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Clinical presentation of ocular surface squamous neoplasia (OSSN). (a) A 74 year old female with OSSN involving nasal peripheral cornea, limbus, and bulbar conjunctiva. The lesion was carcinoma-in-situ on histopathology. (b) A 56 year old female with partially pigmented OSSN involving temporal peripheral cornea, limbus, and bulbar conjunctiva. The lesion was invasive squamous cell carcinoma on histopathology. doi:10.1371/journal.pone.0161800.g001
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Ocular Surface Squamous Neoplasm (OSSN) is the neoplasia arising from the conjunctiva, cornea and limbus. OSSN ranges from mild, moderate, severe dysplasia, carcinoma in situ (CIS) to squamous cell carcinoma (SCC). Recent findings on cancer stem cells theory indicate that population of stem-like cell as in neoplasia determines its heterogeneity and...
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Hyaluronan (HA), a major component of the extracellular matrix, plays a key role in cell proliferation, growth, survival, polarization and differentiation. We investigated the optimization of a HA hydrogel scaffold for culture of human oral mucosal epithelial cells (OMECs) for potential application in limbal stem cell therapy. The effect of the opt...
Citations
... The sections underwent sequential dehydration process with alcohol, were cleared with xylene, and finally mounted with DPX mount medium (Fine-chem limited, Mumbai). [12] ...
Purpose:
Animal models are necessary in understanding the pathogenesis of endophthalmitis and are also necessary to assist the development of new therapeutics for this sight-threatening ocular inflammation. Hamilton syringes are usually preferred to inject pathogens when performing experiments on test subjects, however, this method has technical and financial disadvantages. In this study, we report the findings and assess the related benefits of applying a novel low-cost intravitreal injection technique to initiate endophthalmitis in a mouse model while using the Eppendorf tip and a 26G needle.
Methods:
The 18-hr culture of clinical isolates of bacteria (Staphylococcus aureus and Pseudomonas aeruginosa) and fungus (Aspergillus flavus and Candida albicans) were resuspended to a final concentration of 10,000 colony forming units (CFU)/1 µL which were separately injected intravitreally into C57BL/6 mice (6-8 weeks) using a 0.1-2.5µL pipette attached to the modified Eppendorf tip with a 26G needle. The contralateral eye served as vehicle/uninjected control. Disease progression was determined by assessing the corneal haze, opacity, bacterial burden, and retinal histology of the eyes used in the model. Following euthanization, bacteria-infected mice were enucleated after 24 hr of the initial injection, and fungus-infected mice after 72 hr.
Results:
Of the 50 mice injected, the modified technique was successful in 48 mice. Two mice were excluded due to cataract formed by accidental injury to the lens. The experimental endophthalmitis mice model successfully mimicked the natural clinical course. Clinical assessment and histopathology confirmed the influx of inflammatory cells into the posterior segment of the eye along with dissolution of retinal architecture.
Conclusion:
Our novel method of injection using a modified Eppendorf tip and 26G needle yielded a cost-effective mouse model of clinical endophthalmitis, resulting in reproducible infection for understanding various aspects of its pathobiology.
... modifications. The majority of CRC cases are sporadic and develop slowly for over a decade through the adenoma-carcinoma sequence (6). Although substantial progress has been made in the treatment and understanding of the molecular mechanisms involved in CRC in recent years, the overall survival (OS) rate remains relatively low compared with other types of cancer (7,8). ...
Colorectal cancer (CRC) is one of the most common malignancies worldwide and includes colon cancer (CC) and rectal cancer (RC). Regarding CC, the development of novel molecular biomarkers for the accurate diagnosis and prognosis, as well as the identification of novel targets for therapeutic intervention, are urgently needed. SRY-related high-mobility group box 9 (SOX9), a transcription factor, is involved in development, and has been associated with the progression of human cancer. However, its underlying clinical and functional effects in CRC have not been fully understood. Therefore, the present study aimed to evaluate the clinical and functional relevance of SOX9 expression in CC. The expression of SOX9 in tumor tissues was evaluated in 97 biopsies from Mexican patients with CC with early-stage I and II disease by immunohistochemistry (IHC). In addition, SOX9 silencing in the HCT116 cell line was performed using specific small interfering RNAs, while downregulation efficiency was verified by reverse transcription-quantitative PCR and immunofluorescence. Spheroid-formation assay was carried out using ultra-low attachment plates. The IHC results showed that SOX9 was upregulated in patients with stage II (91%) and advanced T3 stage (67%) CC. Interestingly, higher SOX9 expression was associated with clinical stage, tumor size and tumor location. Furthermore, increased SOX9 expression was found in relapsed cases with local tumors; however, it was not associated with increased survival probability. Additionally, functional analysis indicated that SOX9 silencing significantly attenuated the sphere-formation capability of HCT116 cells. The present study was the first to evaluate the expression levels of SOX9 in Mexican patients diagnosed with early-stage CC. The aforementioned findings indicated that high SOX9 expression could play an important role in tumorigenesis and be associated with advanced T-stages of clinical-stage II patients, but not with relapse-free survival.
... Development of CRC involves different genetic and epigenetic changes. Most cases are sporadic and show a slow development through the time, advancing from adenoma to carcinoma (2). Even though there are important progress in treatment and molecular mechanisms involved in CRC, the OS rate still remains relatively low (3,4). ...
Colorectal cancer (CRC) is a common malignancy with 1.8 million cases in 2018. Autophagy helps to maintain an adequate cancer microenvironment by providing nutritional supplement under starvation and hypoxic conditions. Additionally, most of the cases of CRC are unresponsive to chemotherapy, representing a significant challenge for cancer therapy.
Recently, therapy-induced autophagy has been shown as a novel mechanism of resistance to anticancer agents. In this regard, long noncoding RNAs (lncRNAs) analysis are important for cancer detection, progression, diagnosis, therapy response and prognostic values. With increasing development of quantitative detection techniques, lncRNAs derived from patients’ non-invasive samples (i.e. blood, stools, and urine) has become into a novel approach in precision oncology.
Tumorspecific GAS5, HOTAIR, H19 and MALAT are novels CRC related lncRNAs detected in patients. Nonetheless, the effect and mechanism of lncRNAs in cancer autophagy and chemoresistance have not been extensively characterized.
Chemoresistance and autophagy are relevant for cancer treatment and lncRNAs play a pivotal role in resistance acquisition for several drugs. LncRNAs such as HAGLROS, KCNQ1OT1 and H19 are examples of lncRNA related to chemoresistance leaded by autophagy.
Finally, clinical implications of lncRNAs in CRC are relevant, since they have been associated with tumor differentiation, tumor size, histological grade, histological types, Dukes staging, degree of differentiation, lymph node metastasis, distant metastasis, recurrent free survival and overall survival
... Sunlight-induced epigenetic alteration in p16INK4a plays an important role in the pathogenesis of OSSN. 43 In a study done by Dilip Kumar Mishra et al, it is stated that stem cells expressing p63, c-Kit, ABCG2, and CD44 have a role in the progression of OSSN. The authors also concluded that the screening of cancer stem cells can be used to prognosticate the severity of OSSN and possibly its metastatic potential. ...
Ocular surface squamous neoplasia (OSSN) is one of the most common ocular surface neoplasias encompassing preinvasive, carcinoma insitu and invasive squamous cell carcinoma. Since Lee and Hirst first coined the term in 1995 the classification of OSSN, investigations along with its treatment has undergone a lot of changes. Since it is commonly encountered in a clinician's day to day practice it is important for an ophthalmologist to stay up to date with all the recent developments in OSSN. This review article aims to provide a detailed review of the current literature regarding the etiopathogenesis, clinical features, diagnostic and treatment modalities of OSSN as well as a brief overview of newer frontiers being explored. The authors' experience of treating patients with OSSN is presented in detail in this review article.
... Hematoxylin-eosin staining for mouse and rabbit tissue sections was performed following the standard procedure (Mishra et al., 2016). Briefly, after deparaffinization or the removal of the cryogenic medium (Tissue-Tek™ CRYO-OCT), the slides were washed and stained with Harris's hematoxylin stain (H3136-100G, Sigma-Aldrich, USA) for 10-20 min. ...
... The mouse, rabbit and the deparaffinized human sections were stained using Periodic acid-Schiff (PAS) stain as per the protocol described earlier (Mishra et al., 2016). Briefly, after removal of OCT compound from mice/rabbit sections and deparaffinization and rehydration process of human sections, the sections were dipped in 0.5% periodic acid solution for approximately 5 min. ...
Limbal stem cell deficiency (LSCD) is one of the serious cause of visual impairment and blindness with loss of corneal clarity and vascularization. Factors such as ocular burns (acids, lime, thermal), genetic disorders or infections results in the loss of limbal stem cells leading to LSCD. Reliable animal models of LSCD are useful for understanding the pathophysiology and developing novel therapeutic approaches. The purpose of the present study was to validate small and large animal models of LSCD by immunohistochemcal, clinical and histopathological comparison with human. The animal models of LSCD were created by topical administration of sodium hydroxide on the ocular surface of C57BL/6 mice (m, n = 12) and New Zealand white rabbits (r, n = 12) as per the standard existing protocol. Human corneal specimens (h, n = 12) were obtained from tissue bank who had chemical burn-induced LSCD. All samples were either paraffin embedded or frozen in cryogenic medium and the sections were processed for Hematoxylin-Eosin and Periodic Acid-Schiff staining to analyse the morphology and histopathological features of the corneal surface such as vascularization, inflammation, presence of goblet cells, epithelial hyperplasia and keratinization. Immunofluorescence was performed to distinguish between corneal (CK3+), conjunctival (CK19+) and epidermal (CK10+) epithelial phenotype. Histological analysis of corneal specimens from the three groups showed the presence of goblet cells (h:83%, m:50%, r:50%, p = 0.014), epithelial hypertrophy (h:92%, m:50%, r:66.6%, p = 0.04), epithelial hyperplasia (h:50%, m:17%, r:17%, p = 0.18), intra epithelial edema (h:42%, m:33%, r:100%, p = 0.02), stromal inflammation (h:100%, m:67%, r:67%, p = 0.01) and stromal vascularization (h:100%, m:50%, r:67%), in varying proportions. Immunostaining showed presence of total LSCD (CK19 + and/or CK10+, CK3-) in 92% of human and 50% of animal specimens. While partial LSCD (CK19 + and/or CK10+, CK3+) was seen in 8% of human and 50% of animal specimens. Our study shows the significant differences in the extent of vascularization, inflammation, epithelial thickness and goblet cell formation in mice and rabbit models of LSCD when compared to post-chemical burn LSCD in human corneas. In both mice and rabbit models complete LSCD developed in only 50% of cases and this important fact needs to be considered when working with animal models of LSCD.
... OSSN is strongly associated with several risk factors, including ultraviolet (UV) radiation exposure, human immunodeficiency virus (HIV), human papilloma virus (HPV) infection, chronic use of contact lens, exposure to petroleum product drugs [5,8,9], heavy cigarette smoking [10], age, and male gender [9]. Clinical symptoms are various from patient to patient, from none at all or mild epiphora to severe eyeball pain and visual loss [1,2], but the most frequent presentation of OSSN patients is with red eye and ocular irritation [11]. ...
Ocular surface squamous neoplasia (OSSN) is a malignant or dysplastic lesion that has its origins in the epithelial cells at the ocular surface. The structures from which these lesions can arise are the conjunctiva, the limbus, and the cornea. Our study was conducted on a group of seven patients with ocular surface squamous cell carcinoma (SCC). Histopathologically diagnosed SCCs were then assessed as well, moderately and poorly differentiated, depending on which area of differentiation dominated in Hematoxylin-Eosin staining. For the immunohistochemical analysis, the following antibodies (markers) were used: Ki67, p53 and B-cell lymphoma 2 (Bcl-2), E-cadherin, and vascular endothelial growth factor (VEGF). Our study group was composed of seven cases of SCCs of the ocular surface. Three were below in T1 American Joint Committee on Cancer (AJCC) stage, two cases were in T2 AJCC stage, and two cases were in T3 AJCC stage. None of our cases were T4, N1 or M1 AJCC tumors. Four of the cases were histopathologically moderately differentiated SCCs of the ocular surface and three were poorly differentiated SCCs. None of the seven patients present human immunodeficiency virus (HIV) infection. P53 immunostaining was strongly present in our study. Bcl-2 overexpression is not a fact that our study highlights. The expression of Ki67 proliferation marker was low in our study. Our study on ocular surface SCC reveals negative assessment of VEGF immunostaining. E-cadherin expression in our study was positive. Ocular surface SCCs are slow growing tumors, with very low metastasis potential, when HIV-infection is not present.
... To date, most published studies of the association between HIV seropositivity and OSSN have taken place in Africa, Asia and North America (USA). Other potential risk factors or associations include human papilloma virus (HPV) infection; [17,24,26] sunlight exposure [23,24,27], which can lead to mutations in the tumour suppressor gene p53; [28] p63, a homologue of p53; [29,30] smoking; [24,31] immunosuppression; [32][33][34] and xeroderma pigmentosa [35,36]. There have also been suggestions of a possible association between OSSN and atopic keratoconjunctivitis [23,32,[37][38][39]. ...
Purpose:
To describe the incidence, associations and outcomes of ocular surface squamous neoplasia (OSSN) in the United Kingdom.
Methods:
Prospective, observational study of every new case of OSSN reported via the British Ophthalmological Surveillance Unit reporting scheme over a 12-month period. Cases were followed up for 12 months.
Results:
The reported incidence of OSSN was 0.53 cases/million/year (conjunctival intraepithelial neoplasia: 0.43 cases/million/year; squamous cell carcinoma: 0.08 cases/million/year). Eighty-five per cent of affected patients were male, 97% were Caucasian, and the mean age at presentation was 67.9 (±12.8) years. Information on potential underlying risk factors was frequently unknown. The most commonly affected sites were the limbus and the nasal and temporal bulbar conjunctivae. Most patients presented with a visual acuity of 6/9 or better, without symptoms of pain or visual loss. Excision (with or without additional treatment) was the most common first-line treatment and interferon (with or without additional treatment) was the most common second-line treatment, although management varied widely. Complications of treatment were rare but occasionally severe. Recurrence within 12 months of follow-up occurred in at least 6% of patients.
Conclusion:
Although subject to reporting bias, these data suggest that there has not been a significant change in the incidence of OSSN in the United Kingdom, or its demographic profile, since 1996. The broad range of management approaches identified in this study reflect a lack of consensus as to the optimal referral and treatment pathways.
Purpose
To evaluate the efficacy of topical immunotherapy with Interferon α 2b [INF- α 2b] drops with a concentration of 3 million international units per millilitre (3 MIU/ml), in the treatment of noninvasive Ocular Surface Squamous Neoplasia (OSSN).
Methods
A retrospective case record-based study of patients with noninvasive OSSN, who were treated with INF- α 2b drops (3 MIU/ml) during the period from January 2016 to January 2020 at a tertiary care centre in South India. The demographic details, clinical findings, slit lamp photographs, investigations, histopathological records, clinical course, mean duration of clinical and cytological resolution, any evidence of intolerance to treatment, failure to treatment, and recurrences were analysed.
Results
Fourteen eyes of 12 patients were studied. The majority of patients were male (83%) and aged more than 50 years (83%). 64.28% of cases became disease free clinically and histopathologically in 3 months. 21.4% of cases showed partial resolution.
Conclusion
Topical immunotherapy is an effective mode of treatment for noninvasive OSSN. The 3 MIU/mL dose of topical IFN-α2b drops helped in faster resolution. No recurrences were reported. No severe surface toxicity or intolerance was observed.
Introduction:
Cancer is heavily influenced by epigenetic mechanisms that include DNA methylation, histone modifications and non-coding RNA. A considerable proportion of human malignancies are believed to be associated with global DNA hypomethylation, with localized hypermethylation at promoters of certain genes.
Area covered:
The present review aims to emphasize on recent investigations on the epigenetic landscape of ocular surface squamous neoplasia, that could be targeted/explored using novel approaches such as personalized medicine.
Expert opinion:
While the former is thought to contribute to genomic instability, promoter-specific hypermethylation might facilitate tumorigenesis by silencing tumor suppressor genes. Ocular surface squamous neoplasia, the most prevalent type of ocular surface malignancy, is suggested to be affected by epigenetic mechanisms, as well. Although the exact role of epigenetics in ocular surface squamous neoplasia has mostly been unexplored, recent findings have greatly contributed to our understanding regarding this pathology of the eye.
