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Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed. [PUBLICATION ABSTRACT]

Background: Use of the antiepileptic drug vigabatrin is associated with an elevated risk of visual field loss. Objective: To determine the frequency of, and risk factors for, vigabatrin-attributed visual field loss (VAVFL) in the setting of a large-scale, multinational, prospective, observational study. Study design: A comparative, open-label, parallel-group, multicentre study. Setting: Hospital outpatient clinics at 46 centres in five countries. Patients: 734 patients with refractory partial epilepsy, divided into three groups and stratified by age (8–12 years; >12 years) and exposure to vigabatrin. Group I comprised patients treated with vigabatrin for ≥6 months. Group II comprised patients previously treated with vigabatrin for ≥6 months who had withdrawn from the drug for ≥6 months. Group III comprised patients never treated with vigabatrin. Patients underwent perimetry at either 4- or 6-month intervals, for up to 36 months. Visual field outcome was evaluated masked to drug exposure. Intervention: Perimetry. Main outcome measure: The visual field outcome at each of four analysis points: (i) at enrolment (i.e. baseline, all patients); (ii) for patients exhibiting a conclusive outcome at the initial visual field examination; (iii) for patients exhibiting at least one conclusive outcome to the visual field examinations; and (iv) at the last conclusive outcome to the visual field examinations. Results: Of the 734 patients, 524 yielded one or more conclusive visual field examinations. For Group I, the frequency of VAVFL at the last conclusive examination was 10/38 (26.3%) for those aged 8–12 years and 65/150 (43.3%) for those aged >12 years. For Group II, the respective frequencies were 7/47 (14.9%) and 37/151 (24.5%). One case resembling VAVFL was present amongst the 186 patients in Group III at the last conclusive examination. The frequency of VAVFL in Groups I and II combined was 20.0% for those aged 8–12 years and 33.9% for those aged >12 years. VAVFL was associated with duration of vigabatrin therapy (odds ratio [OR] up to 15.2; 95% CI 4.4, 51.7), mean daily dose of vigabatrin (OR up to 26.4; 95% CI 2.4, 291.7) and male gender (OR 2.51; 95% CI 1.5, 4.1). VAVFL was more frequently detected with static than with kinetic perimetry (OR up to 0.43; 95% CI 0.24, 0.75). Conclusions: Since the probability of VAVFL is positively associated with treatment duration, careful assessment of the risk-benefit ratio of continuing treatment with vigabatrin is recommended in patients currently receiving this drug. All patients continuing to receive vigabatrin should undergo visual field examination at least every 6 months for the duration of treatment. We recommend two-level (three-zone), gradient-adapted, suprathreshold static perimetry of the peripheral field together with threshold perimetry of the central field out to 30° from fixation. The frequency of ophthalmological and perimetric examinations should be increased in the presence of VAVFL.

Proton-pump inhibitors, PPIs, are considered effective therapy for stomach acid suppression due to their irreversible inhibition of the hydrogen/potassium pump in the gastric parietal cells. They are widely prescribed and are considered safe for over-the-counter use. Recent studies have shown an association between PPI use and Alzheimer dementia, while others have disputed that connection. We analyzed over ten million United States Food and Drug Administration Adverse Event Reporting System reports, including over forty thousand reports containing PPIs, and provided evidence of increased propensity for memory impairment among PPI reports when compared to histamine-2 receptor antagonist control group. Furthermore, we found significant associations of PPI use with a wide range of neurological adverse reactions including, migraine, several peripheral neuropathies, and visual and auditory neurosensory abnormalities.

About 1% of non–small-cell lung cancers have ROS1 rearrangements. This oncogene is inhibited by crizotinib. In a cohort of 50 patients with ROS1 -rearranged lung cancer, crizotinib induced responses in 72%; the median duration of response was nearly a year and a half. The ROS1 oncogene encodes an orphan receptor tyrosine kinase related to anaplastic lymphoma kinase (ALK), along with members of the insulin-receptor family. 1 First discovered as the oncogene product of an avian sarcoma RNA tumor virus, 2 – 4 ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) is activated by chromosomal rearrangement in a variety of human cancers, including non–small-cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma multiforme. 5 – 9 Rearrangement leads to fusion of a portion of ROS1 that includes the entire tyrosine kinase domain with 1 of 12 different partner proteins. 10 The resulting ROS1 fusion kinases are constitutively activated and drive . . .

Background/AimsHydroxychloroquine (HCQ) retinopathy may result in severe and irreversible vision loss, emphasising the importance of screening and early detection. The purpose of this study is to report the novel finding of early optical coherence tomography (OCT) abnormalities due to HCQ toxicity that may develop in the setting of normal Humphrey visual field (HVF) testing.MethodsData from patients with chronic HCQ exposure was obtained from seven tertiary care retina centres. Ten patients with HCQ-associated OCT abnormalities and normal HVF testing were identified. Detailed analysis of the OCT findings and ancillary tests including colour fundus photography, fundus autofluorescence, multifocal electroretinography and microperimetry was performed in these patients.ResultsSeventeen eyes from 10 patients illustrated abnormalities with OCT and normal HVF testing. These OCT alterations included (1) attenuation of the parafoveal ellipsoid zone and (2) loss of a clear continuous interdigitation zone. Several eyes progressed to advanced parafoveal outer retinal disruption and/or paracentral visual field defects.ConclusionPatients with high risk HCQ exposure and normal HVF testing may develop subtle but characteristic OCT abnormalities. This novel finding indicates that, in some cases of early HCQ toxicity, structural alterations may precede functional impairment. It is therefore important to employ a screening approach that includes OCT to assess for these early findings. Ancillary testing should be considered in cases with suspicious OCT changes and normal HVFs.

Background/aimsThe antiseizure medication, vigabatrin, is associated with visual field loss (VAVFL). However, the fields can be challenging to interpret due to unfamiliarity with the characteristics of the defect and/or to difficulty in obtaining a reliable examination, particularly in patients with cognitive limitations associated with the epilepsy. Two machine-learning pattern recognition algorithms were developed to identify VAVFL, objectively.MethodsThe algorithms adhered to the European Medicines Agency-approved protocol for the detection of VAVFL (Three Zone Age Corrected Full Field 135 Screening Test (FF135) and the Central C30-2 Threshold Test (C30-2T) with the Humphrey Field Analyzer). Each algorithm compared the similarity of the measured field from each eye to that of modelled reference patterns of VAVFL, matched for equivalent severity, and objectively derived from a previously described case series of 123 adults. The algorithms were augmented by the optional inclusion of symmetrisation, a signal-to-noise enhancement technique based on the between-eye mirror image symmetry of VAVFL. Utility of the algorithms for identifying VAVFL was evaluated against a case series of 89 consecutively identified individuals stratified across six diagnostic categories including homonymous and glaucomatous losses.ResultsThe algorithms exhibited excellent agreement with a ‘gold standard’ clinical interpretation (sensitivity and specificity: FF135, 22/23; 30/30; C30-2T, 17/18; 48/51). Symmetrisation was particularly useful in identifying VAVFL when perimetric learning or fatigue influenced the outcome for one eye and for visualisation in the presence of concomitant homonymous loss.ConclusionThe directly interpretable machine-learning outcome correctly identified VAVFL and could assist patient management in community (neuro-)ophthalmology.

Background With the global increase in the use of injectable fillers, more cases with serious adverse events such vision loss are being reported. This article aims to review the cases of hyaluronic acid (HA) filler-related vision loss and to discuss the potential efficacy of hyaluronidase (HYASE) treatment via different given methods. Methods A total of 29 articles presenting 144 cases of HA filler-related vision loss were included in this study. Results Most cases of HA filler-related vision impairment were reported from China, followed by Korea. The majority of cases were seen in women. The nose, forehead and glabella were the most commonly injection sites. All cases had vision impairment and nearly all cases were unilateral with immediate onset of visual signs and symptoms. Ophthalmic artery occlusion (OAO) and central retinal artery occlusion (CRAO) were the two most commonly involved arterial obstruction patterns featured with a very poor prognosis followed by branch retinal artery occlusion (BRAO), the most favorable involved arterial pattern for a better prognosis. HYASE given subcutaneously and intra-arterially helped with visual recovery to different degrees, while retrobulbar HYASE seemed to be less helpful. Conclusion Complications after HA-based filler injection are extremely rare but can cause disastrous visual impairment. HYASE given subcutaneously and intra-arterially helped with visual recovery to different extents, and the efficacy might be reinforced when performed together, while retrobulbar HYASE seemed to be less helpful. However, to accurately access the efficacy of HYASE via different administration methods, further randomized controlled trials are needed. Level of Evidence III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Amiodarone's role as a cause of toxic optic neuropathy is based on case reports. Annual frequency estimates of 0.36% to 2.0%, which have been made without reference to the dose or duration of treatment, are 12 to 200 times higher than those for idiopathic nonarteritic anterior ischemic neuropathy. The object of this study was to determine the incidence, dose, and time until onset of bilateral vision loss from amiodarone as a secondary end point in an investigation of amiodarone's role in preventing sudden death. Randomized subjects received body weight–determined doses of closed-label amiodarone (n = 837) or placebo (n = 832) in a prospective double-masked manner. Closed-label amiodarone subjects were followed, unless death occurred, for a minimum of 27 months. Median follow-up in survivors was 45.5 months. The end point was removal from the study because of bilateral vision loss. No subject was removed from the study because of bilateral vision loss. Subjects receiving continuous amiodarone for 4 to >60 months at daily doses of >2.0 mg/kg (n = 696), >3.0 mg/kg (n = 559), or >4.0 mg/kg (n = 219) had maximum possible (95% confidence) annual incidences of bilateral toxic vision loss of 0.23%, 0.29%, or 0.74%, respectively. The maximum possible annual incidence rate of bilateral vision loss from amiodarone in all 837 subjects (median age 60 years) receiving a mean daily dose of 3.7 mg/kg (300 mg) was 0.13%. At the doses commonly used clinically, bilateral vision loss from amiodarone toxic optic neuropathy occurs infrequently, if at all.

Background Infantile spasms represent a serious epileptic syndrome that occurs in the early infantile age. ACTH and Vigabatrin are actively investigated drugs in its treatment. This study describes the comparison of their efficacy in a large series of patients with infantile spasms from Pakistan. Methods All patients with infantile spasms who presented to Aga Khan University Hospital, Karachi, Pakistan from January, 2006 to April, 2008 were included in this study. Inclusion criteria were clinical symptoms of infantile spasms, hypsarrythmia or modified hyparrythmia on electroencephalography, at least six months of follow-up period and receipt of any of the two drugs mentioned above. The type of drug distribution was random according to the availability, cost and ease of administration. Results Fifty six cases fulfilled the inclusion criteria. 62.5% were males. Mean age at onset of seizures was 5 ± 1.4 months. Fifty two (92.8%) patients demonstrated hypsarrythmia on electroencephalography. 64.3% cases were identified as symptomatic while 19.6% were cryptogenic and 16.1% were idiopathic. Eighteen patients received ACTH while 38 patients received Vigabatrin as first line therapy. Initial response to first line therapy was similar (50% for ACTH and 55.3% for Vigabatrin). Overall, the symptomatic and idiopathic groups responded better to Vigabatrin. The relapse rate was higher for ACTH as compared to Vigabatrin (55.5% vs. 33.3%) when considering the first line therapy. Four patients evolved to Lennox-Gastaut variant; all of these patients had initially received Vigabatrin and then ACTH. Conclusion Vigabatrin and ACTH showed no significant difference in the initial treatment of infantile spasms. However, patients receiving ACTH were 1.2 times more likely to relapse as compared to the patients receiving Vigabatrin when considering monotherapy. We suggest that Vigabatrin should be the initial drug of choice in patients presenting with infantile spasms. However, larger studies from developing countries are required to validate the therapeutic trends observed in this study.

Summary The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m 2 . Twenty-six patients were enrolled in the study. At 5.7 mg/m 2 , two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1–3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m 2 with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m 2 . The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m 2 and 4.3 mg/m 2 , respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6–13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.