects

The cheek is a term loosely used to refer to the area of the face below the eyes and between the nose and the ears. It is a three-dimensional region which needs to be described in three planes – the anteroposterior, the superoinferior and the mediolateral. The anatomical boundaries are defined as the nasolabial and labio-mental crease anteriorly, the line extending from the lateral canthus to the superior border of the tragus superiorly, the tragus to the angle of the mandible posteriorly and the lower border of the mandible inferiorly. Intraorally, the buccal mucosal boundaries are defined as the commissure of the mouth anteriorly, the pterygomandibular raphe posteriorly and the upper and lower bucco-alveolar sulci superiorly and inferiorly, respectively [Fig. 8.1a, b – anatomic limits of cheek skin surface (1a) and mucosal surface (1b)].