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Epidemiology involving Kawasaki Ailment within The european union.
PURPOSE Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models. EXPERIMENTAL DESIGN Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model. RESULTS Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial. CONCLUSIONS Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI. ©2020 American Association for Cancer Research.PURPOSE In oropharyngeal squamous cell carcinoma (OPC), high CD8-positive tumor-infiltrating lymphocytes (CD8+TIL) density confers improved prognosis. We compared neoadjuvant durvalumab (PD-L1 inhibitor) with durvalumab plus tremelimumab (CTLA-4 inhibitor) in terms of impact on CD8+TIL density, safety, and efficacy in OPC patients. PATIENTS AND METHODS Patients with newly diagnosed stage II-IVA OPC or locoregionally-recurrent OPC amenable to resection were included. Patients were randomized to two cycles of durvalumab or durvalumab plus tremelimumab before surgery. The primary endpoint was change between baseline and resection specimen in CD8+TIL density between arms. Secondary endpoints included safety, response rate per RECIST, major pathologic response (MPR; ≤10% viable tumor cells) rate, and patient-reported outcomes. RESULTS Of 28 eligible patients (14 per arm), 20 (71%) had newly diagnosed OPC, and 24 (86%) were p16-positive. The posttreatment to pretreatment median CD8+TIL density ratio was 1.31 for durvalumab and 1.15 for combination treatment (P=.97, 95%CI(-1.07,2.28)). In each group, 6 patients (43%, 95%CI(17.66,71.14)) had a response. Eight patients (29%) had a MPR at the primary tumor and/or nodal metastases. Neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, but a trend toward greater CD8+TIL change in patients with a MPR was seen (P=.059, 95%CI(-0.33,3.46)). Four patients (14%) had grade ≥3 adverse events. At median follow-up time of 15.79 months, all patients were alive, and one had an additional recurrence. CONCLUSIONS Durvalumab plus tremelimumab did not increase CD8+TIL density more than durvalumab alone did. The observed safety and activity support further investigation of neoadjuvant checkpoint inhibitor for OPC. Copyright ©2020, American Association for Cancer Research.PURPOSE GDC-0084 is an oral, brain-penetrant small molecule inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Since these two targets alter tumor vascularity and metabolism, respectively, we hypothesized multi-parametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. EXPERIMENTAL DESIGN Multiparametric advanced MR-PET imaging was performed to evaluate physiological response in a first-in-man, multicenter, phase I, dose-escalation study of GDC-0084 (NCT01547546) in 47 patients with recurrent malignant glioma. RESULTS Measured maximum concentration (Cmax ) was associated with a decrease in enhancing tumor volume (P=0.0287) and an increase in fractional anisotropy (FA) (P=0.0418). Post-treatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV were able to estimate both Cmax (R2=0.4113, P 1.25 uM*hr demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P=0.0039 and P=0.0296, respectively). CONCLUSION Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies. Copyright ©2020, American Association for Cancer Research.Optic pathway gliomas are commonly associated with vision loss in children. DNA Repair inhibitor We describe an 18-year-old woman with neurofibromatosis, type 1 and an optic nerve glioma who showed reproducible visual field defects that worsened midmenstrual cycle and returned to baseline during menses. To our knowledge, this is the first reported case of visual field fluctuations in a patient with an optic nerve glioma that correlated with her menstrual cycle. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.A 23-year-old man presented to us with multiple episodes of visible haematuria associated with dysuria, but no other symptoms suggestive of infection. His physical examination was completely unremarkable. On detailed evaluation of history, it was noted that he was treated for urinary schistosomiasis as a child in Sudan. A diagnostic flexible cystoscopy, with both white light and narrow band imaging (NBI), was done among other tests as a further diagnostic tool to investigate possible causes. This revealed the characteristic features of bladder schistosomiasis. Urine microscopy for S chistosoma haematobium eggs was negative, and this could have caused the diagnosis to be missed. He was treated with praziquantel for chronic bladder schistosomiasis. This is the first time that the use of NBI as an adjunct to white light imaging in the diagnosis of bladder schistosomiasis has been reported. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.This report highlights the importance of tailored treatment strategies in severe systemic lupus erythematosus (SLE) flares driving the life-threatening condition, macrophage activation syndrome (MAS). We report the case of a 42-year-old woman with active systemic lupus erythematosus (SLE) who was diagnosed with MAS within 3 days of onset of lethargy, rash, joint pain and significant cytopenias. This early diagnosis meant that her condition was managed with less intensive immunosuppression with only modest doses of steroids and mycophenolate mofetil. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients have been included in previous studies. To determine the genomic landscape of gastric cancer in Hispanic/Latino patients, we performed whole-exome sequencing (WES) and RNA sequencing on tumor samples from 57 patients; germline analysis was conducted on 83 patients. The results were compared to data from Asian and White patients published by The Cancer Genome Atlas. Hispanic/Latino patients had a significantly larger proportion of genomically-stable subtype tumors compared to Asian and White patients (65% vs 21% vs 20%, P less then 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type cancer, 7 (16%) had germline mutations in CDH1. Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P less then 0.05). In silico algorithms predicted 5 variants to be deleterious. For two variants that were predicted to be benign, in vitro modeling demonstrated that these mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes, including a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary. Copyright ©2020, American Association for Cancer Research.EIF3H is presumed to be a critical translational initiation factor. Here our unbiased screening for tumor invasion factors has identified an unexpected role for EIF3H as a deubiquitylating enzyme that dictates breast tumor invasion and metastasis by modulating the Hippo-YAP pathway. EIF3H catalyzed YAP for deubiquitylation, resulting in its stabilization. Structure-based molecular modelling and simulations coupled with biochemical characterization unveiled a unique catalytic mechanism for EIF3H in dissociating polyubiquitin chains from YAP through a catalytic triad consisting of Asp90, Asp91, and Gln121. Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation. Stabilization of YAP via elevated EIF3H promoted tumor invasion and metastasis. Interference of EIF3H-mediated YAP deubiquitylation blocked YAP-induced tumor progression and metastasis in breast cancer models. These findings point to a critical role for YAP regulation by EIF3H in tumor invasion and metastasis. Copyright ©2020, American Association for Cancer Research.BACKGROUND The National Early Warning Score (NEWS) was introduced to standardise early warning scores (EWS) in England. It has been recommended that NEWS should be used in pre-hospital care but there is no published evidence that this improves outcomes. In 2015, the West of England Academic Health Science Network region standardised to NEWS across all healthcare settings. Calculation of NEWS was recommended for acutely unwell patients at referral into secondary care. AIM To evaluate whether implementation of NEWS across a healthcare system affects outcomes, specifically addressing the effect on mortality in patients with suspicion of sepsis (SOS). DESIGN AND SETTING A quality improvement project undertaken across the West of England from March 2015 to March 2019, with the aim of standardising to NEWS in secondary care and introducing NEWS into community and primary care. METHOD Data from the national dashboard for SOS for the West of England were examined over time and compared to the rest of England. Quality improvement methodology and statistical process control charts were used to measure improvement.
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