Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma

BACKGROUND: This study was performed to compare levels of serum homocysteine (Hcy), vitamin B12 and folic acid in patients with primary open-angle glaucoma (POAG), pseudoexfoliative glaucoma (PEXG), normotensive glaucoma (NTG) and healthy controls. METHODS: Twentyfive patients with POAG, 24 with PEXG, and 18 with NTG, along with 19 control healthy subjects were included this prospective study. Levels of serum Hcy were measured using immunoassay, and those of serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay. RESULTS: The mean Hcy concentration in the PEXG group was significantly higher (P < 0.001) as compared to the other groups. There were no significant differences with respect to the mean Hcy concentrations among other groups (P > 0.05). There were no statistical differences in serum vitamin B12 levels among POAG, PEXG, NTG and control subjects (P > 0.05). The mean serum folic acid level was significantly lower in the subjects with PEXG (P < 0.009). However, the mean folic acid concentrations among the other groups did not differ significantly (P > 0.05). CONCLUSION: Elevated levels of Hcy in PEXG may explain the role of endothelial dysfunction among patients with PEXG

Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor

We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs

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

Some technique-dependent patterns of collateral flow during cerebral angiography

During selective transfemoral catheter cerebral angiography, anastomoses between external carotid branches and the vertebral artery, between the vertebral and deep or ascending cervical arteries, and between the middle meningeal and ophthalmic arteries can be demonstrated fairly frequently in patients with no known vascular abnormalities. One can occasionally show bidirectional filling of these anastomoses depending on the vessel injected. Visualization of these anastomoses occurs to a variable degree and is sometimes entirely technique-dependent, reflecting a transient increase in the intraluminal pressure during the injection of contrast medium.-Thus, demonstration of extracranial collateral arterial flow during cerebral angiography should not necessarily be interpreted as an abnormal phenomenon, such as may be seen with arterial occlusive disease, vascular malformation, or a very vascular tumor. Au cours de l'angiographie cérébrale parcathétérismes sélectifs par voie fémorale, peuvent apparaître des anastomoses entre des branches carotidiennes externes et l'artère vertébrale, entre l'artère vertébrale et les artères cérébrales profondes ou ascendantes et entre l'artère méningée moyenne et l'artère ophtalmique. Occasionnellement, on peut mettre en évidence un remplissage bidirectionnel de ces anastomoses, en rapport avec le vaisseau injecté. La visualisation de ces anastomoses se produit de facon variable dépend parfois entièrement de la technique, reflétant une augmentation transitoire de la pression dans l'artère durant l'injection du produit de contraste. Par conséquent, l'observation d'une circulation artérielle collatérale extracrânienne pendant une angiographie cérébrale ne représente pas nécéssairement un phénomène anormal tel qu'on le rencontre dans les troubles artériels occlusifs, dans les malformations vasculaires et dans les tumeurs vascularisées. Während der selektiven transfemoralen Katheter-Angiographie können sich Anastomosen zwischen Externa-Gefäßen und der A. vertebralis, zwischen der A. vertebralis und tiefen oder aufsteigenden cervicalen Arterien und zwischen der A. meningica media und der A. ophthalmica darstellen. Diese Befunde finden sich auch bei Patienten, bei denen keine Gef:aßanomalien vorliegen. Gelegentlich wird ein bidirektionaler Kontrastmitteldurchfluß durch diese Anastomosen nachgewiesen, dabei ist die Kontrastmittelfüllung von der Lokalisation der Kontrastmittelinjektion abhängig. Es zeigt sich also, daß diese unterschiedlichen Durchströmungen technisch bedingt werden können und nicht immer als abnormales Phänomen gedeutet werden können.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46671/1/234_2004_Article_BF00341594.pd

Cerebral malaria in children: using the retina to study the brain

Cerebral malaria is a dangerous complication of Plasmodium falciparum infection, which takes a devastating toll on children in sub-Saharan Africa. Although autopsy studies have improved understanding of cerebral malaria pathology in fatal cases, information about in vivo neurovascular pathogenesis is scarce because brain tissue is inaccessible in life. Surrogate markers may provide insight into pathogenesis and thereby facilitate clinical studies with the ultimate aim of improving the treatment and prognosis of cerebral malaria. The retina is an attractive source of potential surrogate markers for paediatric cerebral malaria because, in this condition, the retina seems to sustain microvascular damage similar to that of the brain. In paediatric cerebral malaria a combination of retinal signs correlates, in fatal cases, with the severity of brain pathology, and has diagnostic and prognostic significance. Unlike the brain, the retina is accessible to high-resolution, non-invasive imaging. We aimed to determine the extent to which paediatric malarial retinopathy reflects cerebrovascular damage by reviewing the literature to compare retinal and cerebral manifestations of retinopathy-positive paediatric cerebral malaria. We then compared retina and brain in terms of anatomical and physiological features that could help to account for similarities and differences in vascular pathology. These comparisons address the question of whether it is biologically plausible to draw conclusions about unseen cerebral vascular pathogenesis from the visible retinal vasculature in retinopathy-positive paediatric cerebral malaria. Our work addresses an important cause of death and neurodisability in sub-Saharan Africa. We critically appraise evidence for associations between retina and brain neurovasculature in health and disease, and in the process we develop new hypotheses about why these vascular beds are susceptible to sequestration of parasitized erythrocytes