Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.

Metastatic uveal melanoma: Treatment strategies and survival—results from the dutch melanoma treatment registry

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Up to 50% of UM patients will develop metastases. We present data of 175 metastatic UM patients diagnosed in the Netherlands between July 2012 and March 2018. In our cohort, elevated lactate dehydrogenase level (LDH) is an important factor associated with poorer survival (Hazard Ratio (HR) 9.0, 95% Confidence Interval (CI) 5.63–14.35), and the presence of liver metastases is negatively associated with survival (HR 2.09, 95%CI 1.07–4.08). We used data from the nation-wide Dutch Melanoma Treatment Registry (DMTR) providing a complete overview of the location of metastases at time of stage IV disease. In 154 (88%) patients, the liver was affected, and only 3 patients were reported to have brain metastases. In 63 (36%) patients, mutation analysis was performed, showing a GNA11 mutation in 28.6% and a GNAQ mutation in 49.2% of the analyzed patients. In the absence of standard care of treatment options, metastatic UM patients are often directed to clinical trials. Patients participating in clinical trials are often subject to selection and usually do not represent the entire metastatic UM population. By using our nation-wide cohort, we are able to describe real-life treatment choices made in metastatic UM patients and 1-year surv

WTR-trendrapport 1995

Trends & Visie geeft een overzicht van de talrijke aspecten van IT-gebruik die relevant zijn voor het hoger onderwijs: technische, toepassingsgerichte, economische, beheersmatige. Het bepalen van de koers temidden van de turbulente ontwikkelingen is niet eenvoudig. Toch is het mogelijk om een aantal hoofdlijnen te onderkennen. In de eerste plaats: het is niet langer nodig dat het Nederlandse hoger onderwijs in de breedte als trendsetter fungeert bij het gebruik van nieuwe computertechnologieën. De computer- en communicatietechnologie zal de komende decennia gedomineerd worden vanuit de consumentenmarkt. Dat betekent niet dat het hoger onderwijs achterop moet gaan lopen, er moet tijdig ingesprongen worden op de mogelijkheden die geboden worden vanuit de markt. Resterende knelpunten, bijvoorbeeld in bandbreedte voor de telecommunicatie, moeten zo nodig onder eigen regie opgelost worden. Het feit dat de informatie- en communicatietechnologie volwassen wordt impliceert een overgang van de innovatiefase en de diffusiefase naar een infrastructurele benadering. Hierin spelen het doelmatig beheer van de voorzieningen, de standaardisatie en de integratie met andere infrastructurele middelen een belangrijke rol. De tweede hoofdlijn: de innovatiebehoefte verschuift van de techniek naar de inhoud van de informatievoorziening. De afgelopen jaren is al veel aandacht gegeven aan de elektronische toegankelijkheid en levering van informatie aan de onderzoeker en de student. Vanaf de werkplek wordt de gehele wereld ontsloten, en de intermediaire partijen in de informatieketen, bibliotheken zowel als uitgevers, zijn druk doende hun nieuwe posities te bepalen. Doordat de eigen collectie van de instelling niet meer centraal staat, worden bibliotheken geconfronteerd met marktwerking, een markt waarop 'informatie' centraal staat, en niet de fysieke neerslag in een boek of tijdschrift. De ongebondenheid aan tijd, plaats en fysieke drager in de digitale wereld introduceert concurrentie waar die vroeger afwezig was. Kwaliteitsbeheersing van en navigatie door de informatie-ruimte worden van strategische betekenis. Een nog onvoldoende ontgonnen terrein betreft de relatie tussen de onderzoeker als kennisproducent, de universiteit en de uitgever. Alternatieve uitgeefprocessen worden mogelijk, en het is zaak dat de universiteiten zich daarin zakelijk positioneren. Door de beperkte resultaten van de COO-experimenten tot eind jaren tachtig bestaat er grote scepsis over de mogelijkheden van IT in het leerproces. Door de opkomst van de informatiemaatschappij staat het onderwijs nu voor wezenlijke veranderingen. Dat geldt niet alleen voor de universiteiten en hogescholen, maar ook voor het basis- en voortgezet onderwijs. Kinderen groeien nu op met Nintendo en halen straks met gemak materiaal voor werkstukken van het WorldWide Web. Beeld en geluid vormen een geïntegreerd onderdeel van de 'edutainment' produkten die op grote schaal aangeboden gaan worden. Multimediaal informatie-aanbod op de consumentenmarkt stelt de nieuwe norm. Deze ontwikkeling vergt een debat over de aanpassing van het onderwijs. Een debat omdat deze aanpassing allerminst eenvoudig of eenduidig is, en actie vergt van alle niveaus: van de opleiders, van de studierichting, van de instelling en van de overheid. Hiermee zijn drie rode draden geschetst die de ontwikkelingsrichting van IT in het hoger onderwijs tot 2000 zullen bepalen, althans in de ogen van de Wetenschappelijk Technische Raad. Met Trends & Visie, het tweede trendrapport, hoopt de WTR een bijdrage te leveren aan de strategische beleidsvorming op IT-gebied door de hogescholen en universiteiten

Plasma BRAF Mutation Detection for the Diagnostic and Monitoring Trajectory of Patients with LDH-High Stage IV Melanoma

SIMPLE SUMMARY: For patients with metastatic melanoma, a rapid BRAF mutation assessment is vital to reveal the treatment options per patient. Additionally, close monitoring of the disease during treatment is essential to allow for adjustments in the treatment strategy when needed. The aim of this prospective study was to confirm the clinical validity of circulating tumor DNA (ctDNA) for minimally invasive BRAF mutation testing and treatment monitoring of metastatic melanoma patients with elevated lactose dehydrogenase serum levels. We observed that ctDNA-based BRAF mutation testing was a reliable and minimally-invasive alternative to tissue-based testing in 98% of all patients and was 100% specific. The changes in ctDNA levels during therapy appeared helpful for disease monitoring and outperformed other blood-based biomarkers in predicting treatment response. ABSTRACT: For patients with newly diagnosed metastatic melanoma, rapid BRAF mutation (mBRAF) assessment is vital to promptly initiate systemic therapy. Additionally, blood-based biomarkers are desired to monitor and predict treatment response. Circulating tumor DNA (ctDNA) has shown great promise for minimally invasive mBRAF assessment and treatment monitoring, but validation studies are needed. This prospective study utilized longitudinal plasma samples at regular timepoints (0, 6, 12, 18 weeks) to address the clinical validity of ctDNA measurements in stage IV melanoma patients with elevated serum lactate dehydrogenase (LDH > 250U/L) starting first-line systemic treatment. Using droplet digital PCR, the plasma mBRAF abundance was assessed in 53 patients with a BRAFV600 tissue mutation. Plasma mBRAF was detected in 50/51 patients at baseline (98% sensitivity; median fraction abundance of 19.5%) and 0/17 controls (100% specificity). Patients in whom plasma mBRAF became undetectable during the first 12–18 weeks of treatment had a longer progression-free survival (30.2 vs. 4.0 months; p < 0.001) and cancer-specific survival (not reached vs. 10.2 months; p < 0.001) compared to patients with detectable mBRAF. The ctDNA dynamics outperformed LDH and S100 dynamics. These results confirm the clinical validity of ctDNA measurements as a minimally invasive biomarker for the diagnostic and monitoring trajectory of patients with LDH-high stage IV melanoma

Real-world use, safety, and survival of ipilimumab in metastatic cutaneous melanoma in The Netherlands

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Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands

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Early Recurrence in Completely Resected IIIB and IIIC Melanoma Warrants Restaging Prior to Adjuvant Therapy

PURPOSE: To evaluate the results of restaging completely resected stage IIIB/C melanoma prior to start of adjuvant therapy. PATIENTS AND METHODS: One hundred twenty patients with stage IIIB or IIIC (AJCC 2009) melanoma who underwent complete surgical resection were screened for inclusion in our trial investigating adjuvant dendritic cell therapy (NCT02993315). All patients underwent imaging to exclude local relapse or metastasis before entering the trial. The frequency of recurrent disease within 12 weeks after resection and the method of detection were investigated. RESULTS: Sixty-nine (58%) stage IIIB and 51 (43%) stage IIIC melanoma patients were screened. Median age was 54 (range 27-79) years. Twenty-two (18%) of 120 patients with completely resected stage IIIB/C melanoma had evidence of early recurrent disease, despite exclusion thereof by prior imaging. Median interval between resection and detection of relapse was 7.4 (range 4.3-10.7) weeks. Recurrence was asymptomatic in 17 (77%) patients, but metastasis was noticed by the patient or physician in 5 (23%). Eight patients with local relapse received local treatment with curative intent, and one was treated with systemic therapy. The remaining patients had distant metastasis, 1 of whom underwent resection of a solitary liver metastasis while 12 patients received systemic treatment. CONCLUSIONS: Patients with completely resected stage IIIB/C melanoma have high risk of early recurrence before start of adjuvant therapy. Restaging should be considered for high-risk melanoma patients before start of adjuvant therapy

53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

Contains fulltext : 202591.pdf (publisher's version ) (Closed access)OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting. METHODS: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. RESULTS: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r=0.050; p=0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r=-0.69, p=0.004). CONCLUSION: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers

EU transport accident, incident and casualty databases: current status and future needs

Accident and casualty databases are an indispensable tool to allow for objective assessment of the transport safety problem, the identification of priority areas for action and for monitoring the effectiveness of countermeasures. Such databases at European Union level are needed to describe the current state of transport safety across the EU, to help define target levels of safety for each of the transport modes and to facilitate a data-led systems approach in defining strategies. The process of creating a range of common data sources necessary for the development and monitoring of the Common Transport Policy began in 1993. Progress has been achieved, especially for road transport, but for other modes basic kinds of data are lacking at EU-level. In order to allow meaningful analyses within each mode and comparison across the modes, further progress is needed. The purpose of this report is to review the progress made in the development of databases on accidents, casualties and exposure measures for each transport mode and, where gaps exist, to try to identify various options for EU action