Madhabananda Kar

Malignant peripheral nerve sheath tumors (MPNST)--clinicopathological study and treatment outcome of twenty-four cases.

BackgroundMalignant peripheral nerve sheath tumor (MPNST) is biologically an aggressive tumor for which the treatment of choice is the surgery. We reviewed the clinical profile, diagnostic methods, treatment patterns, and outcome of twenty-four MPNST patients in this study.Patients and methodsA retrospective analysis of 24 MPNST patients, treated from 1994 to 2002, in the department of Surgical Oncology at All India Institute of Medical Sciences, New Delhi, was done. A combination of gross, histopathological and immunohistochemical findings, and proliferation markers (MIB1) were considered for diagnosis and grade of the MPNST. Survival analysis was done by the Kaplan-Meier method and differences were evaluated with the log-rank test. Multivariate analysis was carried out by using Coxs proportional hazards model by using SPSS (Version 9, Chicago, Illinois) software.ResultsMPNST constituted 12% of all soft tissue sarcomas, where 21% (5/24) of patients had associated Von Recklinghausens disease (VRHD). A higher incidence of male preponderance and multifocal MPNST were noted in the present series. At a mean follow-up of 38 months, 13 (54 %) patients had relapse of disease and 5-year over all and disease free survival were 58% and 35% respectively. In univariate analysis, sex (p = 0.05), tumor depth (p < 0.03), and cellular differentiation (p < 0.002) were shown to be adverse prognostic factors for disease free survival and sex (p = 0.04), cellular differentiation (p < 0.0004), and tumor grade (p = 0.05) for overall survival. However, in multivariate analysis, cellular differentiation (p < 0.005) and tumor grade (p < 0.01) emerged as independent prognostic factors for both disease free and overall survival, respectively. Postoperative radiotherapy (RT) has shown a definite role in both disease free and overall survival in this study.ConclusionMPNSTs constituted a significant proportion (12%) of soft tissue sarcoma in our medical center. Heterogeneous differentiation and multifocality of the tumor were few distinct features of MPNST. Sex and cellular differentiation were noticed as the new adverse prognostic factors and adjuvant radiotherapy has been proved to be a significant treatment tool in the current series.

Surgical management of skin cancers: Experience from a regional cancer centre in North India

AIMS To review the disease profile and treatment outcome of patients with primary skin malignancies treated at a regional cancer centre. SETTINGS AND DESIGN Surgical oncology unit of a tertiary care regional cancer centre. Evaluation of treatment outcome of patients with skin cancer from Surgical Oncology database was done. MATERIALS AND METHODS Retrospective analysis of records of 77 patients with skin cancers treated between 1995 and 2002 was conducted. Profile of patients with skin cancer, surgical details including the management of primary tumour, regional lymph nodes and reconstructive procedures performed and survivals were analysed. STATISTICAL ANALYSIS All computations were done using the Statistical Package for Social Sciences (SPSS-9). Descriptive statistics were calculated in a standard fashion and survival analysis was performed using Kaplan-Meier method. RESULTS Skin cancers constituted 2.4% (77/3154) of patients with cancer treated in the surgical oncology department. Squamous cell carcinoma (SCC) was the most common histological type (55.8%) followed by melanoma (26.1%) and basal cell carcinoma (BCC, 18.1%). Forty one percent of patients had undergone some form of intervention elsewhere before being referred. Reconstruction was required in 55.8% patients with large postresection defects. Regional lymph nodal dissection was required in 32.4% of total patients. Five-year median disease-free survival for the entire study population was 75%. CONCLUSIONS Skin cancers constitute a small but significant proportion of patients with cancer. Unlike in the Western countries, SCC is the commonest histologic variety. Primary level inadequate intervention is very common. Optimal results can be obtained with radical surgery and optimal surgical margins along with a reconstructive procedure when needed.

Clinico-Pathological Correlation of β-Catenin and Telomere Dysfunction in Head and Neck Squamous Cell Carcinoma Patients.

Background: Tumorigenesis is a complex process of accumulated alteration in function of multiple genes and pathways. Wnt signalling pathway is involved in various differentiation events during embryonic development and is conserved in various species. Objective: A multicentre collaborative initiative is undertaken to study the occurrence, prognosis and molecular mechanism of HNSCC (Head and Neck Squamous Cell Carcinoma) which is highly prevalent in eastern parts of India. From a large cohort of HNSCC tissue repository, 67 cases were selected for multi-parametric investigation. Results: 67 cases showed stable β-catenin expression. We have seen correlation, if any, of the transcription factor - β-catenin, telomere maintenance and shelterin complex proteins - TRF2, Rap1 and hTert with respect to tumor differentiation and telomere dysfunction. Immunohistochemistry of β-catenin protein showed stable and high expression in tumor when compared to stroma. MDSCC (Moderately Differentiated Squamous cell carcinoma) cases expressed nuclear expression of β-catenin in invasive fronts and showed increased genomic instability. Higher frequency of Anaphase bridges was observed ranging from <3% in normal cut margin to 13% in WDSCC (Well differentiated squamous cell carcinoma) and 18% in MDSCC (Moderately differentiated Squamous cell carcinoma). There was significant decrease in telomere length in MDSCC (<4) when compared to the normal cut margin samples (<7). Quantitative Real Time-PCR confirmed a significant correlationship between stable β-catenin expression and poor clinical and pathological outcome. Conclusion: The Stabilisation and accumulation of β-catenin was significant and correlated well with de-differentiation process as well as prognosis and therapy outcome of the patients in the cohort. Expression status of molecular markers such as β-catenin, hTert, TRF2 and RAP1 correlate significantly with the process of tumorigenesis and prognosis and may play a role in therapeutic management of Head and neck patients.

Reconstruction of complex oral defects using bi-paddle pectoralis major flap - technical modifications and outcome in 54 cancer patients.

ObjectiveReconstruction of locally advanced oral cancer presents a great challenge to the head and neck surgeon. The main goal of reconstruction is to provide intraoral lining and soft tissue cover. We discuss the use of Bipaddle pectoralis major myoculaneous flap (PMMF) and its modifications for reconstruction of complex oral defects following radical resection.Study DesignRetrospective analysis of prospective oral cancer data base.SettingTertiary Care Regional Cancer Center.PatientsThree hundred and ten patients were operated for oral carcinoma in this unit between 1993 and 2001. The oral cancer patients who required soft tissue reconstruction for lining and cover were analyzed. Patients in whom bipaddle PMMF were utilised were studied in terms of surgical technique, morbidity, function and cosmetic outcome.ResultsNinety-one (29.4 %) oral cancer patients required reconstruction for lining as well as cover. Of these, 54 (17.4 %) patients underwent a bipaddle PMMF flap reconstruction. Two horizontal skin islands were used in patients with lateral defects and two vertical islands in patients with central defects. There was no complication in 41 (76%) patients. Complete flap loss was seen in only one patient and differential flap loss in 2 patients (4 %) while seven (13 %) patients had only minor complication. All the patients received post-operative Radiotherapy. Good to average functional and cosmetic outcome was observed in 90% patients.ConclusionsBipaddle PMMF offers an effective and leliahle reconstructive option for complex oral defects. By using certain technical modifications, majority of complex oral defects can be managed successfully using a Bipaddle PMMF. In a developing country like India with a large oral cancer disease burden Bipaddle PMMF should he used routinely for complex oral defects in view of its simplicity, versatility and reliability.

Role of β-catenin in cisplatin resistance, relapse and prognosis of head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer in India with high incidence and rapid recurrence rates. Here, we aimed to investigate the role of β-catenin, a developmental pathway gene, in HNSCC therapy resistance, DNA damage response, recurrence and prognosis.MethodsIn total 80 HNSCC samples were included. Western blot, immunohistochemistry and qRT-PCR analyses were performed to assess β-catenin expression in the cut margin and tumor areas of each sample. Kaplan-Meier analyses were performed to correlate β-catenin expression with the survival and prognosis of HNSCC patients. In addition, chemo-resistance, DNA damage response and DNA repair capacities were evaluated in HNSCC-derived cell lines through LiCl-mediated up-regulation and siRNA-mediated silencing of β-catenin expression.ResultsWe observed β-catenin up-regulation in cut margin areas of recurrent patients compared to their corresponding tumor regions, which subsequently could be associated with poor prognosis. In addition, we found that LiCl-mediated up-regulation of β-catenin in HNSCC-derived cells led to cisplatin resistance, evasion of apoptosis, enhanced DNA repair and enhanced migration. The effects of β-catenin silencing correlated with its putative role in chemo-resistance and DNA damage response.ConclusionFrom our results we conclude that β-catenin may contribute to HNSCC therapy resistance and disease relapse. As such, β-catenin may be explored as a therapeutic target along with conventional therapeutics.

p38 MAPK pathway and its interaction with TRF2 in cisplatin induced chemotherapeutic response in head and neck cancer

TRF2 is a telomere binding protein, a component of the shelterin complex that plays a major role in maintaining the integrity of the genome. TRF2 is over-expressed in a number of human cancers including Head and Neck cancer and might play a key role in tumor initiation and development. p38 MAPK signaling pathway is strongly activated in response to various environmental and cellular stresses and thus overexpressed in most of the Head and Neck cancer cases. In this study, we investigated potential interactions of TRF2 with p38 in HNSCC cells and patient samples. Using in silico experiments, we identified interface polar residue Asp-354 of p38 and Arg-492, Arg-496 of TRF2 as protein–protein interaction hotspots. In addition to these interactions, Arg-49 residue of p38 was also found to interact with Glu-456 of TRF2. A detailed understanding of how phosphorylated and unphosphorylated state of p38 protein can influence the stability, specificity and to some extent a conformational change of p38-TRF2 binding is presented. Silencing of TRF2 significantly decreased the phosphorylation of p38 in HNSCC cells which was confirmed by western blot, immunofluorescence and co-immunoprecipitation and alternatively inhibiting p38 using p38 inhibitor (SB 203580) decreased the expression of TRF2 in HNSCC cells. Furthermore, we checked the effect of TRF2 silencing and p38 inhibition in cisplatin induced chemosensitivity of SCC-131 cells. TRF2 silencing and p38 inhibition chemosensitize HNSCC cells to cisplatin. Thus, targeting TRF2 in combinatorial therapeutics can be a treatment modality for Head and Neck cancer which involves inhibition of p38 MAPK pathway.

Role of p38 MAPK in disease relapse and therapeutic resistance by maintenance of cancer stem cells in head and neck squamous cell carcinoma

AIM This study aimed to investigate the role of p38 MAPK in maintenance of cancer stem cell (CSC) phenotype, therapy resistance, and DNA damage repair and response in head and neck squamous cell carcinoma (HNSCC). METHODS In this study, 104 HNSCC patients were included. Western blot, immunohistochemistry, and qPCR analysis were performed to investigate the expression level of p-p38 and CSC markers in cut margin and tumor area of HNSCC patients. The expression level of p-p38 and CSC markers was also evaluated in HNSCC cells with or without p38 inhibitor. Chemoresistance, wound healing capacity, and multicellular tumor spheroids (MCTS) formation capacity were evaluated in HNSCC-derived cell lines with or without p38 inhibitor. In addition, DNA damage response and repair capacities were also evaluated in HNSCC cells after p38 inhibition using alkaline comet assay and γ-H2 AX immunostaining. RESULT We observed that recurrence could be associated with upregulated status of p-p38 and p38α gene in cut margin area of HNSCC patients as compared to tumor region. p38-inhibited cells showed significantly reduced expression of CSC markers, chemosensitivity toward cisplatin, reduced migration potential, and sphere-forming ability along with increased apoptotic population after treatment with increasing concentration of cisplatin. p38-inhibited cells also exhibited significantly increased comet olive tail moment and accumulation of γ-H2 AX, demonstrating increased DNA damage. CONCLUSION This study demonstrated that p38 MAPK activation may play a role in therapeutic resistance and disease relapse in HNSCC by maintenance of CSCs phenotype.

Role of CDKN2A/p16 expression in the prognostication of oral squamous cell carcinoma

OBJECTIVE CDKN2A/p16 is a known tumor suppressor gene with a homologous deletion in Oral Squamous cell carcinoma. CDKN2A/p16 is found to be inactivated in a broad spectrum of solid tumors and in more than 80% of OSCC. Molecular alteration of CDKN2A/p16 in progression of OSCC can pose an important tool for the prognosis of squamous cell carcinoma. MATERIAL AND METHOD Systematic network analysis was carried out to obtain involvement of CDKN2A/p16 in oral cancer by polysearch and FunDO. In the present study we have screened 104 OSCC patients from eastern region of India for CDKN2A/p16 expression in recurrent and non-recurrent OSCC. The observation was validated by Comparative Genomic Hybridisation and Next generation sequencing in recurrent cases. RESULT Systematic analysis revealed direct involvement of CDKN2A/p16 in oral cancer. There was a consistent downregulated expression of CDKN2A/p16 in the recurrent cases. The gene expression study confirmed a >5-fold downregulation of CDKN2A/p16 in recurrent tumors as compared to non-recurrent ones. Array CGH analysis revealed a copy number deletion in the recurrent case. Furthermore, next generation sequencing validated deletion of CDKN2A/p16 and reported it asa common variant with a nonsense mutation having stop /loss of function of the gene in recurrent cases. Recurrent cases with deleted CDKN2A/p16 expression had poor prognosis and low survival rate. CONCLUSION CDKN2A/p16 frequently alters in oral cancer progression with a deletion/loss of function in the recurrent cases displaying its role in aiding several molecular events for the malignant transformations occurring throughout disease progression.

Role of Telomeric TRF2 in Orosphere Formation and CSC Phenotype Maintenance Through Efficient DNA Repair Pathway and its Correlation with Recurrence in OSCC

The major problem to effective treatment of oral cancer is the presence of therapy resistance. Presence of cancer stem cell in the bulk of tumor have been implicated in therapeutic resistance. In this study, we report a non-telomeric role of TRF2 in formation of oral cancer spheroids and CSC phenotype maintenance via an efficient DNA damage repair mechanism in the presence of chemotherapeutic insult. We report reduced sphere formation efficiency and reduced spheroid size in TRF2 silenced oral cancer cell lines. TRF2 silenced orospheres further reported reduced proliferative capacity as compared to non-silenced orospheres. Furthermore, TRF2 silencing hampered the migratory potential of oral cancer cell line and also reduced the expression of several CSC markers like CD44, Oct4, Sox2, KLF4 and c-Myc along with β-catenin and hTERT molecules both in Cal27 cell line and generated orospheres. TRF2 silencing impaired efficient DNA damage repair capacity of non-orospheric and orospheric cells and repressed ERCC1 expression levels when treated with Cisplatin. TRF2 overexpression was also observed to correlate with poor overall survival and disease relapse of OSCC patients. In silico studies further identified several amino acid residues that show high binding affinity and strong protein-protein interactions among TRF2 and CSC marker KLF4. Hence, our report confirms a non-telomeric role of TRF2 in spheroid generation, maintenance of CSC phenotype and efficient DNA damage repair capacity contributing to chemotherapy resistance in oral cancer cell line. We further iterate the use of TRF2 as a prognostic marker in OSCC for faster detection and improved survival.

Severe angioedema of laryngeal inlet in a woman receiving telmisartan therapy undergoing breast conservation surgery

Pulsed radiofrequency neuromodulation of the SN has been used to treat chronic knee pain;[4] however, pulsed radiofrequency treatment for neuropathic pain due to complex issue of compression of SNs and other nerves in the adductor canal by large metastatic nodule has not been reported earlier. Therefore, this case report provides an insight to use pulsed radiofrequency in other situations where pain is caused by nerve compression and conservative treatment is not effective.