MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects

BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance

Developments in targeted therapy in melanoma

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF- and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy

Restless-Legs-Syndrom

SummaryRestless legs syndrome (RLS) is characterised by an uncontrollable urge to move, in particular the lower limbs, often accompanied by discomfort or a painful sensation that occurs typically at night. It is categorized under the ICD-Classification of extrapyramidal and movement disorders. As patients often suffer from insomnia due to the involuntary nocturnal leg movements and irritable sensations in the legs, RLS is also classified as a sleep-related movement disorder. The incidence of a mild form of RLS is frequent, although it often remains undiagnosed.After the exclusion of other diseases by differential diagnosis, RLS is diagnosed on the basis of a clinical test administering a single dose of levodopa. There are two forms of RLS: idiopathic and secondary. The secondary form is encountered in an astonishing number of diseases, including renal insufficiency, diabetes, chronic obstructive pulmonary disease (COPD) and iron deficiency. The treatment of RLS is complex and the benefits and risks of pharmacotherapy should be considered carefully. Non-ergoline dopamine agonists (e.g. ropinirole, pramipexole) are the first-line treatment in severe cases of RLS. Transdermal rotigotine is also a promising treatment option. Opioids in combination with naloxone are recommended for patients suffering from severe pain. In mild cases of RLS, patients benefit from a balanced lifestyle with gentle physical activity and avoiding the excessive consumption of caffeine or alcohol.</jats:p

Wundschmerz

SummaryIn acute and chronic wounds, pain represents a common and central medical problem. Wound pain can be caused by multiple factors, such as macro- or microvascular as well as inflammatory processes.The basic concept of pain management is based on the WHO pain ladder. Often this concept of pain therapy remains insufficient. Apart from the conventionally used anal-getics, there are not yet established guidelines for the use of alternative substances.Ultimately the adequate wound pain therapy must be adjusted to each patient and his comorbidities.</jats:p

Komplexes regionales Schmerzsyndrom (CRPS)

Einleitung: Das komplexe regionale Schmerzsyndrom (CRPS) ist eine relativ seltene, jedoch für die Betroffenen äußerst gravierende Erkrankung, welche meist distal einer Extremitätenverletzung auftritt. Die klinischen Symptome sowie die Schmerzen stehen in keinem Verhältnis zum auslösenden Ereignis. Bei etwa 10% der Patienten liegt gar kein auslösendes Ereignis vor. Bei ungefähr der Hälfte der Patienten führt CRPS zu dauerhafter Arbeitsunfähigkeit und hohen Behandlungs- und Folgekosten. Klinik: Es werden zwei Formen unterschieden. Beim CRPS 1 lässt sich keine Nervenläsion nachweisen, wohingegen es beim CRPS 2 zu einer Verletzung eines Nerven oder Nervenhauptstamms gekommen ist. Im klinischen Verlauf gibt es jedoch keinen Unterschied zwischen den beiden Formen. In ca. 90 % aller Fälle handelt es sich um ein CRPS 1, früher als „Morbus Sudeck“ bekannt. Das Leitsymptom sind Schmerzen. Zudem können auch trophische Störungen wie Schwelllungen, lokale Verfärbungen der Haut oder asymmetrische Hauttemperaturen auftreten. Häufig finden sich auch eine eingeschränkte Beweglichkeit und Funktionseinbuße der betroffenen Extremität, welche sehr schwer zu therapieren sind. Diagnostik: Initial kann die Unterscheidung eines CRPS von einem normalen posttraumatischen Verlauf schwierig sein. Im weiteren Verlauf stehen die gravierenden Symptome in keinem Verhältnis mehr zum auslösenden Ereignis. Die Diagnose eines CRPS wird primär klinisch gestellt. Die Budapest-Kriterien helfen, die Diagnose zu sichern. Therapie: Eine frühe und interdisziplinäre Rehabilitation ist zentral in der Therapie des CRPS. Ergo- und physiotherapeutische Maßnahmen werden ergänzt mit einer guten medikamentösen Schmerzeinstellung sowie gegebenenfalls auch psychologischer Unterstützung. Medikamentös kommt das analgetische Stufenschema der WHO zum Einsatz, bei starken Hyperalgesien zeigte Methadon gute Erfolge, bei therapieresistenten Schmerzen auch Gabapentin oder Pregabalin. Biphosphonate zeigten einen guten analgetischen Effekt, insbesondere bei nachgewiesenen ossären Läsionen. Die chronischen Ödeme und Entzündungen können einen vorübergehenden Einsatz von Steroiden erfordern. Weiter gilt es, Folgeschäden wie Osteoporose zu verhindern. Patienten, bei welchen der Verdacht auf ein CRPS geäußert wird, sollten durch ein multidisziplinäres Behandlungsteam mit möglicher großer Erfahrung in der Betreuung dieses Krankheitsbildes überwiesen werden. Ein Arzt sollte die Betreuung des Patienten koordinieren. Je früher die Behandlung begonnen wird, desto besser ist die Prognose

An exploratory study investigating the metabolic activity and local cytokine profile in patients with melanoma treated with pazopanib and paclitaxel.

There is a medical need for new drugs in patients with BRAF wild-type metastatic melanoma. Pazopanib is a multitarget tyrosine kinase inhibitor with antitumour and antiangiogenic activity. The primary aim was to investigate the metabolic response to pazopanib monotherapy and pazopanib plus paclitaxel in patients with BRAF wild-type melanoma. Secondary end points were the early cytokine and chemokine profiles and histological findings. Pazopanib (400 mg twice daily) was administered orally from days 1 to 10 and from days 14 to 70. An intravenous infusion with paclitaxel (150 mg m &lt;sup&gt;-2&lt;/sup&gt; body surface) was administered on days 14, 35 and 56. Metabolic response evaluation was performed before treatment, after treatment with pazopanib (day 10) and after treatment with pazopanib and paclitaxel (day 70). Skin biopsy of metastatic tissue for chemokine and cytokine expression analysis and histology and immunohistochemistry (CD68, CD163) evaluation, and blood samples were taken at the same time points. Two patients failed screening and 17 were dosed. Of 67 adverse events, nine (13%) were grade 3 or 4. Five of 14 evaluable patients had a partial metabolic response at day 10 under pazopanib monotherapy. The response rate at day 70 under combined pazopanib-paclitaxel treatment was 0%. Immunohistochemistry revealed an increase of M2-like macrophages in nonresponders compared with responders. We observed a significant upregulation of five cytokines (CXCL1, CXCL2, CXCL13, CCL22 and SPP1) in responding vs. nonresponding lesions. Overall, the median progression-free survival was 70 days (range 5-331), which did not differ significantly between responders (148 days) and nonresponders (70 days, P = 0·17). In this patient population pazopanib efficacy was limited. Response is associated with low M2-like macrophage density and increased expression of several chemokines

Greenhouse vegetable research, 1974

Greenhouse tomato cultivar evaluation trials / W. L. George, Jr. -- The influence of type of irrigation and fertilization on tomato yield and quality / W. L. Bauerle -- Pollinating greenhouse tomatoes with synchronized air cylinders / T. H. Short and W. L. Bauerle -- Effects of evaporative cooling with a horizontal pad-fan system on the yield of a fall crop of greenhouse tomatoes / W. L. George, Jr., G. E. Tolla and R. J. Walker -- Vertical distribution of fusarium oxysporum F. Sp. Lycopersici race 2 in a greenhouse soil / J. D. Farley, N. Hubbeling, C. Jaberg and G. Oakes -- Steam sterilization of tomato greenhouse soils / J. D. Farley, G. Oakes and C. Jaberg -- Effects of leafminer larvae on yields of greenhouse tomatoes: a preliminary report / R. K. Lindquist -- Use of micro-gen insecticide dispersal unit and micro-gen BP-300 insecticide for greenhouse whitefly control on greenhouse tomatoes and cucumbers / R. K. Lindquist -- A leaf lettuce harvester for greenhouses / T. H. Short -- Sex expression of European seedless cucumbers / W. L. George, Jr., W. L. Bauerle and O. S. Well