Activation of the mitogen‐activated protein kinase–extracellular signal‐regulated kinase pathway in childhood B‐cell acute lymphoblastic leukemia

alexandrossfakianakis shared this article with you from Inoreader Activation of the mitogen‐activated protein kinase–extracellular signal‐regulated kinase pathway in childhood B‐cell acute lymphoblastic leukemia via Pediatric Blood & Cancer Abstract RAS mutations are frequently observed in childhood B-cell acute lymphoblastic leukemia (B-ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen-activated protein kinase–extracellular signal-regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of RAS pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal-regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B-ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated/MFI baseline) ranged from 0.76 to 4.40 (median =&n bsp;1.26), and inhibition indexes (MFI stimulated/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median = 1.30), with no significant difference between patients with wildtype versus mutant RAS for either. Logistic regression demonstrated that neither MAPK activation levels nor RAS mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of RAS wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects. View on Web

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Application of an Environmental Monitoring to Assess the Practices and Control the Risk of Occupational Exposure to Cyclophosphamide in Two Sites of a French Comprehensive Cancer Center

alexandrossfakianakis shared this article with you from Inoreader Application of an Environmental Monitoring to Assess the Practices and Control the Risk of Occupational Exposure to Cyclophosphamide in Two Sites of a French Comprehensive Cancer Center via Annals of Work Exposures and Health Advance Access Abstract Objectives The risk of chronic exposure to antineoplastic agents in hospitals, mainly by skin contact with contaminated surfaces, is well established. The aim of this study was to assess indirectly the risk of occupational exposure to antineoplastics drugs at two hospitals by using an environmental monitoring, and to suggest ways of improving the exposure to healthcare workers. Methods An observational study of care practices on both sites was carried out. A wipe sampling campaign was then designed to study environmental contamination throughout the chemotherapy process: receipt, storage, compounding, transport, administration, and elimination areas. Samples were analyzed by a validated LC-MS/MS method allowing trace quantification of cyclophosphamide. A guidance 'safe value' of 0.10 ng/cm2 was considered. Results A total of 293 samples were analyzed, of which 58% were found to be positive. In the compou nding units, the drug vials were contaminated before [range = (non-quantifiable [NQ]-0.71) ng/cm2] and after cleaning procedure [(NQ-0.62) ng/cm2], particularly when the flip-off lid was removed during cleaning. The contamination found on manual preparations was operator-dependent: [non-detectable (ND)-3.51] ng/cm2 on infusion bag surfaces; (780.61–24 698.98) ng/cm2 on medication ports. In the case of automated preparations, the average contamination was higher on infusion bag surfaces [(2.43–36.86) ng/cm2] and lower on medication ports [(0.43–7.65) ng/cm2] than manual preparations. Contamination of the analytical control area was also highlighted. In the daily care unit, the contamination was located near the infusion area (armchairs, infusion stands, floor, and patient toilets), and varied somewhat between the two sites, especially on the floor with (0.46–27.32) compared to (ND-0.18) ng/cm2. We di d not detect contamination on the transport boxes, on the door handles or in the disposal areas. Conclusions The variability of contamination observed between the two sites can be explained in part by the difference in routine practices, especially training of the staff, and cleaning procedures. Findings were communicated to healthcare workers, and news interventions were implemented based on wipe sampling results. This study demonstrated a method for routine environmental monitoring and worker education as a strategy to reduce occupational exposure. View on Web

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Diagnostic potential of extracellular vesicles in meningioma patients

alexandrossfakianakis shared this article with you from Inoreader Diagnostic potential of extracellular vesicles in meningioma patients via Neuro-Oncology Advance Access Abstract Background Extracellular vesicles (EVs) play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. Here, we investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic and proteomic alterations of original tumors. Methods EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis. Results Levels of circulating EVs were elevated in meningioma patients compared to healthy individuals, and the plasma EV concentration correlated with malignanc y grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection. Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in almost all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins that could potentially be utilized to enrich meningioma EVs from biofluids. Conclusions Elevated EV levels in meningioma patient plasma could aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification. View on Web

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Characteristics of Children ≤36 Months of Age with Diffuse Intrinsic Pontine Glioma (DIPG): A Report from the International DIPG Registry

alexandrossfakianakis shared this article with you from Inoreader Characteristics of Children ≤36 Months of Age with Diffuse Intrinsic Pontine Glioma (DIPG): A Report from the International DIPG Registry via Neuro-Oncology Advance Access ABSTRACT: Background Children ≤36 months with Diffuse Intrinsic Pontine Glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. Methods Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. Results Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥ 5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3 -, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (p=0.018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. Conclusions Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis. View on Web

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Outcomes of carotid sparing intensity‐modulated radiotherapy for early stage glottic cancer in 201 patients: Multicenter study of Turkish Radiation Oncology Society/TROD‐01‐007

alexandrossfakianakis shared this article with you from Inoreader Outcomes of carotid sparing intensity‐modulated radiotherapy for early stage glottic cancer in 201 patients: Multicenter study of Turkish Radiation Oncology Society/TROD‐01‐007 via Head & Neck Abstract Background To assess and report clinical outcomes after carotid sparing intensity-modulated radiotherapy for early stage laryngeal cancer. Methods We retrospectively analyzed 201 patients with early stage glottic laryngeal cancer treated with carotid sparing intensity-modulated radiotherapy (IMRT)/volumetric modulated arc therapy (VMAT) techniques in six TROD centers. Results After a median follow-up of 31 months the actuarial 1- and 3-year local and locoregional control rates were 99.4% and 94.7%, 98.4% and 93%, respectively. T classification, anterior commissure involvement, IMRT technique, and type of fractionation were not found to be prognostic for local control. Overall, eight patients had lost their organ function due to recurrence or toxicity. Grade 3 and 4 acute laryngeal edema was seen in eight (4%) and one (0.5%) of patients, respectively. Grade 3 and 4 late laryngeal edema developed in two (1%) and one patient (0.5%), respectively. Conclusion Oncologic outcomes of patients treated with carotid sparing IMRT were excellent; comparable with historical series, with acceptable side effects. Longer follow-up is needed to estimate long term effect on stroke. View on Web

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Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer

alexandrossfakianakis shared this article with you from Inoreader Association of neutrophil-to-lymphocyte ratio, radiotherapy fractionation/technique, and risk of development of distant metastasis among patients with locally advanced rectal cancer via Radiation Oncology - Latest Articles We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced rectal cancer (LARC) and whether modifiable factors in radiotherapy (RT) influenced the NLR. View on Web

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Ralstonia pickettii and Pseudomonas aeruginosa Bloodstream Infections Associated with Contaminated Extracorporeal Membrane Oxygenation Water Heater Devices

alexandrossfakianakis shared this article with you from Inoreader Ralstonia pickettii and Pseudomonas aeruginosa Bloodstream Infections Associated with Contaminated Extracorporeal Membrane Oxygenation Water Heater Devices via Clinical Infectious Diseases Advance Access Abstract We report on probable factory-based contamination of portable water heaters with waterborne pathogens and two bloodstream infections potentially attributable to off-label use of these water heaters to warm extracorporeal membrane oxygenation circuits. Great caution is warranted when using water-based devices to care for critically ill patients. View on Web

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Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent HIV Infection

alexandrossfakianakis shared this article with you from Inoreader Supporting the Art: Medication Adherence Patterns in Persons Prescribed Ingestible Sensor-enabled Oral Pre-Exposure Prophylaxis to Prevent HIV Infection via Clinical Infectious Diseases Advance Access Abstract Background Timely, accurate adherence data may support oral PrEP success and inform prophylaxis choice. We evaluated an FDA-approved digital health feedback system (DHFS) with ingestible-sensor-enabled (IS) tenofovir-disoproxil-fumarate plus emtricitabine (Truvada®) in persons starting oral PrEP. Methods HIV-negative adults were prescribed IS-Truvada® with DHFS for 12 weeks to observe medication taking behavior. Baseline demographics, urine toxicology and self-report questionnaires were obtained. Positive detection accuracy and adverse events were computed as percentages, with Kaplan Meier Estimate for persistence-of-use. In participants persisting ≥ 28 days, adherence patterns (taking and timing) were analyzed and mixed-effects logistic regression modelled characteristics associated with treatment adherence. Results Seventy-one participants enrolled, mean age 37.6 years (range 18-69), 90.1% male, 77.5% white, 33.8% Hispanic, 95.8% housed and 74.6% employed. Sixty-three participants (88.7%) persisted ≥28 days, generating 4987 observation days, average 79.2 (29-105). Total confirmed doses were 86.2% (CI95 82.5, 89.4), decreasing over time, OR 0.899 (CI95 0.876, 0.923) per week, p < 0.001; 79.4% (CI95 66.7%, 87.3%) of participants had ≥80% adherence. Pattern analysis showed days without confirmed doses clustered (p = 0.003); regular dose timing was higher among participants with ≥80% confirmed doses (0.828, CI95 0.796 to 0.859) than among those with <80% (0.542, CI95 0.405 to 0.679) p < 0.001. In multi-predictor models, better adherence was associated with older age, OR 1.060 (CI95 1.033, 1.091) per year, p < 0.001; negative vs positive methamphetamine screen, OR 5.051 (CI95 2.252, 11.494), p < 0.001. Conclusions DHFS with IS-Truvada® distinguished adherent persons from those potentially at risk of prophylactic failure. Ongoing methamphetamine substance use may impact oral PrEP success. View on Web

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