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1.
Jpn J Clin Oncol ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32424430

RESUMO

The development of PD-1 pathway inhibitors has dramatically altered the treatment of advanced/recurrent non-small-cell lung cancer patients. However, the prognostic significance of their ongoing usage is controversial, especially for patients who have not progressed for a period of time. If discontinuation has no negative impact on survival, suspension may reduce side effects from toxicity and help alleviate the economic burdens on health insurance systems and patients. This randomized controlled trial enrolls patients who have responded well to PD-1 pathway inhibitors for >12 months. The aim is to confirm the non-inferiority of discontinuation of PD-1 pathway inhibitors, relative to continuation, in terms of overall survival. A total of 216 patients will be enrolled over 3 years. This trial has been registered in the Japan Registry for Clinical Trials as jRCT1031190032 (https://jrct.niph.go.jp/). An ancillary study examining the prognostic and predictive role of circulating tumor DNA using Guardant360® is planned.

2.
Cancer Sci ; 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32426915

RESUMO

The pathogenesis of lung cancer associated with idiopathic pulmonary fibrosis (IPF) has remained largely uncharacterized. To provide insight into this condition, we performed genomic profiling of IPF-associated lung cancer as well as of adjacent fibrosing lung tissue in surgical specimens. Isolated DNA and RNA from 17 IPF-associated non-small cell lung cancer and 15 paired fibrosing lung tissue specimens were analyzed by next-generation sequencing with a panel that targets 161 cancer-related genes. Somatic genetic alterations were frequently identified in TP53 (n = 6, 35.3%) and PIK3CA (n = 5, 29.4%) genes in tumor samples as well as in EGFR (n = 7, 46.7%), PIK3CA (n = 5, 33.3%), ERBB3 (n = 4, 26.7%), and KDR (n = 4, 26.7%) in IPF samples. Genes related to the RAS-RAF signaling pathway were also frequently altered in tumor (n = 7, 41.2%) and IPF (n = 3, 20.0%) samples. The number of somatic alterations identified in IPF samples was almost as large as that detected in paired tumor samples (81 versus 90, respectively). Only six of the 81 somatic alterations detected in IPF samples overlapped with those in paired tumor samples, however. The accumulation of somatic mutations was thus apparent in IPF tissue of patients with IPF-associated lung cancer, and the RAS-RAF pathway was implicated in lung tumorigenesis. The finding that somatic alterations were not frequently shared between tumor and corresponding IPF tissue indicates that IPF-associated lung cancer does not develop through the stepwise accumulation of somatic alterations in IPF.

3.
Clin Lung Cancer ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32381420

RESUMO

BACKGROUND: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC. PATIENTS AND METHODS: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival. CONCLUSION: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.

4.
Int J Cancer ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32356560

RESUMO

Immunotherapy targeting programmed cell death-1 (PD-1) has become a standard pharmacological therapy. Although tumor mutation burden level was reported to depend on the tumor location in nonsmall cell lung cancer (NSCLC), predictive impact of the tumor location on the response to anti-PD-1 therapy is unknown. Two hundred and seventeen advanced or recurrent NSCLC patients treated with anti-PD-1 therapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. Of the 217 patients, 132, 27, and 58 had primary NSCLC in upper, middle, and lower lobes, respectively. Patients with NSCLC in upper lobe were significantly associated with younger age (P = .0070) and smoker (P = .0003). The epidermal growth factor receptor-wild type and tumor location in upper lobe were independent predictors of disease control (P = .0175 and P = .0425, respectively). The IPTW-adjusted Kaplan-Meier curves showed that patients with NSCLC in the upper lobes had significantly longer progression-free survival (PFS) and overall survival (OS) than those in middle/lower lobes (P = .0026 and P = .0015, respectively). On IPTW adjusted Cox analysis, NSCLC in the upper lobe was an independent predictor of PFS and OS (P = .0078 and P = .0034, respectively). Patients with primary NSCLC in the upper lobes may be good candidates for anti-PD-1 therapy. These findings should be validated prospectively.

5.
Lung Cancer ; 145: 18-26, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32388276

RESUMO

BACKGROUND: Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. MATERIALS AND METHODS: We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: BMI ≥ 19.1 kg/m2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %. CONCLUSIONS: dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy.

6.
Int Immunol ; 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32253426

RESUMO

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3, and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event.

7.
Peptides ; 129: 170313, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32298774

RESUMO

Experimental allergic encephalomyelitis (EAE) is considered to be a useful animal model of human multiple sclerosis (MS). However, among the various symptoms of MS, the mechanisms contributing to inflammatory anorexia remain unclear. In the present study, we used an EAE rat model to examine changes in expression levels of hypothalamic feeding-related peptide genes and neuroendocrine responses such as the hypothalamo-neurohypophysial system and the hypothalamo-pituitary-adrenal (HPA) axis. The weight gain and cumulative food intake in EAE rats in the early days after immunization was significantly lower than that of the control group. The expression of orexigenic peptide genes Npy and Agrp were significantly increased, whereas the levels of anorectic peptide genes (Pomc and Cart) were significantly decreased in the hypothalamus of EAE rats. There was also a significant increase in the mRNA and plasma oxytocin (OXT) but not of arginine vasopressin (AVP) in the supraoptic and paraventricular nuclei (PVN) of EAE rats at days 12 and 18 after immunization. The expression of corticotropin-releasing hormone (Crh) and Avp was downregulated and upregulated, respectively, in the parvocellular division of the PVN at day 12 after immunization. The expression level of Pomc in the anterior pituitary significantly increased, accompanied by increased plasma corticosterone levels, at days 6, 12, and 18 after immunization. These results suggest that inflammatory anorexia in rat EAE may be caused by activation of the OXT-ergic pathway and HPA axis via changes in the expression of hypothalamic feeding-related peptides, including Avp but not Crh.

8.
J Cancer Res Clin Oncol ; 146(5): 1217-1225, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32025867

RESUMO

PURPOSE: The aim of this study was to elucidate the clinical impact of skeletal muscle area (SMA) in patients with non-small cell lung cancer (NSCLC) treated with anti-programmed cell death-1 (PD-1) inhibitors. METHODS: Univariate and multivariate analyses were performed on data of 103 patients with advanced or recurrent NSCLC treated with anti-PD-1 inhibitors. The SMA was measured at the level of the third lumbar vertebral (L3) on computed tomography images using OsiriX software (32-bit, version 5.8; OsiriX, Geneva, Switzerland). The L3 muscle index (cm2/m2) was defined as the SMA (cm2) at the L3 level divided by the height (m) squared. RESULTS: L3 muscle index Low was an independent predictor of both progression-free (P = 0.0399) and overall survival (P = 0.0155). Moreover, the disease control rate was significantly lower in the L3 muscle index Low group (49.0% [25/51]) than in the L3 muscle index High group (73.1% [38/52]; P = 0.0117). However, there was no significant difference between the response rates of the L3 muscle index Low group (21.6% [11/51]) and L3 muscle index High group (32.7% [17/52]; P = 0.2031). CONCLUSIONS: L3 muscle index Low is an independent predictor of worse outcomes in NSCLC patients treated with anti-PD-1 inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Músculo Esquelético/efeitos dos fármacos , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Estudos Retrospectivos
9.
Artigo em Inglês | MEDLINE | ID: mdl-32085898

RESUMO

Upregulation of the Src tyrosine kinase is implicated in the progression of cancer. The oncogenic potential of Src is suppressed via several negative regulation systems including degradation via the ubiquitin-proteasome pathway. Here, we show that ubiquitination of Src promotes its secretion via small extracellular vesicles (sEVs) to suppress its oncogenic potential. In MDCK cells expressing a modified Src that can be activated by hydroxytamoxifen, activated Src was transported to late endosomes/lysosomes and secreted via sEVs. The secretion of Src was suppressed by ablation of Cbl E3-ligase, suggesting the contribution of ubiquitination to this process. Activated Src was ubiquitinated at multiple sites, and Lys429 was identified as a critical site for sEV-mediated secretion. Mutation of Src at Lys429 (R429) caused resistance to ubiquitination and decreased its secretion via sEVs. The activated R429 mutant was also transported to late endosomes/lysosomes, whereas its incorporation into intraluminal vesicles was reduced. Activation of the R429 mutant induced a greater FAK activation than that of wild-type Src, thereby potentiating Src-induced invasive phenotypes, such as invadopodia formation and invasive activity. These findings demonstrate that ubiquitination of activated Src at Lys429 promotes its secretion via sEVs, suggesting a potential strategy to suppress the oncogenic function of upregulated Src.

10.
Sci Rep ; 10(1): 1876, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024862

RESUMO

Over the past 15 years, massive gas hydrate deposits have been studied extensively in Joetsu Basin, Japan Sea, where they are associated primarily with active gas chimney structures. Our research documents the discovery of spheroidal microdolomite aggregates found in association with other impurities inside of these massive gas hydrates. The microdolomites are often conjoined and show dark internal cores occasionally hosting saline fluid inclusions. Bacteroidetes sp. are concentrated on the inner rims of microdolomite grains, where they degrade complex petroleum-macromolecules present as an impurity within yellow methane hydrate. These oils show increasing biodegradation with depth which is consistent with the microbial activity of Bacteroidetes. Further investigation of these microdolomites and their contents can potentially yield insight into the dynamics and microbial ecology of other hydrate localities. If microdolomites are indeed found to be ubiquitous in both present and fossil hydrate settings, the materials preserved within may provide valuable insights into an unusual microhabitat which could have once fostered ancient life.

11.
J Immunother Cancer ; 8(1)2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32066647

RESUMO

BACKGROUND: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. METHODS: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. RESULTS: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. CONCLUSIONS: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

14.
Hypertens Res ; 43(5): 404-411, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31853044

RESUMO

Although high blood pressure (BP) and BP variability have been reported to be associated with cognitive impairment, few studies have investigated the association between home BP (HBP) and cognitive function in the oldest-old. The aim of this study was to evaluate whether the value of and the day-to-day variability in HBP was associated with cognitive function in a Japanese community-dwelling oldest-old population. Among 111 participants aged 85-87 years, cognitive function was assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J). HBP was measured two times every morning for a median of 30 days. The value of and variability in HBP were calculated as the average and coefficient of variation (CV) of the measurements, respectively. The associations of HBP variability with MoCA-J were examined using multiple linear regression models. Of 111 participants, 47.7% were men, and 64.0% were taking medications for hypertension. The mean HBP was 141.9 ± 14.8/72.2 ± 8.4 mmHg, and the mean CV of HBP was 6.7 ± 1.9/6.8 ± 2.4. The mean total MoCA-J score was 22.9 ± 3.5. The MoCA-J score was significantly lower with increasing CVs of both systolic BP (b = -0.36, p = 0.034) and diastolic BP (b = -0.26, p = 0.046) after adjustment for possible confounding factors. The value of HBP was not associated with MoCA-J. In the community-dwelling oldest-old population, higher day-to-day HBP variability, but not the value of HBP, was associated with cognitive impairment. When measuring HBP, attention should be paid not only to the values but also to their variations.

15.
Sci Total Environ ; 705: 135501, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31846816

RESUMO

Trace elements of bivalve shells can potentially record the physical and chemical properties of the ambient seawater during shell formation, thereby providing valuable information on environmental conditions and provenance of the bivalves. In an acidifying ocean, whether and how seawater acidification affects the trace elemental composition of bivalve shells is largely unknown. Here, we investigated the transgenerational effects of OA projected for the end of the 21st century on the incorporation of trace elements into shells of the Manila clam, Ruditapes philippinarum. Neither seawater pH nor transgenerational exposure affected the Mg and Sr composition of the shells. Compared with clams grown under ambient conditions, specimens exposed to elevated CO2 levels incorporated significantly higher amounts of Cu, Zn, Ba and Pb into their shells, in line with the fact that at lower pH, these elements in seawater occur at higher fractions in free forms which are biologically available. Transgenerational effects manifested themselves significantly during the incorporation of Cu and Zn into the shells, most likely because Cu and Zn are biologically essential trace elements for metabolic processes. In addition, the plasticity of metabolism toward energetic efficiency following transgenerational exposure confers the clams enhanced ability to discriminate against Cu and Zn during the uptake from the ambient environment to the site of calcification. In the context of near-future OA scenarios, these findings may provide unique insights into the two primary applications of trace elements of bivalve shells as geographical tracers and proxies of environmental conditions.


Assuntos
Bivalves , Animais , Concentração de Íons de Hidrogênio , Alimentos Marinhos , Água do Mar , Oligoelementos
16.
Chem Asian J ; 14(23): 4415-4419, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31696631

RESUMO

A series of π-extended chelating scaffolds incorporating two hydroxypyridone moieties were synthesized. X-ray crystallographic analysis revealed that a bis(hydroxypyridono)toluene ligand possessed a unique π-extended structure and exhibited efficient phase segregation from the aliphatic chains attached at the heterocyclic nitrogen. The bis-bidentate ligand formed a metal-coordination-induced macrocycle with Cu2+ ions. During the complexation, a spectral change in the visible region was induced. Furthermore, the successful development of a liquid crystal of the metallomacrocycle with appropriate side chains was achieved. Examples of liquid-crystalline macrocycles formed via metal-mediated self-assembly are still rare. Among them, the macrocycle described in this paper showed an obvious hexagonal columnar phase reflecting the three-fold symmetric planar structure of the mesogenic metal complex.

17.
Lung Cancer ; 138: 58-64, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639551

RESUMO

OBJECTIVES: Pleural effusion (PE) occasionally develops in cancer patients during treatment with antibodies to programmed cell death-1 (PD-1) or to its ligand PD-L1 (hereafter, αPD-1 therapy). Such effusion often contains infiltrated mononuclear cells, although the types of immune cell present as well as the outcome of such patients have remained unclear. MATERIALS AND METHODS: We performed a multi-institutional, observational study to examine the clinical outcome of patients who develop PE after the onset of αPD-1 therapy. We compared the immune cell profiles and the immune status of lymphocytes in PE as determined by flow cytometry between nine patients who developed effusion during αPD-1 therapy (αPD-1 group) and 15 patients who developed PE during treatment with other anticancer agents (control group). RESULTS: Most mononuclear cells in PE were lymphocytes in both the αPD-1 and control groups. The frequency of both CD4+ and CD8+ T lymphocytes expressing the immune checkpoint proteins TIM-3 or TIGIT as well as that of CD8+ T lymphocytes expressing PD-L1 were increased in the αPD-1 group compared with the control group. αPD-1 therapy continued for a substantial period after the emergence of PE in six of the nine patients in the αPD-1 group, and the frequency of CD4+ T lymphocytes in PE expressing the immune checkpoint protein LAG-3 or the cytokine interkeukin-17 was lower for these patients than for those who did not receive a sustained treatment benefit. CONCLUSION: Our results suggest a clinical benefit of continuing αPD-1 therapy in some patients who develop PE. We found that infiltrating T lymphocytes in PE manifest a more exhausted phenotype during αPD-1 therapy than during treatment with other cancer drugs, with subpopulations of these cells characterized by specific immune checkpoint protein and cytokine expression profiles possibly contributing to the antitumor immune response.

18.
Proc Natl Acad Sci U S A ; 116(38): 19025-19030, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31484761

RESUMO

Male genital structures are among the most rapidly evolving morphological traits and are often the only features that can distinguish closely related species. This process is thought to be driven by sexual selection and may reinforce species separation. However, while the genetic bases of many phenotypic differences have been identified, we still lack knowledge about the genes underlying evolutionary differences in male genital organs and organ size more generally. The claspers (surstyli) are periphallic structures that play an important role in copulation in insects. Here, we show that divergence in clasper size and bristle number between Drosophila mauritiana and Drosophila simulans is caused by evolutionary changes in tartan (trn), which encodes a transmembrane leucine-rich repeat domain protein that mediates cell-cell interactions and affinity. There are no fixed amino acid differences in trn between D. mauritiana and D. simulans, but differences in the expression of this gene in developing genitalia suggest that cis-regulatory changes in trn underlie the evolution of clasper morphology in these species. Finally, analyses of reciprocal hemizygotes that are genetically identical, except for the species from which the functional allele of trn originates, determined that the trn allele of D. mauritiana specifies larger claspers with more bristles than the allele of D. simulans Therefore, we have identified a gene underlying evolutionary change in the size of a male genital organ, which will help to better understand not only the rapid diversification of these structures, but also the regulation and evolution of organ size more broadly.

19.
Sci Rep ; 9(1): 13362, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527660

RESUMO

To examine the association between 18F-fluorodeoxyglucose (18F-FDG) uptake in positron emission tomography/computed tomography (PET/CT) and the response to anti-programmed cell death-1 (PD-1) monoclonal antibody therapy in non-small cell lung cancer (NSCLC) patients, 89 patients with advanced or recurrent NSCLC were retrospectively analysed. Maximum standardized uptake value (SUVmax) in 18F-FDG PET/CT and the response to anti-PD-1 antibodies were recorded. A cut-off value of SUVmax was determined by receiver operating characteristic curve analysis for patient stratification. Among the 89 patients evaluated, 24 were classified as responders (all partial response), and 65 as non-responders. The average SUVmax of the responders was 15.60 (range, 6.44-51.10), which was significantly higher than that of the non-responders (11.61; range, 2.13-32.75; P = 0.0168, Student's t-test). The cut-off SUVmax value selected for stratification was 11.16 (sensitivity and specificity, 0.792 and 0.585, respectively). The response rate of patients with SUVmax value ≥ 11.16 (41.3% [19/46]) was significantly higher than that of patients with SUVmax < 11.16 (11.6% [5/43], P = 0.0012, Chi-squared test). The SUVmax in 18F-FDG PET/CT is a potential predictive marker of response to anti-PD-1 antibody therapy in NSCLC patients. Further prospective studies of large populations are necessary to validate these results.

20.
Eur J Clin Microbiol Infect Dis ; 38(12): 2365-2369, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31482417

RESUMO

Gentamicin (GM) is used for neonates as the initial treatment for neonatal bacterial infection. An association between high trough GM levels and the elevation of the serum creatinine (sCr) level and hearing loss has been reported, although there have been no reports investigating the serial changes in the sCr level in preterm neonates treated with GM. The present study evaluated the serial changes in the sCr level and the incidence of hearing loss in preterm neonates treated with GM. This study included 56 neonates born at a gestational age of 32-36 weeks. Fifteen (group 1) and 20 (group 2) neonates were treated with 2.5 mg/kg of GM every 12 h and 4 mg/kg of GM every 36 h, respectively. Group 3 included 21 neonates without GM therapy. Serum GM levels, serial changes in the sCr levels, and the incidence of hearing loss were then compared among the three groups. The serum trough GM level in group 2 was significantly lower than that in group 1 (P < 0.001), whereas the serum peak GM levels in these groups were almost the same. The ratio of the sCr level at birth to that at the 5th day of life in group 1 was the lowest among the 3 groups. No neonates had hearing loss. GM therapy worsened the sCr level in late preterm neonates, especially those with multiple doses per day. The appropriate use of GM is needed in order to prevent the occurrence of nephrotoxicity.


Assuntos
Antibacterianos/efeitos adversos , Creatinina/sangue , Gentamicinas/efeitos adversos , Recém-Nascido Prematuro , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Infecções Bacterianas/prevenção & controle , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Gentamicinas/administração & dosagem , Gentamicinas/sangue , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Japão , Masculino
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