B7-H3 Expression in Breast Cancer and Brain Metastasis.

Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management.

Success rates of lateral canthotomy and cantholysis for treatment of orbital compartment syndrome.

PURPOSE: Vision loss after facial trauma can occur from orbital compartment syndrome (OCS). Orbital compartment syndrome is commonly treated surgically with a lateral canthotomy and cantholysis (C&C). Our study investigates success rates of lateral C&C for the treatment of OCS amongst emergency medicine (EM) and ophthalmology providers. METHODS: A retrospective cohort study was performed. Cases were identified and the electronic medical record of patients was interrogated for clinical and procedural information. Success of a lateral C&C was defined as a decrease in intraocular pressure (IOP) to <30 mmHg after the first attempt at the procedure. Inclusion criteria included documentation of a procedural attempt, a pre-procedure IOP >30 mmHg and a post-procedure IOP measurement; or alternatively if no pre-procedure IOP was documented but the IOP was >30 on arrival to the level 1 trauma center. Exclusion criteria included periprocedural use of ocular hypotensive medications and comorbid hyphema. RESULTS: The final analysis included 74 eyes from 64 patients. Emergency medicine providers performed the initial lateral C&C in 68% of cases compared to 32% by ophthalmologists, and success rates were comparable - 68% vs 79.2%, respectively (p = 0.413). Poorer visual outcomes were associated with the initial failure of a lateral C&C and head trauma without an orbital fracture. All patients treated with a vertical lid split procedure met the criteria for 'success' as defined by this study. CONCLUSIONS: The success rate of a lateral C&C is comparable amongst EM and ophthalmology providers. Improved training of physicians on the lateral C&C or other simpler procedures, such as the vertical lid split, could improve outcomes in OCS.

PHOTODYNAMIC THERAPY FOR THE TREATMENT OF CHOROIDAL METASTASES: A Case Series and Meta-analysis.

PURPOSE: To investigate the efficacy and safety of photodynamic therapy (PDT) in the treatment of choroidal metastasis. METHODS: We conducted a systematic review of all reported cases of choroidal metastases treated with PDT in literature, and included the cases from our institution, for a comprehensive meta-analysis. RESULTS: We identified 52 tumors in 40 eyes of 34 patients. The mean age was 60 years (range 28-77). The mean tumor thickness was 1.9 mm (range 0-4.8 mm), whereas the mean largest basal diameter was 8.2 mm (range 1.5-30 mm) on presentation. After an average of 1.4 treatment visit, PDT resulted in decreased tumor thickness (mean 1.9 mm before vs. 1.0 mm after PDT, P < 0.0001) and decreased central macular thickness (mean 454 µm before vs. 289 µm after PDT, P = 0.03). After PDT, 82% of tumors had reduced thickness, and subretinal fluid resolved in 75% of eyes. Photodynamic therapy also resulted in stable or improved vision in 78% of treated eyes (logMAR 0.50 before vs. 0.56 after PDT, P = 0.54). No adverse events were reported, and PDT was effective in treating the most common choroidal metastases (tumor control rate of 94% in 16 lung adenocarcinoma and 92% in 26 breast carcinoma metastasis cases). CONCLUSION: Photodynamic therapy is effective at controlling tumors and preserving vision in patients with some choroidal metastases. Because of its minimal time commitment and good safety profile, PDT should be considered as a potential first-line treatment for small choroidal metastases.

International travel to obtain medical treatment for primary retinoblastoma: A global cohort study.

Early diagnosis and treatment of retinoblastoma (Rb), the most common intraocular malignancy, can save both the child's life and vision. However, access to services and hence chances for survival and preserving the eye and its vision vary widely across the globe. Some families have to, or make a choice to, leave their home country to seek planned medical treatment abroad. We aimed to investigate how frequently this cross-border travel occurs and the factors associated with it. A total of 278 Rb centres in 153 countries were recruited to participate in a global cross-sectional analysis of newly diagnosed Rb patients in 2017. Number and proportions of children who travelled from their home country for treatment were analysed by country, continent, socioeconomic stratum and clinical and demographic features. The cohort included 4351 new patients of whom 223 [5.1%, 95% confidence interval 4.5-5.8] were taken across country borders for planned medical treatment. Independently significant predictors of travelling across borders included: being from a country with a smaller population, being from a country classified as low socioeconomic status, having bilateral Rb and having intraocular disease without extraocular spread. The factors that determine international travel for Rb treatment are complex and deserve further investigation. We may need to rethink the way services are delivered in the light of the threat of severe curtailment of international travel from pandemics like corona virus disease 2019.

Radiation dose reduction during intra-arterial chemotherapy for retinoblastoma: a retrospective analysis of 96 consecutive pediatric interventions using five distinct protocols.

BACKGROUND: Intra-arterial chemotherapy (IAC) represents a mainstay of retinoblastoma treatment in children. Patients with retinoblastoma are uniquely at risk for secondary malignancies and are sensitive to the ionizing effects of radiation. OBJECTIVE: To retrospectively review a single institution's experience with IAC for retinoblastoma and the effect of variable intra-procedural imaging techniques on radiation exposure. MATERIALS AND METHODS: Twenty-four consecutive patients, with a mean age of 30.8±16.3 months (range: 3.2-83.4 months), undergoing IAC for retinoblastoma between May 2014 and May 2020 (72 months) were included. No patients were excluded. The primary outcome was radiation exposure and secondary outcomes included technical success and procedural adverse events. Technical success was defined as catheterization of the ophthalmic or meningolacrimal artery and complete delivery of chemotherapy. Each procedure was retrospectively reviewed and categorized as one of five imaging protocol types. Protocol types were characterized by uniplanar versus multiplanar imaging and digital subtraction angiographic versus roadmap angiographic techniques. Radiation exposure, protocol utilization, the association of protocol and radiation exposure were assessed. RESULTS: During 96 consecutive interventions, 109 ocular treatments were performed. Thirteen of the 96 (15.5%) treatments were bilateral. Ocular technical success was 106 of 109 (97.2%). All three treatment failures were successfully repeated within a week. Mean fluoroscopy time was 6.4±6.2 min (range: 0.7-31.1 min). Mean air kerma was 36.2±52.2 mGy (range: 1.4-215.0 mGy). There were two major (1.8%) complications and four (3.7%) minor complications. Of the 96 procedures, 10 (10.4%), 9 (9.4%), 13 (13.5%), 28 (29.2%) and 36 (37.5%) were performed using protocol types A, B, C, D and E, respectively. For protocol type A, mean fluoroscopy time was 10.3±6.8 min (range: 3.0-25.4 min) and mean air kerma was 118.2±61.2 mGy (range: 24.5-167.3 mGy). For protocol type E, mean fluoroscopy time was 3.1±3.2 min (range: 0.7-15.1 min) and mean air kerma was 5.4±4.2 mGy (range: 1.4-19.5 mGy). Fluoroscopy time and air kerma decreased over time, corresponding to the reduced use of multiplanar imaging and digital subtraction angiography. In the first quartile (procedures 1-24), 8 (33.3%), 7 (29.2%), 2 (8.3%), 6 (25.0%) and 1 (4.2%) were performed using protocol types A, B, C, D and E, respectively. Mean fluoroscopy time was 10.5±8.2 min (range: 2.4-28.1 min) and mean air kerma was 84.2±71.6 mGy (range: 12.8-215.0 mGy). In the final quartile (procedures 73-96), 24 (100%) procedures were performed using protocol type E. Mean fluoroscopy time was 3.5±4.0 min (range: 0.7-15.1 min) and mean air kerma was 5.0±4.3 mGy (range: 1.4-18.0 mGy), representing 66.7% and 94.1% reductions from the first quartile, respectively. Technical success in the second half of the experience was 100%. CONCLUSION: Sequence elimination, consolidation from biplane imaging to lateral-only imaging, and replacing digital subtraction with roadmap angiography dramatically reduced radiation exposure during IAC for retinoblastoma without adversely affecting technical success or safety.

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes.

PURPOSE: To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. DESIGN: Retrospective analysis. PARTICIPANTS: A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. METHODS: Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. MAIN OUTCOME MEASURES: High-risk histopathologic features, metastasis, and death. RESULTS: Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n = 2 and pT3bNxM0, n = 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n = 2, pT3aNxM0, n = 2 and pT3cNxM0, n = 1). Absence of vitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P = 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P = 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range, 13.7-153.0). CONCLUSIONS: The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.

Focal laser treatment in addition to chemotherapy for retinoblastoma.

BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy of childhood. Systemic chemotherapy is a common treatment for intraocular retinoblastoma, and laser treatment is used as adjuvant therapy during or immediately after chemotherapy courses in selected cases. OBJECTIVES: To compare the effectiveness and safety of adding focal laser therapy to systemically-delivered chemotherapy in treating intraocular retinoblastoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), MEDLINE Ovid (1946 to 20 October 2016), Embase Ovid (1980 to 20 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 20 October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 20 October 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 20 October 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 20 October 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of systemic chemotherapy with versus without adjuvant laser therapy for postequatorial retinoblastoma. DATA COLLECTION AND ANALYSIS: We planned to use standard methodological procedures expected by Cochrane. We planned to meta-analyse the primary outcome, that is the proportion of eyes with recurrence of tumours within three years from treatment MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: No evidence from randomised controlled trials was found to support or refute laser therapy in addition to systemic chemotherapy for postequatorial retinoblastoma.

Simultaneous Versus Staged Balanced Decompression for Thyroid-Related Compressive Optic Neuropathy.

PURPOSE: To compare the visual and exophthalmometry outcomes of simultaneous versus staged balanced decompression in patients with thyroid-related compressive optic neuropathy (CON). METHODS: All consecutive patients who underwent simultaneous or staged balanced decompressions for clinically diagnosed thyroid-related CON performed by 4 surgeons at the Kellogg Eye Center of the University of Michigan between 1999 and 2014 were included in the study. Demographic, medical, and surgical covariates were collected. Orbits were stratified by decompression technique. Primary outcomes were improvement in CON score (which quantifies visual dysfunction using logarithm of the minimum angle of resolution, color vision, and Humphrey visual field mean deviation), and improvement in proptosis. The authors performed univariate and descriptive statistics to identify baseline differences and covariates associated with the outcomes of interest; multivariate mixed linear regression models (to adjust for interorbit correlation) were then constructed with inclusion of potential confounders with p value ≤0.1. RESULTS: In total, 80 orbits of 53 patients were included in the study. Of the 80 orbits, 61% underwent simultaneous balanced decompression, and 39% underwent staged balanced decompression. Mean CON score reduction was 6.12 ± 9.7 and mean proptosis reduction was 5.63 ± 2.6 mm. Staged balanced decompression was significantly associated with greater CON score reduction (p = 0.038). However, staged (vs. simultaneous) decompression technique did not remain an independent predictor (p = 0.950) after multivariate analysis adjusted for confounders. For proptosis reduction, there were no statistically significant differences between simultaneous and staged balanced decompression on univariate (p = 0.122) or multivariate mixed linear regression models (p = 0.812). CONCLUSION: Simultaneous and staged balanced decompression are equally efficacious in treating visual dysfunction and exophthalmos due to thyroid eye disease in patients with clinically diagnosed CON. Patient choice should be the primary consideration and care should be individualized. Further studies validating the CON score used in the study and comparative studies individualizing surgical treatment of thyroid eye disease are warranted.

Nasolacrimal System Aeration on Computed Tomographic Imaging: Sex and Age Variation.

PURPOSE: To investigate variation in aeration of the nasolacrimal drainage system between age groups and genders, and to report the reliability of repeated aeration grading and nasolacrimal canal measurements on CT. METHODS: Retrospective review of CT images from 92 individuals, 60 female and 32 male, was conducted by 3 independent reviewers for the presence of air within the nasolacrimal drainage system. Diameter and area measurements were also obtained at the smallest identifiable portion of the nasolacrimal canal by 2 independent reviewers. RESULTS: When air is present on CT, it is seen more fully throughout the nasolacrimal system in men as compared to women. Age data demonstrate that patients from the third and fourth decade have significantly more aeration than older patients. Diameter and area of the nasolacrimal duct within the canal at its narrowest point revealed no correlation with sex, age, or nasolacrimal system aeration. Inter-reviewer reliability shows strong repeatability of aeration grading and nasolacrimal duct measurements between multiple reviewers. CONCLUSIONS: The results suggest CT is reliable and repeatable modality to assess nasolacrimal system aeration and nasolacrimal duct diameter. Decreased aeration of the nasolacrimal system in females and the elderly mirrors epidemiologic trends for those at risk to develop primary acquired nasolacrimal duct obstruction. Variables in nasolacrimal drainage system anatomy, specifically nasolacrimal duct diameter and area, did not vary between sexes or age groups, suggesting aeration may be an overlooked variable in nasolacrimal system function.

Vision Loss Caused by Retinal and Lateral Geniculate Nucleus Infarction in H1N1 Influenza.

A 13-year-old girl developed encephalopathy and severe bilateral vision loss to the level of light perception within 24 hours of having fever and myalgias heralding H1N1 influenza A. Ophthalmoscopy demonstrated findings of confluent ischemic retinopathy. Brain MRI disclosed lateral geniculate body signal abnormalities indicative of hemorrhagic infarction. Despite aggressive treatment with intravenous corticosteroids, intravenous immunoglobulin, and plasmapheresis, vision did not substantially improve. This case demonstrates that H1N1 can cause simultaneous retinal and lateral geniculate body infarctions, a combination of findings not previously described in any condition. We postulate an immunologic response to the virus marked by occlusive damage to arteriolar endothelium.

Management of Orbital and Periocular Vascular Anomalies.

PURPOSE: To review the treatment modalities available to clinicians who treat orbital and periocular vascular anomalies, with a focus on newer approaches. METHODS: The authors' experience, along with a literature review, was used to provide a concise summary of the available approaches to the treatment of periocular vascular anomalies. Emerging diagnostic tools and therapies are highlighted. RESULTS: The treatment of orbital and periocular vascular anomalies, including vascular malformations and tumors, increasingly utilizes a multidisciplinary team and a combination of endovascular, percutaneous, and open surgical techniques. CONCLUSIONS: A growing reliance on new instrumentation and tools in a team-oriented approach to treatment may lead to better results with improved visual function and cosmesis and with reduced risk of complications.

Risk of ocular blood splatter during oculofacial plastic surgery.

PURPOSE: To assess intraoperative blood splatter to the ocular surface and adnexa during oculofacial surgery. METHODS: Four surgeons and multiple assistants at three separate locations wore a total of 331 protective eye shields during 131 surgeries. Postoperatively, a luminol blood detection system was used to identify blood splatter on the shields. In the event of positive blood splatter, the total number of blood spots was counted. Controls were used to verify the blood detection protocol. A postoperative questionnaire was given to all surgeons and assistants after each case, and they were asked whether intraoperative blood splatter was noticed. RESULTS: Blood was detected on 61% of eye shields and in a total of 80% of surgical cases. However, only 2% of blood splatters were recognized intraoperatively by the surgical participants. There was no significant difference in the splatter rate between surgeons (64%), assistants (60%), and surgical technicians (58%) (p = 0.69). Shields worn during full-thickness eyelid procedures, direct brow lifting, orbitotomy with bony window, and orbital fracture repairs were more likely to be splattered (p = 0.03), and there was a significant difference between splatter rates among different surgeons (range, 29-90%; p = 0.0004), suggesting that blood splatter rate may be both procedure dependent and surgeon dependent. CONCLUSIONS: Mucocutaneous and transconjunctival transmission of human immunodeficiency virus and viral hepatitis has been documented. These results suggest that oculofacial plastic surgeons should consider eye protection for patients with known blood-borne diseases and in cases where blood splatter is expected. This precautionary practice is supported by the high incidence (98%) of undetected, intraoperative blood splatter.

Synthesising Topological Links.

We discuss the chemical synthesis of topological links, in particular higher order links which have the Brunnian property (namely that removal of any one component unlinks the entire system). Furthermore, we suggest how to obtain both two dimensional and three dimensional objects (surfaces and solids, respectively) which also have this Brunnian property.