Ibrutinib-related uveitis: A case series.

PURPOSE: Four cases of ibrutinib-related uveitis are presented, which are to the best of our knowledge the first in the literature. Possible mechanisms of ibrutinib-mediated uveitis are explored. OBSERVATIONS: Case 1 is a 60-year-old female who had been stable on 1 year of ibrutinib for chronic lymphocytic leukaemia. She was diagnosed with ibrutinib-related uveitis, which responded well to topical steroids. Case 2 is a 63-year-old male diagnosed with uveitis after 2 years of ibrutinib treatment for chronic lymphocytic leukaemia. He responded well to topical and oral steroids; however, he continued to have uveitis relapses after weaning steroids. Case 3 is a 69-year-old male diagnosed with uveitis after 18 months of ibrutinib treatment. He was trialed on topical and intravenous steroids, and restarted ibrutinib without worsening of symptoms. Case 4 is a 66-year-old female who developed uveitis after being stable on ibrutinib for 3 years. She responded well to topical steroids. CONCLUSIONS AND IMPORTANCE: Inflammatory complications of tyrosine kinase inhibitors are well described. While ibrutinib, and other kinase inhibitors, are generally well-tolerated, there are increasing reports of ocular toxicities, including uveitis. It is recommended to monitor patients for potential ocular adverse effects and facilitate rapid ophthalmologic assessment.

Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments.

Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent.

Syphilitic punctate inner retinitis in immunocompetent gay men.

PURPOSE: To describe the features of an unusual syphilitic uveitis syndrome in a cluster of homosexual patients. DESIGN: Retrospective case series. PARTICIPANTS: Five consecutive patients diagnosed with syphilitic retinitis in our Melbourne uveitis clinic over a period of 8 months. METHODS: The case notes of patients diagnosed with syphilitic retinitis were reviewed and the clinical features are presented and discussed. MAIN OUTCOME MEASURES: Description of retinal findings and documentation of any associated sequelae. RESULTS: All patients were homosexual men. Two were human immunodeficiency virus positive. None of the patients had been previously diagnosed with syphilis, although 3 presented with systemic symptoms and signs of secondary syphilis. All patients had marked anterior uveitis and vitritis. All patients had acute retinal arteriolitis and inner retinitis, with distinctive, inner retinal and preretinal white dots. These retinal findings were remarkably similar in all patients, and resolved with little or no sequelae after standard systemic treatment for syphilis, combined with oral prednisolone. CONCLUSIONS: Syphilitic retinitis may be an increasingly common clinical problem, reflecting the growing incidence of syphilis among homosexual men in Australia. Our patients showed stereotypical ocular and systemic features, which are useful in differentiating this condition clinically from other types of acute posterior uveitis, such as necrotizing viral retinitis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Paraneoplastic syndromes associated with visual loss.

PURPOSE OF REVIEW: The recent literature was reviewed to analyze the developments in the diagnosis, pathogenesis, and immunology of this group of paraneoplastic syndromes. Clinical features and pathologic findings are summarized. RECENT FINDINGS: The mechanism of cell death in cancer-associated retinopathy appears to occur through apoptotic pathways. Caspase inhibitors and a calcium antagonist have been used in animal models to block or suppress the effect of the antirecoverin antibodies on the retina with significant response. These agents are possible treatment options for cancer-associated retinopathy. Aberrant expression of recoverin by tumor cells does not necessarily induce antirecoverin antibodies and cancer-associated retinopathy. Many tumors, not just those producing the clinical picture of cancer-associated retinopathy, have been shown to express recoverin. Recoverin appears to play a functional role in tumor cells, and antirecoverin antibodies may have tumor-suppressing effects. Further research into this area may help design epitope-based immunotherapy for patients with recoverin-expressing tumors. Further evidence has emerged to support the initial observation that depolarizing bipolar cells are the likely retinal target in melanoma-associated retinopathy. Intravitreal injection of melanoma-associated retinopathy serum produced electroretinogram changes in animals very similar to the clinical findings in humans. Many new antibodies and antigens had been discovered to be linked to various paraneoplastic syndromes. Anti-collapsing response-mediating protein-5 is likely to be an important one; it was found to be the second most common autoantibody related to paraneoplastic neurologic syndromes. SUMMARY: Further research into the functional role of recoverin in cancer cells may advance our understanding in cancer immunology. Immunotherapy may be possible if a specific epitope of recoverin can be found to contain the antigenic site for antitumor antibodies and not cross-react with retinal antigens. Research into the pathogenesis of the other paraneoplastic syndromes is required for a better understanding and treatment of these rare conditions. The missing link between primary cutaneous melanoma and uveal melanocytes still eludes investigators in bilateral diffuse uveal melanocytic proliferation. The discovery of the missing link may provide us with some understanding of the development of uveal melanoma.