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Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer. In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18–75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506. 400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67–1·05; median progression-free survival 4·6 months [95% CI 3·5–6·3] vs 3·4 months [2·3–3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033). Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer. Zhejiang Beta Pharma (China), the Chinese National Key Special Program for Innovative Drugs, the 863 Project, and Zhejiang Provincial Key Special Program.

\"The Portuguese in West Africa, 1415-1670 brings together a collection of documents - all in new English translation - that illustrate aspects of the encounters between the Portuguese and the peoples of North and West Africa in the period from 1400 to 1650. This period witnessed the diaspora of the Sephardic Jews, the emigration of Portuguese to West Africa and the islands, and the beginnings of the black diaspora associated with the slave trade. The documents show how the Portuguese tried to understand the societies with which they came into contact and to reconcile their experience with the myths and legends inherited from classical and medieval learning. They also show how Africans reacted to the coming of Europeans, adapting Christian ideas to local beliefs and making use of exotic imports and European technologies. The documents also describe the evolution of the black Portuguese communities in Guinea and the islands, as well as the slave trade and the way that it was organized, understood, and justified\"-- Provided by publisher.

Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12–16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m2) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% CI 4·1–8·3) with olaratumab plus doxorubicin and 4·1 months (2·8–5·4) with doxorubicin (stratified hazard ratio [HR] 0·67; 0·44–1·02, p=0·0615). Median overall survival was 26·5 months (20·9–31·7) with olaratumab plus doxorubicin and 14·7 months (9·2–17·1) with doxorubicin (stratified HR 0·46, 0·30–0·71, p=0·0003). The objective response rate was 18·2% (9·8–29·6) with olaratumab plus doxorubicin and 11·9% (5·3–22·2) with doxorubicin (p=0·3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26·2) to 487 μg/mL (CV% 33·0) and from 123 μg/mL (CV% 31·2) to 156 μg/mL (CV% 38·0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. Eli Lilly and Company.

'Galileo Unbound' traces the journey that brought us from Galileo's law of free fall to today's geneticists measuring evolutionary drift, entangled quantum particles moving among many worlds, and our lives as trajectories traversing a health space with thousands of dimensions. Remarkably, common themes persist that predict the evolution of species as readily as the orbits of planets or the collapse of stars into black holes. This book tells the history of spaces of expanding dimension and increasing abstraction and how they continue today to give new insight into the physics of complex systems.-- Publisher's description.

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. 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. 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. 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. Eli Lilly and Co.

The relation between platelet reactivity and stent thrombosis, major bleeding, and other adverse events after coronary artery implantation of drug-eluting stents has been incompletely characterised. We aimed to determine the relation between platelet reactivity during dual therapy with aspirin and clopidogrel and clinical outcomes after successful coronary drug-eluting stent implantation. ADAPT-DES was a prospective, multicentre registry of patients successfully treated with one or more drug-eluting stents and given aspirin and clopidogrel at 10–15 US and European hospitals. We assessed platelet reactivity in those patients after successful percutaneous coronary intervention using VerifyNow point-of-care assays, and assigned different cutoffs to define high platelet reactivity. The primary endpoint was definite or probable stent thrombosis; other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. We did a propensity-adjusted multivariable analysis to determine the relation between platelet reactivity and subsequent adverse events. This study is registered with ClinicalTrials.gov, number NCT00638794. Between Jan 7, 2008, and Sept 16, 2010, 8665 patients were prospectively enrolled at 11 sites, of which 8583 were eligible. At 1-year follow-up, stent thrombosis had occurred in 70 (0·8%) patients, myocardial infarction in 269 (3·1%), clinically relevant bleeding in 531 (6·2%), and death in 161 (1·9%) patients. High platelet reactivity on clopidogrel was strongly related to stent thrombosis (adjusted HR 2·49 [95% CI 1·43–4·31], p=0·001) and myocardial infarction (adjusted HR 1·42 [1·09–1·86], p=0·01), was inversely related to bleeding (adjusted HR 0·73 [0·61–0·89], p=0·002), but was not related to mortality (adjusted HR 1·20 [0·85–1·70], p=0·30). High platelet reactivity on aspirin was not significantly associated with stent thrombosis (adjusted HR 1·46 [0·58–3·64], p=0·42), myocardial infarction, or death, but was inversely related to bleeding (adjusted HR 0·65 [0·43–0·99], p=0·04). The findings from this study emphasise the counter-balancing effects of haemorrhagic and ischaemic complications after stent implantation, and suggest that safer drugs or tailored strategies for the use of more potent agents must be developed if the benefits of greater platelet inhibition in patients with cardiovascular disease are to be realised. Boston Scientific, Abbott Vascular, Medtronic, Cordis, Biosensors, The Medicines Company, Daiichi-Sankyo, Eli Lilly, Volcano, and Accumetrics

Accurate detection of driver gene mutations is crucial for treatment planning and predicting prognosis for patients with lung cancer. Conventional genomic testing requires high-quality tissue samples and is time-consuming and resource-consuming, and as a result, is not available for most patients, especially those in low-resource settings. We aimed to develop an annotation-free Deep learning-enabled artificial intelligence method to predict GEne Mutations (DeepGEM) from routinely acquired histological slides. In this multicentre retrospective study, we collected data for patients with lung cancer who had a biopsy and multigene next-generation sequencing done at 16 hospitals in China (with no restrictions on age, sex, or histology type), to form a large multicentre dataset comprising paired pathological image and multiple gene mutation information. We also included patients from The Cancer Genome Atlas (TCGA) publicly available dataset. Our developed model is an instance-level and bag-level co-supervised multiple instance learning method with label disambiguation design. We trained and initially tested the DeepGEM model on the internal dataset (patients from the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China), and further evaluated it on the external dataset (patients from the remaining 15 centres) and the public TCGA dataset. Additionally, a dataset of patients from the same medical centre as the internal dataset, but without overlap, was used to evaluate the model's generalisation ability to biopsy samples from lymph node metastases. The primary objective was the performance of the DeepGEM model in predicting gene mutations (area under the curve [AUC] and accuracy) in the four prespecified groups (ie, the hold-out internal test set, multicentre external test set, TCGA set, and lymph node metastases set). Assessable pathological images and multigene testing information were available for 3697 patients who had biopsy and multigene next-generation sequencing done between Jan 1, 2018, and March 31, 2022, at the 16 centres. We excluded 60 patients with low-quality images. We included 3767 images from 3637 consecutive patients (1978 [54·4%] men, 1514 [41·6%] women, 145 [4·0%] unknown; median age 60 years [IQR 52–67]), with 1716 patients in the internal dataset, 1718 patients in the external dataset, and 203 patients in the lymph node metastases dataset. The DeepGEM model showed robust performance in the internal dataset: for excisional biopsy samples, AUC values for gene mutation prediction ranged from 0·90 (95% CI 0·77–1·00) to 0·97 (0·93–1·00) and accuracy values ranged from 0·91 (0·85–0·98) to 0·97 (0·93–1·00); for aspiration biopsy samples, AUC values ranged from 0·85 (0·80–0·91) to 0·95 (0·86–1·00) and accuracy values ranged from 0·79 (0·74–0·85) to 0·99 (0·98–1·00). In the multicentre external dataset, for excisional biopsy samples, AUC values ranged from 0·80 (95% CI 0·75–0·85) to 0·91 (0·88–1·00) and accuracy values ranged from 0·79 (0·76–0·82) to 0·95 (0·93–0·96); for aspiration biopsy samples, AUC values ranged from 0·76 (0·70–0·83) to 0·87 (0·80–0·94) and accuracy values ranged from 0·76 (0·74–0·79) to 0·97 (0·96–0·98). The model also showed strong performance on the TCGA dataset (473 patients; 535 slides; AUC values ranged from 0·82 [95% CI 0·71–0·93] to 0·96 [0·91–1·00], accuracy values ranged from 0·79 [0·70–0·88] to 0·95 [0·90–1·00]). The DeepGEM model, trained on primary region biopsy samples, could be generalised to biopsy samples from lymph node metastases, with AUC values of 0·91 (95% CI 0·88–0·94) for EGFR and 0·88 (0·82–0·93) for KRAS and accuracy values of 0·85 (0·80–0·88) for EGFR and 0·95 (0·92–0·96) for KRAS and showed potential for prognostic prediction of targeted therapy. The model generated spatial gene mutation maps, indicating gene mutation spatial distribution. We developed an AI-based method that can provide an accurate, timely, and economical prediction of gene mutation and mutation spatial distribution. The method showed substantial potential as an assistive tool for guiding the clinical treatment of patients with lung cancer. National Natural Science Foundation of China, the Science and Technology Planning Project of Guangzhou, and the National Key Research and Development Program of China. For the Chinese translation of the abstract see Supplementary Materials section.