Prognostic Value of Lymph Node Density in Node-Positive Oral Squamous Cell Carcinoma.

Lymph node status is an important prognostic factor in head and neck cancer. The purpose of this study is to investigate the prognostic value of lymph node density (LND) in node-positive oral cavity cancer patients who received surgery plus adjuvant radiotherapy. From January 2008 to December 2013, a total of 61 oral cavity squamous cell cancer patients who had positive lymph node and received surgery and adjuvant radiotherapy were analysed. LND was calculated for each patient. The endpoints were 5-year overall survival (OS) and 5-year disease-free survival. All patients were followed for a period of 5 years. Mean 5-year overall survival for cases with LND of ≤ 0.05 was 56.1 ± 11.6 months, whereas mean 5-year overall survival for cases with LND > 0.05 was 40.0 ± 21.6 months. Log rank is 0.04 95% CI = 53.4-65. Mean 5-year disease-free survival for cases with LND of ≤ 0.05 was 50.5 ± 15.8 months, whereas mean disease-free survival for cases with LND > 0.05 was 15.8 ± 22.9 months. Log rank 0.03 95% CI = 43.3-57.6. Nodal status, disease stage and lymph node density were found to be significant predictors of prognosis in univariate analysis. In multivariate analysis, only lymph node density is found to be the predictor of prognosis. LND is an important prognosis factor for 5-year OS and 5-year DFS in oral cavity squamous cell carcinoma.

Oral cavity adjuvant therapy (OCAT) -a phase III, randomized controlled trial of surgery followed by conventional RT (5 fr/wk) versus concurrent CT-RT versus accelerated RT (6fr/wk) in locally advanced, resectable, squamous cell carcinoma of oral cavity.

BACKGROUND: Limited data exists regarding the impact of intensification of adjuvant therapy in resected Oral Cavity Squamous Cell Carcinomas (OCSCC) with adverse prognostic features on histopathology. PATIENTS AND METHODS: This was a three-arm phase III, randomised trial including patients with resected advanced OCSCC. Randomisation was done in a 1:1:1 ratio: Arm-A- standard adjuvant radiation therapy (RT) 60Gy/30 fractions over 6 weeks versus Arm-B-concurrent chemoradiation versus Arm-C-accelerated radiation therapy (6 d a week). The trial was powered to detect an absolute difference of 10% in 5-year Locoregional Control (LRC). RESULTS: The trial was conducted between June 2005 and March 2013. Majority of the patients were males, had T3-T4 disease, had N2-N3 nodal status and had Extra-Capsular Extension (ECE) in nodes. The median follow-up was 95.9 months. There was no difference between the three arms (A versus B versus C) for 10-year locoregional control (LRC): 60.2% versus 61.4% versus 65.7%, p = 0.57; disease free survival (DFS): 37.4% versus 43.9% versus 39.6%, p = 0.40; or Overall Survival (OS): 39.7% versus 46.6% versus 40.4%, p = 0.40. There was no benefit of intensification with either modality in patients with any single adverse pathological factor. A benefit of intensification could be seen in patients with a combination of high-risk features: T3-T4 primary tumours with N2-N3 nodes along with ECE for DFS (Arm B versus Arm A HR) = 0.53, Arm C versus Arm A HR = 0.63) and OS (Arm B versus Arm A HR = 0.58, Arm C versus Arm A HR = 0.60). CONCLUSIONS: All optimally resected OCSCC with adverse features did not benefit from intensification of adjuvant therapy. Only a cohort of patients with a combination of high-risk features are likely candidates for intensification. CLINICAL TRIAL REGISTRATION: NCT00193843.

Oral mucositis-case series of a rare adverse effect associated with immunotherapy.

Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, act by inhibiting programmed death-1 and activating the T cells against cancer. An imbalance in this immune response, however, could lead to immune-related adverse events (irAEs) involving multiple organs like rash, fatigue, hypo and hyperthyroidism, pneumonitis, hepatitis, and colitis, among others. Oral irAEs are not uncommon among immune checkpoint inhibitors which include xerostomia, dysgeusia, and lichenoid reactions; however, oral mucositis is rarely seen or reported in patients receiving PD-1 inhibitors. We present 3 cases of this rare complication in varying grades of severity. The patients were managed with steroids, either topical or systemic, depending on the severity of the lesions with either postponement or withholding therapy due to toxicity. Through this article, we hope to bring to light this overlooked and underdiagnosed oral adverse event associated with the use of immunotherapy and various treatment options for its management.

Robotic retroauricular thyroidectomy: initial experience from India.

Robotic thyroidectomy is getting accepted worldwide, but, majority of the literature is from South Korea. The purpose of this paper is to review the early experiences with robotic retroauricular (RA) thyroidectomy from India. The rationale for robotic thyroidectomy, its advantages and disadvantages are reviewed. The reasons for selecting the RA approach and the criteria used for selecting the patients are discussed. The early experience and outcomes of 29 patients, from three centres across India is presented. Robotic approaches score above endoscopic methods. RA approach may have some technical advantages for the head and neck surgeons. Sufficient cadaver and preclinical training should be undertaken. Standardized and formal teaching for robotic surgical skill is necessary. Case selection is important especially in the initial phases of the learning curve. Our early experience with robotic thyroidectomy was encouraging.

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis.

The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1ß, impaired blood-brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10(low)IL-23/IL-1ß/IL-6(high)), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35-55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35-55-primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4(+) T cells were due to an autocrine effect of IL-1ß/IL-23-mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype-Th17 axis in an animal model of multiple sclerosis.

Cell-free Epstein-Barr virus-DNA in patients with nasopharyngeal carcinoma: Plasma versus urine.

BACKGROUND: The purpose of this study was to explore urinary Epstein-Barr virus (EBV)-DNA as a potential biomarker in patients with nasopharyngeal carcinoma (NPC). METHODS: EBV-DNA copies were estimated in plasma/urine of patients with NPC (n = 76) by real-time polymerase chain reaction (PCR) at baseline, during therapy, and at follow-up. Their correlation with EBV-RNA expression in tissues (n = 53) was used to assess sensitivity and specificity of plasma/urine EBV-DNA. Correlation of urine and plasma EBV-DNA with each other and with radiological response was evaluated. RESULTS: This study demonstrated that urine EBV-DNA has high sensitivity (96%) at diagnosis and it correlates well with plasma EBV-DNA at baseline and after neoadjuvant chemotherapy. The EBV-DNA copies reduced significantly with therapy (plasma: p < .001; urine: p = .011). Patients with low EBV-DNA copies demonstrated improved survival (plasma: p = .023; urine: p = .083). CONCLUSION: Plasma EBV-DNA is a good prognostic marker, whereas further study on a larger cohort may help in developing urine EBV-DNA as a surrogate prognostic marker for patients with NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1666-E1673, 2016.

Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.

This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO), a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04) in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF) induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6)) were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001) in the peritoneal cavity compared to vehicle (phosphate buffered saline) treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO) for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

Prospective analysis of reasons for non-enrollment in a phase III randomized controlled trial.

AIM: This study aims to provide information on the accrual rate and to identify the reasons for non-enrollment of oral cancer patients into a clinical trial. SETTING AND DESIGN: Prospective study conducted at the Tertiary Cancer Centre (India). MATERIALS AND METHODS: Patients eligible and screened for the oral cancer adjuvant therapy (OCAT) were logged prospectively and reasons for non-enrollment were documented which were broadly divided into patient and trial related. STATISTICAL ANALYSIS USED: Demographic characteristics of the non-enrolees were compared with the enrolled. Factors predicting non-enrollment were analyzed using multivariate logistic regression test. RESULTS: A total of 1335 patients with locally advanced cancer of the oral cavity were screened of whom 498 (37%) could be enrolled. Among non enrolled 837 patients, 182 (22%) had the trial-related reasons and 655 (78%) had patient-related reasons. Most important patient-related reasons were patients' preference of taking treatment closer to their native place (26.2%), lack of interest (16.8%) in trial participation. Anticipated poor compliance to treatment (5.9%) and follow-up (6.6%), inability to start treatment in time (6.2%) were important trial-related reasons for non-enrollment. Multivariate analysis identified the genders (female), education (illiterate), occupation (laborer) and non availability of support system in the city as significant predictors of non-enrollment. CONCLUSIONS: Both trial design and patient factors were important causes of non enrollment in eligible patients. Patients' need for being closer to home and refusal to participate were the most common reasons for non-enrollment.

Prognostic factors for loco-regional failure in early stage (I and II) squamous cell carcinoma of the gingivobuccal complex.

The objective of the article is to study the prognostic indicators of loco-regional failure in patients with early stage cancers of the gingivobuccal complex (GBC) treated at a single institution. The study design is based on retrospective chart review. A review of 2,275 patients diagnosed with GBC was conducted from January 1997 to December 1999, wherein 207 patients who fulfilled our inclusion criteria were analyzed. Univariate analysis, multivariate analysis, and disease-free survival are reported. During a median follow-up of 2.85 years there were 85 (43%) loco-regional failures of which 64% could be salvaged. As much as 80% of all failures occurred within the first 24 months and the mean survival for patients with recurrences was 9.6 months. Two and five-year disease-free survival for the entire cohort was 65% and 52%, respectively. Nodal metastasis, soft tissue infiltration, and pathological bone involvement correlated with poor disease-free survival on multivariate analysis. Early stage tumors of the GBC as evaluated clinically are often upstaged pathologically due to a high rate of occult nodal metastasis and local failure as they tend to invade bone and infiltrate adjacent soft tissue. Consequently, we recommend aggressive surgical therapy as we would recommend for advanced stage cancers of the GBC which includes a wide three-dimensional resection to account for soft tissue and bony infiltrations and adjuvant therapy in the presence of adverse features since salvage rates for recurrent tumors are poor.

Squamous cell carcinoma of base of tongue in a patient with Fanconi's anemia treated with radiation therapy: case report and review of literature.

BACKGROUND: Fanconi's anemia (FA) is a rare autosomal recessive genetic disorder characterized by congenital anomalies, progressive aplastic anemia, and a predisposition for malignancies. Solid tumors in the head and neck region, especially in the tongue, are rarely observed. Management of these patients is a challenge because of hematological complications and increased toxicities. METHODS: We report a case of Fanconi's anemia in a 27-year-old man with carcinoma of the base of tongue (T2N0M0) who was treated with radical radiation therapy to a dose of 70 Gy/35 fractions/51 days. We have also done in vitro radiosensitivity tests. RESULTS: The patient tolerated the radiation treatment well and completed it without any interruptions. In vitro studies did not show any increased radiosensitivity in this patient. CONCLUSION: Head and neck cancer in a patient with FA requires individualized treatment. The decision about opting for different modalities should be based on a balanced approach with respect to locoregional control and toxicities of the treatment.

Quality of life in head and neck cancer survivors: a cross-sectional survey.

PURPOSE: Head and neck cancer (HNC) survivors have substantial psychological distress in addition to treatment-related side effects. This study examines the long-term quality of life (QOL) of HNC survivors in a busy tertiary care center. MATERIAL AND METHODS: A prospective, cross-sectional survey was conducted studying 212 HNC survivors 1 year after completion of their treatment at a tertiary cancer center. Quality of life assessments were performed using the 2 standardized health-related QOL questionnaires: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and The Quality of Life Questionnaire Head and Neck Cancer Module. RESULTS: The overall global QOL rating for the study cohort was satisfactory. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 scores showed that the domains where most patients faired poorly included financial difficulties (54%), appetite loss (36%), fatigue (33%), and cough (30%). The Quality of Life Questionnaire Head and Neck Cancer Module scale identified the domains with poor scores to be dry mouth (64%), dental problems (42%), sticky saliva (40%), cough (39%), and problems with mouth opening (32%). Patients with early-stage tumors and those treated with surgery alone had significantly better QOL scores when compared with advanced stage tumors and patients receiving either radiation alone or multimodality treatment, respectively. CONCLUSIONS: Quality of life questionnaires provide a medium for patients to effectively communicate with their physician in a busy tertiary care facility and provide an insight into the physical, psychological, and social problems affecting our patients which can then direct future interventions.

Elective neck dissection for the management of the N0 neck in early cancer of the oral tongue: need for a randomized controlled trial.

BACKGROUND: The aim of this study is to determine the need for a randomized controlled trial in order to define the role of an elective neck dissection (END) in the treatment of early tongue cancers. METHODS: We present a large retrospective analysis of patients with T1-2 N0 squamous cell cancers of the oral anterior tongue treated at a single institution. A total of 359 eligible patients with early tongue cancers were divided into 2 groups: END and wait and watch (WW). An analysis for survival outcomes and prognostic factors was conducted. RESULTS: The estimated 3- and 5-year disease-free survival for the END group was 76% and 74% versus 71% and 68% for the WW group, respectively (p = .53). The 3- and 5-year overall survival (OS) rate for the END group was 69% and 60% versus 62% and 60% for the WW group, respectively (p = .24). Tumor grade and perineural invasion were independent predictors of recurrence. CONCLUSION: END did not impact disease-free or OS. Current literature still remains divided on this issue emphasizing the need for a randomized controlled trial.

Validation and assessment of voice-related quality of life in Indian patients undergoing total laryngectomy and primary tracheoesophageal puncture.

BACKGROUND: Voice-related quality of life (V-RQOL) has never been studied in Indian patients. This study was planned to validate and assess V-RQOL in patients using tracheoesophageal puncture (TEP). METHODS: A cross-sectional study was undertaken to validate V-RQOL questionnaire by testing reliability, validity, and responsiveness. V-RQOL was assessed in patients undergoing total laryngectomy with primary TEP. RESULTS: One hundred thirty-two patients filled 188 questionnaires. Analysis was carried out on 122 patients. Reliability and validity of questionnaire were tested by Cronbach's alpha (.84-.91) and item-scale correlation (.67-.86). Median V-RQOL-Total score was 76.2 indicating excellent V-RQOL. Higher scores were observed in patients less than 50 years (82.5 vs 72.5, p = .08). There was no effect of time interval between laryngectomy and assessment of questionnaire on the V-RQOL scores. CONCLUSION: V-RQOL questionnaire can be used reliably to assess V-RQOL, which is found to be excellent in Indian patients undergoing TEP.

Verrucous carcinoma of the oral cavity: A clinical and pathological study of 101 cases.

This paper studies the clinical and pathological predictors of local recurrence and disease-free survival (DFS) in patients with oral verrucous carcinoma (OVC) treated surgically, through a retrospective chart review. Three hundred and two patients with OVC were identified from January 1990 to December 2000, of which, 101 surgically treated patients who fulfilled our inclusion criteria were analyzed. A univariate analysis (UVA) of important prognostic factors, patterns of recurrence, and DFS is reported. Seventy-nine patients were male (M:F ratio, 3.6:1) and the mean age at presentation was 53.9 years (range, 23-90 years). The median follow up was 4.61 years (range, 0.51-14.3 years). The incidence of tobacco chewing, smoking, and alcohol intake was 77%, 42%, and 10%, respectively. Thirty-four patients (33.7%) had either leukoplakia or submucous fibrosis (SMF) on oral cavity examination. Early-stage tumors accounted for 39.7%; while 60.4% were late-stage tumors. On UVA, tumor location, presence of a premalignant lesion, smoking, and positive margins were statistically significant. Sixty-eight percent (19/28) recurred locally. The salvage rate for recurrent tumors was 66.7% (16/28) with a median post-recurrence survival of 16 months (range, 10-83 months). The five year DFS with surgical therapy was 77.6%. OVC has an excellent prognosis with surgical treatment. The significance of positive margins emphasizes the need for adequate surgical resection. Additionally, the presence of either leukoplakia or SMF and tumor location in the upper alveolar-palatal complex is associated with worse outcomes. Neck dissection, if considered, may be limited to a supra-omohyoid neck dissection (SOHND).

Squamous cell carcinoma of the gingivobuccal complex: predictors of locoregional failure in stage III-IV cancers.

The purpose of our study was to analyze the indicators of loco-regional failure in a large cohort of patients with gingivobuccal complex tumors treated at a single institution. A retrospective review of 2275 patients diagnosed with tumors of the gingivobuccal complex was conducted from January 1997 to December 1999; 642 patients who fulfilled our inclusion criteria were analyzed. A univariate analysis, multivariate analysis, and disease-free survival are reported. During a median follow up of 2.51 years, there were 228 (35.5%) recurrences with a median post-recurrence survival of 2.7 months. The incidence of occult neck metastasis was 29%. The 2- and 5-year DFS rates were 63.8% and 53.3%, respectively. On multivariate analysis, tumor depth and metastatic lymphadenopathy were found to be independent prognostic factors for disease-free survival. Advanced gingivobuccal cancers fail loco-regionally. Cervical metastasis and tumor depth influence disease-free survival. Elective neck dissection due to a high incidence of occult neck disease is recommended.

Percutaneous endoscopic gastrostomy site metastases in head and neck cancer: use of FDG PET-CT.

PURPOSE: To retrospectively evaluate the utility of positron emission tomography-computed tomography (PETCT) in the diagnosis of percutaneous endoscopic gastroscopy (PEG) site metastases in head and neck cancer. MATERIALS AND METHODS: From the database of 250 patients of head and neck cancer who were referred for PET-CT over 2 years (from January 2005 to January 2007), 6 patients who had PEG tube placement were considered for the study. Imaging was performed on a GE Discovery ST PET-CT system after intravenous injection of 370 MBq (10 mCi) of < sup > 18 < /sup > F-fluorodeoxyglucose (FDG). RESULTS: Intense FDG uptake with an associated soft tissue mass was seen at the PEG site in 3 patients and mild uptake was seen in 2 patients. Biopsy revealed PEG site metastases in 2 patients, abscess in 1 patient, and granulation tissue in 1 patient. Intense uptake with an associated soft tissue mass suggested the diagnosis of metastasis. Stranding of the peristomal fat seen on the CT component of the PET-CT indicated an infective/inflammatory pathology. PET-CT findings showed local recurrence in 3 patients and disseminated metastases (excluding the PEG site) in 1 patient. CONCLUSION: The functional information provided by PET combined with the morphologic detail of CT can improve characterizing of the stoma site abnormality and help in distinguishing recurrence from infective/inflammatory changes. Whole body combined PET-CT is a useful modality for evaluating gastrostomy site metastases and for detecting coexisting local recurrences and distant metastases in head and neck cancer patients. In addition it can detect early asymptomatic recurrences at the gastrostomy site.

Extensive tubercular neck lymphadenopathy in a man with early-stage tongue cancer.

BACKGROUND: A 66-year-old Asian man presented with a tongue ulcer and without palpable metastases to the neck nodes. A thorough clinical examination of the head and neck region did not reveal any other primary lesion. To assess the status of the neck, PET-CT imaging was advised. INVESTIGATIONS: Physical examination, punch biopsy, PET-CT imaging, blood tests, chest radiograph, fine-needle aspiration biopsy, tumor biopsy, neck incision, tuberculin test, sputum culture and histopathology. DIAGNOSIS: Carcinoma of the tongue of pathologic stage T2 N0 M0, with tubercular lymphadenitis and no nodal metastases. MANAGEMENT: Surgical excision and multidrug antitubercular therapy.

Squamous cell carcinoma of the superior gingival-buccal complex.

Squamous cell carcinoma of the superior gingival-buccal complex are rare and few English-language data have been published on their biological behaviour. Reported in this paper are the clinical behaviour and treatment outcomes of squamous cell carcinoma of the upper gingival-buccal complex. We reviewed the charts of 110 patients with squamous cell carcinoma restricted to the upper gingiva, superior gingival-buccal sulcus and adjoining buccal mucosa, seen between 1997 and 2001. Separate outcome analyses were carried out among 86 patients who had undergone surgery, and 24 patients treated by radiotherapy or chemo-radiation. Disease-free survival at 2 and 5 years was 48.9% and 36%, respectively, and was independent of epicentre of disease. Five-year, disease-free survival was 48.8% and 0% for surgical treatment and non-surgical treatment groups. T stage (p=0.024) and extra-capsular spread of disease (p=0.036) were independent predictors of disease-free survival on multivariate analysis. Adequate surgical resection and adjuvant treatment, in the first instance, offers the best chance of disease control.

Malignant pilar tumor of the scalp: a case report and review of literature.

Pilar tumor is a rare neoplasm arising from the external root sheath of the hair follicle and is most commonly observed on the scalp. These tumors are largely benign, often cystic, and are characterized by trichilemmal keratinization. Wide local excision has been the standard treatment. Recent reports have described a rare malignant variant with an aggressive clinical course and a propensity for nodal and distant metastases which, therefore, merits aggressive treatment. In this report, we present a case of malignant pilar tumor of the scalp with multiple nodal metastases at presentation. Diagnostic and therapeutic considerations, in the form of adjuvant radiotherapy, are subsequently discussed.