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Composite solid electrolytes combining the advantages of inorganic and polymer electrolytes are considered as one of the promising candidates for solid-state lithium metal batteries. Compared with ceramic-in-polymer electrolyte, polymer-in-ceramic electrolyte displays excellent mechanical strength to inhibit lithium dendrite. However, polymer-in-ceramic electrolyte faces the challenges of lack of flexibility and severely blocked Li+transport. In this study, we prepared polymer-in-ceramic film utilizing ultra-high molecular weight polymers and ceramic particles to combine flexibility and mechanical strength. Meanwhile, the ionic conductivity of polymer-in-ceramic electrolytes was improved by adding excess lithium salt in polymer matrix to form polymer-in-salt structure. The obtained film shows high stiffness (10.5 MPa), acceptable ionic conductivity (0.18 mS cm-1) and high flexibility. As a result, the corresponding lithium symmetric cell stably cycles over 800 h and the corresponding LiFePO4cell provides a discharge capacity of 147.7 mAh g-1at 0.1 C without obvious capacity decay after 145 cycles.
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The demand for Lithium-ion batteries (LIBs) has significantly grown in the last decade due to their extensive use electric vehicles. To further advance the commercialization of LIBs for various applications, there is a pressing need to develop electrode materials with enhanced performance. The porous microsphere morphology LiNixMn2-xO4(LNMO) is considered to be an effective material with both high energy density and excellent rate performance. Nevertheless, LNMO synthesis technology still has problem such as long reaction time, high energy consumption and environmental pollution. Herein, LNMO microsphere was successfully synthesized with short precursors reaction time (18 s) at 40 °C without using chelating agent by microreaction technology combined solid-state lithiation. The optimized LNMO cathode shows microsphere (â¼8µm) morphology stacked by nano primary particles, with abundant mesoporous and fully exposed low-energy plane. The electrochemical analysis indicates that the optimized LNMO cathode demonstrates 97.33% capacity retention even after 200 cycles at 1C. Additionally, the material shows a highly satisfactory discharge capacity of 92.3 mAh·g-1at 10C. Overall, microreaction technology is anticipated to offer a novel approach in the synthesis of LNMO cathode materials with excellent performance.
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BACKGROUND: This study aimed to evaluate the presence of symptoms of Internet Gaming Disorder (IGD) and examined associations between IGD and depressive symptoms, family and peer support among male college students in Nanchong, China. METHODS: A cross-sectional study was conducted among 2533 male students in three colleges. Background characteristics, depressive symptoms, family and peer support and IGD information were collected. Binary logistic regression was performed to access the relationship between variables and IGD. PROCESS macro was used to examine the mediation analysis of family and peer support on the relationship between depressive symptoms and IGD. RESULTS: The estimated presence of symptoms of IGD was 11.6%. The most commonly endorsed items were escapism, continuation and preoccupation both among total participates and the IGD group. In the binary logistic regression, general expenditure per month, depressive symptoms, and family and peer support revealed their significance in associations with IGD. Adjusted for the significant background variable, depressive symptoms and family and peer support remained significance. Additionally, family and peer support would attenuate the relationship between depressive symptoms and IGD. CONCLUSIONS: This study found that one in ten male college students reported clinically significant IGD symptoms, which indicate that IGD is an important public health problem in Nanchong, China.
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Comportamento Aditivo , Jogos de Vídeo , Humanos , Masculino , Comportamento Aditivo/diagnóstico , Comportamento Aditivo/epidemiologia , China/epidemiologia , Estudos Transversais , Internet , Transtorno de Adição à Internet , EstudantesRESUMO
With the continuous development of artificial intelligence, embedding object detection algorithms into autonomous underwater detectors for marine garbage cleanup has become an emerging application area. Considering the complexity of the marine environment and the low resolution of the images taken by underwater detectors, this paper proposes an improved algorithm based on Mask R-CNN, with the aim of achieving high accuracy marine garbage detection and instance segmentation. First, the idea of dilated convolution is introduced in the Feature Pyramid Network to enhance feature extraction ability for small objects. Secondly, the spatial-channel attention mechanism is used to make features learn adaptively. It can effectively focus attention on detection objects. Third, the re-scoring branch is added to improve the accuracy of instance segmentation by scoring the predicted masks based on the method of Generalized Intersection over Union. Finally, we train the proposed algorithm in this paper on the Transcan dataset, evaluating its effectiveness by various metrics and comparing it with existing algorithms. The experimental results show that compared to the baseline provided by the Transcan dataset, the algorithm in this paper improves the mAP indexes on the two tasks of garbage detection and instance segmentation by 9.6 and 5.0, respectively, which significantly improves the algorithm performance. Thus, it can be better applied in the marine environment and achieve high precision object detection and instance segmentation.
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Algoritmos , Inteligência ArtificialRESUMO
BACKGROUND: Secondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis. METHODS: This 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, 'switch' study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium-phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231. RESULTS: Overall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and â¼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from -25.4% to -26.1% for PTH, -8.3% to -9.1% for Ca, -3.6% to -4.1% for P and -12.0% to -12.6% for Ca × P. CONCLUSIONS: Etelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.
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Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/administração & dosagem , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Administração Intravenosa , Idoso , Cálcio/sangue , Método Duplo-Cego , Feminino , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/patologia , Masculino , Hormônio Paratireóideo/sangue , Prognóstico , Insuficiência Renal Crônica/terapiaRESUMO
OBJECTIVE: To study the chemical constituents of Armadillidium vulgare. METHODS: Compounds were isolated and purified by various column chromatography, spectroscopic methods were used to identify their structures. RESULTS: Seven compounds were isolated from Armadillidium vulgare and identified as vulgarine A (1), o-hydroxylbenzoic acid (2), dipyrrolopiperazine-2,5-dione (3), 4(1-H)-quinolone (4), adenine (5), n-acetyltyramine (6) and 4-methyl-5-thiazoleethanol (7). CONCLUSION: Compound 1 is a new alkaloid, compounds 3-7 are all nitrogen containing substances, which are isolated from Armadillidae family for the first time.
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Alcaloides/análise , Isópodes/química , AnimaisRESUMO
In recent years, Kubernetes (K8s) has become a dominant resource management and scheduling system in the cloud. In practical scenarios, short-running cloud workloads are usually scheduled through different scheduling algorithms provided by Kubernetes. For example, artificial intelligence (AI) workloads are scheduled through different Volcano scheduling algorithms, such as GANG_MRP, GANG_LRP, and GANG_BRA. One key challenge is that the selection of scheduling algorithms has considerable impacts on job performance results. However, it takes a prohibitively long time to select the optimal algorithm because applying one algorithm in one single job may take a few minutes to complete. This poses the urgent requirement of a simulator that can quickly evaluate the performance impacts of different algorithms, while also considering scheduling-related factors, such as cluster resources, job structures and scheduler configurations. In this paper, we design and implement a Kubernetes simulator called K8sSim, which incorporates typical Kubernetes and Volcano scheduling algorithms for both generic and AI workloads, and provides an accurate simulation of their scheduling process in real clusters. We use real cluster traces from Alibaba to evaluate the effectiveness of K8sSim, and the evaluation results show that (i) compared to the real cluster, K8sSim can accurately evaluate the performance of different scheduling algorithms with similar CloseRate (a novel metric we define to intuitively show the simulation accuracy), and (ii) it can also quickly obtain the scheduling results of different scheduling algorithms by accelerating the scheduling time by an average of 38.56×.
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INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic, inflammatory skin disease, with high disease burden, that is often refractory to treatment. There is a high unmet clinical need for the treatment of patients with PPP. The objectives of this study were to evaluate the safety and efficacy of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients with PPP. METHODS: This was a phase IIa, multicenter, double-blind, randomized, placebo-controlled pilot study comparing 900 mg spesolimab (n = 19), 300 mg spesolimab (n = 19), and placebo (n = 21) administered intravenously every 4 weeks until week 12 in patients with PPP. The primary efficacy endpoint was the achievement of Palmoplantar Pustulosis Area and Severity Index 50 (PPP ASI50) at week 16, defined as achieving an ≥ 50% decrease from baseline PPP ASI. RESULTS: At week 16, 31.6% of patients in both spesolimab dose groups achieved PPP ASI50 versus 23.8% receiving placebo (risk difference 0.078; 95% confidence interval -0.190, 0.338). Thus, the primary endpoint was not met. Spesolimab was well tolerated with no clinically relevant treatment-emergent safety signals observed. CONCLUSIONS: PPP severity declined over time in all treatment groups after the start of treatment, with a faster decline in the spesolimab arms than in the placebo arm, indicating a potential treatment effect for spesolimab. Limitations to the study included a small sample size and lower overall disease severity than expected at baseline. It is possible that the primary efficacy endpoint may have coincided with natural disease resolution in some patients. Further effects of the efficacy of spesolimab in PPP are being explored in a phase IIb trial.
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INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare. METHODS AND ANALYSIS: At least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated. ETHICS AND DISSEMINATION: The study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation's Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov identifier: NCT03782792; Pre-results.
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Psoríase , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , Humanos , Japão , Estudos Multicêntricos como Assunto , Psoríase/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taiwan , Tailândia , Resultado do TratamentoRESUMO
BACKGROUND: Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials. METHODS: This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed. RESULTS: Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients. CONCLUSIONS: This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.
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Calcimiméticos/uso terapêutico , Cálcio/metabolismo , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Diálise Renal , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Fósforo/metabolismo , PrognósticoRESUMO
The immunogenicity risk assessment and bioanalytical strategy for novel therapeutics should account for both unique biophysical properties and potential consequences of immunogenicity. When assessing the immunogenicity risk of etelcalcetide, a peptide agonist of the calcium-sensing receptor, we considered the potential that the d-amino acid 'backbone' and biotransformation of etelcalcetide could allow the drug to act as a hapten. As a consequence, we validated and implemented a surface plasmon resonance immunoassay platform with both etelcalcetide and etelcalcetide-'carrier' surfaces to detect anti-drug antibodies (ADA). No evidence of in-vitro neutralizing activity with surrogate controls was detected despite multiple immunization approaches and a sensitive cell-based activity assay. Therefore, a neutralizing assay was not implemented for clinical support. We conducted an integrated analysis of immunogenicity data pooled from two pivotal placebo-controlled trials to define the clinical impact of anti-etelcalcetide antibodies. While both pre-existing and developing anti-etelcalcetide antibodies were detected, we show here that they have no consequences for clinical exposure, efficacy, or safety of etelcalcetide.
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Imunoensaio , Peptídeos/imunologia , Ressonância de Plasmônio de Superfície , Animais , Anticorpos/imunologia , Humanos , CoelhosRESUMO
BACKGROUND: Kidney transplantation corrects or improves many complications of chronic kidney disease, but its impact on disordered mineral metabolism is incompletely understood. METHODS: We performed a multicenter, prospective, observational cohort study of 246 kidney transplant recipients in the United States to investigate the evolution of mineral metabolism from pretransplant through the first year after transplantation. Participants were enrolled into 2 strata defined by their pretransplant levels of parathyroid hormone (PTH), low PTH (>65 to ≤300 pg/mL; n = 112), and high PTH (>300 pg/mL; n = 134) and underwent repeated, longitudinal testing for mineral metabolites. RESULTS: The prevalence of posttransplant, persistent hyperparathyroidism (PTH >65 pg/mL) was 89.5%, 86.8%, 83.1%, and 86.2%, at months 3, 6, 9, and 12, respectively, among participants who remained untreated with cinacalcet, vitamin D sterols, or parathyroidectomy. The results did not differ across the low and high PTH strata, and rates of persistent hyperparathyroidism remained higher than 40% when defined using a higher PTH threshold greater than 130 pg/mL. Rates of hypercalcemia peaked at 48% at week 8 in the high PTH stratum and then steadily decreased through month 12. Rates of hypophosphatemia (<2.5 mg/dL) peaked at week 2 and then progressively decreased through month 12. Levels of intact fibroblast growth factor 23 decreased rapidly during the first 3 months after transplantation in both PTH strata and remained less than 40 pg/mL thereafter. CONCLUSIONS: Persistent hyperparathyroidism is common after kidney transplantation. Further studies should determine if persistent hyperparathyroidism or its treatment influences long-term posttransplantation clinical outcomes.
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Hiperparatireoidismo/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim , Adulto , Idoso , Biomarcadores/sangue , Cálcio/sangue , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Hipercalcemia/sangue , Hipercalcemia/epidemiologia , Hiperparatireoidismo/sangue , Hiperparatireoidismo/diagnóstico , Hipofosfatemia/sangue , Hipofosfatemia/epidemiologia , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Prevalência , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: This first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors. METHODS: Three to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208. RESULTS: Fifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed. CONCLUSIONS: In this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.
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Biomarcadores Tumorais/metabolismo , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Triazóis/farmacocinética , Triazóis/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/genética , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Feminino , Humanos , Hipertensão/induzido quimicamente , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/efeitos adversos , Indução de Remissão , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
BACKGROUND: The symptoms and pathogenesis of Parkinson's disease (PD) are complicated and an accurate diagnosis of PD is difficult, particularly in early-stage. Because functional magnetic resonance imaging (fMRI) is non-invasive and is characterized by the integration of different brain areas in terms of functional connectivity (FC), fMRI has been widely used in PD research. Non-motor symptom (NMS) features are also frequently present in PD before the onset of classical motor symptoms with pain as the primary NMS. Considering that PD could affect the pain process at multiple levels, we hypothesized that pain is one of the earliest symptoms in PD and investigated whether FC of the pain network was disrupted in PD without pain. To better understand the pathogenesis of pain in PD, we combined resting state and pain-stimuli-induced task state fMRI to identify alterations in FC related to pain in PD. METHODS: Fourteen early drug-naïve PD without pain and 17 age- and sex-matched healthy controls (HC) participated in our testing task. We used independent component analysis to select seven functional networks related to PD and pain. We focused on abnormalities in FC and in functional network connectivity (FNC) in PD compared with HC during the task (51°C heat pain stimuli) and at rest. RESULTS: Compared with HC, PD showed decreased FC in putamen within basal ganglia network (BGN) in task state and decreased FC in putamen of salience network (SN) and mid-cingulate cortex of sensorimotor network in rest state. FNC between the BGN and the SN are reduced during both states in PD compared with HC. In addition, right frontoparietal network (RFPN), which is considered as a bridge between the SN and default-mode network, was significantly disturbed during the task. CONCLUSION: These findings suggest that BGN plays a role in the pathological mechanisms of pain underlying PD, and RFPN likely contributes greatly to harmonization between intrinsic brain activity and external stimuli.
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PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC. EXPERIMENTAL DESIGN: Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work. RESULTS: In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints. CONCLUSIONS: Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Panitumumabe , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. RESULTS: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. CONCLUSIONS: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma.
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Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Receptor IGF Tipo 1/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/patologia , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/sangue , Desoxicitidina/administração & dosagem , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , PTEN Fosfo-Hidrolase/genética , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Receptor IGF Tipo 1/genética , Análise de Sobrevida , Proteínas ras/genética , GencitabinaRESUMO
PURPOSE: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS: Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
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Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Tumor Desmoplásico de Pequenas Células Redondas/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Tumor Desmoplásico de Pequenas Células Redondas/sangue , Tumor Desmoplásico de Pequenas Células Redondas/imunologia , Tumor Desmoplásico de Pequenas Células Redondas/mortalidade , Tumor Desmoplásico de Pequenas Células Redondas/secundário , Feminino , Humanos , Hibridização in Situ Fluorescente , Fator de Crescimento Insulin-Like I/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Receptor IGF Tipo 1/imunologia , Sarcoma de Ewing/sangue , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/mortalidade , Sarcoma de Ewing/secundário , Análise de Sequência de RNA , Fatores de Tempo , Translocação Genética , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab. RESULTS: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses. CONCLUSIONS: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/efeitos adversos , Biomarcadores Tumorais , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Panitumumabe , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Sorafenibe , GencitabinaRESUMO
PURPOSE: This phase Ib study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 102, a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in combination with bevacizumab or motesanib in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with treatment-refractory advanced solid tumors were sequentially enrolled into four cohorts (3, 10, or 20 mg/kg AMG 102 plus 10 mg/kg bevacizumab i.v. every 2 weeks, or 3 mg/kg AMG 102 i.v. every 2 weeks plus 75 mg motesanib orally once daily). RESULTS: Fourteen patients were enrolled and received AMG 102. The combination of AMG 102 with bevacizumab (n = 12) seemed to have acceptable toxicity. The number of patients (n = 2) who received AMG 102 plus motesanib was insufficient to adequately assess safety. No dose-limiting toxicities were reported. Enrollment in the motesanib cohort was suspended because of reports of cholecystitis in other motesanib studies. Treatment-emergent adverse events among patients receiving AMG 102 plus bevacizumab were generally mild and included fatigue (75%), nausea (58%), constipation (42%), and peripheral edema (42%). No anti-AMG 102 antibodies were detected. Bevacizumab did not seem to affect AMG 102 pharmacokinetics. Circulating total HGF/SF increased from baseline throughout the study. Eight of 10 evaluable patients had reductions in tumor dimensions, and stable disease at > or =8, > or =16, and > or =24 weeks occurred in 9, 7, and 4 patients, respectively. Progression-free survival ranged from 7.9 to 121.9 weeks. CONCLUSIONS: AMG 102 in combination with bevacizumab was well tolerated. Further evaluation of AMG 102 in combination with antiangiogenic agents is warranted.