Sarcoid-like reaction of the orbit in diffuse large B-cell lymphoma.

Sarcoid-like reaction (SLR) has been reported in patients with solid tumor malignancies, lymphomas, and patients receiving immunotherapy. SLR is often incidentally found during positron emission tomography/computed tomography scans as hilar and/or mediastinal lymphadenopathy. SLR has also been found in the lung, spleen, bone marrow, and skin. Biopsy of these lesions shows noncaseating granulomas. When systemic criteria are not met for sarcoidosis, these noncaseating granulomas are termed SLR. We present the first case in the literature of a case of orbital SLR in a patient with concomitant diffuse large B-cell lymphoma and inverted papilloma of the maxillary sinus. This case highlights the importance of including malignancy in the differential for the presence of a noncaseating granuloma in the orbit.

Targeting osteosarcoma with canine B7-H3 CAR T cells and impact of CXCR2 Co-expression on functional activity.

The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. The goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed B7-H3; whereas, levels were undetectable on normal dog tissues. Both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little anti-tumor activity was generated by B7-H3 CAR T cells; whereas, B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.

Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment.

Cancer progression and metastasis due to tumor immune evasion and drug resistance is strongly associated with immune suppressive cellular responses, particularly in the case of metastatic tumors. The myeloid cell component plays a key role within the tumor microenvironment (TME) and disrupts both adaptive and innate immune cell responses leading to loss of tumor control. Therefore, strategies to eliminate or modulate the myeloid cell compartment of the TME are increasingly attractive to non-specifically increase anti-tumoral immunity and enhance existing immunotherapies. This review covers current strategies targeting myeloid suppressor cells in the TME to enhance anti-tumoral immunity, including strategies that target chemokine receptors to deplete selected immune suppressive myeloid cells and relieve the inhibition imposed on the effector arms of adaptive immunity. Remodeling the TME can in turn improve the activity of other immunotherapies such as checkpoint blockade and adoptive T cell therapies in immunologically "cold" tumors. When possible, in this review, we have provided evidence and outcomes from recent or current clinical trials evaluating the effectiveness of the specific strategies used to target myeloid cells in the TME. The review seeks to provide a broad overview of how myeloid cell targeting can become a key foundational approach to an overall strategy for improving tumor responses to immunotherapy.

Utility of Direct Immunofluorescence Using Buccal Mucosal Biopsies in Those with Suspected Isolated Ocular Mucous Membrane Pemphigoid.

PURPOSE: To determine the rate of positivity of immunofluorescence studies in buccal biopsies in patients with cicatrizing conjunctivitis undergoing workup for ocular mucous membrane pemphigoid (MMP)/ocular cicatricial pemphigoid (OCP). DESIGN: Retrospective cohort review. PARTICIPANTS: Forty-one patients with cicatrizing conjunctivitis undergoing workup for OCP. METHODS: A retrospective chart review of direct immunofluorescence (DIF) studies in buccal mucosal biopsies was performed. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of positivity of direct and indirect immunofluorescence studies on buccal mucosal biopsies. RESULTS: Twenty-two patients (54%) had a positive buccal mucosal biopsy; 64% of patients (14/22) demonstrated +DIF on initial biopsy and an additional 36% of patients (8/22) on the second biopsy. Eighteen patients underwent conjunctival biopsy. In the 6 patients with a negative conjunctival biopsy, 4 (67%) had a positive buccal biopsy. CONCLUSIONS: Buccal mucosal immunofluorescence studies may be positive in patients with OCP even in the absence of extraocular disease. Buccal mucosal biopsy may be considered as an alternative to or attempted before conjunctival biopsy for the diagnosis of OCP, particularly in patients in whom conjunctival biopsy may be difficult or imminently visually threatening.

Longitudinal Changes in Size of Conservatively Managed Flow-Related Aneurysms Associated with Brain Arteriovenous Malformations.

BACKGROUND: Flow aneurysms (FAs) associated with brain arteriovenous malformations (AVMs) are thought to arise from increased hemodynamic stress due to high-flow shunting. This study aims to describe the changes in conservatively managed FAs after successful AVM treatment. METHODS: Patients with symptomatic AVMs and associated FAs who underwent successful treatment of the AVM between 2008 and 2017 were included. FA dimensions were measured on surveillance angiography to assess longitudinal changes. RESULTS: Thirty-two patients were identified with 48 FAs. Sixteen (33%) FAs were treated endovascularly; 18 (38%) FAs were treated surgically; and 14 (29%) FAs (11 patients) were monitored. FAs demonstrated a decrease in size from 5.0 mm to 3.8 mm (24%; P = 0.016) and 4.9 mm to 3.6 mm (27%; P = 0.013) in height and width, respectively, over a median 35 months. However, on subgroup analysis, only class IIb aneurysms demonstrated a significant decrease in size (51% reduction in largest diameter, P = 0.046) and only 3 FAs (21%) resolved. There were no hemorrhages observed during follow-up. CONCLUSIONS: While conservatively managed FAs demonstrated a reduction in size after the culprit AVM was treated, this was only significant in FAs located close to an AVM nidus (class IIb). There were no hemorrhages during the median 35 months' follow-up; however, long-term data are lacking. Our data support close observation of all conservatively managed aneurysms and a tailored approach based on the proximity to the nidus and observed changes in size.

The Detection of Occult Retinal Vasculitis on Fluorescein Angiography in Pediatric Uveitis.

PURPOSE: To evaluate the usefulness of fluorescein angiography (FA) to detect occult retinal vasculitis in children with otherwise apparently quiescent intermediate uveitis, posterior uveitis, and panuveitis based on clinical examination alone. DESIGN: Retrospective chart review. PARTICIPANTS: Pediatric uveitis patients evaluated at the Children's Medical Center in Dallas, Texas. METHODS: Retrospective chart review of pediatric patients treated with immunosuppressive therapy in the uveitis clinic at the Children's Medical Center, Dallas, Texas, between September 2015 and September 2016. Patients with noninfectious uveitis requiring immunosuppressive therapy, in which posterior segment involvement (intermediate uveitis, posterior uveitis, or panuveitis) was known or suspected, and whose disease apparently was quiescent on clinical examination were included. MAIN OUTCOME MEASURES: The incidence of occult retinal vasculitis detected on FA alone. RESULTS: Fourteen pediatric patients met inclusion criteria. Six patients (43%) demonstrated intermediate uveitis, and 8 patients (57%) demonstrated panuveitis. Eleven patients (79%) were found to show additional evidence of occult retinal vasculitis on FA. CONCLUSIONS: Fluorescein angiography can be an important tool in evaluating pediatric uveitis patients with known or suspected posterior involvement for the presence of occult retinal vasculitis. Failure to control occult retinal vasculitis adequately may be a contributing factor to seemingly recalcitrant cases, inability to wean off immunomodulatory therapy, and long-term complications leading to poor prognosis.

The effect of patient compliance on remission rates in pediatric noninfectious uveitis.

PURPOSE: To identify barriers to compliance in pediatric noninfectious uveitis, and to examine its association with achieving steroid-free remission. METHODS: A retrospective analysis was performed on pediatric patients with noninfectious uveitis on immunomodulatory therapy treated at the University of Texas Southwestern Medical School and Children's Medical Center (Dallas, TX) between September 2015 and March 2017. Compliance barriers were identified and rates of achieving steroid-free remission were calculated. RESULTS: A total of 57 patients with noninfectious uveitis requiring immunosuppressive therapy met inclusion criteria. Thirty-three (58%) of patients were compliant. Notable barriers to compliance included regimens requiring >3 medications, patient/parent negligence, transportation issues, family strife, and presence of an associated systemic autoimmune disease (P < 0.050). At a median follow-up of 24 months, a total of 28 (49%) achieved steroid-free remission. The presence of 3 or more compliance barriers was associated with decreased remission rates (P < 0.050). Poor compliance was associated with decreased rates of steroid-free remission (21% vs 79% [P = 0.002]). CONCLUSIONS: Noncompliant patients with noninfectious pediatric uveitis requiring immunomodulatory therapy were found to have a lower rate of achieving steroid-free remission compared to patients who exhibited full compliance.

Vitreoretinal lymphoma, secondary to non-CNS systemic lymphoma, masquerading as an infectious retinitis.

PURPOSE: To report an atypical case of vitreoretinal lymphoma, secondary to non-central nervous system (non-CNS) systemic lymphoma, masquerading as an infectious retinitis. OBSERVATIONS: A 76-year-old female with a history of cecal diffuse large B-cell lymphoma with two prior occurrences of posterior segment ocular involvement presented with a complaint of blurry vision in the right eye. Exam findings were significant for large areas of retinal whitening and retinal hemorrhages in the absence of choroidal lesions or significant vitritis. The clinical suspicion of an infectious retinitis, was supported by a presumptive immunosuppressive state secondary to her recent treatment (within 1 month) with both intravitreal and systemic rituximab plus high-dose methotrexate. Aggressive treatment with intravitreal and systemic antivirals and antibiotics was initiated. However, polymerase chain reaction (PCR) testing of aqueous fluid was negative for cytomegalovirus (CMV), herpes simplex virus, herpes zoster virus and toxoplasma, and her condition continued to worsen, so suspicion was raised for a masquerading recurrent malignancy. She was treated empirically with serial intravitreal injections of methotrexate and showed dramatic clinical improvement. A subsequent relapse occurred that responded rapidly to intravitreal methotrexate in the absence of antiviral/antibiotics. CONCLUSION: It is important for clinicians to be aware of atypical presentations of vitreoretinal lymphoma. This case emphasizes the fact that secondary ocular lymphoma after systemic lymphoma can have a vitreoretinal presentation rather than the more common choroidal involvement. Furthermore, it shows that recurrences of this disease in the same patient can have very different manifestations, including an appearance indistinguishable from a viral retinitis.

Successful treatment with infliximab after adalimumab failure in pediatric noninfectious uveitis.

PURPOSE: To describe the use of infliximab after adalimumab failure in the treatment of pediatric noninfectious uveitis. METHODS: A retrospective analysis was performed on the medical records of pediatric patients with noninfectious uveitis treated with infliximab for a minimum of 6 months after previously failing to achieve steroid-free remission using adalimumab at the University of Texas Medical School and Children's Medical Center between September 2015 and March 2018. Rates of achieving disease activity quiescence and steroid-free remission as well as incidence of adverse events were calculated. RESULTS: A total of 13 patients with noninfectious uveitis refractory to treatment with adalimumab met inclusion criteria. Three (23%) had anterior uveitis, 4 (31%) had pars planitis, and 6 (46%) had panuveitis. Eleven (85%) patients had preexisting ocular comorbidities. Of these, 4 (31%) had retinal vasculitis, and 1 (7.7%) had cystoid macular edema. There was a 100% response rate to treatment with infliximab following failure to achieve disease quiescence on adalimumab. At mean follow-up time of 21 months (range, 8-31) from initiation of infliximab, there was a reduction in steroid dependence from 100% to 15% after transitioning from adalimumab to infliximab (P < 0.001). Nine patients (69%) had achieved steroid-free remission on infliximab therapy. The mean time to steroid-free remission was 8.7 months. CONCLUSIONS: In our study cohort, infliximab was used successfully in all cases of recalcitrant pediatric noninfectious uveitis that previously failed adalimumab therapy.

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity.

The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity.

Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State.

The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.

MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.

Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.

A Case of Endophthalmitis After Bilateral Medial Rectus Recession.

A 9-month-old male infant with a history of Down syndrome underwent bilateral medial rectus recession. Two weeks postoperatively, he developed leukocoria of the left eye with a white opacity posterior to the lens, numerous undulations, necrosis, and hemorrhages in the retrolental space. His contralateral eye had white retinal lesions nasally. Ultrasound examination of the left eye showed a funnel retinal detachment, loculated debris, and a small, central, hyperechoic area concerning for calcification. He underwent enucleation because retinoblastoma could not be definitively ruled out. Given this patient's low visual potential, enucleation was a definitive and safe treatment option. Ocular pathology showed significant inflammation and necrosis. There was an area of scleral perforation by a suture adherent to the retina and vitreous, surrounded by inflammatory cells. This case uniquely demonstrates pediatric endophthalmitis following strabismus surgery, secondary to scleral perforation confirmed by histopathological analysis. Care must be taken during scleral passage of sutures to prevent inadvertent scleral perforation and the potential complication of endophthalmitis. [J Pediatr Ophthalmol Strabismus. 2017;54:e37-e41.].

ACCIDENTAL DUPLICATION: Colorado-Retinopathy of Prematurity (CO-ROP) Screening Algorithm: a validation study at a tertiary care center.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Systematic Quantification of Population Cell Death Kinetics in Mammalian Cells.

Cytotoxic compounds are important drugs and research tools. Here, we introduce a method, scalable time-lapse analysis of cell death kinetics (STACK), to quantify the kinetics of compound-induced cell death in mammalian cells at the population level. STACK uses live and dead cell markers, high-throughput time-lapse imaging, and mathematical modeling to determine the kinetics of population cell death over time. We used STACK to profile the effects of over 1,800 bioactive compounds on cell death in two human cancer cell lines, resulting in a large and freely available dataset. 79 potent lethal compounds common to both cell lines caused cell death with widely divergent kinetics. 13 compounds triggered cell death within hours, including the metallophore zinc pyrithione. Mechanistic studies demonstrated that this rapid onset lethal phenotype was caused in human cancer cells by metabolic disruption and ATP depletion. These results provide the first comprehensive survey of cell death kinetics and analysis of rapid-onset lethal compounds.

Validation of WINROP for detecting retinopathy of prematurity in a North American cohort of preterm infants.

BACKGROUND: WINROP (weight, insulin-like growth factor 1, neonatal, retinopathy of prematurity) is a web-based retinopathy of prematurity (ROP) risk algorithm that uses postnatal weight gain as a surrogate of insulin-like growth factor-1 (IGF-1) to predict the risk of severe ROP in premature infants. The purpose of this study was to validate the web-based algorithm WINROP in detecting severe (type 1 or type 2) ROP in a North American cohort of infants. METHODS: The records of consecutive infants who underwent ROP examinations between 2008 and 2011 were reviewed retrospectively. Infants were classified into categories of "alarm" (at risk for developing severe ROP) and "no alarm" (minimal risk for severe ROP). RESULTS: A total of 483 were included. Alarm occurred in 241 neonates (50%), with the median time from birth to alarm of 2 weeks. WINROP had a sensitivity of 81.8% (95% CI, 67.3%-91.8%) and specificity of 53.3% (95% CI, 48.5%-58.0%) for identifying infants with severe ROP. Eight of the 44 infants with severe ROP were not detected (5 with type 1 and 3 with type 2). Of these 8 infants, 7 (88%) had birth weight in excess of the 70th pecentile. With additional weight data entry, sensitivity of WINROP rose to 88.6%. CONCLUSIONS: Very preterm infants (gestational age of ≤27 weeks) with relatively high birth weight for gestational age may not be detected by WINROP as high risk for developing severe ROP.

Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP): a validation study at a tertiary care center.

PURPOSE: The Colorado Retinopathy of Prematurity Screening Algorithm (CO-ROP) recommends screening for infants meeting the following criteria for retinopathy of prematurity (ROP): gestational age ≤30 weeks, birth weight of ≤1500 g, and net weight gain of ≤650 g between birth and 4 weeks of age. This study was performed to evaluate the validity of CO-ROP in a tertiary referral county hospital. METHODS: CO-ROP was used to retrospectively analyze the data from consecutive newborns screened for ROP using national screening guidelines at Parkland Hospital, Dallas, Texas, between April 1, 2009, to August 30, 2013. Sensitivities and specificities for identifying ROP were calculated. RESULTS: A total of 374 infants were included, of whom 29 (7.8%) developed type 1 ROP and 12 (3.2%) developed type 2 ROP. The CO-ROP model would have decreased number of infants screened by 34% compared to current national screening criteria. CO-ROP had sensitivity of 93.1% (95% CI, 77.2-99.1) and 92.7% (95% CI, 61.5-99.8) for identifying type 1 and type 2 ROP, respectively. Of 29 patients who developed type 1 ROP, 2 were not identified using CO-ROP. CONCLUSIONS: The CO-ROP model significantly reduced total number screened but failed to detect 2 infants with type 1 ROP, suggesting the need for further modification of the algorithm.

Birdshot Retinochoroidopathy: Differences in Clinical Characteristics between Patients with Early and Late Age of Onset.

PURPOSE: To describe differences in the clinical characteristics of birdshot retinochoroidopathy (BSRC) patients diagnosed early and later in life. METHODS: This is a retrospective cohort study. Age was primarily analyzed and 50 years of age at diagnosis was selected as a cut-off point. RESULTS: A total of 144 patients (288 eyes) were included; 68 with early-onset and 76 with late-onset BSRC. The younger group had a statistically significant higher rate of more severe iritis (p = 0.04); an average number of non-steroidal immunosuppressants and biologic agents (NSIB) (p = 0.04); and a prolonged time to initiation of NSIB (p = 0.01). There were only four patients (3%) who had >0.5+ cells in the anterior chamber. CONCLUSIONS: Patients with early-onset BSRC carried a higher risk for anterior segment inflammation, had a more prolonged delay to initiation of treatment with NSIB, and required a greater number of NSIBs to achieve remission.