Vascular co-option in lung cancer metastatic to the eye after treatment with bevacizumab

Abstract Background Chemotherapy with bevacizumab alters the angiogenic environment, and therefore, the growth and spread of metastases. We present a patient with metastatic lung adenocarcinoma to the eye with findings suggestive of retinal vascular co-option. Methods Case report. Results A 57-year-old male, receiving systemic bevacizumab for metastatic lung adenocarcinoma, presented with vitreous opacities and clumped deposits adherent to the retinal vessels. No choroidal metastases were present. Diagnostic vitrectomy yielded cellular evidence of adenocarcinoma, with thyroid transcription factor-1 staining confirming a lung primary. Conclusion The perivascular growth of small foci of metastatic vitreous cells suggests vascular co-option from the native retinal circulation. Similar modification of metastatic disease by bevacizumab has been observed in animal models and selected human cases

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Branch Retinal Vein Occlusion: Pathogenesis, Visual Prognosis, and Treatment Modalities

In branch retinal vein occlusion (BRVO), abnormal arteriovenous crossing with vein compression, degenerative changes of the vessel wall and abnormal hematological factors constitute the primary mechanism of vessel occlusion. In general, BRVO has a good prognosis: 50–60% of eyes are reported to have a final visual acuity (VA) of 20/40 or better even without treatment. One important prognostic factor for final VA appears to be the initial VA. Grid laser photocoagulation is an established treatment for macular edema in a particular group of patients with BRVO, while promising results for this condition are shown by intravitreal application of steroids or new vascular endothelial growth factor inhibitors. Vitrectomy with or without arteriovenous sheathotomy combined with removal of the internal limiting membrane may improve vision in eyes with macular edema which are unresponsive to or ineligible for laser treatment

Toxic epidermal necrolysis and Stevens-Johnson syndrome

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease

Ocular Biopsy, Diagnostic Vitrectomy

Invasive diagnostic procedures are appropriate in cases of uveitis in which the diagnosis is uncertain, and the differential diagnosis includes significant disorders, such as sight-threatening infections or neoplasia. Small and large case series document the diagnostic utility of biopsy of the vitreous, retina, or choroid in selected cases. Vitreous biopsy has reported overall diagnostic yields from a low of 30 % to a high of 82 %. For lymphoma, the diagnostic yield ranges from 10 to 64 %. Several small case series have included retinal biopsy for diagnosis of viral retinitis, sometimes incidental to retinal detachment repair

Evaluation of the reactive T-cell infiltrate in uveitis and intraocular lymphoma with flow cytometry of vitreous fluid (an American Ophthalmological Society thesis)

To describe the reactive T-cell infiltrate in uveitis and intraocular lymphoma using flow cytometry of clinical intraocular specimens acquired during diagnostic pars plana vitrectomy. This was a retrospective review of diagnostic vitreous specimens (1992-2011) obtained at a university-based, tertiary care center. Seventy-eight patients with uveitis or lymphoma undergoing pars plana vitrectomy were selected for intraocular testing based on clinical diagnostic uncertainty. Pars plana vitrectomy with flow cytometry, gene rearrangement studies, and cytology was performed. T-cell infiltrates were found in all diagnostic categories with limited power to discriminate between uveitis and T-lymphocyte reactive infiltrates in response to intraocular lymphoma. Statistically significant differences by two-sample test of means between group means were found between 35 uveitis and 35 B-cell lymphoma cases for T-cell markers CD2, 3, 4, 5, and 7, but not for CD8. The CD4:CD8 ratio had a higher mean value in the uveitis group (P=.0113), and 8 T-cell lymphomas had a statistically greater number of CD3+ lymphocytes compared to uveitis (P=.0199) by two-sample test of means. Likelihood ratios were highest for CD2, CD5, CD7, CD4:CD8 ratio, CD20, and CD22. Discrimination between uveitis and lymphoma based on cell identification by flow cytometry was limited because of the prevalence of T lymphocytes in all diagnostic categories, emphasizing the importance of a reactive T-cell infiltrate in B-cell lymphomas, which may impede diagnosis. Flow cytometry may allow identification of more cases of T-cell lymphoma than reported when it is combined with gene rearrangement and cytology