RESUMO
AIM: To evaluate whether sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with a reduction of renal events compared with other glucose-lowering drugs (oGLDs) among Japanese people with type 2 diabetes (T2D) and grade 3 (G3) chronic kidney disease (CKD) in a real-world clinical practice setting. MATERIALS AND METHODS: People with T2D who were newly prescribed an SGLT2i or an oGLD from April 2014 to November 2021 (without prior use of index drugs for ≥ 1 year prior to index date) and G3 CKD (estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) were selected from the Medical Data Vision database (MDV-DB) and the Real-World Data database (RWD-DB). SGLT2i and oGLD users were matched (1:1) using propensity score on patient background characteristics. The primary endpoint was a composite of the development of end-stage kidney disease or a sustained decline in eGFR of 50% or more. Hazard ratios (HRs) were estimated using the Cox proportional hazards model. RESULTS: Overall, 3190 (1595 per group) patients in the MDV-DB and 2572 (1286 per group) patients in the RWD-DB were included in the analyses. The composite outcome was significantly lower in the SGLT2i group than in the oGLD group in the MDV-DB (HR 0.49, 95% confidence interval [CI] 0.33 to 0.74, P < 0.001) and in the RWD-DB (HR 0.57, 95% CI 0.37 to 0.88, P = 0.011). CONCLUSIONS: Japanese people with T2D and G3 CKD initiating an SGLT2i had a lower risk of renal events than people initiating an oGLD.
Assuntos
Diabetes Mellitus Tipo 2 , População do Leste Asiático , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
BACKGROUND AND AIMS: Conversion to laparotomy is among the serious intraoperative complications and carries an increased risk of postoperative complications. In this cohort study, we investigated whether or not the Endoscopic Surgical Skill Qualification System (ESSQS) affects the conversion rate among patients undergoing laparoscopic surgery for rectal cancer. METHODS: We performed a retrospective secondary analysis of data collected from patients undergoing laparoscopic surgery for cStage II and III rectal cancer from 2014 to 2016 across 56 institutions affiliated with the Japan Society of Laparoscopic Colorectal Surgery. Data from the original EnSSURE study were analyzed to investigate risk factors for conversion to laparotomy by performing univariate and multivariate analyses based on the reason for conversion. RESULTS: Data were collected for 3,168 cases, including 65 (2.1%) involving conversion to laparotomy. Indicated conversion accounted for 27 cases (0.9%), while technical conversion accounted for 35 cases (1.1%). The multivariate analysis identified the following independent risk factors for indicated conversion to laparotomy: tumor diameter [mm] (odds ratio [OR] 1.01, 95% confidence interval [CI] 1.01-1.05, p = 0.0002), combined resection of adjacent organs [+/-] (OR 7.92, 95% CI 3.14-19.97, p < 0.0001), and surgical participation of an ESSQS-certified physician [-/+] (OR 4.46, 95% CI 2.01-9.90, p = 0.0002). The multivariate analysis identified the following risk factors for technical conversion to laparotomy: registered case number of institution (OR 0.99, 95% CI 0.99-1.00, p = 0.0029), institution type [non-university/university hospital] (OR 3.52, 95% CI 1.54-8.04, p = 0.0028), combined resection of adjacent organs [+/-] (OR 5.96, 95% CI 2.15-16.53, p = 0.0006), and surgical participation of an ESSQS-certified physician [-/+] (OR 6.26, 95% CI 3.01-13.05, p < 0.0001). CONCLUSIONS: Participation of ESSQS-certified physicians may reduce the risk of both indicated and technical conversion. Referral to specialized institutions, such as high-volume centers and university hospitals, especially for patients exhibiting relevant background risk factors, may reduce the risk of conversion to laparotomy and lead to better outcomes for patients. TRIAL REGISTRATION: This study was registered with the Japanese Clinical Trials Registry as UMIN000040645.
Assuntos
Competência Clínica , Conversão para Cirurgia Aberta , Laparoscopia , Laparotomia , Neoplasias Retais , Humanos , Neoplasias Retais/cirurgia , Feminino , Masculino , Japão , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Conversão para Cirurgia Aberta/estatística & dados numéricos , Protectomia/métodos , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). METHODS: We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. RESULTS: Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 - 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). CONCLUSION: This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.
Assuntos
Laparoscopia , Neoplasias Retais , Humanos , Estudos Retrospectivos , Perda Sanguínea Cirúrgica , Pontuação de Propensão , Laparoscopia/métodos , Neoplasias Retais/cirurgia , Estudos de Coortes , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Physiological and prognostic associations of centrilobular emphysema (CLE) and paraseptal emphysema (PSE) in smokers with and without chronic obstructive pulmonary disease (COPD) have been increasingly recognized, but the associations with extrapulmonary abnormalities, such as muscle wasting, osteoporosis, and cardiovascular diseases, remain unestablished. OBJECTIVES: The aim of the study was to investigate whether CLE was associated with extrapulmonary abnormalities independent of concomitant PSE in smokers without airflow limitation. METHODS: This retrospective study consecutively enrolled current smokers without airflow limitation who underwent lung cancer screening with computed tomography and spirometry. CLE and PSE were visually identified based on the Fleischner Society classification system. Cross-sectional areas of pectoralis muscles (PM) and adjacent subcutaneous adipose tissue (SAT), bone mineral density (BMD), and coronary artery calcification (CAC) were evaluated. RESULTS: Of 310 current smokers without airflow limitation, 83 (26.8%) had CLE. The PSE prevalence was higher (67.5% vs. 23.3%), and PM area, SAT area, and BMD were lower in smokers with CLE than in those without (PM area (mean), 34.5 versus 38.6 cm2; SAT area (mean), 29.3 versus 36.8 cm2; BMD (mean), 158.3 versus 178.4 Hounsfield unit), while CAC presence did not differ. In multivariable models, CLE was associated with lower PM area but not with SAT area or BMD, after adjusting for PSE presence, demographics, and forced expiratory volume in 1 s. CONCLUSIONS: The observed association between CLE and lower PM area suggests that susceptibility to skeletal muscle loss could be high in smokers with CLE even without COPD.
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Enfisema , Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Enfisema Pulmonar/diagnóstico por imagem , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/complicações , Fumantes , Estudos Retrospectivos , Músculos Peitorais/diagnóstico por imagem , Detecção Precoce de Câncer , Neoplasias Pulmonares/complicaçõesRESUMO
PURPOSE: In this follow-up of the R-NAC-01 study, we assessed the long-term oncological benefit of four courses of modified leucovorin, 5-fluorouracil (FU), and oxaliplatin (mFOLFOX6) chemotherapy before rectal surgery. METHODS: In this prospective, multicenter study (UMIN 000012559) involving 11 hospitals in Japan, patients with lower rectal cancer underwent four cycles of mFOLFOX6 chemotherapy and subsequent surgery within four to six weeks. The 3-year recurrence-free survival and local recurrence rates were then reported. RESULTS: Of 41 patients (36 males, 5 females; mean age: 60.8 years old) who received 4 courses of chemotherapy, 40 underwent total mesorectal excision, and 1 underwent total pelvic exenteration. R0 resection was achieved in 40 patients, but none showed a pathological complete response. Twenty-nine patients received adjuvant chemotherapy for an average of 4 months. The 3 year recurrence-free survival and local recurrence rates in patients undergoing curable resection were 72.8% and 8.5%, respectively. cStage III patients with adjuvant chemotherapy had a significantly higher 3 year recurrence-free survival than those without adjuvant chemotherapy (76.6 vs. 40.0%, log-rank p = 0.03). CONCLUSION: Four courses of mFOLFOX6 chemotherapy before surgery may be a promising treatment strategy for locally advanced rectal cancer. Adjuvant chemotherapy might be needed for cStage III patients, even after four courses of neoadjuvant mFOLFOX6.
Assuntos
Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Estudos Prospectivos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/cirurgiaRESUMO
The clinical importance of Mycobacterium abscessus subsp. abscessus (M. abscessus) lung disease has been increasing, but few studies have assessed the clinical characteristics associated with the treatment outcome. We retrospectively analyzed 75 consecutive patients with M. abscessus lung disease diagnosed at a tertiary hospital from January 2004 to April 2018. Among 52 patients with sufficient clinical data, 19 patients (42.2%) achieved treatment success. Compared with 26 (57.8%) patients in the treatment failure group, body mass index (BMI) (19.8 vs 17.5 kg/m2, P = 0.022), previous nontuberculous mycobacterial (NTM) lung disease (26.3% vs 61.5%, P = 0.034), the presence of cavitary lesions (31.6% vs 69.2%, P = 0.017), and the bronchiectasis score (3.0 vs 5.0, P = 0.003) were significantly different in the treatment success group. Multivariate analysis showed that age (adjusted hazard ratio (aHR), 0.94; 95% confidence interval (CI), 0.90 to 0.99; P = 0.010), the presence of cavitary lesions (aHR, 0.34; 95% CI, 0.12 to 0.94; P = 0.039), and previous NTM lung disease (aHR, 0.28; 95% CI, 0.09 to 0.86; P = 0.026) were negatively associated with treatment success. This is the first study to show that previous NTM lung disease might be a clinically important factor related to unfavorable treatment outcomes in M. abscessus lung disease patients. To increase our understanding the characteristics of M. abscessus lung disease, this factor should be independently analyzed in future research.
Assuntos
Pneumopatias/terapia , Infecções por Mycobacterium não Tuberculosas/terapia , Idoso , Feminino , Humanos , Pneumopatias/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Falha de TratamentoRESUMO
BACKGROUND: An orosomucoid-like 3 (ORMDL3)/gasdermin B (GSDMB) gene locus on chromosome 17q is consistently associated with childhood-onset asthma, which is highly atopic. As some evidence suggests the relationship between asthma and allergic sensitization reflects asthma patient susceptibility to augmented IgE responses driven by common environmental allergens rather than an increased asthma risk after allergen exposure, we aimed to determine any relationships between this locus region and childhood-onset adult asthma with regard to serum total IgE levels or allergic sensitization. METHODS: We conducted a case-control association study using three independent Japanese populations (3869 total adults) and analyzed the ORs for association of rs7216389, an expression quantitative trait locus for ORMDL3/GSDMB, with adult asthma according to onset age. Additionally, associations between the rs7216389 genotype and total serum IgE levels or allergic sensitization was examined. RESULTS: Rs7216389 was associated with both childhood-onset adult asthma (OR for asthmatic patients afflicted at the age of 10 years or younger = 1.61, p = 0.00021) and asthmatic patients with higher levels of total serum IgE (OR for asthmatic patients with IgE ≥1000IU/mL = 1.55, p = 0.0033). In both healthy controls and in the combined healthy and asthmatic individuals, rs7216389 was correlated with increased total serum IgE levels (p < 0.0005), but not allergic sensitization (p > 0.1). CONCLUSIONS: ORMDL3/GSDMB is an important susceptibility gene for childhood-onset adult asthma in Japanese populations and this association is linked to elevated total serum IgE levels but not to allergic sensitization.
Assuntos
Asma/sangue , Asma/etiologia , Predisposição Genética para Doença , Genótipo , Imunoglobulina E/sangue , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Adulto , Idade de Início , Alelos , Alérgenos/imunologia , Asma/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Humanos , Imunização , Imunoglobulina E/imunologiaRESUMO
BACKGROUND: Adult-onset asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases caused by complex gene-environment interactions. A functional single nucleotide polymorphism of cadherin-related family member 3 (CDHR3), known as a receptor of rhinovirus-C, is associated with childhood-onset asthma especially in atopic individuals. OBJECTIVE: Here, we identified risk factors for adult-onset asthma and COPD, focusing on the impact of the CDHR3 variant in atopic individuals. METHODS: We conducted a longitudinal, retrospective, observational cohort study of 1523 healthy adults with baseline examinations at Tsukuba Medical Center Hospital in 2008 and retrospectively identified new-onset, physician-diagnosed asthma or COPD from 2009 to 2018. We assessed risk factors by the Cox regression analysis. The impact of CDHR3 variant rs6967330 was also examined in individuals with pre-existing atopy. RESULTS: Over 10 study years, 103 people developed airway diseases (79 asthma and 24 COPD; 52 females, average onset-age 55 years old, range 38-80). Higher body mass index (BMI) and lower forced expiratory volume in one second/forced vital capacity (FEV1 /FVC) ratio were significant risk factors (BMI: HR 1.072 [95% CI 1.005-1.14], P = .034; FEV1 /FVC ratio: HR 1.091 [1.044-1.14], P = .00011). Restriction to atopic individuals saw the A allele at rs6967330 and lower FEV1 /FVC ratio to associate with adult-onset disease (A allele: HR 2.89 [1.57-5.20], P = .00062; FEV1 /FVC ratio: HR 1.10 [1.04-1.17], P = .0010). CONCLUSION AND CLINICAL RELEVANCE: Genetic susceptibility to rhinovirus-C infection in atopic individuals is a risk factor for chronic airway diseases even in later life.
Assuntos
Asma/genética , Caderinas/genética , Infecções por Enterovirus/genética , Enterovirus/patogenicidade , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Asma/diagnóstico , Asma/epidemiologia , Proteínas Relacionadas a Caderinas , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Pegfilgrastim has equivalent efficacy to daily granulocyte colony-stimulating factor (G-CSF) in enhancing neutrophil recovery after chemotherapy, but data on its use for peripheral blood stem cell (PBSC) mobilization are limited. We evaluated the safety and efficacy of CD34+ PBSC mobilization by low-dose (3.6 mg) pegfilgrastim after chemotherapy in patients with malignant lymphoma. STUDY DESIGN AND METHODS: Twenty patients with malignant lymphoma were enrolled in this study. Cytotoxic chemotherapy was started on day 1, and 3.6 mg of pegfilgrastim was subcutaneously administered on day 7. CD34+ cells were counted in the peripheral blood daily from days 11 to 14 using a flow cytometric analysis. RESULTS: In 19 of the 20 patients (95%), the CD34+ cell counts in the peripheral blood exceeded 10 × 106/L, with a mean value of 20.3 on day 11, 38.0 on day 12, 40.3 on day 13, and 40.1 on day 14. Older age was associated with lower maximum CD34+ cell mobilization. The most frequent adverse events associated with pegfilgrastim were back pain, nausea, appetite loss, and lactate dehydrogenase elevation. CONCLUSION: Our data indicated that a single dose of 3.6 mg pegfilgrastim on day 7 after chemotherapy safely and effectively mobilized CD34+ cells.
Assuntos
Filgrastim/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Polietilenoglicóis/farmacologia , Adulto , Idoso , Estudos de Viabilidade , Feminino , Filgrastim/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Estudos ProspectivosRESUMO
PURPOSE: The prognostic benefits of primary tumor resection in patients with unresectable distant metastatic colorectal cancer remain unclear. A high pre-treatment lymphocyte-to-monocyte ratio (LMR) was previously shown to be associated with a better prognosis. We assessed whether or not primary tumor resection was associated with an improved survival if the peripheral lymphocyte-to-monocyte ratio increased after primary site resection. METHODS: The survival in 64 and 59 patients with and without primary tumor resection, respectively, was retrospectively compared. After resection, the survival in 39 patients with a postoperatively increased LMR (LMR-increase) and 25 patients with a decreased LMR (LMR-decrease) was compared. RESULTS: Primary tumor resection prolonged the median survival more frequently in cases of non-differentiated adenocarcinoma, obstructive symptoms, high serum albumin levels, and no lymph-node metastasis than in others. Cox regression showed that the potential independent prognostic variable was non-resection of the primary lesion. After resection, the median survival in the LMR-increase vs. LMR-decrease groups was significantly different (27.3 vs. 20.8 months). There were no marked differences in patient background characteristics between the groups, except for in the number of pre-operative peripheral blood lymphocytes. The resected specimens showed significantly lower CD8+:CD163+ invading leukocyte ratios in the LMR-increase group than in the LMR-decrease group. CONCLUSIONS: Primary tumor resection in patients with unresectable metastatic colorectal cancer may be associated with an improved survival, especially when the LMR is increased after primary tumor resection.
Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Contagem de Leucócitos , Linfócitos/patologia , Monócitos/patologia , Idoso , Neoplasias Colorretais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes. METHODS: This case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters. RESULTS: In the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07-1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03-1.61; P = 0.027). CONCLUSIONS: The genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.
Assuntos
Idade de Início , Alelos , Asma/genética , Proteína 1 Semelhante à Quitinase-3/genética , Locos de Características Quantitativas , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Estudo de Associação Genômica Ampla , Humanos , Japão , FenótipoRESUMO
PURPOSE: The aim of this study was to assess the safety of rectal surgery after 5-fluorouracil-leucovorin-oxaliplatin chemotherapy (FOLFOX6). METHODS: This was a prospective, multicenter study in 11 Japanese hospitals. We included patients with rectal cancer who received 4 courses of modified FOLFOX6 (mFOLFOX6) before rectal surgery and examined the postoperative complication rate, the clinicopathological response, and the rate of chemotherapy-related adverse events (UMIN 000012559). RESULTS: The study population included 36 men and 5 women. The average age of the patients was 60.8 years and the average body mass index was 23.1 kg/m2. After 4 courses of chemotherapy, grade 2 peripheral nerve disorder and other grade 3 adverse events were seen in 3 patients each (7.3%). Twenty-eight (73.7%) and 8 (21.1%) patients underwent low anterior resection and abdominoperineal resection, respectively. The pelvic nerves were preserved in 35 patients. Surgical morbidity (grade ≥ 3) occurred in 4 patients (10.5%). Anastomotic leakage occurred after surgery in 2 patients (7.1%). No patients achieved pathologically complete remission. However, downstaging of the clinical stage and N stage was seen in 17 (41.5%) and 22 (53.7%) patients, respectively. CONCLUSIONS: Surgery after four courses of mFOLFOX6 chemotherapy can be a safe and promising strategy for patients with locally advanced rectal cancer.
Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Terapia Combinada , Procedimentos Cirúrgicos do Sistema Digestório , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Cuidados Pré-Operatórios , Estudos Prospectivos , Segurança , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family and functions to limit type 2 immune responses implicated in allergic sensitization. Recent studies have shown that multiple intronic variants of TYRO3 were associated with asthma, implying that genetic variation could contribute to errant immune activation. We therefore hypothesized that expression quantitative trait loci (eQTLs) of the TYRO3 gene influence the development of allergic diseases (including asthma and allergic rhinitis) in Japanese populations. METHODS: We performed a candidate gene case-control association study of 8 eQTLs of TYRO3 on atopy, asthma, and allergic rhinitis using 1168 unrelated Japanese adults who had GWAS genotyping. We then examined the genetic impact of rs2297377 (TYRO3) on atopy and allergic rhinitis in 2 other independent Japanese populations. RESULTS: A meta-analysis of 3 Japanese populations (a total of 2403 Japanese adults) revealed that rs2297377 was associated with atopy and allergic rhinitis (OR = 1.29 and 1.31; P = 0.00041 and 0.0010, respectively). The risk allele at rs2297377 correlated with decreased expression of TYRO3 mRNA. The gene-gene interaction between HLA-DPB1 and TYRO3 was not significant with regard to sensitization. The estimated proportion of atopy and allergic rhinitis cases attributable to the risk genotype was 14% and 16%, respectively. CONCLUSIONS: Our study identified TYRO3 as an important susceptibility gene to atopy and allergic rhinitis in Japanese.
Assuntos
Predisposição Genética para Doença , Hipersensibilidade/genética , Receptores Proteína Tirosina Quinases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipersensibilidade/epidemiologia , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adulto JovemRESUMO
Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).
Assuntos
Técnicas Biossensoriais/métodos , Transferência Ressonante de Energia de Fluorescência/métodos , Proteínas de Fusão bcr-abl/análise , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Sodium glucose co-transporter 2 (SGLT2) inhibitors have been associated with increased serum ketone body levels in patients with type 2 diabetes mellitus (T2DM). In the present analysis we evaluated serum ketone body levels and variability in 1278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. The median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for ß-hydroxybutyrate. Approximately two-thirds of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Patients in the lowest response tertile exhibited no increase in ketones. Those in the highest response tertile tended to be male and have higher fasting plasma glucose levels, lower insulin levels, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese patients with T2DM.
Assuntos
Variação Biológica da População/efeitos dos fármacos , Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Corpos Cetônicos/sangue , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Glicemia/análise , Canagliflozina/administração & dosagem , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/sangue , Cetoacidose Diabética/induzido quimicamente , Cetoacidose Diabética/fisiopatologia , Cetoacidose Diabética/prevenção & controle , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Feminino , Seguimentos , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Japão , Masculino , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Caracteres Sexuais , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (-0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.
Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/prevenção & controle , Moduladores de Transporte de Membrana/uso terapêutico , Pirazóis/uso terapêutico , Tiazolidinas/uso terapêutico , Idoso , Canagliflozina/efeitos adversos , Terapia Combinada/efeitos adversos , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Exercício Físico , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Japão , Masculino , Moduladores de Transporte de Membrana/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Transportador 2 de Glucose-Sódio/metabolismo , Tiazolidinas/efeitos adversosRESUMO
AIM: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. MATERIALS AND METHODS: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. RESULTS: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.
Assuntos
Canagliflozina/administração & dosagem , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/administração & dosagem , Insulina/efeitos adversos , Adulto , Povo Asiático , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy. METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward). RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52. CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.
Assuntos
Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Pirazóis/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinas/uso terapêutico , Idoso , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/uso terapêutico , Índice de Massa Corporal , Canagliflozina/efeitos adversos , Estudos de Coortes , Terapia Combinada/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Dieta Redutora , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Exercício Físico , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Japão , Masculino , Moduladores de Transporte de Membrana/efeitos adversos , Moduladores de Transporte de Membrana/uso terapêutico , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/metabolismo , Sobrepeso/prevenção & controle , Sobrepeso/terapia , Pirazóis/efeitos adversos , Transportador 2 de Glucose-Sódio/metabolismo , Tiazolidinas/efeitos adversosRESUMO
BACKGROUND: The use of laparoscopic colectomy is becoming widespread and acquisition of its technique is challenging. In this study, we investigated whether supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. METHODS: The outcomes of 23 right colectomies and 19 high anterior resections for colon cancers performed by five novice surgeons (experience level of <10 cases) between 2014 and 2016 were assessed. A laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System (Japan Society for Endoscopic Surgery) participated in surgeries as the teaching assistant. RESULTS: In the right colectomy group, one patient (4.3%) required conversion to open surgery and postoperative morbidities occurred in two cases (8.6%). The operative time moving average gradually decreased from 216 to 150 min, and the blood loss decreased from 128 to 28 mL. In the CUSUM charts, the values for operative time decreased continuously after the 18th case, as compared to the Japanese standard. The values for blood loss also plateaued after the 18th case. In the high anterior resection group, one patient (5.2%) required conversion to open surgery and no postoperative complication occurred in any patient. The operative time moving average gradually decreased from 258 to 228 min, and the blood loss decreased from 33 to 18 mL. The CUSUM charts showed that the values of operative time plateaued after the 18th case, as compared to the Japanese standard. In the CUSUM chart for blood loss, no distinguishing peak or trend was noted. CONCLUSIONS: Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. The trainee's learning curve in this study represents successful mentoring by the laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System.