This review presents the current data on the efficacy and safety of the selective mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib in patients with metastatic BRAF V600-positive melanoma. The pharmacological, safety, and efficacy data come from the Phase I, II, and III studies of trametinib monotherapy, as well as those in combination with the BRAF inhibitor dabrafenib. The most common adverse effects of trametinib therapy are rash, dermatitis, diarrhea, and fatigue. The Phase III METRIC study showed significant improvement in overall survival and progression-free survival in favor of trametinib over standard dacarbazine or paclitaxel chemotherapy. Therefore, trametinib was approved by the US Food and Drug Administration and European Medicines Agency as a single agent for the treatment of patients with V600E-mutated metastatic melanoma. Progression-free survival and response rates for trametinib monotherapy were lower than those noted with BRAF inhibitors. The second step in developing trametinib was to use the combination of trametinib with the BRAF inhibitor, eg, dabrafenib, to postpone the progression on MEK or BRAF inhibitors. The recently published data showed significant improvement in overall survival and progression-free survival in favor of the combination of trametinib and dabrafenib over vemurafenib therapy or dabrafenib alone, with good tolerance. The US Food and Drug Administration has approved the combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma, and their use seems to be currently the best approach. While BRAF-MEK inhibition is a standard, molecular targeted therapy in BRAF-mutated melanomas, its future utility has to be established in the rapidly changing landscape of immunotherapeutics.
Our analysis confirms the long-term efficacy of sunitinib in patients with advanced ASPS.
The basic principle for the diagnosis of melanoma metastases in the brain should be the management of multidisciplinary teams including at least a neurosurgeon, radiotherapist and clinical oncologist experienced in the treatment of melanoma and melanoma metastases in the CNS. Detection of brain lesions is associated with poor prognosis; metastases in the brain are the cause of death in 20-50% patients, and symptomatic tumours are a direct cause of death in about 90% patients. Treatment of melanoma with CNS metastases may include local management and/or systemic and symptomatic treatment. In the last 5 years, 10 new advanced melanoma drugs have been registered in Europe. Two-drug therapy anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) is the treatment of choice for asymptomatic melanoma metastases in the brain, while in the presence of BRAF mutations and asymptomatic metastases systemic treatment with BRAFi and MEKi may be the first-choice treatment.
Objective: We assessed the status of the BRAF V600E mutation in cell-free circulating tumor DNA (cfDNA) isolated from the plasma of patients with metastatic melanoma treated with the BRAF inhibitor vemurafenib, collected at different time points during therapy to evaluate the sensitivity and specificity of quantitative polymerase chain reaction and droplet digital polymerase chain reaction (ddPCR) and the correlation between the level of plasma cfDNA p.V600E and the long-term clinical outcome. Methods: cfDNA in patients with BRAF-mutated melanoma ( n = 62) was analyzed at baseline and at 4−8 weeks from the start of vemurafenib therapy. BRAF mutations were assessed using tumor tissue-derived DNA and circulating cfDNA from plasma samples. Quantification of BRAF V600E was performed in cfDNA using ddPCR. Results: cfDNA V600E was detected in the plasma of 48/62 (77%) patients at baseline and in 18/62 (29%) patients after 4–8 weeks of treatment. Patients positive for BRAF mutations in cfDNA at baseline had shorter progression-free survival (PFS) and overall survival (OS) compared with patients with undetectable cfDNA BRAF mutations. Undetectable cfDNA p.V600E at baseline and after 4–8 weeks of therapy was associated with the best prognosis. When treated as a continuous variable, the log-transformed concentration of baseline cfDNA p.V600E was significantly associated with both PFS and OS. This effect was retained in the multivariate OS Cox model adjusted for Eastern Cooperative Oncology Group performance status, the presence of brain metastases, patient age, and previous systemic treatment. Conclusions: Monitoring of plasma BRAF p.V600E cfDNA concentrations in patients with metastatic melanoma on targeted therapy may have prognostic value. Undetectable cfDNA p.V600E before and during treatment was associated with a favorable prognosis.
and searched portable document format (PDF) versions of the studies for the complete questionnaire or a Uniform Resource Locator (URL) providing access to the questionnaire. When the questionnaire was not provided in the publication or a published URL, the authors requested it from the corresponding author in writing up to three times over a 6-week period. Of 93 publications with novel questionnaires, four printed the questionnaire in the article and three provided online access. Corresponding authors failed to provide questionnaires for 37 of 81 (46%) studies. Novel questionnaires used in published research are frequently not available to readers or researchers. Policies that improve access to novel questionnaires will allow better assessment of study results, reduce duplicated efforts, and improve authorship attribution for questionnaire design. data collection; methods; peer review; questionnaires; research design Editor's note: An invited commentary on this article is published on page 1145.Because inaccessible questionnaires hinder the evaluation and interpretation of survey results (1-3), researchers have called for better access to novel questionnaires used in published research (4-6). Finding no previous studies of novel questionnaire availability, we systematically examined access to novel questionnaires used in research published in three prominent medical journals. Printed portable document format (PDF) versions of putative qualifying articles were examined by two investigators who independently extracted methods and results to determine which articles met inclusion criteria, including original research with a main outcome that reported results from a novel questionnaire. Questionnaires generally were classified into one of three categories. Many manuscripts stated that the questionnaires were developed for the purpose of the study; these were deemed novel. The second category included published, validated instruments with proper names, for example, The Edinburgh Postnatal Depression Scale and the Behavioral Risk Factor Surveillance System. The third category included questionnaires that were not clearly in either of the first two categories and required further investigation. In these instances, the questionnaires' references were reviewed to determine whether they cited a previously published questionnaire (nonnovel) or publications that supported the design of the study's questionnaire (novel). PDF versions of qualifying studies were manually searched independently by two investigators for publication of a complete questionnaire or publication of a Uniform Resource Locator (URL) providing access to the questionnaire. MATERIALS AND METHODS A MEDLINE search (USDuring the summer of 2004, requests for questionnaires were sent to unique corresponding authors of studies with unpublished novel questionnaires. Only one questionnaire was requested from each author (when the same corresponding author represented more than one publication, the questionnaire from only one randomly selected publication meeting ...
Due to the heterogeneity of soft tissue sarcomas (STS), the choice of the proper perioperative treatment regimen is challenging. Neoadjuvant therapy has attracted increasing attention due to several advantages, particularly in patients with locally advanced disease. The number of available neoadjuvant modalities is growing continuously. We may consider radiotherapy, chemotherapy, targeted therapy, radiosensitizers, hyperthermia, and their combinations. This review discusses possible neoadjuvant treatment options in STS with an emphasis on available evidence, indications for each treatment type, and related risks. Finally, we summarize current recommendations of the STS neoadjuvant therapy response assessment.
Ewing sarcoma (ES) is a group of highly aggressive small round cell tumors of bone or soft tissue with high metastatic potential and low cure rate. ES tumors are associated with a rapid osteolysis and necrosis. The currently accepted clinical prognostic parameters do not accurately predict survival of high-risk patients. Moreover, neither the subtype of EWS–FLI1/ERG in the tumor, nor the detection of fusion transcripts in the peripheral blood (PB) samples, has prognostic value in ES patients. We evaluated the prevalence of circulating tumor cells (CTCs) in 34 adult ES patients. Since CTCs were confirmed in only small subset of patients, we further explored the expression profiles of PB leukocytes using a panel of genes associated with immune system status and increased tumor invasiveness. Moreover, we analyzed the alterations of the routine blood tests in the examined cohort of patients and correlated our findings with the clinical outcome. A uniform decrease in ZAP70 expression in PB cells among all ES patients, as compared to healthy individuals, was observed. Monocytosis and the abnormal expression of CDH2 and CDT2 genes in the PB cells significantly correlated with poor prognosis in ES patients. Our study supports the previously proposed hypothesis of systemic nature of ES. Based on the PB cell expression profiles, we propose a mechanism by which immune system may be involved in intensification of osteoclastogenesis and disease progression in ES patients. Moreover, we demonstrate the prognostic value of molecular PB testing at the time of routine histopathological diagnosis.
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