Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. ...In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
Summary Background VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 ...antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01140347. Findings Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0–10·6) versus 7·6 months (6·0–9·3) for the placebo group (HR 0·87 95% CI 0·72–1·05; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 5% of 277 patients treated with ramucirumab vs 11 4% of 276 patients treated with placebo), hypertension (34 12% vs ten 4%), asthenia (14 5% vs five 2%), malignant neoplasm progression (18 6% vs 11 4%), increased aspartate aminotransferase concentration (15 5% vs 23 8%), thrombocytopenia (13 5% vs one <1%), hyperbilirubinaemia (three 1% vs 13 5%), and increased blood bilirubin (five 2% vs 14 5%). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. Interpretation Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. Funding Eli Lilly and Co.
Summary Background VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would ...increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov , number NCT01170663 , and has been completed; patients who are still receiving treatment are in the extension phase. Findings Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment—330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months 95% CI 8·5–10·8 vs 7·4 months 95% CI 6·3–8·4, hazard ratio 0·807 95% CI 0·678–0·962; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 41% of 327 vs 62 19% of 329), leucopenia (57 17% vs 22 7%), hypertension (46 14% vs eight 2%), fatigue (39 12% vs 18 5%), anaemia (30 9% vs 34 10%), and abdominal pain (20 6% vs 11 3%). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten 3% vs eight 2%). Interpretation The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Funding Eli Lilly and Company.
Summary Background Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. ...We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer. Methods We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00917384. Findings 355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio HR 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 16% vs nine 8%), whereas rates of other adverse events were mostly similar between groups (223 94% vs 101 88%). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug. Interpretation Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer. Funding ImClone Systems.
The hormone fibroblast growth factor 21 (FGF21) exerts diverse, beneficial effects on energy balance and insulin sensitivity when administered systemically to rodents with diet-induced obesity (DIO). ...The current studies investigate whether central FGF21 treatment recapitulates these effects.
After preliminary dose-finding studies, either saline vehicle or recombinant human FGF21 (0.4 microg/day) was infused continuously for 2 weeks into the lateral cerebral ventricle of male Wistar rats rendered obese by high-fat feeding. Study end points included measures of energy balance (body weight, body composition, food intake, energy expenditure, and circulating and hepatic lipids) and glucose metabolism (insulin tolerance test, euglycemic-hyperinsulinemic clamp, and hepatic expression of genes involved in glucose metabolism).
Compared with vehicle, continuous intracerebroventricular infusion of FGF21 increased both food intake and energy expenditure in rats with DIO, such that neither body weight nor body composition was altered. Despite unchanged body fat content, rats treated with intracerebroventricular FGF21 displayed a robust increase of insulin sensitivity due to increased insulin-induced suppression of both hepatic glucose production and gluconeogenic gene expression, with no change of glucose utilization.
FGF21 action in the brain increases hepatic insulin sensitivity and metabolic rate in rats with DIO. These findings identify the central nervous system as a potentially important target for the beneficial effects of FGF21 in the treatment of diabetes and obesity.
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Even though the last decade has seen a surge in the identification of molecular targets and targeted therapies in pediatric brain tumors, the blood brain barrier (BBB) remains a ...significant challenge in systemic drug delivery. This continues to undermine therapeutic efficacy. Recent efforts have identified several strategies that can facilitate enhanced drug delivery into pediatric brain tumors. These include invasive methods such as intra-arterial, intrathecal, and convection enhanced delivery and non-invasive technologies that allow for transient access across the BBB, including focused ultrasound and nanotechnology. This review discusses current strategies that are being used to enhance delivery of different therapies across the BBB to the tumor site – a major unmet need in pediatric neuro-oncology.
The Laramide orogeny is a pivotal time in the geological development of western North America, but its driving mechanism is controversial. Most prominent models suggest this event was caused by the ...collision of an oceanic plateau with the Southern California Batholith (SCB) which caused the angle of subduction beneath the continent to shallow and led to shut-down of the arc. Here, we use over 280 zircon and titanite Pb/U ages from the SCB to establish the timing and duration of magmatism, metamorphism and deformation. We show that magmatism was surging in the SCB from 90 to 70 Ma, the lower crust was hot, and cooling occurred after 75 Ma. These data contradict plateau underthrusting and flat-slab subduction as the driving mechanism for early Laramide deformation. We propose that the Laramide orogeny is a two-stage event consisting of: 1) an arc 'flare-up' phase in the SCB from 90-75 Ma; and 2) a widespread mountain building phase in the Laramide foreland belt from 75-50 Ma that is linked to subduction of an oceanic plateau.
Washing with chlorine bleach leads to high mixing ratios of gas-phase HOCl. Using two methods that are sensitive to surface film compositionattenuated total reflection fourier transform infrared ...(ATR-FTIR) spectroscopy and direct analysis in real time mass spectrometry (DART-MS)we present the first study of the chlorination chemistry that occurs when gaseous HOCl reacts with thin films of squalene and oleic acid. At mixing ratios of 600 ppbv, HOCl forms chlorohydrins by adding across carbon–carbon double bonds without breaking the carbon backbone. The initial uptake of one HOCl molecule occurs on the time scale of a few minutes at these mixing ratios. For oleic acid, ester formation proceeds immediately thereafter, leading to dimeric and trimeric chlorinated products. For squalene, subsequent HOCl uptake occurs until all six of its carbon–carbon double bonds become chlorinated within 1–2 h. These results indicate that chlorination of skin oil, which contains substantial carbon unsaturation, is likely to occur rapidly under common cleaning conditions, potentially leading to the irritation associated with chlorinated bleach. This chemistry will likely also proceed with cooking oils, in the human respiratory system which has unsaturated surfactants as important components of lung fluid, and with organic components of the sea surface microlayer.
To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC).
Adults with ...organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay.
The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma.
We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.
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