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BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
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BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.
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Acrilamidas , Compostos de Anilina , Anticorpos Biespecíficos , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Morfolinas , Pirazóis , Pirimidinas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carbazóis , Crizotinibe , Humanos , Japão , Piperidinas , Inibidores de Proteínas Quinases , Análise de SobrevidaRESUMO
The goal of the present study was to determine the effect of sole horn thickness (SHT) and sole horn hardness (SHD) on ultrasonographic visualization of sole structures in the inner and outer claws of 150 Holstein-Friesian cows, and to evaluate different ultrasound frequencies for this purpose. Ultrasonographic views of the sole structure were considered complete when 3 echogenic lines, representing the ventral surface of the sole horn, the borders of the sole horn and soft-tissue layer, and the ventral surface of the distal phalanx, were seen. The proportion of complete ultrasonographic views of the sole structures, designated as the ultrasonographic visualization proportion (UVP), and the measurement errors of SHT were evaluated by comparing images from computed tomography (CT) and ultrasonography. The latter images were generated using 3 different probes, frequencies of 6.5 and 5.0 MHz, and 2 different ultrasound machines (#1 and #2) to assess the apex, middle, and heel regions of the claws. The UVP were 60.8 to 77.9% for the 6.5-MHz probe in ultrasound machine #1 (probe A), which were lower than those (>90%) for both the 5.0-MHz probe in ultrasound machine #1 (probe B) and the 5.0-MHz probe in ultrasound machine #2 (probe C). The UVP was significantly lower in claws with an SHD ≥50 units than in claws with an SHD <40 or 40 to <50 units (UVP: 77.1% compared with 93.7 and 91.4%, respectively) when measured with probe B. In claws with an SHT <10 mm, the UVP was significantly lower when SHD was ≥50 units compared with <40 or 40 to >50 units; the values were 69.0% versus 91.3 and 85.9%, respectively, for probe A, and 89.7% versus 100 and 100%, respectively, for probe B. When SHT were measured by either probes A or B in ultrasound machine #1, the proportions of claws in which ultrasonographic values were within a ±1 mm range compared with the values obtained by CT were 84.9 to 91.3% for CT-determined SHT <5 mm, 66.7 to 71.9% for CT-determined SHT 5 to <7 mm, 28.9 to 51.2% for CT-determined SHT 7 to <10 mm, and 6.2 to 19.7% for CT-determined SHT ≥10 mm. The data indicated that increased SHT was associated with a decrease in ultrasonographic measurement accuracy. In claws with an SHT <5 mm, the high proportion of ultrasonographic values that were accurate within a ±1 mm range suggests that this imaging modality would be useful in cows with thin soles.
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Bovinos/anatomia & histologia , Casco e Garras/diagnóstico por imagem , Tomografia Computadorizada por Raios X/veterinária , Ultrassonografia/veterinária , Animais , Feminino , Dureza , Reprodutibilidade dos TestesRESUMO
Marine biogenic sulphur affects Earth's radiation budget and may be an indicator of primary productivity in the Southern Ocean, which is closely related to atmospheric CO2 variability through the biological pump. Previous ice-core studies in Antarctica show little climate dependence of marine biogenic sulphur emissions and hence primary productivity, contradictory to marine sediment records. Here we present new 720,000-year ice core records from Dome Fuji in East Antarctica and show that a large portion of non-sea-salt sulphate, which was traditionally used as a proxy for marine biogenic sulphate, likely originates from terrestrial dust during glacials. By correcting for this, we make a revised calculation of biogenic sulphate and find that its flux is reduced in glacial periods. Our results suggest reduced dimethylsulphide emissions in the Antarctic Zone of the Southern Ocean during glacials and provide new evidence for the coupling between climate and the Southern Ocean sulphur cycle.
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Camada de Gelo , Fitoplâncton/metabolismo , Água do Mar/química , Enxofre/metabolismo , Regiões Antárticas , Atmosfera/química , Dióxido de Carbono/metabolismo , Clima , Geografia , Oceanos e Mares , Ácidos de Enxofre/metabolismo , TemperaturaRESUMO
Cardiovascular surgery is a highly invasive intervention that is often performed in elderly patients at risks of complications because of malnutrition and reduced immunity. This study investigated nutritional factors that affected length of hospital stay in patients undergoing cardiovascular surgery. Among 68 patients who underwent surgery at the Department of Cardiovascular Surgery of Gifu Municipal Hospital between April 2013 and March 2015, 55 with complete data were included in the analysis. Data on serum albumin (ALB), transferrin (Tf), pre-albumin (PA) and retinol binding protein (RBP) levels were collected. The median length of hospital stay was 29 days (stays of ≥30 days were considered long-term hospitalization). Multivariate analysis (multiple logistic regression) included age (≥ 65 years), sex (female), and ALB (≤ 3.0 g/dL), Tf (≤ 150.0 mg/dL), PA (≤ 10.0 mg/dL) and RBP (≤ 1.5 mg/dL) levels. ALB [odds ratio (OR) 10.37, 95% CI (confidence interval): 1.185-90.80, P = 0.035] and Tf [OR 4.743, 95% CI: 1.375-16.36, P = 0.014] were significantly associated with length of hospital stay. Nutritional management of patients and careful monitoring of ALB and Tf levels can shorten length of hospital stay in patients undergoing cardiovascular surgery.
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Procedimentos Cirúrgicos Cardiovasculares , Hospitalização , Tempo de Internação , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Albumina Sérica/análise , Transferrina/análiseRESUMO
OBJECTIVES: Although inflammatory markers, such as the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and local immune markers have been shown to have prognostic utility, limited information is available regarding inflammatory and pre-existing tumour-infiltrating lymphocyte density and their association with prognosis in patients with hypopharyngeal squamous cell carcinoma. We investigated the prognostic ability of inflammatory markers and tumour-infiltrating lymphocyte density in stage III and stage IV hypopharyngeal squamous cell carcinoma patients receiving definitive treatment. DESIGN: Retrospective cohort study. SETTING: Kurume University Hospital. PARTICIPANTS: Ninety-six stage III or stage IV hypopharyngeal squamous cell carcinoma patients treated at the Kurume University Hospital between 2000 and 2014. MAIN OUTCOME MEASURES: Inflammatory markers and pre-treatment tumour-infiltrating lymphocyte density were examined from recorded haematologic data and immunohistochemical analysis. RESULTS: Multivariate analyses showed that the CD8+ tumour-infiltrating lymphocyte density was an independent predictive factor for distant metastasis and overall survival, whereas inflammatory markers, including the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, were not correlated with distant metastasis or overall survival. CONCLUSIONS: Higher pre-treatment CD8+ tumour-infiltrating lymphocyte density is a useful predictive biomarker for reduced distant metastasis and better prognosis.
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Linfócitos T CD8-Positivos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias Hipofaríngeas/metabolismo , Neoplasias Hipofaríngeas/patologia , Linfócitos do Interstício Tumoral , Adulto , Idoso , Biomarcadores , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos RetrospectivosRESUMO
The Northern Hemisphere experienced dramatic changes during the last glacial, featuring vast ice sheets and abrupt climate events, while high northern latitudes during the last interglacial (Eemian) were warmer than today. Here we use high-resolution aerosol records from the Greenland NEEM ice core to reconstruct the environmental alterations in aerosol source regions accompanying these changes. Separating source and transport effects, we find strongly reduced terrestrial biogenic emissions during glacial times reflecting net loss of vegetated area in North America. Rapid climate changes during the glacial have little effect on terrestrial biogenic aerosol emissions. A strong increase in terrestrial dust emissions during the coldest intervals indicates higher aridity and dust storm activity in East Asian deserts. Glacial sea salt aerosol emissions in the North Atlantic region increase only moderately (50%), likely due to sea ice expansion. Lower aerosol concentrations in Eemian ice compared to the Holocene are mainly due to shortened atmospheric residence time, while emissions changed little.
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INTRODUCTION: The aim of this study was to examine whether a combined test using both cell sediment and supernatant cytology cell-free DNA (ccfDNA) is more useful in detecting EGFR mutation than using cell sediment DNA or supernatant ccfDNA alone in pleural effusion of lung cancer patients. METHODS: A total of 74 lung adenocarcinoma patients with paired samples between primary tumour and corresponding metastatic tumour with both cell sediment and supernatant ccfDNA of pleural effusion cytology were enrolled in this study. Cell sediment and supernatant ccfDNA were analysed separately for EGFR mutations by polymerase chain reaction. RESULTS: Out of 45 patients with mutant EGFR in primary tumours, EGFR mutations were detected in 23 cell sediments of corresponding metastases (sensitivity; 51.1%) and 20 supernatant ccfDNA corresponding metastases (sensitivity; 44.4%). By contrast, the combined test detected EGFR mutations in 27 corresponding metastases (sensitivity; 60.0%), and had a higher sensitivity than the cell sediment or the supernatant ccfDNA alone (P < .05). Out of 45 patients with mutant EGFR, 24, three and 18 were cytologically diagnosed as positive, atypical or negative, respectively. The detection rate in the combined test was highest (95.8%) in the positive group, and mutant EGFR was also detected in four of 18 samples (22.2%) in the negative group. CONCLUSIONS: A combined test using both cell sediment DNA and supernatant ccfDNA samples increases the concordance rate of EGFR mutations between primary tumour and corresponding metastases. Our findings indicate that supernatant ccfDNA is useful even in cases where the cytological diagnosis is negative.
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DNA Tumoral Circulante , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Derrame Pleural Maligno/genética , Reação em Cadeia da Polimerase/métodos , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/isolamento & purificação , Análise Mutacional de DNA/métodos , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Derrame Pleural Maligno/patologiaRESUMO
BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.
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Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Incidência , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Fatores de Risco , Adulto Jovem , alfa-Fetoproteínas/análiseRESUMO
Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.
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Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , DNA Tumoral Circulante/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Quinazolinas/uso terapêutico , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Adenocarcinoma de Pulmão , Afatinib , DNA Tumoral Circulante/sangue , Receptores ErbB/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Biópsia Líquida , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/enzimologia , Masculino , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase/métodos , Estudos Prospectivos , Quinazolinas/efeitos adversosRESUMO
5-Aminolevulinic acid (5-ALA) is widely used in photodynamic detection (PDD) and therapy. We evaluated the pharmacokinetics of 5-ALA-induced porphyrins and its effectiveness in PDD in dogs with mammary gland tumours (MGTs) following oral administration. Healthy dogs and those with MGTs (nine each) were orally administered 4 mg kg-1 5-ALA. Protoporphyrin IX (PpIX) was not detected in the plasma of healthy dogs but it peaked in dogs with MGT at 2 h after 5-ALA administration. In the PDD study, 16 dogs with MGT were orally administered 40 mg kg-1 5-ALA, and MGT but not normal tissue showed red fluorescence after 2-4 h. Photon counts were 6635-63 890 and 59-4011 (median, 19 943 and 919) for MGT and non-tumour tissues, respectively. Cell density strongly correlated with PpIX photon counts of MGT tissue of the dogs (R = 0.743, P = 0.0009). We suggest that 5-ALA-PDD might be an effective diagnostic tool for MGTs.
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Ácido Aminolevulínico/farmacologia , Doenças do Cão/diagnóstico , Neoplasias Mamárias Animais/diagnóstico , Fármacos Fotossensibilizantes/farmacologia , Espectrometria de Fluorescência/veterinária , Administração Oral , Ácido Aminolevulínico/administração & dosagem , Animais , Cães , Feminino , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/metabolismoRESUMO
BACKGROUND: There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS: Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS: Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION: The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER: UMIN000004863.
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Cisplatino/administração & dosagem , Granisetron/administração & dosagem , Isoquinolinas/administração & dosagem , Neoplasias/tratamento farmacológico , Quinuclidinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Granisetron/efeitos adversos , Humanos , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/patologia , Neoplasias/patologia , Palonossetrom , Quinuclidinas/efeitos adversos , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/efeitos adversos , Vômito/induzido quimicamente , Vômito/patologiaRESUMO
BACKGROUND: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/metabolismo , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Quinolinas/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Taxa de SobrevidaRESUMO
Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.
Assuntos
Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Simeprevir/uso terapêutico , Idoso , Antivirais/uso terapêutico , Proteínas de Transporte/genética , Quimioterapia Combinada , Feminino , Hepacivirus/classificação , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Humanos , Interferon alfa-2 , Peptídeos e Proteínas de Sinalização Intracelular , Japão , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Recidiva , Simeprevir/efeitos adversos , Falha de Tratamento , Proteínas não Estruturais Virais/genéticaRESUMO
A nationwide cross-sectional study of 3335 employees was conducted in 320 offices in Japan to estimate the prevalence of building-related symptoms (BRSs) and determine the risk factors related to work environment, Indoor Air Quality, and occupational stress. Data were collected through self-administered questionnaires. The prevalences of general symptoms, eye irritation, and upper respiratory symptoms were 14.4%, 12.1%, and 8.9%, respectively. Multiple logistic regression analyses revealed that eye irritation was significantly associated with carpeting [odds ratio (OR), 1.73; 95% confidence interval (CI), 1.24-2.41], coldness perception (OR, 1.28; 95% CI, 1.13-1.45), and air dryness perception (OR, 1.61; 95% CI, 1.42-1.82). General symptoms were significantly associated with unpleasant odors (OR, 1.37; 95% CI, 1.13-1.65), amount of work (OR, 1.24; 95% CI, 1.06-1.45), and interpersonal conflicts (OR, 1.44; 95% CI, 1.23-1.69). Upper respiratory symptoms were significantly associated with crowded workspaces (OR, 1.36; 95% CI, 1.13-1.63), air dryness perception (OR, 2.07; 95% CI, 1.79-2.38), and reported dustiness on the floor (OR, 1.39; 95% CI, 1.16-1.67). Although psychosocial support is important to reduce and control BRSs, maintaining appropriate air-conditioning and a clean and uncrowded workspace is of equal importance.
Assuntos
Poluição do Ar em Ambientes Fechados , Exposição Ocupacional/efeitos adversos , Síndrome do Edifício Doente/epidemiologia , Adulto , Estudos Transversais , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Síndrome do Edifício Doente/etiologia , Estresse Psicológico/complicações , Adulto JovemRESUMO
BACKGROUND: Xenotransplantation with porcine islets is a promising approach to overcome the shortage of human donors. This is the first report of phase 1/2a xenotransplantation study of encapsulated neonatal porcine islets under the current framework of regulations for xenotransplantation in New Zealand. METHODS: Newborn piglets were anesthetized and bled, and the pancreata were removed with the use of sterile technique and processed. Encapsulated neonatal porcine islets were implanted with the use of laparoscopy into the peritoneal cavity of 14 patients with unstable type 1 diabetes without any immunosuppressive drugs. The patients received encapsulated islets of 5,000 (n = 4; group 1), 10,000 (n = 4; group 2), 15,000 (n = 4; group 3), or 20,000 (n = 2; group 4) islet equivalents per kg body weight. Outcome was determined from adverse event reports, HbA1c, total daily insulin dose, and frequency of unaware hypoglycemic events. To assess graft function, transplant estimated function (TEF) scores were calculated. Sufficient or marginal numbers of encapsulated neonatal porcine islets were transplanted into streptozotocin-induced diabetic B6 mice as an in vivo functional assay. RESULTS: There were 4 serious adverse events, of which 3 were considered to be possibly related to the procedure. Tests for porcine endogenous retrovirus DNA and RNA were all negative. The numbers of unaware hypoglycemia events were reduced after transplantation in all groups. Four of 14 patients attained HbA1c <7% compared with 1 at baseline. The average TEF scores were 0.17, 0.02, -0.01, and 0.08 in groups 1, 2, 3, and 4 respectively. The in vivo study demonstrated that a sufficient number of the transplanted group reversed diabetes with positive porcine C-peptide. CONCLUSIONS: Transplantation of encapsulated neonatal porcine islets was safe and was followed by a reduction in unaware hypoglycemia events in unstable type 1 diabetic patients. The mouse in vivo assessment data demonstrated certain graft function.
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Transplante das Ilhotas Pancreáticas/métodos , Transplante Heterólogo/métodos , Animais , Animais Recém-Nascidos , Peptídeo C/sangue , Diabetes Mellitus Experimental/cirurgia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Camundongos , Pessoa de Meia-Idade , Nova Zelândia , Suínos , Resultado do TratamentoRESUMO
Computed tomography (CT) was performed on 800 untrimmed claws (400 inner claws and 400 outer claws) of 200 pairs of bovine hindlimbs to investigate the relationships between dorsal wall length and sole thickness, and between dorsal wall length and the relative rotation angle of distal phalanx-to-sole surface (S-D angle). Sole thickness was 3.8 and 4.0 mm at the apex of the inner claws and outer claws, respectively, with dorsal wall lengths <70 mm. These sole thickness values were less than the critical limit of 5 mm, which is associated with a softer surface following thinning of the soles. A sole thickness of 5 mm at the apex was estimated to correlate with dorsal wall lengths of 72.1 and 72.7 mm for the inner and outer claws, respectively. Sole thickness was 6.1 and 6.4 mm at the apex of the inner and outer claws, respectively, with dorsal wall lengths of 75 mm. These sole thickness values were less than the recommended sole thickness of 7 mm based on the protective function of the soles. A sole thickness >7 mm at the apex was estimated to correlate with a dorsal wall length of 79.8 and 78.4mm for the inner and outer claws, respectively. The S-D angles were recorded as anteversions of 2.9° and 4.7° for the inner and outer claws, respectively, with a dorsal wall length of 75 mm. These values indicate that the distal phalanx is likely to have rotated naturally forward toward the sole surface. The distal phalanx rotated backward to the sole surface at 3.2° and 7.6° for inner claws with dorsal wall lengths of 90-99 and ≥100 mm, respectively; and at 3.5° for outer claws with a dorsal wall length ≥100 mm. Dorsal wall lengths of 85.7 and 97.2 mm were estimated to correlate with a parallel positional relationship of the distal phalanx to the sole surface in the inner and outer claws, respectively.
Assuntos
Bovinos/anatomia & histologia , Casco e Garras/diagnóstico por imagem , Falanges dos Dedos do Pé/diagnóstico por imagem , Tomografia Computadorizada por Raios X/veterinária , Animais , Feminino , Pé/anatomia & histologia , Pé/diagnóstico por imagem , Membro Posterior/anatomia & histologia , Casco e Garras/anatomia & histologia , Lactação , Rotação , Falanges dos Dedos do Pé/anatomia & histologia , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Recent clinical trials have shown that immune-checkpoint blockade yields a clinical response in a subset of individuals with advanced nonsmall-cell lung cancer (NSCLC). We examined whether the expression of programmed death-ligand 1 (PD-L1) is related to clinicopathologic or prognostic factors in patients with surgically resected NSCLC. PATIENTS AND METHODS: The expression of PD-L1 was evaluated by immunohistochemical analysis in 164 specimens of surgically resected NSCLC. Cell surface expression of PD-L1 in NSCLC cell lines was quantified by flow cytometry. RESULTS: Expression of PD-L1 in tumor specimens was significantly higher for women than for men, for never smokers than for smokers, and for patients with adenocarcinoma than for those with squamous cell carcinoma. Multivariate analysis revealed that the presence of epidermal growth factor receptor gene (EGFR) mutations and adenocarcinoma histology were significantly associated with increased PD-L1 expression in a manner independent of other factors. Cell surface expression of PD-L1 was also significantly higher in NSCLC cell lines positive for activating EGFR mutations than in those with wild-type EGFR. The EGFR inhibitor erlotinib downregulated PD-L1 expression in the former cell lines but not in the latter, suggesting that PD-L1 expression is increased by EGFR signaling conferred by activating EGFR mutations. A high level of PD-L1 expression in resected tumor tissue was associated with a significantly shorter overall survival for NSCLC patients. CONCLUSIONS: High expression of PD-L1 was associated with the presence of EGFR mutations in surgically resected NSCLC and was an independent negative prognostic factor for this disease.