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. The current immunohistochemistry study in patient specimens (n = 67) indicated that AURKA is overexpressed in RB, and this 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 confirmed that RB cells are highly sensitive to a lack of functional AURKA. In addition, AURKA and N-myc proto-oncogene protein (MYCN) associate with each other to regulate their levels in RB cells. Overall, these results demonstrate a previously unknown up-regulation of AURKA in RB, facilitated by its crosstalk with MYCN. The 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.

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.

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.

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.

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.

Primary De novo ductal adenocarcinoma of the lacrimal gland.

BACKGROUND: Primary ductal adenocarcinoma of the lacrimal gland is a rare and aggressive malignant epithelial lacrimal gland neoplasm, morphologically and phenotypically resembles salivary duct carcinoma, and both strongly resemble infiltrating ductal carcinoma of breast. METHOD: Retrospective Chart review of cases of malignant lacrimal gland tumors from 2013 July to 2020 July. Authors describe the clinico radiological, morphological and immunohistochemical features of primary ductal adenocarcinoma (PDA) of lacrimal gland. Extensive review of literature of PDA of lacrimal gland and salivary gland ductal carcinoma has been performed. RESULTS: Retrospective chart review of the last 7 years yielded 22 malignant lacrimal gland neoplasms of which 4 cases demonstrated features of primary ductal adenocarcinoma of lacrimal gland, 2/4 cases showed an evidence of a pre existing pleomorphic adenoma and 2 were found to be de novo ductal adenocarcinomas. PDA of lacrimal gland showed expression of CK7, CK19, AR, HER2, cyclin D1 and were negative for CK5/14, CK 20, ER, PR, PSA, TTF-1, S-100 and SMA. Expression of GCDFP-15 was noted in one case. The presence of multiple events of loco-regional recurrences and/or distant metastasis necessitated a multidisciplinary approach. CONCLUSIONS: Authors have expressed the need of clinical correlation; thorough tissue sampling and extensive immunohistochemical work up in identification of de novo PDA's and their molecular subtypes. A multi-institutional study might help in formulating the diagnostic criteria, identification of actionable targets, and thus study the role of targeted therapy in this rare and aggressive tumor which may result in better patient outcomes.

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.

Behavior and outcomes of 70 adult lacrimal sac mucoceles.

Purpose: To study the clinical profile and outcomes in adults with lacrimal sac mucoceles.Methods: A retrospective, interventional study on consecutive adult patients with lacrimal sac mucoceles who underwent dacryocystorhinostomy (DCR)/dacryocystectomy surgery. Primary outcome measure was subsidence of lacrimal sac swelling after intervention. Secondary outcome measure was anatomical patency of the lacrimal system.Results: A total of 70 patients were studied, mean age of the group being 49.2 ± 13.5 years. Majority of the patients were female (n = 49; 70%) and all had unilateral disease. An appreciable number (n = 14; 20%) presented with acute dacryocystitis of which 6(8%) developed a lacrimal sac fistula. Encystment of the lacrimal sac mucocele was seen in 47 (67%) patients, 3(4%) developed preseptal cellulitis and 3(4%) needed imaging. Resolution of sac swelling after intervention was seen in 70 (100%) patients. Definitive management was DCR in 57 (81%) patients, of which anatomical patency was achieved in 55 (96%) patients, mean duration of follow up of the group being 138 ± 70.2 days. A trend to prefer adjuvants like Mitomycin-C and/or intubation was noted in 56 (98%) of patients.Conclusions: Adult lacrimal sac mucocele is more commonly seen in females and unilaterally. Complications of this entity include encysted mucocele (67%), acute dacryocystitis (20%), lacrimal sac fistula (8%), and preseptal cellulitis (4%). It is essentially a clinical diagnosis and favourable outcomes are seen with DCR surgery.

Desmoplastic Melanoma of the Periorbital Region.

Desmoplastic melanoma (DM) is a rare subtype of melanoma and an even smaller proportion of periocular melanomas. Here, the authors report 2 cases of DM in the periocular region. Staged according to the American Joint Committee on Cancer (AJCC) eighth edition classification, patient 1 presented with a stage IIIC (pT4apN1cM0) DM in the left lateral canthus with upper and lower eyelid and patient 2 presented with a stage IIIB (T4aN1bM0) DM in the left brow and supraorbital region with a parotid lymph node metastasis. In both patients, the lesions were amelanotic, with inflammatory appearance, and had been noted for several years before the correct diagnosis was made. In both patients, wide excision led to large surgical defects, and perineural invasion prompted adjuvant radiation therapy postoperatively. Patient 2 was treated with an immune checkpoint inhibitor for his parotid metastasis. Ophthalmologists should be aware of DM, its neurotrophic nature, and potential to metastasize with locally advanced lesions.

Unilateral Migratory Relapsing Orbital Myositis While on Immunosuppressant Therapy: An Uncommon Entity.

A young healthy female presented with acute onset left ocular pain, restricted ocular motility, and binocular diplopia. CT imaging showed left lateral rectus myositis that resolved with oral corticosteroids. Two sequential relapses occurred subsequently involving the superior rectus-levator complex followed by the medial rectus. Biopsy revealed orbital inflammatory disease with lymphocytic vasculitis. Detailed systemic work up was normal. The second relapse was seen while on long-term oral methotrexate although initial disease remission had been achieved with the same drug. A changeover to oral azathioprine was able to achieve disease remission after the second relapse. All relapses involved the same side and the contralateral orbit was not affected. This report presents the curious phenomenon of unilateral migratory relapsing orbital myositis of unknown cause that recurred even while on immunosuppressant therapy. It highlights the unpredictable nature of this uncommon entity and the challenges faced in managing such cases.

Primary Nonendoscopic Endonasal Versus Delayed External Dacryocystorhinostomy in Acute Dacryocystitis.

PURPOSE: Conventional treatment for acute dacryocystitis consists of medical management followed by elective delayed external dacryocystorhinostomy (EXT-DCR). The purpose of this study was to compare the outcome after primary nonendoscopic endonasal dacryocystorhinostomy (NEN-DCR) versus conventional treatment in acute dacryocystitis. METHODS: Retrospective chart analysis of all consecutive patients of acute dacryocystitis presenting between 2011 and 2015 was performed. Group A had patients who underwent primary NEN-DCR within 2 weeks of presentation. Group B comprised age- and gender-matched patients who received conventional treatment. RESULTS: Forty-six patients were included with 23 patients in each group. Mean age (45.2 ± 14.7 vs. 47.5 ± 14 years) and gender distribution (women 17/23 in group A vs. 15/23 in group B) in both groups were comparable. Mean duration from presentation to surgery was 7.82 ± 4.65 days for group A versus 27.3 ± 12 days for group B (p = 0.00001, independent T test). Mean time for complete resolution of symptoms was 21.4 ± 6 days for group A versus 38.69 ± 15.8 for group B (p = 0.000014, independent T test). Mitomycin-C usage (0.04%; 17 vs. 14) and mean follow up of both groups (6.4 vs. 5.7 months) were comparable. While functional success was similar (20/23) in both, anatomical success was seen in 22/23 and 21/23 in groups A and B, respectively. Complications included disfiguring scar in 4, recurrent acute dacryocystitis in 3, and punctal ectropion in one patient in the EXT-DCR group. CONCLUSIONS: Primary NEN-DCR leads to faster resolution facilitating earlier rehabilitation with comparable anatomical and functional outcomes compared with conventional delayed EXT-DCR in acute dacryocystitis.

Comparative Evaluation of the Ostium After External and Nonendoscopic Endonasal Dacryocystorhinostomy Using Image Processing (Matlabs and Image J) Softwares.

PURPOSE: The purpose of this study was to compare the characteristics of the ostium after external dacryocystorhinostomy and nonendoscopic endonasal dacryocystorhinostomy (NEN-DCR). METHODS: This cross-sectional study included patients who underwent a successful external dacryocystorhinostomy or NEN-DCR and had ≥1 month follow up. Pictures of the ostium were captured with a nasal endoscope (4 mm, 30°) after inserting a lacrimal probe premarked at 2 mm. Image analyses were performed using Image J and Contour softwares. RESULTS: Of the 113 patients included, external dacryocystorhinostomy group had 53 patients and NEN-DCR group had 60 patients. The mean age of patients in the NEN-DCR group (38 years) was significantly (p < 0.05) lower than the external dacryocystorhinostomy group (50 years). There was no statistically significant difference (2 sample t test, p > 0.05) in mean follow up (6 vs. 4 months), maximum diameter of ostium (8 vs. 7 mm), perpendicular drawn to it (4 vs. 4 mm), area of ostium (43 vs. 36 mm), and the minimum distance between common internal punctum and edge of the ostium (1 vs. 1 mm) between the external and NEN-DCR groups. CONCLUSIONS: Image processing softwares offer simple and objective method to measure the ostium. While ostia are comparable in size, their relative position differs with posteriorly placed ostia in external compared with inferior in NEN-DCR.

Canalicular lacerations: Factors predicting outcome at a tertiary eye care centre.

To determine the factors predictive of outcome in canalicular laceration repair at a tertiary eye care centre. A retrospective review of the medical records of all primary canalicular laceration repairs managed at a tertiary eye care centre between the years 2006 and 2014 was done. Thirty-nine patients were included and majority were male (79.5%) with a mean age of 30.05 + 16.2 years (range 2-65). Most (n = 34) had monocanalicular laceration and 5 had bicanalicular laceration. All surgeries were done in the operating room setting. Overall patency by irrigation was seen in 74.4% at a median follow-up of 19.89 weeks (range 21-910). Anatomical outcome was different among the stents and best after Mini-Monoka monocanalicular stent (17/19; 89.5%) followed by bicanalicular annular stents (n = 6; 60%) and 20G Silicone rod (8/14, 57%). The factors predictive of poor outcome were related to the mode of injury [road traffic accidents; Hazard ratio (HR)19.57; p = 0.048] and the type of stent [20G silicone rod (HR 35.7; C.I 3.04 - 419.14; p = 0.004)] by multivariate analysis. Skill of the surgeon was critical as the outcome for fellows-in-training showed a trend towards failure (HR 6.66, p = 0.07). Complications included stent extrusion (n = 28.2%), punctal granuloma (n = 5.1%) and stent exposure (n = 2.5%). The mode of injury - road traffic accidents and type of stent - 20 G silicone rod were risk factors predictive of poorer outcome after canalicular laceration repair. Individual skill of operating surgeon may be a critical factor suggesting a review of training protocols.

Orbital tuberculosis: Clinicopathological correlation and diagnosis using PCR in formalin-fixed tissues.

This article describes the clinicopathological correlation and challenges encountered in the diagnosis of orbital tuberculosis (TB). Retrospective, interventional case series. A chart review of six patients who underwent biopsy for an orbital mass between January 2012 and December 2013 was performed. Institutional review board approval was obtained for the study. Clinical, radiological, and laboratory findings were documented, and response to antitubercular therapy (ATT) was noted. Age at presentation ranged from 18 to 64 years and duration of complaints varied from 2 weeks to 2 months. Pain, redness, and swelling with an orbital mass on computerized tomography (CT) were the common features. None of the patients was clinically suspected to have orbital TB at presentation. History of prior contact with a patient of TB and history of prior TB were present in one case each. Chest radiography (CXR) showed pulmonary consolidation in one case. Tuberculin skin test (TST) readings ranged from nonreactive to 23 mm. The presence of sputum acid fast bacilli (AFB) was tested in three cases and was negative. Polymerase chain reaction (PCR) for MPB64 gene was positive in all six cases. All cases responded to ATT. Clinical presentation of orbital TB can be variable and can simulate conditions like inflammatory disease and malignancy. Biopsy with histopathology plays a key role in diagnosis. Supportive laboratory investigations are necessary to clinch the diagnosis in cases where histopathology is suggestive of TB. In this regard, PCR for Mycobacterium tuberculosis (MTB) on tissue biopsy specimens may be a sensitive diagnostic tool.

Spindle cell lipoma of the orbit.

A 30-year-old otherwise healthy female patient presented to the oculoplastic service with complaints of gradually increasing proptosis and discomfort of the OD of about 4 months' duration. On imaging, an ill-defined mass was seen in the right orbit which, on biopsy, turned out to be a spindle cell lipoma. Lipomas, the commonest among the mesenchymal soft tissue tumors, are surprisingly of rare occurrence in the orbit, despite the presence of abundant fat in the intraorbital space. The authors describe the presentation, management, and outcome of a rare orbital pathology--an orbital spindle cell lipoma.

Evisceration with Primary Orbital Implant in Fulminant Endophthalmitis/Panophthalmitis.

PURPOSE: To compare the outcome of evisceration with primary orbital implant in blind eyes with and without fulminant infection (endophthalmitis/panophthalmitis). METHODS: Retrospective nonrandomized comparative interventional case series. Patients with a minimum postoperative follow-up of 6 months were considered for inclusion. Thirty-four eyes of 34 patients were included. Sixteen eyes were infective and 18 noninfective. Nonporous silicone implants were used for all cases and the main outcome measure was successful retention of the primary implant. Major and minor complications and successful prosthesis fitting were also noted. RESULTS: All except 3 cases were able to retain the primary implant successfully and all but 2 patients underwent successful prosthesis fitting. Major complications included implant extrusion in 3 cases (2 infective, 1 noninfective) and implant exposure in 1 case (noninfective). The difference in major complications between the groups was not statistically significant (p = 0.66, Fisher exact test). CONCLUSION: Our data suggest that evisceration with primary orbital implant is a feasible option in fulminant endophthalmitis/panophthalmitis and provides a good postoperative cosmetic outcome to the anophthalmic socket at an economical cost.