Manju Sengar

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Sinonasal malignancies with neuroendocrine differentiation: Case series and review of literature

Primary sinonasal tumors with neuroendocrine differentiation (SCND) are uncommon tumors with considerable overlap of histological features. Based on their neuroendocrine differentiation they can be sub categorized into sinonasal undifferentiated carcinoma (SNUC), sinonasal neuroendocrine carcinoma (SNEC), esthesioneuroblastoma (ENB) and small cell carcinoma (SmCC). The natural history and biological behavior varies in this group of tumors. Hence the histo-morphological diagnosis coupled with grading/staging is important for the prognostication of these tumors. Aim : To study the clinicopathological characteristics of sinonasal neuroendocrine malignancies at our institute. Material and Methods : We searched our institutes pathology database for the period from 2002 to 2007, for the four subcategories of sinonasal tumors with neuroendocrine differentiation. Morphological and immunohistochemical features were studied and, grading, staging was done in accordance with standard criteria. The clinical treatment and follow- up data were retrieved from the case files in available cases. Results : A total of 37 cases were retrieved from our database which include 14 cases of SNUC, 14 cases of ENB and nine cases of SNEC. The cases of SNUC were immunopositive for cytokeratin, epithelial membrane antigen and weakly for neuron-specific enolase. SNEC showed strong reactivity with epithelial and neuroendocrine markers whereas ENB demonstrated immunoreactivity to synaptophysisn and chromogranin strongly, with weak to negative expression of epithelial markers. All cases of SNUC and SNEC were of high grade and stage whereas 50% of ENB cases were of grade II but high stage tumors. Most of the SNUC and SNEC patients had been treated with multimodality treatment regimens including upfront chemotherapy followed by surgery and loco- regional radiation. In contrast, ENB patients had undergone surgical extirpation followed by radiation therapy in majority of cases. With limited follow-up data, it was observed that four out of five SNUC patients and three out of four SNEC patients developed either loco-regional (three of SNUC and two of SNEC) or distant metastasis (one patient each of SNUC and SNEC). ENB patients also had loco-regional recurrences (five out of seven patients) with a more protracted course but no distant metastases were observed during the follow up in available cases. Conclusion : Sino nasal tumors with neuroendocrine differentiation are a heterogenous group of tumors with overlapping histo-morphological features. They can be distinguished based on immunohistochemical characteristics. Pathological sub categorization is imperative for management and prognostication of these aggressive tumors.

Comparison of the efficacy and safety of Rituximab (Mabthera™) and its biosimilar (Reditux™) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: A retrospective analysis

Background: Rituximab (Mabthera™) have been in use in India since 2000. A biosimilar molecule of rituximab (Reditux™) was approved in India in 2007. This retrospective audit was done to compare the efficacy and safety of Mabthera™ with Reditux™. Materials and Methods: We reviewed the charts of 223 adult diffuse large B-cell lymphoma patients who had received cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab chemotherapy. Tumor recurrence, survival and toxicities experienced during chemotherapy were obtained from the patient charts. The survival analysis was restricted to patients who received at least 4 cycles of the same brand. Results: Of the 223 patients evaluated, 101 received Mabthera™, 72 received Reditux™. There were no differences in the infusional reaction rates, grades 3 and 4 neutropenia and oral mucositis between the two brands. Complete-remission (CR) rates were similar with Mabthera™ and Reditux™ (75% and 82%, respectively; P = 0.294). The progression free survival (PFS) rate at 5 years were 72% in Mabthera™ and 81% in Reditux™ (P = 0.382). The overall survival (OS) at 5 years were comparable in the two groups (66% in Mabthera™ and 76% in Reditux™; P = 0.264). Conclusion: We observed no significant differences in the toxicity, tumor response rates, PFS and OS between the two available brands of rituximab.

Clinicopathologic study and outcome analysis of thyroid lymphomas: Experience from a tertiary cancer center

The aim of this study was to review clinicopathologic presentations of patients diagnosed with thyroid lymphomas at a tertiary cancer center. Thyroid lymphomas represent less than 2% of all lymphomas.

Immunophenotyping of mature B-cell non Hodgkin lymphoma involving bone marrow and peripheral blood: critical analysis and insights gained at a tertiary care cancer hospital.

We evaluated the diagnostic utility of flow cytometry immunophenotyping in bone marrow aspirates and peripheral blood, in the assessment of mature B-cell non-Hodgkin lymphoma (MBNHL). We analyzed 356 cases of MBNHL received for immunophenotyping over a 4 year period. All cases were reviewed, correlated with biopsy specimen (lymph node and splenectomy). Discrepant cases were re-evaluated. Common subtypes included chronic lymphocytic leukemia (CLL) (243 cases, 68.5%), follicular lymphoma (30 cases, 8.5%), mantle cell lymphoma (20 cases, 5.5%), splenic marginal zone lymphoma (18 cases, 5%), hairy cell leukemia (18 cases, 5%). CD5+/CD23+ had a high positive predictive value (PPV) for diagnosing CLL whereas CD5+/CD23− had a high negative predictive value (NPV) for diagnosing mantle-cell lymphoma (MCL). Limited panel of 9 antibodies mainly CD19, CD5, CD23, CD10, FMC7, kappa, lambda, CD3 and CD20 help diagnose more than 92% of cases of MBNHL. Minimal diagnostic panels become important in countries with limited resources.

Prognostic factors in oropharyngeal cancer--analysis of 627 cases receiving definitive radiotherapy.

Introduction. The aim of this retrospective analysis was to analyze the results of conventional radical radiotherapy in the treatment of oropharyngeal cancer and to identify pre-treatment and treatment-related prognostic factors for outcome. Material and methods. The records of 627 patients with oropharyngeal cancer treated with radical radiotherapy with conventional techniques were analyzed. Results. The median age was 56 years. History of tobacco abuse was present in 80.5%. Eighty six percent had stage III or IV disease. Radical radiotherapy alone was the treatment modality for 71.2% and concomitant or neoadjuvant chemotherapy was used in 28.8%. The 3-year local control (LC), loco-regional control (LRC), disease-free survival (DFS) and overall survival (OS) was 49%, 40.6%, 38.9% and 36.1% respectively. The 3-year DFS rates were 80.3% for stage I, 65.8% for stage II, 46.1% for stage III and 25.2% for stage IV disease. Multivariate analysis was performed for prognostic factors. Prior history of tobacco abuse was an independent prognostic factor for both DFS and LRC. Karnofsky Performance Score (KPS) < 80, higher nodal stage, lower total radiotherapy dose (<66 Gy) in those receiving > 60 Gy, and overall treatment time > 50 days were other independent prognostic factors for inferior DFS and LRC. KPS < 80, higher T stage, higher nodal stage, RT dose < 66 Gy and longer overall treatment time (>50 days) were independent prognostic factors for poorer local control. Conclusions. Several patient-, disease- and treatment-related variables independently affect survival outcomes after radical radiotherapy for oropharyngeal cancer. Oropharyngeal cancers in those without a history of tobacco abuse may be biologically different and more amenable to cure with radiotherapy.

Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: Results of a prospective randomized trial

The purpose of this study was to report the results of a phase III, 3‐arm, randomized trial comparing conventional radiotherapy (RT) to concurrent chemoradiotherapy (CRT) and accelerated RT in advanced head and neck squamous cell carcinoma (HNSCC).

Management and clinical outcome of sinonasal teratocarcinosarcoma: single institution experience.

PURPOSE To study the outcome of patients with sinonasal teratocarcinosarcoma treated at a single institution. METHODS We reviewed the medical records of 22 patients with histopathologically proven sinonasal teratocarcinosarcoma diagnosed during the period 1993-2007. Treatment was completed in 16 patients. RESULTS Fourteen patients underwent surgery (six received craniofacial resection, four open surgery and four endoscopic resection); this was followed by radiation therapy with or without chemotherapy in 11 patients. Two patients received chemoradiation as the definitive treatment. At median follow up in surviving patients of 34 months (range one to 180 months), only five were controlled. Disease recurred in 11 patients, with a median time to recurrence of seven months. The two-year disease-free survival rate and the overall survival rate were 28 and 46 per cent, respectively. CONCLUSION Sinonasal teratocarcinosarcoma appears to be an aggressive disease, with the majority of patients suffering locoregional failure. Multimodality treatment, in the form of a combination of surgery, radiation therapy and chemotherapy, appears to be the optimal approach.

A retrospective audit of clinicopathological attributes and treatment outcomes of adolescent and young adult non-Hodgkin lymphomas from a tertiary care center

Background: The uniqueness of adolescent and young adult (AYA) non-Hodgkin lymphomas (NHL) with respect to biology and treatment have largely remained unanswered due to marked heterogeneity in treatment, paucity of prospective, or retrospective studies and poor representation of AYA in clinical trials. This audit attempts to put forward the clinicopathological attributes and treatment outcomes of AYA NHL treated with both pediatric and adult protocols from a single centre in a developing country. Patients and Methods: Hospital records of all consecutive NHL patients registered in lymphoma clinic from January 2007 to May 2010 were reviewed for information on demography, clinical features, histology subtype, staging, treatment regimen, response rates, toxicities, and follow up. Two-year progression-free (PFS) and overall survival (OS) were calculated with Kaplan-Meier method. Results: AYA NHL constituted 4% of all lymphomas. Diffuse large B-cell (DLBL) was the most frequent subtype. Following were the 2-year PFS and OS - DLBL 64%, 76.9%, Burkitts lymphoma: 56%, 56%, lymphoblastic lymphoma: 33.2%, 44%. Our results did not show any improvement in outcome of DLBL with the use of Burkitts lymphoma like regimen. Conclusions: This study highlights some of the key features of AYA NHL occurring in developing world.

SQUAMOUS CELL CARCINOMA OF BASE OF TONGUE IN A PATIENT WITH FANCONI'S ANEMIA TREATED WITH RADIATION THERAPY: CASE REPORT AND REVIEW OF LITERATURE

Fanconis 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.