Seema Kashyap | All India Institute of Medical Sciences, New Delhi (original) (raw)

Papers by Seema Kashyap

Research paper thumbnail of Serum survivin as biomarker in retinoblstoma: Hope or hype?

Pediatric Hematology Oncology Journal

Research paper thumbnail of Glial heterotopia of the orbit and extranasal region: an unusual entity

Clinical and Experimental Ophthalmology, Oct 1, 2005

Glial heterotopia or the occurrence of isolated non‐teratomatous extracranial glial tissue is rar... more Glial heterotopia or the occurrence of isolated non‐teratomatous extracranial glial tissue is rare. Most of the reported cases of this entity arise in the nose. Herein a rare case of heterotopic glial tissue in the orbit and extranasal region without bony defect is described.

Research paper thumbnail of Clinical Significance of Cyclin Expression Profiling in Ocular Surface Squamous Neoplasia

Applied Immunohistochemistry & Molecular Morphology, Oct 18, 2021

Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins re... more Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins regulate the cell cycle progression at different phases and its dysregulation is associated with uncontrollable cell growth and malignant transformation of the cell. Overexpression of cyclin has been reported in various malignancies and is associated with poor prognosis. However, the role of cyclins in OSSN remains unexplored. This study has been designed to assess the prognostic significance of cyclin (cyclin B1, E1, and D1) immunoexpression in 100 OSSN patients. The targeted proteins demonstrated overexpression of cyclin B1, cyclin E1, and cyclin D1 in 55%, 37%, and 56% OSSN cases prospectively. A gradual and significant increase in the cyclin B1 (P=0.01) and cyclin D1 (P=0.005) expression was seen from Tis to the T4 category. Overexpression of cyclin B1 was associated with poor disease-free survival and worst prognosis in both early (P=0.03) as well as advanced T staged (P=0.038) OSSN patients. Overexpression of cyclin E1 was associated with worst disease-free survival (P=0.01) and poor prognosis in advanced stage OSSN patients. Our findings suggest that cyclin B1 and cyclin E1 have prognostic relevance in OSSN patients, and therefore are recommended for detecting high-risk category cases. A significant increase in the expression of cyclins from early to advanced stage indicates that cyclins play an important role in the pathogenesis of OSSN patients.

Research paper thumbnail of Stratifin in ocular surface squamous neoplasia and its association with p53

Acta Ophthalmologica, Mar 26, 2021

PurposeSunlight‐induced p53 mutations are known to contribute towards increased risk of ocular su... more PurposeSunlight‐induced p53 mutations are known to contribute towards increased risk of ocular surface squamous neoplasia (OSSN). Stratifin (14‐3‐3σ)/HEM (human epithelial marker) is a p53‐mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status as well as expression of mutant p53 in early and advanced AJCC stages (8th edition) of OSSN, was evaluated.MethodsSixty‐four OSSN [20 conjunctival intraepithelial neoplasia (CIN) and 44 squamous cell carcinoma (SCC)] patients were registered for this study, and they were followed up for 36–58 months (mean 48 ± 3.6). Immunoexpression of Stratifin and mutant p53 protein, mRNA expression of Stratifin by reverse transcription polymerase chain reaction (PCR) and methylation status of Stratifin by methylation‐specific PCR, was undertaken.ResultsHypermethylation of Stratifin promoter in 63% (40/64), loss of Stratifin expression in 75% (48/64) and downregulation of Stratifin mRNA in 61% (39/64) were observed. Stratifin hypermethylation was significantly associated with reduced disease‐free survival in both early and advanced T stage SCC cases.Expression of mutant p53 expression was seen in 48% (31/64) OSSN cases. Of the 31 patients with mutant p53 expression, 87% (27/31) also demonstrated loss of Stratifin immunoexpression. A significant association was seen between mutant p53 expression and Stratifin loss (p = 0.01) in advanced T stage SCC cases.ConclusionsHypermethylation of Stratifin gene and its reduced mRNA expression both are potential biomarkers for identifying high‐risk OSSN patients. Aberrant methylation of Stratifin and simultaneous mutant p53 expression implicates involvement of p53‐Stratifin mediated signalling pathway in the pathogenesis of OSSN.

Research paper thumbnail of American Joint Committee on Cancer Staging and Clinicopathological High-Risk Predictors of Ocular Surface Squamous Neoplasia: A Study From a Tertiary Eye Center in India

Archives of Pathology & Laboratory Medicine, Nov 1, 2014

Research paper thumbnail of Eyelid pilomatrixoma masquerading as chalazion

Canadian journal of ophthalmology, Apr 1, 2017

location did mimic a subperiosteal abscess and this confounded the initial working diagnosis and ... more location did mimic a subperiosteal abscess and this confounded the initial working diagnosis and management. Thus, it is important to include metastatic disease as part of the differential diagnosis along with infectious and inflammatory processes. In patients with a recent history of cancer, orbitotomy becomes crucial for definitive diagnosis as orbital metastasis can present as an inflammatory phlegmon with subperiosteal involvement. 12

Research paper thumbnail of Role of microphthalmia-associated transcription factor in uveal melanoma and its association with clinicopathological parameters

JCO Global Oncology

153 Background: High melanin content could lead to high metastatic potential in Uveal Melanoma (U... more 153 Background: High melanin content could lead to high metastatic potential in Uveal Melanoma (UM). In the Asian population, Microphthalmia-Associated Transcription Factor (MITF) regulates the melanogenesis pathway and activates Silver Protein (SILV) for eumelanin synthesis. MITF also stimulates the hypoxia–inducible factor 1-alpha (HIF-1α) gene that regulates hypoxia around the tumor microenvironment. Although their oncogenic potential has been observed in a variety of malignancies, MITF and SILV have not been investigated in UM in the Asian population. Therefore, our study aimed to detect the prognostic significance of MITF, SILV, and HIF1-α gene/protein expression levels in UM patients. Methods: Immunohistochemistry of MITF, SILV & HIF-1 α was performed on 82 UM tissue samples. Western blot of all three markers was carried out on representative cases. The mRNA expression level was done by qRT-PCR in 70 fresh UM cases. Cox proportional hazard model and log-rank test were used to ...

Research paper thumbnail of Tubercular DNA PCR of ocular fluids and blood in cases of presumed ocular tuberculosis: a pilot study

Therapeutic Advances in Ophthalmology

Background: The definitive diagnosing of ocular tuberculosis (TB) is difficult; therefore, there ... more Background: The definitive diagnosing of ocular tuberculosis (TB) is difficult; therefore, there is a need of better understanding of investigating TB DNA in presumed ocular TB patients. Objectives: The aim of this study is to correlate tubercular DNA PCR of aqueous/vitreous and blood in cases of presumed ocular TB. Design: A prospective study. Methods: DNA was extracted from aqueous of cases of choroidal tuberculoma (group 1) and serpiginous choroiditis (group 2) and from vitreous of cases of vasculitis (group 3) and macular hole/retinal detachment (group 4). Gel-based PCR and real-time PCR amplification were performed using IS6110 primer on ocular fluids. The same was also performed on the blood samples of cases in which tubercular DNA was detected in the ocular fluids. Results: Overall, 31 cases were analysed in our study. Tubercular DNA was detected in ocular fluids of seven cases: group 1, two cases (67%); group 2, one case (17%); group 3, four cases (27%); and no case of group...

Research paper thumbnail of Unilateral retinal dysplasia simulating retinoblastoma

Research paper thumbnail of Clinico-demographic profile of orbital exenteration in a tertiary eye care centre – a 20 years’ experience

Background This study aimed to determine the clinical indications for orbital exenteration, demog... more Background This study aimed to determine the clinical indications for orbital exenteration, demographic profile of these patients and clinicopathological correlations in current times, and to compare these results with previous published data. Methods A retrospective analysis was conducted of exenterations performed at a tertiary eye care centre over a period of 20 years(January 2001 to June 2020). Patient records were reviewed to obtain demographic data, presenting symptoms and their duration, laterality, and clinical and histopathological diagnosis. Results A total of 352 cases(males: females, 222:130) were identified who underwent exenteration. Patients ranged in age from 11months to 87 years(mean: 43.86 years, median: 50 years). The most common indication for exenteration was found to be eyelid malignancy in 54.36% followed by retinoblastoma in 18.75% and primary orbital tumors in 14.49%. Squamous cell carcinoma(SCC)(60.26%) was most common histologic subtype of eyelid malignanc...

Research paper thumbnail of Interaction of Immune Checkpoints in Tumor-Stromal Microenvironment of Primary and Chemoreduced Retinoblastoma

Investigative Ophthalmology & Visual Science, Jul 22, 2019

Research paper thumbnail of Role of Apoptotic Regulatory Proteins in Retinoblastoma

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Stratifin- A novel biomarker in the prognosis of Ocular Surface Squamous Neoplasia patients

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of 16P PD-1/PD-L1 expression in uveal melanoma: Prognostic significance with tumour-infiltrating lymphocytes and clinicopathological parameters

Research paper thumbnail of Association of BAP1 with ATR protein and their clinical significance with patient outcome in uveal melanoma

Annals of Oncology, 2019

Abstract Background Uveal melanoma (UM) is an intraocular malignancy commonly arising from the ch... more Abstract Background Uveal melanoma (UM) is an intraocular malignancy commonly arising from the choroid. There is a lack of effective therapy to detect and treat early metastatic spread in these patients. Therefore, it is important to find new biomarkers that help in early detection of metastasis. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1. Loss of BAP1 is a known poor prognostic marker of uveal melanoma. There is no current study available on UM with respect to ATR protein that induces DNA damage response. Therefore, the aim of the study is to detect the expression of ATR protein in the UM patients and correlate its expression with BAP1 loss. Methods Expression of nuclear ATR was investigated on sixty-nine UM patients which were divided into two groups on the basis of BAP1 expression. Formalin-fixed paraffin embedded choroidal melanoma samples were taken to evaluate the expression of ATM and BAP1 by immunohistochemistry and validated by semi-quantitative PCR. Results were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan–Meier and multivariate analysis were performed. Results Patients with BAP1 loss also showed ATR loss in 62% of the cases which was statistically significant with high tumor pigmentation, LTD >10mm and cell type. At transcription level, down-regulation of ATR gene was found in 45% of cases and these results were in line with the IHC results. On multivariate analysis, advanced tumor staging and loss of ATR protein found to be independent prognostic factors. Conclusions Our study emphasized the fact that loss of ATR could be a potential biomarker to detect the early metastasis in uveal melanoma. Hence, it could have a key role for therapeutic purpose. However, further studies are required in a larger cohort of patients with longer follow up and translational validation needs to be performed. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Research paper thumbnail of 5P Differential expression patterns of immune checkpoint markers in tumour-stromal microenvironment of primary and chemoreduced retinoblastoma

Annals of Oncology, 2019

Background The goal of this study is to identify the pathological findings and expression of immu... more Background The goal of this study is to identify the pathological findings and expression of immune checkpoint marker (PD-1, PD-L1, and CTLA-4) in the tumor microenvironment of both primary and chemoreduced retinoblastoma and correlate with clinicopathological parameters and patient outcome. Methods Total of 262 prospective cases was included prospectively in which 144 cases underwent primary enucleation and 118 cases received chemotherapy/radiotherapy before enucleation (chemoreduced retinoblastoma). Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of immune checkpoint markers in primary and chemoreduced retinoblastoma. Results Tumor microenvironment was different for both primary and chemoreduced retinoblastoma. Expression of PD-1 was found in 29/144 (20.13%) and 48/118 (40.67%) in primary and chemoreduced retinoblastoma respectively, whereas PD-L1 was expressed in 46/144 (31.94%) and 22/118 (18.64%) in cases of primary and chemo...

Research paper thumbnail of Mutational Analysis of the Mitochondrial DNA Displacement-Loop Region in Human Retinoblastoma with Patient Outcome

Pathology oncology research : POR, Jan 12, 2018

Alteration in mitochondrial DNA plays an important role in the development and progression of can... more Alteration in mitochondrial DNA plays an important role in the development and progression of cancer. The Displacement Loop (D-loop) region of mitochondrial DNA (mtDNA) is the regulatory region for its replication and transcription. Therefore, we aimed to characterize mutations in the D-loop region of mitochondrial DNA along with the morphological changes and analyzed their impact on survival in retinoblastoma patients. mtDNA D-loop region was amplified by Nested-Polymerase Chain Reaction (Nested-PCR) and mutations were analyzed in 60 tumor samples from retinoblastoma patients by DNA sequencing. Transmission electron microscopy was performed on 5 retinoblastoma specimens. Mutations were correlated with clinical, histopathological parameters and patient survival. D-loop mutations were found in total of 52/60 (86.6%) patients. The most common mutations were T to C and C to T followed by A to G. There were 5.81% mutations which were not previously reported in the MITOMAP database. A73G...

Research paper thumbnail of Giant myxofibrosarcoma of the orbit: a rare case and a review of the literature

Research paper thumbnail of Uveal melanoma

Seminars in Diagnostic Pathology, 2016

Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with... more Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with a high rate of distant tumor spread and consequent mortality. Unlike retinoblastoma, for which treatment advances over the last few decades have resulted in a dramatic improvement in survival, outcomes for patients with uveal melanoma remain unchanged. Despite improvement in local control of this tumor, roughly 50% of patients develop metastatic disease within 15 years. Delays in diagnosis and marked vascularity of this tumor may underlie that situation. Tumor size, location, histopathologic appearance, cytogenetic abnormalities, and molecular profiling are used in prognostication. The revised 7th edition of the American Joint Committee on Cancer (AJCC) manual has presented new information that may improve that process as well. Herein, we review current knowledge on uveal melanoma.

Research paper thumbnail of DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome

Clinical and Translational Oncology, 2020

Background The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma.... more Background The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma. ATR belongs to one of those proteins that induce DDR by arresting the cell cycle which leads to DNA repair. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1 which is a known poor prognostic marker of UM. The aim of our study is to detect the expression of ATR at the protein and RNA levels and determine its prognostic significance. Methods Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fixed paraffin-embedded choroidal melanoma samples were taken to evaluate the expression of ATR. Fifty samples were also validated by real-time PCR. Results of both protein and mRNA were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan-Meier and multivariate analyses were performed. Results Loss of ATR protein was seen in 72% cases which was statistically significant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic figures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically significant with metastasis (p = 0.046), staging (0.044) and loss of BAP1 (p = 0.022). On multivariate analysis loss of ATR and tumor staging came out to be independent prognostic parameters. Conclusion Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.

Research paper thumbnail of Serum survivin as biomarker in retinoblstoma: Hope or hype?

Pediatric Hematology Oncology Journal

Research paper thumbnail of Glial heterotopia of the orbit and extranasal region: an unusual entity

Clinical and Experimental Ophthalmology, Oct 1, 2005

Glial heterotopia or the occurrence of isolated non‐teratomatous extracranial glial tissue is rar... more Glial heterotopia or the occurrence of isolated non‐teratomatous extracranial glial tissue is rare. Most of the reported cases of this entity arise in the nose. Herein a rare case of heterotopic glial tissue in the orbit and extranasal region without bony defect is described.

Research paper thumbnail of Clinical Significance of Cyclin Expression Profiling in Ocular Surface Squamous Neoplasia

Applied Immunohistochemistry & Molecular Morphology, Oct 18, 2021

Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins re... more Ocular surface squamous neoplasia (OSSN) can recur, metastasize, and even cause death. Cyclins regulate the cell cycle progression at different phases and its dysregulation is associated with uncontrollable cell growth and malignant transformation of the cell. Overexpression of cyclin has been reported in various malignancies and is associated with poor prognosis. However, the role of cyclins in OSSN remains unexplored. This study has been designed to assess the prognostic significance of cyclin (cyclin B1, E1, and D1) immunoexpression in 100 OSSN patients. The targeted proteins demonstrated overexpression of cyclin B1, cyclin E1, and cyclin D1 in 55%, 37%, and 56% OSSN cases prospectively. A gradual and significant increase in the cyclin B1 (P=0.01) and cyclin D1 (P=0.005) expression was seen from Tis to the T4 category. Overexpression of cyclin B1 was associated with poor disease-free survival and worst prognosis in both early (P=0.03) as well as advanced T staged (P=0.038) OSSN patients. Overexpression of cyclin E1 was associated with worst disease-free survival (P=0.01) and poor prognosis in advanced stage OSSN patients. Our findings suggest that cyclin B1 and cyclin E1 have prognostic relevance in OSSN patients, and therefore are recommended for detecting high-risk category cases. A significant increase in the expression of cyclins from early to advanced stage indicates that cyclins play an important role in the pathogenesis of OSSN patients.

Research paper thumbnail of Stratifin in ocular surface squamous neoplasia and its association with p53

Acta Ophthalmologica, Mar 26, 2021

PurposeSunlight‐induced p53 mutations are known to contribute towards increased risk of ocular su... more PurposeSunlight‐induced p53 mutations are known to contribute towards increased risk of ocular surface squamous neoplasia (OSSN). Stratifin (14‐3‐3σ)/HEM (human epithelial marker) is a p53‐mediated inhibitor of cell cycle progression and has been shown to be a target of epigenetic deregulation in various carcinomas. In the present study, Stratifin expression, its promoter methylation status as well as expression of mutant p53 in early and advanced AJCC stages (8th edition) of OSSN, was evaluated.MethodsSixty‐four OSSN [20 conjunctival intraepithelial neoplasia (CIN) and 44 squamous cell carcinoma (SCC)] patients were registered for this study, and they were followed up for 36–58 months (mean 48 ± 3.6). Immunoexpression of Stratifin and mutant p53 protein, mRNA expression of Stratifin by reverse transcription polymerase chain reaction (PCR) and methylation status of Stratifin by methylation‐specific PCR, was undertaken.ResultsHypermethylation of Stratifin promoter in 63% (40/64), loss of Stratifin expression in 75% (48/64) and downregulation of Stratifin mRNA in 61% (39/64) were observed. Stratifin hypermethylation was significantly associated with reduced disease‐free survival in both early and advanced T stage SCC cases.Expression of mutant p53 expression was seen in 48% (31/64) OSSN cases. Of the 31 patients with mutant p53 expression, 87% (27/31) also demonstrated loss of Stratifin immunoexpression. A significant association was seen between mutant p53 expression and Stratifin loss (p = 0.01) in advanced T stage SCC cases.ConclusionsHypermethylation of Stratifin gene and its reduced mRNA expression both are potential biomarkers for identifying high‐risk OSSN patients. Aberrant methylation of Stratifin and simultaneous mutant p53 expression implicates involvement of p53‐Stratifin mediated signalling pathway in the pathogenesis of OSSN.

Research paper thumbnail of American Joint Committee on Cancer Staging and Clinicopathological High-Risk Predictors of Ocular Surface Squamous Neoplasia: A Study From a Tertiary Eye Center in India

Archives of Pathology & Laboratory Medicine, Nov 1, 2014

Research paper thumbnail of Eyelid pilomatrixoma masquerading as chalazion

Canadian journal of ophthalmology, Apr 1, 2017

location did mimic a subperiosteal abscess and this confounded the initial working diagnosis and ... more location did mimic a subperiosteal abscess and this confounded the initial working diagnosis and management. Thus, it is important to include metastatic disease as part of the differential diagnosis along with infectious and inflammatory processes. In patients with a recent history of cancer, orbitotomy becomes crucial for definitive diagnosis as orbital metastasis can present as an inflammatory phlegmon with subperiosteal involvement. 12

Research paper thumbnail of Role of microphthalmia-associated transcription factor in uveal melanoma and its association with clinicopathological parameters

JCO Global Oncology

153 Background: High melanin content could lead to high metastatic potential in Uveal Melanoma (U... more 153 Background: High melanin content could lead to high metastatic potential in Uveal Melanoma (UM). In the Asian population, Microphthalmia-Associated Transcription Factor (MITF) regulates the melanogenesis pathway and activates Silver Protein (SILV) for eumelanin synthesis. MITF also stimulates the hypoxia–inducible factor 1-alpha (HIF-1α) gene that regulates hypoxia around the tumor microenvironment. Although their oncogenic potential has been observed in a variety of malignancies, MITF and SILV have not been investigated in UM in the Asian population. Therefore, our study aimed to detect the prognostic significance of MITF, SILV, and HIF1-α gene/protein expression levels in UM patients. Methods: Immunohistochemistry of MITF, SILV & HIF-1 α was performed on 82 UM tissue samples. Western blot of all three markers was carried out on representative cases. The mRNA expression level was done by qRT-PCR in 70 fresh UM cases. Cox proportional hazard model and log-rank test were used to ...

Research paper thumbnail of Tubercular DNA PCR of ocular fluids and blood in cases of presumed ocular tuberculosis: a pilot study

Therapeutic Advances in Ophthalmology

Background: The definitive diagnosing of ocular tuberculosis (TB) is difficult; therefore, there ... more Background: The definitive diagnosing of ocular tuberculosis (TB) is difficult; therefore, there is a need of better understanding of investigating TB DNA in presumed ocular TB patients. Objectives: The aim of this study is to correlate tubercular DNA PCR of aqueous/vitreous and blood in cases of presumed ocular TB. Design: A prospective study. Methods: DNA was extracted from aqueous of cases of choroidal tuberculoma (group 1) and serpiginous choroiditis (group 2) and from vitreous of cases of vasculitis (group 3) and macular hole/retinal detachment (group 4). Gel-based PCR and real-time PCR amplification were performed using IS6110 primer on ocular fluids. The same was also performed on the blood samples of cases in which tubercular DNA was detected in the ocular fluids. Results: Overall, 31 cases were analysed in our study. Tubercular DNA was detected in ocular fluids of seven cases: group 1, two cases (67%); group 2, one case (17%); group 3, four cases (27%); and no case of group...

Research paper thumbnail of Unilateral retinal dysplasia simulating retinoblastoma

Research paper thumbnail of Clinico-demographic profile of orbital exenteration in a tertiary eye care centre – a 20 years’ experience

Background This study aimed to determine the clinical indications for orbital exenteration, demog... more Background This study aimed to determine the clinical indications for orbital exenteration, demographic profile of these patients and clinicopathological correlations in current times, and to compare these results with previous published data. Methods A retrospective analysis was conducted of exenterations performed at a tertiary eye care centre over a period of 20 years(January 2001 to June 2020). Patient records were reviewed to obtain demographic data, presenting symptoms and their duration, laterality, and clinical and histopathological diagnosis. Results A total of 352 cases(males: females, 222:130) were identified who underwent exenteration. Patients ranged in age from 11months to 87 years(mean: 43.86 years, median: 50 years). The most common indication for exenteration was found to be eyelid malignancy in 54.36% followed by retinoblastoma in 18.75% and primary orbital tumors in 14.49%. Squamous cell carcinoma(SCC)(60.26%) was most common histologic subtype of eyelid malignanc...

Research paper thumbnail of Interaction of Immune Checkpoints in Tumor-Stromal Microenvironment of Primary and Chemoreduced Retinoblastoma

Investigative Ophthalmology & Visual Science, Jul 22, 2019

Research paper thumbnail of Role of Apoptotic Regulatory Proteins in Retinoblastoma

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Stratifin- A novel biomarker in the prognosis of Ocular Surface Squamous Neoplasia patients

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of 16P PD-1/PD-L1 expression in uveal melanoma: Prognostic significance with tumour-infiltrating lymphocytes and clinicopathological parameters

Research paper thumbnail of Association of BAP1 with ATR protein and their clinical significance with patient outcome in uveal melanoma

Annals of Oncology, 2019

Abstract Background Uveal melanoma (UM) is an intraocular malignancy commonly arising from the ch... more Abstract Background Uveal melanoma (UM) is an intraocular malignancy commonly arising from the choroid. There is a lack of effective therapy to detect and treat early metastatic spread in these patients. Therefore, it is important to find new biomarkers that help in early detection of metastasis. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1. Loss of BAP1 is a known poor prognostic marker of uveal melanoma. There is no current study available on UM with respect to ATR protein that induces DNA damage response. Therefore, the aim of the study is to detect the expression of ATR protein in the UM patients and correlate its expression with BAP1 loss. Methods Expression of nuclear ATR was investigated on sixty-nine UM patients which were divided into two groups on the basis of BAP1 expression. Formalin-fixed paraffin embedded choroidal melanoma samples were taken to evaluate the expression of ATM and BAP1 by immunohistochemistry and validated by semi-quantitative PCR. Results were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan–Meier and multivariate analysis were performed. Results Patients with BAP1 loss also showed ATR loss in 62% of the cases which was statistically significant with high tumor pigmentation, LTD >10mm and cell type. At transcription level, down-regulation of ATR gene was found in 45% of cases and these results were in line with the IHC results. On multivariate analysis, advanced tumor staging and loss of ATR protein found to be independent prognostic factors. Conclusions Our study emphasized the fact that loss of ATR could be a potential biomarker to detect the early metastasis in uveal melanoma. Hence, it could have a key role for therapeutic purpose. However, further studies are required in a larger cohort of patients with longer follow up and translational validation needs to be performed. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Research paper thumbnail of 5P Differential expression patterns of immune checkpoint markers in tumour-stromal microenvironment of primary and chemoreduced retinoblastoma

Annals of Oncology, 2019

Background The goal of this study is to identify the pathological findings and expression of immu... more Background The goal of this study is to identify the pathological findings and expression of immune checkpoint marker (PD-1, PD-L1, and CTLA-4) in the tumor microenvironment of both primary and chemoreduced retinoblastoma and correlate with clinicopathological parameters and patient outcome. Methods Total of 262 prospective cases was included prospectively in which 144 cases underwent primary enucleation and 118 cases received chemotherapy/radiotherapy before enucleation (chemoreduced retinoblastoma). Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of immune checkpoint markers in primary and chemoreduced retinoblastoma. Results Tumor microenvironment was different for both primary and chemoreduced retinoblastoma. Expression of PD-1 was found in 29/144 (20.13%) and 48/118 (40.67%) in primary and chemoreduced retinoblastoma respectively, whereas PD-L1 was expressed in 46/144 (31.94%) and 22/118 (18.64%) in cases of primary and chemo...

Research paper thumbnail of Mutational Analysis of the Mitochondrial DNA Displacement-Loop Region in Human Retinoblastoma with Patient Outcome

Pathology oncology research : POR, Jan 12, 2018

Alteration in mitochondrial DNA plays an important role in the development and progression of can... more Alteration in mitochondrial DNA plays an important role in the development and progression of cancer. The Displacement Loop (D-loop) region of mitochondrial DNA (mtDNA) is the regulatory region for its replication and transcription. Therefore, we aimed to characterize mutations in the D-loop region of mitochondrial DNA along with the morphological changes and analyzed their impact on survival in retinoblastoma patients. mtDNA D-loop region was amplified by Nested-Polymerase Chain Reaction (Nested-PCR) and mutations were analyzed in 60 tumor samples from retinoblastoma patients by DNA sequencing. Transmission electron microscopy was performed on 5 retinoblastoma specimens. Mutations were correlated with clinical, histopathological parameters and patient survival. D-loop mutations were found in total of 52/60 (86.6%) patients. The most common mutations were T to C and C to T followed by A to G. There were 5.81% mutations which were not previously reported in the MITOMAP database. A73G...

Research paper thumbnail of Giant myxofibrosarcoma of the orbit: a rare case and a review of the literature

Research paper thumbnail of Uveal melanoma

Seminars in Diagnostic Pathology, 2016

Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with... more Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with a high rate of distant tumor spread and consequent mortality. Unlike retinoblastoma, for which treatment advances over the last few decades have resulted in a dramatic improvement in survival, outcomes for patients with uveal melanoma remain unchanged. Despite improvement in local control of this tumor, roughly 50% of patients develop metastatic disease within 15 years. Delays in diagnosis and marked vascularity of this tumor may underlie that situation. Tumor size, location, histopathologic appearance, cytogenetic abnormalities, and molecular profiling are used in prognostication. The revised 7th edition of the American Joint Committee on Cancer (AJCC) manual has presented new information that may improve that process as well. Herein, we review current knowledge on uveal melanoma.

Research paper thumbnail of DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome

Clinical and Translational Oncology, 2020

Background The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma.... more Background The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma. ATR belongs to one of those proteins that induce DDR by arresting the cell cycle which leads to DNA repair. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1 which is a known poor prognostic marker of UM. The aim of our study is to detect the expression of ATR at the protein and RNA levels and determine its prognostic significance. Methods Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fixed paraffin-embedded choroidal melanoma samples were taken to evaluate the expression of ATR. Fifty samples were also validated by real-time PCR. Results of both protein and mRNA were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan-Meier and multivariate analyses were performed. Results Loss of ATR protein was seen in 72% cases which was statistically significant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic figures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically significant with metastasis (p = 0.046), staging (0.044) and loss of BAP1 (p = 0.022). On multivariate analysis loss of ATR and tumor staging came out to be independent prognostic parameters. Conclusion Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.