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1.
Mod Rheumatol ; 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35484824

RESUMO

OBJECTIVES: Histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) regulate the activation of neutrophils and vascular endothelium. The aim of this study was to quantify HRG and HMGB1 levels in patients with Kawasaki disease (KD) and evaluate their use in the clinical management of KD. METHODS: This study was prospectively performed. Patients were divided into two groups and analyzed depending on whether KD symptoms improved by day 10 of illness. HRG, HMGB1, and other laboratory variables were measured before the first treatment in all cases and, in most cases, afterwards, for assessing trends. RESULTS: In this prospective study, we enrolled 60 patients with KD and 48 healthy controls. The HRG level in the KD group was significantly lower than that in the healthy control group; HMGB1 levels showed no obvious differences. In the KD group, HRG levels were negatively correlated with white blood cell and neutrophil counts. In the poor responders and responders groups, a tendency for a decrease in HRG and HMGB1 levels, respectively, was observed from pretreatment to post-treatment. CONCLUSIONS: HRG and HMGB1 are related to the pathogenesis of KD; low HRG and high HMGB1 levels cause resistance against KD treatment.

2.
Trauma Case Rep ; 38: 100631, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35265746

RESUMO

The absolute indications for lower limb replantation are not unequivocally established; rather, this procedure is still challenging and controversial. We report a case of a young male who underwent bilateral leg amputation, followed by unilateral replantation. The patient demonstrated good 10-year outcomes. A 23-year-old man had both of his lower legs crushed by heavy machinery that fell from the back of a truck, leading to amputation of bilateral lower limbs. Although bilateral amputation was recommended due to severe contusion on both sides, the patient and his family strongly requested replantation of the right leg, and surgery was started approximately 3 h after the injury. In addition to the emergency replantation, six surgeries were performed thereafter. Five months after the first surgery, the patient was fitted with a left lower leg prosthesis and started gait training. He was discharged 8 months later. Ten years after the replantation, the patient is satisfied with his leg. He has a normal gait with a prosthesis and has integrated into society with no functional deficit. There are still no clear standards for replantation after leg amputation, and individual decisions must be made based on the severity of the injury and the patient's general condition. In this case, we respected the patient's strong will to preserve the right leg and decided on the treatment plan. As a result, the patient was highly satisfied, and the spared right leg facilitated the patient's physical and mental recovery.

3.
JA Clin Rep ; 8(1): 17, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35244794

RESUMO

INTRODUCTION: Precision medicine is a phrase used to describe personalized medical care tailored to specific patients based on their clinical presentation and genetic makeup. However, despite the fact that several single nucleotide polymorphisms (SNPs) have been reported to be associated with increased susceptibility to particular anesthetic agents and the occurrence of perioperative complications, genomic profiling and thus precision medicine has not been widely applied in perioperative management. METHODS: We validated six SNP loci known to affect perioperative outcomes in Japanese patients using genomic DNA from saliva specimens and nanopore sequencing of each SNP loci to facilitate allele frequency calculations and then compared the nanopore results to those produced using the conventional dideoxy sequencing method. RESULTS: Nanopore sequencing reads clustered into the expected genotypes in both homozygous and heterozygous cases. In addition, the nanopore sequencing results were consistent with those obtained using conventional dideoxy sequencing and the workflow provided reliable allele frequency estimation, with a total analysis time of less than 4 h. CONCLUSION: Thus, our results suggest that nanopore sequencing is a promising and versatile tool for SNP genotyping, allowing for rapid and feasible risk prediction of perioperative outcomes.

4.
Artigo em Inglês | MEDLINE | ID: mdl-35201525

RESUMO

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17 years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17 years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17 years receiving an initial antipsychotic prescription.

5.
Liver Cancer ; 10(3): 249-259, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34239811

RESUMO

INTRODUCTION: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. METHODS: Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. RESULTS: Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (n = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (n = 5 [22.7%]), and decreased appetite (n = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9-34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9-54.9%) per mRECIST for HCC. CONCLUSION: Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

6.
Medicina (Kaunas) ; 57(2)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567770

RESUMO

Background and objectives: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread to more than 200 countries. In light of this situation, the Japanese Government declared a state of emergency in seven regions of Japan on 7 April 2020 under the provisions of the law. The medical care delivery system has been under pressure. Although various surgical societies have published guidelines on which to base their surgical decisions, it is not clear how general anesthesia has been performed and will be performed in Japan. Materials and Methods: One of the services provided by the social network service Twitter is a voting function-Twitter Polls-through which anonymous surveys were conducted. We analyzed the results of a series of surveys 17 times over 22 weeks on Twitter on the status of operating restrictions using quadratic programming to solve the mathematical optimizing problem, and public data provided by the Japanese Government were used to estimate the current changes in the number of general anesthesia performed in Japan. Results: The minimum number of general anesthesia cases per week was estimated at 67.1% compared to 2015 on 27 April 2020. The timeseries trend was compatible with the results reported by the Japanese Society of Anesthesiologists (correlation coefficient r = 0.69, p < 0.001). Conclusions: The number of general anesthesia was reduced up to two-thirds during the pandemic of COVID-19 in Japan and was successfully quantitatively estimated using a quick questionnaire on Twitter.


Assuntos
Anestesia Geral/estatística & dados numéricos , Anestesiologia/estatística & dados numéricos , COVID-19 , Utilização de Instalações e Serviços/estatística & dados numéricos , Mídias Sociais/estatística & dados numéricos , Humanos , Japão , Computação Matemática , Projetos de Pesquisa , SARS-CoV-2 , Sociedades Médicas/estatística & dados numéricos , Inquéritos e Questionários
7.
Stat Med ; 40(10): 2413-2421, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33580519

RESUMO

In event-driven clinical trials comparing the survival functions of two groups, the number of events required to achieve the desired power is usually calculated using the Freedman formula or the Schoenfeld formula. Then, the sample size and the study duration derived from the required number of events are considered; however, their combination is not uniquely determined. In practice, various combinations are examined considering the enrollment speed, study duration, and the cost of enrollment. However, effective methods for visually representing their relationships and evaluating the uncertainty in study duration are insufficient. We developed a graphical approach for examining the relationship between sample size and study duration. To evaluate the uncertainty in study duration under a given sample size, we also derived the probability density function of the study duration and a method for updating the probability density function according to the observed number of events (ie, information time). The proposed methods are expected to improve the operation and management of clinical trials with a time-to-event endpoint.


Assuntos
Projetos de Pesquisa , Humanos , Tamanho da Amostra , Incerteza
8.
Medicina (Kaunas) ; 56(10)2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33053765

RESUMO

Background and objectives: The coronavirus disease 2019 (COVID-19) pandemic is overwhelming Japan's intensive care capacity. This study aimed to determine the number of patients with COVID-19 who required intensive care and to compare the numbers with Japan's intensive care capacity. Materials and Methods: Publicly available datasets were used to obtain the number of confirmed patients with COVID-19 undergoing mechanical ventilation and extracorporeal membrane oxygenation (ECMO) between 15 February and 19 July 2020 to determine and compare intensive care unit (ICU) and attending bed needs for patients with COVID-19, and to estimate peak ICU demands in Japan. Results: During the epidemic peak in late April, 11,443 patients (1.03/10,000 adults) had been infected, 373 patients (0.034/10,000 adults) were in ICU, 312 patients (0.028/10,000 adults) were receiving mechanical ventilation, and 62 patients (0.0056/10,000 adults) were under ECMO per day. At the peak of the epidemic, the number of infected patients was 651% of designated beds, and the number of patients requiring intensive care was 6.0% of ICU beds, 19.1% of board-certified intensivists, and 106% of designated medical institutions in Japan. Conclusions: The number of critically ill patients with COVID-19 continued to rise during the pandemic, exceeding the number of designated beds but not exceeding ICU capacity.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Cuidados Críticos/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , COVID-19 , Estado Terminal/epidemiologia , Emergências/epidemiologia , Humanos , Japão , Masculino , Pandemias , SARS-CoV-2
9.
JA Clin Rep ; 6(1): 71, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32930910

RESUMO

BACKGROUND: Pulmonary vein thrombosis (PVT) and cerebral infarction are rare but critical complications after video-assisted thoracic surgery (VATS). CASE PRESENTATION: We experienced two cases of massive middle cerebral artery infarction after VATS for the left upper lobe. Although the precise source of their embolus was never identified, both cases were clinically suspected PVT. Unfortunately, case 2 died because of progressive cerebral herniation. We decided to perform contrast-enhanced computed tomography routinely after VATS for the left upper lobectomy (VATS-LUL) after these cases. Case 3, a 79-year-old female patient, underwent VATS-LUL for lung cancer. She developed PVT in the stump of the left upper pulmonary vein on postoperative day 4. Anti-coagulation therapy was begun immediately and continued for 3 months. She was free of complications 7 months after the operation. CONCLUSION: PVT and cerebral infarction may occur after VATS-LUL. Appropriate postoperative management is required to recognize PVT and to prevent life-threatening stroke.

10.
Cancer Sci ; 111(3): 907-923, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883418

RESUMO

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/metabolismo , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Neoplasias Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão
11.
BMJ Open ; 9(12): e033131, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31796494

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS. METHODS AND ANALYSIS: An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers. ETHICS AND DISSEMINATION: This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Compostos de Anilina/administração & dosagem , Nitrilas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Adulto , Ensaios Clínicos Fase I como Assunto , Reposicionamento de Medicamentos/métodos , Feminino , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Neurônios Motores/efeitos dos fármacos , Células-Tronco Pluripotentes/efeitos dos fármacos
12.
Int J Hematol ; 110(6): 709-722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31655984

RESUMO

Inotuzumab ozogamicin (InO) is a targeted treatment for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). InO was previously studied in INO-VATE, an international, open-label, randomized phase 3 trial comparing InO against standard of care (SoC). In the present subgroup analysis, we evaluated outcomes in the 55 Asian patients who were randomized in INO-VATE (31 InO and 24 SoC). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 22/31 patients treated with InO versus 5/24 treated with SoC. In the InO arm, more of the patients achieving CR/CRi were minimal residual disease (MRD)-negative (17/22 versus 1/5), and more patients proceeded directly to hematopoietic stem cell transplantation (15/31 versus 3/24). Median overall survival for the respective arms was 5.8 versus 3.9 months (hazard ratio 0.67; 97.5% CI 0.28, 1.62). In the safety analysis (n = 51), the most common adverse events were hematologic. Sinusoidal obstruction syndrome was reported in five InO patients and one SoC patient. In conclusion, Asian patients with relapsed or refractory B-cell ALL experienced improved efficacy with InO versus SoC, with an efficacy and safety profile consistent with results of the overall INO-VATE population.Clinical trial registration: ClinicalTrials.gov identifier: NCT01564784.


Assuntos
Inotuzumab Ozogamicina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Inotuzumab Ozogamicina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Indução de Remissão/métodos , Terapia de Salvação/efeitos adversos , Terapia de Salvação/normas , Padrão de Cuidado
13.
Front Mar Sci ; 6: 391, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31534949

RESUMO

Developments in observing system technologies and ocean data assimilation (DA) are symbiotic. New observation types lead to new DA methods and new DA methods, such as coupled DA, can change the value of existing observations or indicate where new observations can have greater utility for monitoring and prediction. Practitioners of DA are encouraged to make better use of observations that are already available, for example, taking advantage of strongly coupled DA so that ocean observations can be used to improve atmospheric analyses and vice versa. Ocean reanalyses are useful for the analysis of climate as well as the initialization of operational long-range prediction models. There are many remaining challenges for ocean reanalyses due to biases and abrupt changes in the ocean-observing system throughout its history, the presence of biases and drifts in models, and the simplifying assumptions made in DA solution methods. From a governance point of view, more support is needed to bring the ocean-observing and DA communities together. For prediction applications, there is wide agreement that protocols are needed for rapid communication of ocean-observing data on numerical weather prediction (NWP) timescales. There is potential for new observation types to enhance the observing system by supporting prediction on multiple timescales, ranging from the typical timescale of NWP, covering hours to weeks, out to multiple decades. Better communication between DA and observation communities is encouraged in order to allow operational prediction centers the ability to provide guidance for the design of a sustained and adaptive observing network.

14.
Biol Pharm Bull ; 42(3): 389-393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828071

RESUMO

Warfarin is a drug used for anticoagulation management, with a narrow therapeutic range and multiple drug-drug interactions. Adherence and proper use of concomitant medication are thus fundamental to the efficacy and safety of warfarin therapy. In 2012, we retrospectively analyzed data from three large-scale pharmacy chains in Japan. We included all adults (≥ 20 years old) with at least one record of warfarin dispensation. We examined patient demographic data, adherence as measured by medication possession ratio (MPR), and co-dispensation focusing on the number of concomitant dispensations and concurrent use of medications that increase bleeding risk. Thresholds of underadherence and overadherence were set at <0.9 and >1.1, considering the narrow therapeutic window. We reviewed 443007 warfarin dispensation records of 71340 individuals (median age, 73 years; 62% male). The MPR was 1.0 (interquartile range: 0.96-1.0), and underadherence and overadherence was found in 16.3 and 1.9% of individuals, respectively. The median number of co-dispensed drugs was eight at each pharmacy encounter, which did not differ by age group. Drugs associated with a high bleeding risk were dispensed in 40.0% of encounters and accounted for 16.4% of all co-dispensed drugs. In summary, we found optimal overall adherence, as assessed by MPR, among our Japanese study population, even when defining a strict cut-off value. However, polypharmacy was common in all age groups and medications with a high bleeding risk profile were often co-dispensed with warfarin. Future research addressing how these dispensation patterns affect patient outcome is warranted.


Assuntos
Bases de Dados Factuais , Adesão à Medicação , Varfarina/administração & dosagem , Varfarina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Assistência Farmacêutica/estatística & dados numéricos , Farmácias , Polimedicação , Adulto Jovem
15.
BMC Cancer ; 19(1): 17, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616534

RESUMO

BACKGROUND: A prospective, randomised phase II study demonstrated clinical benefit of axitinib dose titration in a subset of treatment-naïve patients treated with axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with axitinib dose titration. METHODS: Following a 4-week lead-in period during which all patients received axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive axitinib 5 mg bid plus either axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus < 24 months, and compared their baseline characteristics with Fisher's exact test or Cochran-Armitage trend exact test, with a 5% significance level. Potential predictive baseline characteristics associated with effect of axitinib dose titration on OS were investigated using a Cox proportional hazard model. RESULTS: Overall, 112 patients were randomised. Three of 56 patients receiving axitinib titration were censored; of the remaining 53, 33 (62%) achieved OS ≥24 months versus 20 (38%) with OS < 24 months. Patients with OS ≥24 vs. < 24 months, respectively, had significantly fewer metastatic sites (≤2 metastases: 52% vs. 10%; ≥3 metastases: 48% vs. 90%), fewer lymph node (45% vs. 75%) or liver (15% vs. 45%) metastases, higher haemoglobin level (i.e., ≥ lower limit of normal: 67% vs. 25%) at baseline, lower neutrophil (≤ upper limit of normal, 97% vs. 75%) and platelet (≤ upper limit of normal, 82% vs. 50%) levels at baseline and ≥ 1 year between histopathological diagnosis and treatment (64% vs. 15%). The primary reason for treatment discontinuation in both OS groups was disease progression. The frequency of toxicity-related discontinuation was comparable between the 2 groups, indicating that it was not a factor for a shorter OS. The multivariate analysis showed that ≥1 year from histopathological diagnosis to treatment and baseline haemoglobin level equal or greater than lower limit of normal were significant covariates associated with favourable OS in patients receiving axitinib titration. CONCLUSIONS: The current analyses identified potentially predictive factors that could help selecting patients who may benefit from axitinib dose titration. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00835978. Registered prospectively, February 4, 2009.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/secundário , Idoso , Antineoplásicos/administração & dosagem , Axitinibe/administração & dosagem , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , Suspensão de Tratamento
17.
J Med Virol ; 91(3): 361-369, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30281823

RESUMO

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Ciclopentanos/uso terapêutico , Guanidinas/uso terapêutico , Proteína HMGB1/imunologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Ácidos Carbocíclicos , Animais , Citocinas/antagonistas & inibidores , Quimioterapia Combinada , Inflamação/tratamento farmacológico , Injeções Intramusculares , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Infecções por Orthomyxoviridae/virologia
18.
Int Immunol ; 31(3): 127-139, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30534943

RESUMO

Hassall's corpuscles (HCs) are composed of cornifying, terminally differentiated medullary thymic epithelial cells (mTECs) that are developed under the control of Aire. Here, we demonstrated that HC-mTECs show features of cellular senescence and produce inflammatory cytokines and chemokines including CXCL5, thereby recruiting and activating neutrophils to produce IL-23 in the thymic medulla. We further indicated that thymic plasmacytoid dendritic cells (pDCs) expressing IL-23 receptors constitutively produced Ifna, which plays a role in single positive (SP) cell maturation, in an Il23a-dependent manner. Neutrophil depletion with anti-Ly6G antibody injection resulted in a significant decrease of Ifna expression in the thymic pDCs, suggesting that thymic neutrophil activation underlies the Ifna expression in thymic pDCs in steady state conditions. A New Zealand White mouse strain showing HC hyperplasia exhibited greater numbers and activation of thymic neutrophils and pDCs than B6 mice, whereas Aire-deficient B6 mice with defective HC development and SP thymocyte maturation showed significantly compromised numbers and activation of these cells. These results collectively suggested that HC-mTECs with cell-senescence features initiate a unique cell activation cascade including neutrophils and pDCs leading to the constitutive IFNα expression required for SP T-cell maturation in the thymic medulla.


Assuntos
Senescência Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon-alfa/biossíntese , Neutrófilos/imunologia , Neutrófilos/metabolismo , Timo/imunologia , Animais , Células Cultivadas , Células Dendríticas/citologia , Humanos , Interferon-alfa/metabolismo , Camundongos , Camundongos Endogâmicos , Neutrófilos/citologia , Timo/citologia
19.
Sci Rep ; 8(1): 13138, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177702

RESUMO

A matrix that enabled chirality and structure-selective detection in matrix assisted laser desorption ionization mass spectrometry (MALDI MS) has been developed. Molds of L- or D- alanine were made on a thermoreversible polymer (polyvinyl methyl ether) with 2,4,6-trihydroxyacetophenone, and this was used as a matrix. Separate detection of one optical isomer of alanine was realized in MALDI MS. This technique was also applied to the detection of trisaccharides having the same molecular weight but different structures. Separate detection of raffinose and maltotriose in MALDI MS were presented.

20.
J Hum Genet ; 63(10): 1097-1098, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30069028

RESUMO

Since the advance online publication of this article, the authors of the above paper have noticed errors in the list of authors and affiliations. The article with correct author information now appears in this issue.

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