Phenotypic and Functional Characteristics of Th17 (CD4+IL17A+) Cells in Human Oral Squamous Cell Carcinoma and Its Clinical Relevance.

Recent studies have suggested an important role of T helper 17 (Th17) cells in tumor biology however, their phenotypic and functional aspects are poorly understood in context with oral cancer. We therefore, investigated the various phenotypic and functional markers of Th17 cells elucidating their relevance in oral squamous cell carcinoma (OSCC). Multi-color flow cytometry (FACs) was used to analyze the frequency and different markers of circulating Th17 cells ex vivo in peripheral blood mono-nuclear cells (PBMCs) from 69 OSCC patients and 35 healthy controls. Percent Mean ± SEM of different types of cells were compared between the two groups using Mann-Whitney U test. We found significantly (p < 0.0001) increased frequency of Th17 cells in patients as compared to controls. These cells were found to express CCR6 profoundly but not CXCR4, CD62L, and CCR7 as chemokine receptors. Additionally, it expressed HLA-DR, CD69, and CD25 moderately but CD28 and CD161 highly. The cytokine profiling revealed 3 subsets namely Th17/1 (IL17A+IFNγ+), Th17/inflammatory (IL17A+IL8+), and Th17/2 (IL17A+IL4+) which were found to be elevated in patients as compared to controls. The early stage patients had a shift toward Th17/1 type and vice versa. Our results suggest that Th17 cells may have effector immune functions in oral cancer immunity through CCR6, CD161, HLA-DR, CD69, CD28 receptors and inducing Th17/1 type of cells expressing polyfunctional antitumor IFNγ cytokine. Thus, novel immune-boosting regimens based on enhancement of Th17 cells in oral cancer patients may provide therapeutic benefits in them.

Compliance and outcomes of concurrent Chemo-radiation in patients with peri-ampullary cancer undergoing curative resections.

OBJECTIVES: We aimed to study the compliance and treatment outcome of patients who received adjuvant treatment following curative resection for periampullary cancers periampullary cancers. MATERIALS AND METHODS: Institute medical records of PAC treated during 2007-2014 were retrieved. Demographics, treatment, and outcome in patients who were intended to receive adjuvant chemoradiation after curative resection were analyzed. Patients received first cycle chemotherapy with 5-fluorouracil folinic acid/capecitabine, followed by external radiotherapy 45 Gy/25 fractions/5 weeks and second and third cycle concurrent chemotherapy. Fourth and fifth cycle chemotherapy were administered after radiotherapy). Various prognostic factors, disease-free survival (DFS), and overall survival (OS) were evaluated. RESULTS: Sixty-five patients were evaluated. Median age was 50 years. 96.9% patients completed the intended course of radiation and overall adherence to chemotherapy was 86.2%. Median follow-up and DFS were 20 and 29.64 months, respectively (range: 1.9-97.3 months). Estimated 1-, 2-, 5-year DFS was 77.8%, 59.3%, and 37.6%, respectively. One-year estimated OS was 92.7%. Median DFS for node-negative and node-positive patients was 88.6 and 24.33 months (P = 0.06). Grade ≥III hematological toxicity was 20%. CONCLUSION: Positive node indicated a trend toward poor survival. The study highlights high compliance to multimodal management of PAC with acceptable toxicity in and out of clinical trial setting in a tertiary cancer center in India.

Nonrhabdomyosarcomatous abdominopelvic sarcomas: Analysis of prognostic factors.

BACKGROUND: Data concerning treatment outcome and prognostic factors in sarcomas of abdomen and pelvis are sparse in literature. METHODS AND RESULTS: Of 696 patients with nonrhabdomyosarcomatous soft tissue sarcoma registered at our center between June 2003 and December 2012, 112 (16%) patients of sarcomas arising from abdomen and pelvis were identified, of which 88 patients were analyzed for treatment outcome and prognostic factors. The median age was 40 years (range: 1-78 years) with a male: female ratio of 0.7:1. Twenty-one (24%) patients were metastatic at baseline. The most common tumor sites were retroperitoneum in 70% patients and abdominal wall in 18% patients. Leiomyosarcoma was the most common histological subtype in 36% patients followed by liposarcoma in 17% patients. Thirty-five (40%) patients had Grade III tumors. Forty-six (52%) patients underwent surgical resection. At a median follow-up of 43 months (range: 2-94 months), the 5-year event-free survival (EFS) and overall survival (OS) were 35% and 42%, with a median of 22 months and 43 months, respectively. Multivariate analysis identified male gender (P - 0.03, hazard ratio [HR] - 0.46, 95% confidence interval [CI] - 0.23-0.92), baseline metastatic disease (P - 0.01, HR - 2.98, 95% CI - 1.27-6.98) and Grade III tumors (P - 0.02, HR - 1.84, 95% CI - 1.08-3.13) as factors associated with poor EFS, whereas baseline metastatic disease (P < 0.001, HR - 5.45, 95% CI - 2.31-12.87) and unresectability (P - 0.01, HR - 2.72, 95% CI - 1.27-5.83) were associated with poor OS. CONCLUSION: This is a single-institutional study of patients with abdominopelvic sarcomas where gender was identified as a new factor affecting survival apart from baseline presentation, histologic grade, and surgical resection.

Kimura Disease of the Breast - A Previously Undescribed Entity.

Kimura disease (KD) is a rare chronic inflammatory disorder of unknown etiology, primarily seen in young Asian males. The disease is characterized by a triad of painless subcutaneous masses in the head and neck region, blood and tissue eosinophilia, and elevated serum immunoglobulin E levels. We report an unusual case of a 40-year-old woman found to have KD of the breast which presented clinically as carcinoma, leading to a diagnostic dilemma. To the best of our knowledge, this is the first case of KD in the breast to be documented in the literature. The patient also had scabies, which may have provided the stimulus for hypersensitivity, which is considered to be the pathogenetic mechanism responsible for development of KD.

Inter-relation of Th1, Th2, Th17 and Treg cytokines in oral cancer patients and their clinical significance.

BACKGROUND: Altered cytokine production can lead to immune dysfunction in cancer patients. Hence, we investigated the cytokine balance in oral squamous cell carcinoma (OSCC) patients and their significance in providing new therapeutic insights. METHODS: We quantified Th17 (IL17A), Treg (TGFß1), Th1 (IL2, IFNγ) and Th2 (IL4, IL10) like cytokines in the sera of 78 cases and 39 controls by ELISA. The intracellular expression of these cytokines was analyzed in 10 subjects from each group by flow cytometry. RESULTS: Serum levels of IL17A, TGFß1, IL4 and IL10 were significantly higher while IL2 and IFNγ were relatively lower in patients as compared to controls. TGFß1 (r=0.55), IL4 (r=0.75) and IL10 (r=0.80) significantly (P<0.0001) correlated with disease progression and their elevated levels showed increased odd ratios of approximately 18, 14 and 37, respectively. IL17A appeared as a risk factor (OR=2.21, 95% CI=0.89-5.42) although statistically insignificant. The levels neither correlated with disease progression nor with TGFß1, IL4 and IL10 but showed positive association with IL2 (r=0.51, P<0.0001) and IFNγ (r=0.24). Flow cytometry data also showed similar trend. CONCLUSIONS: We reported a distinct TGFß1 and Th2 (IL4, IL10) polarization with a borderline elevation of IL17A while, a suppression of Th1 (IL2, IFNγ) cytokines in OSCC patients.

Association of mutation and hypermethylation of p21 gene with susceptibility to breast cancer: a study from north India.

p21 gene located at chromosome 6p21.2 is a possible tumour suppressor gene involved in the pathogenesis of breast cancer. Both genetic and epigenetic alterations in p21 have been implicated in breast carcinoma. In the present study, our main aim was to study the impact of these two kinds of alterations of p21 gene in Indian female breast cancer patients. A total of 150 female breast cancer patients of north India were screened by PCR-SSCP followed by direct sequencing and methylation specific PCR. Mutational screening of p21 gene revealed significant amount of mutations [32.66% (49/150)] in exon 2, whereas p21 promoter was found hypermethylated in 42 of 150 (28%) breast cancer patients in our population. The intriguing feature of the study was the G>T transition (GAG>TAG) at codon 107 and the A>C transition (AGC>CGC) at codon 146 possibly rendering p21 completely ineffective in its anti- proliferative activity. Our results suggest a significant association between the mutational and hypermethylation profile of p21 gene. Therefore, we show for the first time that the significant association of p21 mutation and hypermethylation leads to the complete inactivation of p21 gene in Indian female breast cancer patients. Complete silencing of the p21 gene seems to be the result not only of genetic alterations but also of epigenetic modification.

Gall bladder cancer and the role of dietary and lifestyle factors: a case-control study in a North Indian population.

Most patients with gall bladder cancer (GBC) present in the advanced stage with a poor response to therapy. Prevention or early detection is the best way to prevent death, but this requires identification of susceptible subgroups. Keeping this in mind, this study was carried out to evaluate the association between selected demographic, lifestyle, and dietary factors and GBC. A hospital-based case-control study was carried out at the All India Institute of Medical Sciences (New Delhi, India). Cases were defined as newly registered confirmed primary GBC patients. Controls were defined as healthy relatives of patients other than that of GBC. Data were collected from February 2008 to October 2009 using a semistructured interview schedule from both cases and controls. Analysis was carried out using SPSS version 15 and Epi-Info version 6. Factors found to be significant in the bivariate analysis were entered in a multivariate logistic regression analysis. A total of 122 cases and 122 controls were included in the study. There was no significant difference in age (P=0.06) and sex (P=0.66) between the cases and the controls. In the bivariate analysis, factors found to be significantly associated with GBC were illiteracy [odds ratio (OR) 8.00, P=0.000], lower socioeconomic status (OR 2.45, P=0.000), parity more than 3 (OR 9.06, P=0.000), age at first pregnancy less than 20 years (OR 2.03, P=0.018), and the use of nonliquefied petroleum gas cooking fuel (OR 4.17, P=0.000). Higher vitamin C intake had a protective effect (OR 0.33, P=0.004). In the multivariate analysis, education, intake of vitamin C, parity, and type of fuel used were significant factors. The risk factors for GBC that have been identified in the present study delineate a high-risk population group that can be targeted for preventive measures including improvement in socioeconomic status, education and lifestyle, and dietary intervention, and avoidance of the use of nonliquefied petroleum gas as cooking fuel.

Aggressive multimodality management of locally advanced retromolar trigone tumors.

BACKGROUND: Retromolar trigone tumors are rare and aggressive malignancies. There is lack of quality evidence pertaining to their management due to the heterogeneity in treatment policies adopted. We retrospectively reviewed the patients of locally advanced retromolar trigone tumors treated with a standard and uniform multimodality management. METHODS: A retrospective review of patients with locally advanced retromolar trigone tumors was performed and an analysis of clinicopathologic profile, treatment details, and survival outcomes was carried out. RESULTS: Forty-two patients of locally advanced retromolar trigone tumors underwent the standard multimodality treatment. The majority of them presented with stage IVa disease. Margin negative resection could be achieved in 93% of patients. Histopathologically proven bone and node involvement was seen in 20 patients (47.6%) and 21 patients (50%), respectively. The 3-year disease-free and overall survival rates were 64% and 71%, respectively. CONCLUSIONS: Treatment of patients with locally advanced retromolar trigone tumors is challenging. However, good oncologic outcomes can be achieved by advocating an aggressive surgical approach with postoperative radiation therapy.

Abnormal expression of PI3K isoforms in patients with tobacco-related oral squamous cell carcinoma.

BACKGROUND: The phosphatidylinositol 3-kinase (PI3K) signaling regulates several cellular functions such as motility, proliferation, angiogenesis and survival. METHODS: Since there is no information on expression of PI3K isoforms in oral cancer, we studied the expression of different isoforms of PI3K (p110α, p110γ, PI3K-C2, Vps34p and p85α) in tumor samples and PBMC by RT and q-RTPCR and serum levels of PI3K p110α by SPR and ELISA techniques in 108 patients with tobacco-related oral squamous cell carcinoma (OSCC) and 46 normal subjects. RESULTS: We observed significantly higher PI3K p110α (p<0.0001) and lower (p<0.0001) vesicular sorting protein 34p (Vps34p) mRNA both in PBMC and tissue samples of oral cancer patients as compared to the normal controls. Other PI3K isoforms did not show such change. Circulating PI3K p110α levels were higher in patients (p<0.0001) as compared to healthy subjects, the SPR data showed direct correlation with advancing stage of the disease. PI3K p110α was overexpressed in tumor samples but not in the normal buccal mucosa. CONCLUSIONS: Upregulation of circulating PI3K p110α isoform and its direct correlation with increasing tumor load in OSCC patients indicates that it may be a significant prognostic indicator and a suitable target for therapeutic/chemo-preventive strategies for tobacco-related OSCC.

Updates on the multimodality management of desmoplastic small round cell tumor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and an aggressive malignancy with poor outcome. This tumor can co-express epithelial, neural, and mesenchymal markers. The molecular hallmark of DSRCT is the EWS-WT1 fusion protein. Despite the diversities in treatment modality, the best results have been seen with radical surgery and adjuvant or neoadjuvant chemotherapy.

Locally advanced salivary duct carcinoma of the parotid gland.

Due to the low incidence of salivary duct carcinoma (SDC), there is limited data in regard to the biologic behavior of this tumor, histopathological characteristics and its management. There is diversity in the management of parotid SDC. Various authors manage it with radical parotidectomy with or without neck dissection; others add adjuvant radiotherapy with radical surgery. The objective of the study is to see the biological behavior and management of the three patients with locally advanced SDC and review with the literature.

A rare case of giant leiomyosarcoma in a filarial scrotum: a case report.

Giant leiomyosarcoma of scrotum is a rare tumour. A case of scrotum leiomyosarcoma is presented in a 67 year old patient with scrotal filariasis which was managed successfully with total scrotectomy with bilateral orchidectomy, degloved penis reconstructed with rotation advancement supra pubic fasciocutaneous flap. We made a literature search proving the rarity of this lesion type. Only 36 cases have been described and the first case in a filarial scrotum.

Salivary gland tumours: profile and management at a tertiary cancer centre.

Salivary gland tumours comprise a varied group of benign and malignant neoplastic lesions posing a challenge to surgeon. To review the profile of salivary gland tumours presenting to a referral cancer centre and their overall management, a retrospective analysis of prospective head and neck cancer database of the surgical oncology department of Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences (AIIMS) was performed. Forty patients of salivary gland tumours treated between 1995 and 2003 were analysed. All computations including recurrences and survival were carried out using the statistical package for social sciences (SPSS) for windows software (SPSS Inc, USA). The profile of salivary gland tumours presenting to a cancer centre setting was found to be different - 77.5% being malignant tumours and the remaining 22.5% werebenign tumours. Most common site of involvement was the parotid gland (72.5%). Muco-epidermoid carcinoma and adenocarcinomas were the most common histological types. Conservative resection was adequate for benign tumours. For primary malignant tumours, radical surgery with or without neck dissection and appropriate reconstruction, combined with postoperative radiotherapy was effective in achieving good locoregional control. Optimal management of primary tumour along with appropriate neck dissection including resection of the involved salivary gland is necessary for the management of metastatic salivary gland tumours.

Prognostic significance of nuclear pSTAT3 in oral cancer.

BACKGROUND: Aberrant nuclear accumulation of proteins influences tumor development and may predict biologic aggressiveness and disease prognosis. This study determined the prognostic significance of pSTAT3 (phosphorylayed signal transducer and activator of transcription 3) in oral squamous cell carcinomas (OSCCs). METHODS AND RESULTS: Using immunohistochemistry, a significant increase in nuclear accumulation of pSTAT3 was observed in 49 of 90 leukoplakias (54.4%) and 63/94 OSCCs (67%) (p(trend) < .001). Increased pSTAT3 was associated with tumor stage (p = .01), nodal metastasis (p = .0018), and tobacco consumption (p = .004). Kaplan-Meier analysis demonstrated that OSCC with increased nuclear pSTAT3 showed significantly reduced disease-free survival (13 months), compared with the patients with no nuclear pSTAT3 expression (64 months, p = .019). Cox regression analysis revealed nuclear pSTAT3 as the most significant predictor of poor prognosis (p = .024, hazard ratio [HR] = 2.7). CONCLUSIONS: Increased nuclear accumulation of pSTAT3 occurs in early premalignant stages and is a marker for poor prognosis of OSCC.

Clinical significance of phosphatidyl inositol synthase overexpression in oral cancer.

BACKGROUND: We reported increased levels of phosphatidyl inositol synthase (PI synthase), (enzyme that catalyses phosphatidyl inositol (PI) synthesis-implicated in intracellular signaling and regulation of cell growth) in smokeless tobacco (ST) exposed oral cell cultures by differential display. This study determined the clinical significance of PI synthase overexpression in oral squamous cell carcinoma (OSCC) and premalignant lesions (leukoplakia), and identified the downstream signaling proteins in PI synthase pathway that are perturbed by smokeless tobacco (ST) exposure. METHODS: Tissue microarray (TMA) Immunohistochemistry, Western blotting, Confocal laser scan microscopy, RT-PCR were performed to define the expression of PI synthase in clinical samples and in oral cell culture systems. RESULTS: Significant increase in PI synthase immunoreactivity was observed in premalignant lesions and OSCCs as compared to oral normal tissues (p = 0.000). Further, PI synthase expression was significantly associated with de-differentiation of OSCCs, (p = 0.005) and tobacco consumption (p = 0.03, OR = 9.0). Exposure of oral cell systems to smokeless tobacco (ST) in vitro confirmed increase in PI synthase, Phosphatidylinositol 3-kinase (PI3K) and cyclin D1 levels. CONCLUSION: Collectively, increased PI synthase expression was found to be an early event in oral cancer and a target for smokeless tobacco.

Cytoplasmic accumulation of activated leukocyte cell adhesion molecule is a predictor of disease progression and reduced survival in oral cancer patients.

Activated leukocyte cell adhesion molecule (ALCAM) has been proposed to function as a cell surface sensor for cell density, controlling the transition between local cell proliferation and tissue invasion in cancer progression. Herein, we determined ALCAM expression in 107 oral squamous cell carcinomas (OSCCs), 78 oral lesions (58 hyperplasias and 20 dysplasias) and 30 histologically normal oral tissues using immunohistochemistry and correlated with clinicopathological parameters. Significant increase in ALCAM immunopositivity was observed from normal oral mucosa, hyperplasia, dysplasia to OSCCs (p(trend) < 0.001). Increased ALCAM expression was observed in cytoplasm of epithelial cells as early as in hyperplasia (p = 0.001, OR = 3.8). Sixty-five of 107 (61%) OSCCs showed significant overexpression of ALCAM protein in cytoplasm/membrane of tumor cells (p = 0.043; OR = 3.3) in comparison with the normal oral tissues. Among OSCCs, cytoplasmic ALCAM was associated with advanced tumor size, tumor stage and tobacco consumption. Importantly, cytoplasmic ALCAM was an independent predictor of poor prognosis of OSCCs in multivariate analysis (p = 0.012, OR = 6.2). In an attempt to understand the molecular basis of cytoplasmic localization of ALCAM, 14-3-3 zeta and 14-3-3 sigma were identified as its novel binding partners in oral cancer cells. In conclusion, increased expression of ALCAM is an early event in oral tumorigenesis; its cytoplasmic accumulation in tumor cells is a predictor of poor prognosis of OSCCs, underscoring its potential as a candidate prognostic marker for oral cancer.

Phantom breast syndrome.

Phantom breast syndrome is a type of condition in which patients have a sensation of residual breast tissue and can include both non-painful sensations as well as phantom breast pain. The incidence varies in different studies, ranging from approximately 30% to as high as 80% of patients after mastectomy. It seriously affects quality of life through the combined impact of physical disability and emotional distress. The breast cancer incidence rate in India as well as Western countries has risen in recent years while survival rates have improved; this has effectively increased the number of women for whom post-treatment quality of life is important. In this context, chronic pain following treatment for breast cancer surgery is a significantly under-recognized and under-treated problem. Various types of chronic neuropathic pain may arise following breast cancer surgery due to surgical trauma. The cause of these syndromes is damage to various nerves during surgery. There are a number of assumed factors causing or perpetuating persistent neuropathic pain after breast cancer surgery. Most well-established risk factors for developing phantom breast pain and other related neuropathic pain syndromes are severe acute postoperative pain and greater postoperative use of analgesics. Based upon current evidence, the goals of prophylactic strategies could first target optimal peri-operative pain control and minimizing damage to nerves during surgery. There is some evidence that chronic pain and sensory abnormalities do decrease over time. The main group of oral medications studied includes anti-depressants, anticonvulsants, opioids, N-methyl-D-asparate receptor antagonists, mexilitine, topical lidocaine, cannabinoids, topical capsaicin and glysine antagonists. Neuromodulation techniques such as motor cortex stimulation, spinal cord stimulation, and intrathecal drug therapies have been used to treat various neuropathic pain syndromes.