Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ...ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors.
We conducted a scientific literature search using the PubMed database up to July 2018 with the terms "MEK inhibitors" with a "review" filter and "MEK inhibitors" with a "clinical trials" filter. Phase I-III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other OAEs are discussed.
In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities are described, including visual disturbances, a 2-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities, such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion.
MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal OAE, causing visual disturbances or discomfort. One of the most relevant OAE of MEK therapy is MEK inhibitor-associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so the communication with the oncologist is fundamental.
The general election does not always run smoothly where in some practices there is money politics carried out by prospective leaders by distributing some money to the public with the aim of electing ...the prospective leader at the time of voting. This research uses the empirical normative legal research method which is a merger of normative legal approaches with the addition of various empirical elements. Normative-empirical research methods regarding the implementation of normative legal provisions (laws) in every particular legal event that occurs in a society. The method of approach in this research uses secondary data consisting of primary legal materials (data obtained directly from people's lives by means of interviews), secondary legal materials and tertiary legal materials. Money politics activities carried out by prospective leaders become a habit in conducting general elections to attract the public so that they vote because most people do not believe or are not affected by the vision and mission and programs presented by the prospective leaders. Money politics has become a recognized practice at various levels of the general elections from the presidential election to the village head due to the lack of strict supervision and enforcement of general elections that should be free, safe, honest, fair, and secret.
MEK signaling pathway targeting has emerged as a valuable addition to the options available for the treatment of advanced cancers including melanoma and non-small cell lung cancer. Ophthalmologic ...monitoring of patients taking part in clinical trials of MEK inhibitors has shown that while ocular effects are common, generally emerging during the first days to weeks of treatment, the majority are either asymptomatic or have minimal visual impact and are benign, resolving without intervention or the need to reduce or stop MEK inhibitor therapy. However rare cases of serious, potentially vision-threatening ocular toxicities have been reported during MEK inhibitor therapy. There is currently no recommendation for routine ophthalmologic screening or monitoring of patients with advanced cancer who are initiating MEK inhibitor therapy. However, baseline ophthalmologic examination may be useful for all patients initiating MEK inhibitor therapy to allow the differentiation of preexisting pathology versus the development of MEK inhibitor-associated retinopathy in the event of the emergence of symptomatic ocular events. Regular ophthalmologic examination may be appropriate for patients at increased risk for ocular events, such as patients with a history of ocular inflammation, infection, or underlying macular/retinal disease. All patients reporting visual disturbance should be referred for prompt ophthalmologic review to determine the potential seriousness of any underlying abnormalities and whether there is a need for treatment modification or specific intervention. Understanding the potential consequences of ocular toxicities is of particular importance in the context of decision-making for the continuation of potentially life-prolonging medications such as MEK inhibitors.
Erdheim–Chester disease (ECD) is a rare clonal histiocytic neoplasm with less than 1200 documented cases to date. The disease is life-threatening and difficult to recognize, although increasing ...awareness as well as the integration of clinical, imaging, pathology information, and genetic studies have led to a recent exponential increase in new reported cases. ECD affects multiple organs and systems, including skeletal, neurologic, and cardiovascular. Pulmonary, retroperitoneal, and cutaneous lesions have also been reported in various combinations. Until the discovery that more than half of ECD patients harbor the BRAF-V600E mutation or other mutations in the mitogen-activated protein kinase (MAPK) and RAS pathways, Interferon-a was the first-line treatment. Nowadays BRAF and MEK-inhibitors targeted therapies are the mainstay of treatment. Ophthalmologic involvement occurs in 25% −30% of ECD cases, usually in the form of orbital involvement presenting with exophthalmos and ophthalmoplegia. Other ophthalmologic manifestations include palpebral xanthelasmas, anterior uveitis and vitritis, optic disk edema, choroidal infiltration, recurrent serous retinal detachment, retinal drusen–like deposits and retinal pigment epithelial changes. ECD patients can also present with ocular symptoms as a result of adverse effects of the treatment regimens. In some cases with smoldering or protean symptoms, the emergence of eye manifestations triggered the diagnosis. Ophthalmologists have to be aware of the disease, recognize the constellation of ECD symptoms, and contribute to the diagnosis, treatment, and follow-up of ECD patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitogen-activated protein kinase kinase (MEK) inhibitors have significantly improved the prognosis of various types of cancer such as metastatic melanoma. However, their use is usually associated ...with ocular side effects. A retinopathy associated with these agents (MEKAR) has been described, consisting of the development of neurosensory detachments, generally bilateral and multiple, similar to those that appear in the central serous chorioretinopathy (CSC). Generally, optical coherence tomography allows us to differentiate the two conditions. We present the case of a 55-year-old woman in treatment with a MEK inhibitor, who developed bilateral neurosensory detachments and blurred vision, which resolved with the discontinuance of the treatment due to tumour progression.
Los inhibidores de la proteína quinasa de activación mitogénica (MEK) son fármacos utilizados para el tratamiento de neoplasias tales como el melanoma metastásico. Su introducción ha mejorado el pronóstico de estas enfermedades, pero su uso no está exento de complicaciones oculares. Se ha descrito una retinopatía asociada a estos fármacos (MEKAR) consistente en la aparición de desprendimientos neurosensoriales (DNS), generalmente bilaterales y múltiples similares a los que aparecen en la coriorretinopatía serosa central (CSC). En la mayoría de casos la tomografía de coherencia óptica es suficiente para diferenciar esta entidad de una CSC. Presentamos el caso de una paciente de 55 años que, en este contexto, desarrolló DNS bilaterales que asociaron disminución de agudeza visual, y que se resolvieron cuando se suspendió la terapia por progresión tumoral.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
Retinopathy is a common adverse event with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors. Little is known about the pathophysiology of MEK inhibitor-associated ...retinopathy (MEKAR). Since MEKAR has many similarities to central serous chorioretinopathy (CSCR), they may share common risk factors. The aim of this study was to evaluate the association between baseline characteristics and MEKAR in melanoma patients initiating MEK inhibitor treatment.
Methods:
Data from patients treated with cobimetinib and vemurafenib for advanced melanoma in the coBRIM trial were subjected to secondary analysis. Consistent with CSCR risk factors, assessed baseline characteristics included: age, gender, past ocular disease, weight, hypertension, diabetes, dyslipidemia, glomerular filtration rate (eGFR) and corticosteroid use. Associations between characteristics and retinopathy events (any grade and symptomatic) were evaluated using univariate logistic regression and represented as odds ratios (OR).
Results:
A total of 247 patients were treated with cobimetinib and vemurafenib, of whom 72 (29%) had retinopathy of any grade and 33 (13%) had symptomatic retinopathy. Patients with a history of ocular disease were at significantly higher risk of retinopathy (any grade, 44%; symptomatic, 22%) than those with no ocular disease history (any grade, 22%; symptomatic, 10%). Individuals with a history of ocular inflammation or infection were at highest risk: 4 of 5 developed symptomatic retinopathy during MEK inhibitor therapy. Increased age was associated with a higher risk of any grade retinopathy {decade increase OR 95% confidence interval (CI) = 1.03 (1.01–1.05); p = 0.009}, while increasing eGFR was significantly associated with a decreased risk of any grade retinopathy 0.98 (0.96–0.99); p = 0.004; the associations were not statistically significant with symptomatic retinopathy. Other assessed CSCR risk factors were not significantly associated with MEKAR.
Conclusion:
Age, glomerular filtration rate and history of ocular disease (particularly inflammatory eye disease) were associated with a risk of MEK inhibitor induced retinopathy. Patients who are at increased risk of MEKAR may benefit from more regular ophthalmologic assessment during treatment.
Mitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of ...BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combination with vemurafenib.
In the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to participate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT).
Five out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema.
Multiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy.
The purpose of this study is to evaluate the effect of Tunas Mekar Programme on the student's entrepreneurial intention in terms of personal feasibility of starting a business. The objective of this ...study is to identify the levels of personal feasibility among Tunas Mekar apprentice involving in business and to identify the factors influencing the apprentice to involve in business. Mean analysis is used to identify the factors influencing the apprentice involving in business. By understanding the factors and the level of personal feasibility involving in business among these students will give some input towards policy makers to develop appropriate educational programmes to encourage students to involve in business and to reduce employability.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
