High-Risk Histopathological Features of Retinoblastoma following Primary Enucleation: A Global Study of 1426 Patients from 5 Continents.

PURPOSE: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents. METHODS: Retrospective study of 1426 primarily enucleated RB eyes from five continents. RESULTS: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients. CONCLUSION: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

Aurora Kinase A Is Overexpressed in Human Retinoblastoma and Correlates with Histopathologic High-Risk Factors: Implications for Targeted Therapy.

Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term adverse effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis, especially in RB1-deficient and MYCN-dysregulated tumors. Our immunohistochemistry study in patient specimens (n = 67) discovered that AURKA is overexpressed in RB, and elevated expression correlates with one or more histopathologic high-risk factors, such as tumor involvement of the optic nerve, choroid, sclera, and/or anterior segment. More specifically, AURKA is ubiquitously expressed in most advanced-stage RB tumors that show a suboptimal response to chemotherapy. shRNA-mediated depletion/pharmacologic inhibition studies in cell lines, patient-derived cells, in vivo xenografts, and enucleated patient specimens confirm that RB cells are highly sensitive to a lack of functional AURKA. In addition, we deciphered that AURKA and MYCN associate with each other to regulate their levels in RB cells. Overall, our results demonstrate a previously unknown up-regulation of AURKA in RB, facilitated by its crosstalk with MYCN, and elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.

Quantum information scrambling in two-dimensional Bose-Hubbard lattices.

It is a well-understood fact that the transport of excitations throughout a lattice is intimately governed by the underlying structures. Hence, it is only natural to recognize that the dispersion of information also has to depend on the lattice geometry. In the present work, we demonstrate that two-dimensional lattices described by the Bose-Hubbard model exhibit information scrambling for systems as little as two hexagons. However, we also find that the out-of-time-ordered correlator (OTOC) shows the exponential decay characteristic for quantum chaos only for a judicious choice of local observables. More generally, the OTOC is better described by Gaussian-exponential convolutions, which alludes to the close similarity of information scrambling and decoherence theory.

When the second comes first- rhabdomyosarcoma preceding heritable retinoblastoma- a case report.

BACKGROUND: Retinoblastoma (rb) is the most frequent intraocular tumor, accounting for 3% of all childhood cancers. Heritable rb survivors are germline carriers for an RB1 mutation and have a lifelong risk to develop non-ocular second primary tumors (SPTs) involving multiple other organs like the bones, soft tissues, or skin. These SPTs usually become manifest several years succeeding the diagnosis of rb. In our instance, however, a non-ocular SPT presented prior to the diagnosis of heritable rb. CASE PRESENTATION: We report a rare case of a monozygotic twin who presented with primary rhabdomyosarcoma (RMS) preceding the manifestation of heritable rb. The rb was diagnosed when the child developed strabismus while already on therapy for the RMS. The child underwent therapy for both as per defined treatment protocols. The rb regressed well on treatment, but the RMS relapsed and the child developed multiple refractory metastatic foci and succumbed to his disease. CONCLUSIONS: Non-ocular SPTs like sarcomas are usually known to manifest in heritable rb survivors with a lag of two to three decades (earlier if exposure to radiation is present) from the presentation of the rb. However, in our case, this seemed to be reversed with the RMS being manifest at an unusual early age and the rb being diagnosed at a later point in time.

Lymphangiectasia Hemorrhagica Conjunctivae Regression with Bleomycin Sclerotherapy on Anterior-Segment Optical Coherence Tomography.

This case report discusses treatment of lymphangiectasia hemorrhagica conjunctivae with bleomycin sclerotherapy in a patient aged 47 years with a history of recurrent subconjunctival hemorrhage.

Intravitreal chemotherapy-induced cataract in retinoblastoma: challenges and outcome.

A toddler with bilateral retinoblastoma (Rb) received intravenous chemotherapy for advanced tumours in both eyes. The right eye required enucleation due to a poor response, but the left eye was salvaged by additional treatment with intravitreal chemotherapy for tumour vitreous seeds. Though the vitreous seeds regressed, a gradually progressive cataract developed likely due to drug toxicity. On ensuring continued regression of tumour within the eye, cataract extraction was performed. Surgery was uneventful and the child recovered good functional vision in the left eye. Salvaging the eyeball followed by vision restoration through cataract surgery in the only remaining eye of the child necessitated a multidisciplinary approach involving the ocular oncologist, the paediatric medical oncologist and the paediatric ophthalmologist. Ensuring tumour quiescence within the eye clinically before cataract surgery was the most crucial element of management. Additionally, close monitoring of the progress of the cataract to decide when to intervene was also necessary to keep the risk of amblyopia at bay. The patient recovered good functional vision in the left eye after the surgery and remained free of any tumour recurrence or systemic metastasis at 10 months of follow-up.

Retinal and optic nerve relapse in retinoblastoma secondary to epiretinal and epipapillary vitreous seeds implantation documented by optical coherence tomography.

BACKGROUND: Retinal retinoblastoma growth phenotypes can be endophytic, exophytic, diffuse infiltrating or anterior diffuse. Herein, we describe a novel tumor growth pattern in two patients. MATERIAL AND METHODS: Imaging with spectral-domain optical coherence tomography (SD-OCT). RESULTS: Both cases were diagnosed with unilateral group D retinoblastoma treated with first-line or bridge intra-arterial chemotherapy (IAC). Case 1 had a new intravitreal/epiretinal relapse 3 months after brachytherapy and intravitreal chemotherapy. SD-OCT showed a disruption of the inner limiting membrane (INL) underneath a parapapillary epiretinal seed. The intravitreal/epiretinal disease completely regressed with intravitreal melphalan. Three months later, an isolated intraretinal growth was documented on SD-OCT at the site of previously INL disruption, which was treated by thermotherapy. He remained disease-free at 1-year follow-up with 0.6 visual acuity. Case 2 was seen 2 months after treatment interruption due to the COVID-19 pandemic. Fundus examination showed a massive intravitreal/epipapillary invasion completely obscuring the papilla. Salvage treatment of this seeing eye consisted of combined intra-arterial and intravitreal melphalan and topotecan injections. An infraclinical papillary regrowth 4 months later was treated with additional IAC. Six months later, enucleation was performed due to an infraclinical papillary relapse with suspicion of intralaminar invasion. Histopathology showed retrolaminar optic nerve invasion with tumor-free surgical section. The child received four cycles of adjuvant chemotherapy and remained disease-free at 1-year follow-up. CONCLUSION: Epiretinal/epipapillary vitreous seeding can be the source of a secondary intraretinal/optic nerve head relapse. SD-OCT is instrumental to follow such cases. Enucleation remains the safest option if secondary optic nerve invasion is suspected.

Long term outcomes of transcutaneous non-image guided bleomycin sclerotherapy in orbital/adnexal lymphatic malformations: a protocol-based management in 69 eyes.

OBJECTIVES: To study the efficacy and the long-term outcomes of treating micro and macrocystic orbital and/or adnexal lymphatic malformations (OA-LM) with protocol-based bleomycin sclerotherapy. METHODS: A retrospective interventional study of 69 eyes having OA-LM treated with non-image guided transcutaneous or transconjunctival bleomycin sclerotherapy (1IU/ml aqueous solution) between December 2014 and December 2018. Based on clinical regression, the outcomes were classified as excellent, good, fair and poor. RESULTS: The mean age at presentation was 20 ± 16 years (median 16; range 1 month to 70 years). The orbital-palpebral variant was the most common presentation, seen in 29 patients (42%). Microcystic morphology was seen in 34(49%), macrocystic in 22 (32%) and mixed cyst in 13 (19%) patients. Mean units of bleomycin injected per patient were 9 ± 8 IU (median 5.5 IU, range 1-38 IU). Mean number of treatment sessions required were 2 ± 1 (median 2, range 1-6). The response was excellent in 43 (62%), good in 12 (17%), fair in 9 (13%) and poor in 5 (7%) patients. These responses were comparable across the morphological subgroups (p = 0.24, chi-square test). Adverse reactions noted were inflammation in 11 eyes (16%) and peri-ocular pigmentation in 15 (22%). There was a sustained tumour regression over a mean follow-up duration of 3.5 years (median 3; range 1.5-5 years). CONCLUSIONS: Seventy-nine percent of eyes with OA-LM showed a good outcome with transcutaneous and/or transconjunctival non-image guided bleomycin sclerotherapy with no serious adverse events. The results were promising over long-term follow-up.

Costal tubercular osteomyelitis presenting as an orbital abscess.

Orbital abscesses are most commonly associated with co-existing active paranasal sinus infection. Herein, the authors present the case of an orbital abscess in the setting of costal tubercular osteomyelitis and an anterior chest wall abscess in the absence of any paranasal sinus pathology in an immunocompetent patient. Costal tuberculosis is a very rare form of extrapulmonary skeletal tuberculosis and is challenging to diagnose. Initial presentation as an orbital abscess remote from the site of the primary pathology is of extremely rare occurrence. In this instance, the diagnosis of tuberculous osteomyelitis was suspected primarily on the basis of clinicoradiological features. The patient was treated with, and responded well to, standard first-line anti-tubercular therapy (ATT) for extrapulmonary tuberculosis.

The Oncogene MYCN Modulates Glycolytic and Invasive Genes to Enhance Cell Viability and Migration in Human Retinoblastoma.

Retinoblastoma is usually initiated by biallelic RB1 gene inactivation. In addition, MYCN copy number alterations also contribute to RB pathogenesis. However, MYCN expression, its role in disease progression and correlation with RB histological risk factors are not well understood. We studied the expression of MYCN in enucleated RB patient specimens by immunohistochemistry. MYCN is overexpressed in RB compared to control retina. Our microarray gene expression analysis followed by qRT-PCR validation revealed that genes involved in glucose metabolism and migration are significantly downregulated in MYCN knockdown cells. Further, targeting MYCN in RB cells using small molecule compounds or shRNAs led to decreased cell survival and migration, increased apoptosis and cell cycle arrest, suggesting that MYCN inhibition can be a potential therapeutic strategy. We also noted that MYCN inhibition results in reduction in glucose uptake, lactate production, ROS levels and gelatinolytic activity of active-MMP9, explaining a possible mechanism of MYCN in RB. Taking clues from our findings, we tested a combination treatment of RB cells with carboplatin and MYCN inhibitors to find enhanced therapeutic efficacy compared to single drug treatment. Thus, MYCN inhibition can be a potential therapeutic strategy in combination with existing chemotherapy drugs to restrict tumor cell growth in RB.

Isolation of unusual bacteria in canaliculitis: A series of four cases.

With increased availability of sophisticated microbiological techniques for isolation, growth and identification of micro-organisms the spectrum of organisms is rapidly. Herein we report four cases of canaliculitis with unusual organisms and highlight their clinical significance. To the best of our knowledge, there are no reports of isolation of Brucella melitensis and Leuconostoc species reported in English literature; and only one report of isolation of Myroides species from canaliculitis exists. Sphingomonas paucimobilis, is an uncommon isolate in canaliculitis. Extremes of age and occupational exposure may be possible risk factors for infection with uncommon organisms. Clinical features at presentation do not vary greatly with uncommon or multi drug resistant organisms' hence sampling and microbiological assessment is warranted. The benefit of curettage in canaliculitis is manifold. Unusual organisms and opportunistic pathogens can be multi-drug resistant and determination of antibiotic susceptibility is important to initiate targeted therapy to ensure disease cure and prevent recurrences.

Aurora Kinase B Expression, Its Regulation and Therapeutic Targeting in Human Retinoblastoma.

Purpose: Aurora kinase B (AURKB) plays a pivotal role in the regulation of mitosis and is gaining prominence as a therapeutic target in cancers; however, the role of AURKB in retinoblastoma (RB) has not been studied. The purpose of this study was to determine if AURKB plays a role in RB, how its expression is regulated, and whether it could be specifically targeted. Methods: The protein expression of AURKB was determined using immunohistochemistry in human RB patient specimens and immunoblotting in cell lines. Pharmacological inhibition and shRNA-mediated knockdown were used to understand the role of AURKB in cell viability, apoptosis, and cell cycle distribution. Cell viability in response to AURKB inhibition was also assessed in enucleated RB specimens. Immunoblotting was employed to determine the protein levels of phospho-histone H3, p53, p21, and MYCN. Chromatin immunoprecipitation-qPCR was performed to verify the binding of MYCN on the promoter region of AURKB. Results: The expression of AURKB was found to be markedly elevated in human RB tissues, and the overexpression significantly correlated with optic nerve and anterior chamber invasion. Targeting AURKB with small-molecule inhibitors and shRNAs resulted in reduced cell survival and increased apoptosis and cell cycle arrest at the G2/M phase. More importantly, primary RB specimens showed decreased cell viability in response to pharmacological AURKB inhibition. Additional studies have demonstrated that the MYCN oncogene regulates the expression of AURKB in RB. Conclusions: AURKB is overexpressed in RB, and targeting it could serve as a novel therapeutic strategy to restrict tumor cell growth.

Point-of-care rapid antigen testing for COVID-19 at a tertiary eye care facility: Role in commencement of elective surgeries, contact tracing and implementation of back-to-work policy.

PURPOSE: The aim of this study was to report the use and the impact of a point-of-care rapid antigen test (PoC-RAT) at a tertiary eye care facility in facilitating commencement of elective surgeries, contact tracing of exposed health care professionals (HCPs) and ancillary hospital staff, and implementation of back-to-work (BTW) policy for them. METHODS: Retrospective analysis of subjects undergoing PoC-RAT for COVID-19 infection at a tertiary level dedicated eye care facility. Decision making with regard to commencement of elective surgeries post COVID-19 related discontinuation of services, contact tracing of HCPs and ancillary hospital staff exposed to known COVID-19 cases and implementation of back-to-work policy for all staff based upon the results of PoC-RAT were studied. RESULTS: A total of 311 subjects (224 patients and 87 hospital staff) were tested. Overall positivity rate was around 7%. Asymptomatic patients who were screened preoperatively had a lower positivity rate at around 3% compared to the staff (who were either known contacts or were symptomatic) at around 17%. Contact tracing found three-quarters of the staff at low risk and only one quarter at medium or high risk. Among patients, 97% of those followed up for at least 2 weeks after the test remained healthy. For staff, this was around 65%. CONCLUSION: Based on our preliminary results, we suggest that PoC-RAT may be considered routinely for indication-based preoperative screening of asymptomatic patients, and for on-campus screening, contact tracing and implementation of BTW policies for HCPs and ancillary hospital staff at a tertiary level eye care facility.

Sight-Threatening Thyroid Eye Disease: Role of Diabetes Mellitus and Interaction with Other Risk Factors.

PURPOSE: The aim of the study was to investigate whether diabetes mellitus (DM) is an independent risk factor in sight-threatening thyroid eye disease (ST-TED) and explore the interaction of DM with other known risk factors in TED. METHODS: This was a retrospective cohort study and included 202 consecutive TED patients presenting between 2013 and 2019. Data collected included demography, history of smoking, thyroid dysmetabolism, and presence of DM, TED-duration, activity and severity, best-corrected visual acuity (BCVA), and follow-up. Primary outcome measure was development of ST-TED and secondary outcome measures included change in BCVA, activity, and bilateral ST-TED. RESULTS: Mean age of the cohort was 52.14 + 9.14 years and 74 (36%) were male. DM was present in 49 (24%) and a positive history of smoking in 65 (32%) TED patients. Cox's proportional hazards showed the presence of DM (hazard ratio [HR] 2.22; P = 0.02) and a positive history of smoking (HR 3.62; P = 0.003) were significant risk factors for development of ST-TED and dysthyroid optic neuropathy (DON). Older age was a risk factor (HR 1.05; P = 0.02) for DON. DM increased the risk of developing bilateral ST-TED (OR 4.14; P = 0.004). Median follow-up was 4 months (range 0.1-96 months). A linear mixed model to predict longitudinal interaction between risk factors, found TED patients in DM group were likely to have worsening of visual function and a positive history of smoking accentuated this adverse outcome. CONCLUSION: DM and smoking are major independent risk factors predictive of ST-TED. Coexisting DM either singularly or in combination with smoking may predict worsening of visual function in TED patients.