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Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.
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COVID-19 , Malus , Camundongos , Animais , Leptina/genética , Citocinas , COVID-19/complicações , Estudos Retrospectivos , SARS-CoV-2 , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/genética , Interleucina-6 , Camundongos ObesosRESUMO
BACKGROUND: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune-checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. METHODS: The number of patients expected to be enrolled was 15-25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7-8.6 months) and the median OS was 15.8 months (95% CI, 8.2-not reached). CONCLUSIONS: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.
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Nivolumabe , Sarcoma Alveolar de Partes Moles , Sarcoma de Células Claras , Humanos , Sarcoma Alveolar de Partes Moles/tratamento farmacológico , Sarcoma Alveolar de Partes Moles/patologia , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Feminino , Masculino , Adulto , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/patologia , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Intervalo Livre de Progressão , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversosRESUMO
A subset of clear cell renal cell carcinomas (ccRCCs) exhibits various growth patterns that infiltrate the normal renal parenchyma; however, our understanding of its association with cancer aggressiveness is incomplete. Here, we show that the morphology of the tumor interface with normal renal parenchyma is robustly associated with cancer recurrence after surgery, even when compared with the TNM staging system or the World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade in nonmetastatic ccRCC. Hematoxylin and eosin-stained slides of whole tissue sections from surgical specimens were analyzed using a cohort of 331 patients with nonmetastatic ccRCC treated with radical nephrectomy. The patients were classified into 10 subgroups based on our classification algorithms for assessing the tumor interface with normal renal parenchyma. Among the 10 subgroups, 4 subgroups consisting of 40 patients (12%) were identified to have aggressive forms of nonmetastatic ccRCC associated with poor prognosis and unified as renal parenchymal infiltration or micronodular spread (RPI/MNS) phenotypes. Multivariable analyses showed that RPI/MNS phenotypes were robustly associated with shorter disease-free survival, independently of existing pathological factors including the TNM staging system and WHO/ISUP nuclear grade. The hazard ratio was highest for RPI/MNS (4.62), followed by WHO/ISUP grades 3 to 4 (2.11) and ≥pT3a stage (2.05). In addition, we conducted genomic analyses using next-generation sequencing of infiltrative lesions in 18 patients with RPI/MNS and tumor lesions in 33 patients without RPI/MNS. Results showed that alterations in SETD2 and TSC1 might be associated with RPI/MNS phenotypes, whereas alterations in PBRM1 might be associated with non-RPI/MNS phenotypes. These data suggest that RPI/MNS may be associated with aggressive genomic backgrounds of ccRCC, although more comprehensive analyses with a larger sample size are required. Future studies may further elucidate the clinical implications of RPI/MNS, particularly for deciding the indication of adjuvant treatment after nephrectomy.
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BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.
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Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Cisplatino , Neoplasias Gástricas/patologia , Paclitaxel , Neoplasias Peritoneais/secundário , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
BACKGROUND: The significance of resection of para-aortic lymph node metastasis in colorectal cancer is controversial. OBJECTIVE: To clarify the prognosis of colorectal cancer after para-aortic lymph node metastasis resection. DESIGN: Multicenter retrospective study. SETTINGS: Thirty-six institutions in Japan participated in this study. Database and medical records at each institution were used for data collection. PATIENTS: Patients with resected and pathologically proven para-aortic lymph node metastasis of colorectal cancer between 2010 and 2015 were included. MAIN OUTCOME MEASURES: Overall survival after para-aortic lymph node metastasis resection, recurrence-free survival, and recurrence patterns after R0 resection of para-aortic lymph node metastasis. RESULTS: A total of 133 patients were included in the primary analysis population in this study. The 5-year overall survival rate (95% CI) was 41.0% (32.0-49.8), and the median survival (95% CI) was 4.1 (3.4-4.7) years. Independent prognostic factors for overall survival were the pathological T stage (pT4 vs pT1- 3, adjusted HR: 1.91, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.98, p = 0.005), time to metastases (synchronous vs metachronous adjusted HR: 2.02, p = 0.02), and the number of para-aortic lymph node metastasis (3 or more vs less than 3, adjusted HR: 2.13, p = 0.001). The 5-year recurrence-free survival rate (95% CI) was 21.1% (13.5-29.7), with a median (95% CI) of 1.2 (0.9-1.4) years. The primary tumor location (left- vs right-sided colon, adjusted HR: 4.77, p = 0.01; rectum vs right-sided colon, adjusted HR: 5.27, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.90, p = 0.03), number of para-aortic lymph node metastases (3 or more vs less than 3, adjusted HR: 2.20, p = 0.001), and hospital volume (less than 10 vs 10 or more, adjusted HR: 2.18, p = 0.02) were identified as independent prognostic factors for recurrence-free survival. Para-aortic lymph node recurrence was the most common at 33.3%. LIMITATIONS: Selection bias cannot be ruled out because of the retrospective nature of the study. CONCLUSIONS: Less than 3 para-aortic lymph node metastases were a favorable prognostic factor for overall and recurrence-free survival. However, para-aortic lymph node metastases were considered to be a systemic disease, and the significance of resection was limited. See Video Abstract . RESULTADO A LARGO PLAZO POSTERIOR A LA RESECCIN QUIRRGICA DE METSTASIS EN GANGLIOS LINFTICOS PARAARTICOS DE CNCER COLORRECTAL UN ESTUDIO RETROSPECTIVO MULTICNTRICO: ANTECEDENTES:La importancia de la resección de metástasis en los ganglios linfáticos paraaórticos (PALNM) en el cáncer colorrectal (CCR) es controvertida.OBJETIVO:Aclarar el pronóstico del CCR después de la resección PALNM.DISEÑO:Estudio retrospectivo multicéntrico.ENTORNO CLINICO:Treinta y seis instituciones en Japón participaron en este estudio.PACIENTES:Pacientes con PALNM de CCR resecado y patológicamente probado entre 2010 y 2015.FUENTES DE DATOS:Base de datos y registros médicos de cada institución.PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia general (SG) después de la resección PALNM, supervivencia libre de recurrencia (SLR) y patrones de recurrencia después de la resección R0 de PALNM.RESULTADOS:Se incluyó un total de 133 pacientes en la población de análisis primario de este estudio. La tasa de SG a 5 años (intervalo de confianza [IC] del 95 %) fue del 41,0 % (32,0, 49,8) y la mediana de supervivencia (IC del 95 %) fue de 4,1 (3,4, 4,7) años. Los factores de pronóstico independientes para la SG fueron el estadio T patológico (pT4 vs. pT1-3, índice de riesgo ajustado [aHR]: 1,91, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,98, p = 0,005), tiempo hasta las metástasis (síncronas vs. metacrónicas, aHR: 2,02, p = 0,02) y número de PALNM (≥3 vs. <3, aHR: 2,13, p = 0,001). La tasa de SLR a 5 años (IC del 95%) fue del 21,1% (13,5, 29,7), con una mediana (IC del 95%) de 1,2 (0,9, 1,4) años. La ubicación del tumor primario (colon del lado izquierdo vs. derecho, aHR: 4,77, p = 0,01; recto vs. colon del lado derecho, aHR: 5,27, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,90, p = 0,03), el número de PALNM (≥3 vs. <3, aHR: 2,20, p = 0,001) y el volumen hospitalario (<10 vs. ≥10, aHR: 2,18, p = 0,02) se identificaron como independientes factores pronósticos del SLR. La recurrencia de los ganglios linfáticos paraaórticos fue la más común con un 33,3%.LIMITACIONES:No se puede descartar un sesgo de selección debido a la naturaleza retrospectiva del estudio.CONCLUSIONES:Menos de tres PALNM fue un factor pronóstico favorable tanto para la SG como para la SLR. Sin embargo, las PALNM se consideraron una enfermedad sistémica y la importancia de la resección fue limitada. (Traducción- Dr. Francisco M. Abarca-Rendon ).
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Neoplasias Colorretais , Excisão de Linfonodo , Linfonodos , Metástase Linfática , Estadiamento de Neoplasias , Humanos , Masculino , Feminino , Estudos Retrospectivos , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/mortalidade , Pessoa de Meia-Idade , Excisão de Linfonodo/métodos , Japão/epidemiologia , Linfonodos/patologia , Linfonodos/cirurgia , Taxa de Sobrevida , Prognóstico , Recidiva Local de Neoplasia/epidemiologia , Intervalo Livre de Doença , Idoso de 80 Anos ou maisRESUMO
Falls from height pose a significant public health concern in urban regions, including the highly urbanized Greater Tokyo Area. The Japanese population is characterized by high rates of suicide and psychoactive drug usage, underscoring the importance of investigating these attributes in falls from height. This study aimed to retrospectively analyze the alcohol and toxicological aspects influencing falls from height in the Greater Tokyo Area between 2014 and 2022 and compare the findings with existing reports on other populations. In total, 75 cases of falls from height and 159 cases of natural deaths were included. Consistent with previous findings, Fisher's exact test revealed a predominance of males (66.67%, 50/75) and young adults (57.33%, 43/75) in falls from height. Multivariate logistic regression analysis identified antidepressant usage as the most significant risk factor within the target population, while younger individuals under alcohol influence constituted another high-risk group. Notably, contradictory to other populations, female individuals involved in fatal falls in the Greater Tokyo Area exhibited a higher frequency of alcohol consumption than males (48.00%, 12/25 vs. 26.00%, 13/50), and most of them were associated with suicide (83.33%, 10/12). These findings elucidate the population characteristics that pose a high risk for fatal falls from height in Japan and can serve as a reference for other Asian populations residing in similar megacities.
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Suicídio , Masculino , Adulto Jovem , Humanos , Feminino , Estudos Retrospectivos , Tóquio/epidemiologia , EtanolRESUMO
BACKGROUND: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors. METHODS: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias. RESULTS: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002). CONCLUSION: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors.
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Laparoscopia , Exenteração Pélvica , Neoplasias Pélvicas , Pontuação de Propensão , Procedimentos Cirúrgicos Robóticos , Humanos , Feminino , Laparoscopia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Japão , Neoplasias Pélvicas/cirurgia , Idoso , Exenteração Pélvica/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Adulto , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Transfusão de Sangue/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Duração da CirurgiaRESUMO
BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterized by high interleukin-6 levels. Clinical data supporting tocilizumab, a monoclonal antibody that targets interleukin-6 receptor-alpha, for treating Japanese patients with severe COVID-19 pneumonia are needed. METHODS: This single-arm phase 3 study investigated tocilizumab (8 mg/kg) plus standard of care (SOC) in Japanese patients hospitalized with severe COVID-19 pneumonia. Clinical status was assessed using a 7-category ordinal scale on day 28 (primary endpoint) and day 14 (secondary endpoint). Other secondary endpoints were time to improvement (≥2 category improvement) and time to hospital discharge. Safety was assessed as the incidence of adverse events (AEs). RESULTS: Among 48 patients enrolled, 44 (91.7 %) scored ≥3 on the 7-category ordinal scale at baseline. At day 28, 35 patients (72.9 %) scored 1 and 5 (10.4 %) scored 7 on the 7-category ordinal scale; 36 (75.0 %, 95 % confidence interval [CI]: 60.40 %-86.36 %) and 39 (81.3 %, 95 % CI: 67.37 %-91.05 %) patients achieved ≥2- and ≥1-category improvement, respectively; 6 patients (12.5 %, 95 % CI: 4.73 %-25.25 %) demonstrated ≥1-category worsening. At day 14, 25 (52.1 %, 95 % CI: 37.19 %-66.71 %) and 33 patients (68.8 %, 95 % CI: 53.75 %-81.34 %) achieved ≥2- and ≥1-category improvement, respectively; 5 patients (10.4 %, 95 % CI: 3.47 %-22.66 %) demonstrated ≥1-category worsening. Median times (95 % CI) to improvement and hospital discharge were 11 (9-15) and 15 (11-18) days, respectively. Forty patients (83.3 %) experienced AEs; the incidence of ≥grade 3 AEs was 25 %. CONCLUSION: Tocilizumab plus SOC may provide improved clinical status in Japanese patients with severe COVID-19 pneumonia; no new safety signals were identified.
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BACKGROUND: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. METHODS: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. RESULTS: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). CONCLUSIONS: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).
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COVID-19 , Humanos , COVID-19/epidemiologia , Ivermectina/efeitos adversos , SARS-CoV-2 , Tratamento Farmacológico da COVID-19 , Japão/epidemiologia , Tailândia/epidemiologia , Método Duplo-Cego , Resultado do TratamentoRESUMO
INTRODUCTION: Measurements of diaphragm function by ultrasonography are affected by body position, but reference values in the seated position have not been established for an Asian population. This study aimed to determine reference values for diaphragm thickness, thickening fraction, and dome excursion by ultrasonography and to investigate the effects of sex, height, and body mass index. METHODS: Diaphragm ultrasonography was performed on 109 seated Japanese volunteers with normal respiratory function who were enrolled between March 2022 and January 2023. Thickness, thickening fraction, and excursion were measured. Reference values and the measurement success rate were calculated. Multivariate analysis adjusted for sex, height, and body mass index was performed. RESULTS: The measurement success rate was better for thickness than for excursion. The mean (lower limit of normal) values on the right/left sides were as follows. During quiet breathing, thickness at end expiration(mm) was 1.7 (0.9)/1.6 (0.80), thickening fraction(%) was 50 (0.0)/52 (0.0), and excursion(cm) was 1.7 (0.5)/1.9 (0.5). During deep breathing, the thickening fraction was 111 (24)/107 (22), and the excursion was 4.4 (1.7)/4.1 (2.0). In multivariate analysis, body mass index was positively associated with thickness but not with the thickening fraction. CONCLUSION: The reference values in this study were smaller than those in previous reports from Europe. Considering that thickness is influenced by body mass index, using Western reference values in Asia, where the average body mass index is lower, might not be appropriate. The thickening fraction in deep breathing is unaffected by other items and can be used more universally.
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Diafragma , Postura Sentada , Humanos , Diafragma/diagnóstico por imagem , Valores de Referência , Ultrassonografia , RespiraçãoRESUMO
PURPOSE: Diaphragm ultrasonography is used to identify causes of diaphragm dysfunction. However, its correlation with pulmonary function tests, including maximal inspiratory (MIP) and expiratory pressures (MEP), remains unclear. This study investigated this relationship by measuring diaphragm thickness, thickening fraction (TF), and excursion (DE) using ultrasonography, and their relationship to MIP and MEP. It also examined the influence of age, sex, height, and BMI on these measures. METHODS: We recruited healthy Japanese volunteers and conducted pulmonary function tests and diaphragm ultrasonography in a seated position. Diaphragm ultrasonography was performed during quiet breathing (QB) and deep breathing (DB) to measure the diaphragm thickness, TF, and DE. A multivariate analysis was conducted, adjusting for age, sex, height, and BMI. RESULTS: Between March 2022 and January 2023, 109 individuals (56 males) were included from three facilities. The mean (standard deviation) MIP and MEP [cmH2O] were 72.2 (24.6) and 96.9 (35.8), respectively. Thickness [mm] at the end of expiration was 1.7 (0.4), TF [%] was 50.0 (25.9) during QB and 110.7 (44.3) during DB, and DE [cm] was 1.7 (0.6) during QB and 4.4 (1.4) during DB. Multivariate analysis revealed that only DE (DB) had a statistically significant relationship with MIP and MEP (p = 0.021, p = 0.008). Sex, age, and BMI had a statistically significant influence on relationships between DE (DB) and MIP (p = 0.008, 0.048, and < 0.001, respectively). CONCLUSION: In healthy adults, DE (DB) has a relationship with MIP and MEP. Sex, age, and BMI, but not height, are influencing factors on this relationship.
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Diafragma , Expiração , Masculino , Adulto , Humanos , Diafragma/diagnóstico por imagem , Voluntários Saudáveis , Testes de Função Respiratória , UltrassonografiaRESUMO
OBJECTIVES: The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition has proposed micrometastasis as a lymph node metastasis (LN+) of diameter ≤2 mm in prostate cancer. However, supporting evidence has not described. We evaluated LN+ patients' survival after radical prostatectomy (RP) based on the LN maximum tumor diameter (MTD). METHODS: Data from 561 LN+ patients after RP and pelvic LN dissection (PLND) treated between 2006 and 2019 at 33 institutions were retrospectively investigated. Patients were stratified by a LN+ MTD cutoff of 2 mm. Outcomes included castration resistance-free survival (CRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: In total, 282 patients were divided into two groups (LN+ MTD >2 mm [n = 206] and ≤2 mm [n = 76]). Patients of LN+ status >2 mm exhibited significantly decreased CRFS and MFS, and poorer CSS and OS. No patients developed CRPC in the LN+ status ≤2 mm group when the PLND number was ≥14. Multivariate analysis showed the number of LN removed, RP Gleason pattern 5, and MTD in LN+ significantly predicted CRFS. CONCLUSIONS: Patients of LN+ status ≤2 mm showed better prognoses after RP. In all the patients in the ≤2-mm group, the progression to CRPC could be prevented with appropriate interventions, particularly when PLND is performed accurately. Our findings support the utility of the pN substaging proposed by the AJCC/UICC 8th edition; this will facilitate precision medicine for patients with advanced prostate cancer.
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Excisão de Linfonodo , Linfonodos , Metástase Linfática , Estadiamento de Neoplasias , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/mortalidade , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Metástase Linfática/patologia , Japão , Excisão de Linfonodo/métodos , Linfonodos/patologia , Linfonodos/cirurgia , Micrometástase de Neoplasia/patologia , Prognóstico , População do Leste AsiáticoRESUMO
INTRODUCTION: We examined the efficacy of a multidomain intervention in preventing cognitive decline among Japanese older adults with mild cognitive impairment (MCI). METHODS: Participants aged 65-85 years with MCI were randomized into intervention (management of vascular risk factors, exercise, nutritional counseling, and cognitive training) and control groups. The primary outcome was changes in the cognitive composite score over a period of 18 months. RESULTS: Of 531 participants, 406 completed the trial. The between-group difference in composite score changes was 0.047 (95% CI: -0.029 to 0.124). Secondary analyses indicated positive impacts of interventions on several secondary health outcomes. The interventions appeared to be particularly effective for individuals with high attendance during exercise sessions and those with the apolipoprotein E ε4 allele and elevated plasma glial fibrillary acidic protein levels. DISCUSSION: The multidomain intervention showed no efficacy in preventing cognitive decline. Further research on more efficient strategies and suitable target populations is required. HIGHLIGHTS: This trial evaluated the efficacy of multidomain intervention in individuals with MCI. The trial did not show a significant difference in preplanned cognitive outcomes. Interventions had positive effects on a wide range of secondary health outcomes. Those with adequate adherence or high risk of dementia benefited from interventions.
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Disfunção Cognitiva , Demência , Humanos , Masculino , Feminino , Idoso , Japão , Idoso de 80 Anos ou mais , Disfunção Cognitiva/prevenção & controle , Demência/prevenção & controle , Resultado do Tratamento , Terapia Cognitivo-Comportamental/métodos , Fatores de Risco , Apolipoproteína E4/genética , Terapia por Exercício/métodosRESUMO
INTRODUCTION: Arthrodesis is a reliable surgical procedure for treatment of thumb carpometacarpal (CMC) osteoarthritis that provides hand strength and pain relief. Locking plate fixation is a common technique that provides rigid fixation and a high rate of bone union; however, it requires extensive surgical exploration of the first metacarpal and trapezium. Here, we report the surgical outcome of minimally invasive arthroscopy-assisted thumb CMC arthrodesis that preserves soft tissue supplying the blood flow to the bones. MATERIALS AND METHODS: Nine thumbs of nine patients who underwent arthroscopy-assisted thumb CMC arthrodesis were retrospectively analysed (mean postoperative follow-up, 19.7 months). We investigated the time from surgery to bone union, grip strength, pinch strength (pulp and key), range of motion (ROM) of the thumb, visual analogue scale (VAS) score for pain, Disabilities of Arm, Shoulder, and Hand (DASH) score, and Hand20 questionnaire score preoperatively and at the final follow-up. RESULTS: Bone union was observed in eight of the nine patients. The mean time to bone union was 2.9 months (range 8 weeks-9 months). Although grip strength changed from 24.0 kg preoperatively to 25.8 kg at the final follow-up (not significant), the pulp pinch strength and key pinch strength significantly increased from 2.3 kg and 3.7 kg preoperatively to 3.8 kg and 5.6 kg at the final follow-up, respectively. No significant change occurred in the thumb ROM. The DASH score, Hand20 questionnaire score, and VAS score for pain significantly improved from 29.8, 42.2, and 78.4 preoperatively to 12.4, 11.2, and 13.2 at the final follow-up, respectively. Non-union was observed in one patient. No other complications were observed. CONCLUSIONS: Arthroscopy-assisted arthrodesis is a valuable procedure for thumb CMC osteoarthritis. However, the learning curve for this procedure must be overcome before the operative time can be shortened and successful bone union and satisfactory outcomes achieved.
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Articulações Carpometacarpais , Osteoartrite , Humanos , Polegar/cirurgia , Estudos Retrospectivos , Artroscopia , Articulações Carpometacarpais/cirurgia , Artrodese/métodos , Osteoartrite/cirurgia , Amplitude de Movimento Articular , DorRESUMO
BACKGROUND: Allergen immunotherapy (AIT) is the only disease-modifying treatment for immunoglobulin (Ig) E-mediated allergy. Owing to the high prevalence and early onset of hay fever and pollen-food allergy syndrome (PFAS), a safer and simpler treatment method than conventional AIT is needed. To develop a local nasal immunotherapy using an ointment containing hypoallergenic pollen and assess its efficacy in mice and healthy humans. METHODS: Hypoallergenicity was achieved by combining pollen and galactomannan through the Maillard reaction to create birch pollen-galactomannan conjugate (BP-GMC). The binding of galactomannan to Bet v 1 was confirmed using electrophoresis and Western blotting (WB). Binding of specific IgE antibodies to BP-GMC was verified using enzyme-linked immunosorbent assay (ELISA) and basophil activation test (BAT). The localization of BP-GMC absorption was confirmed using a BALB/c mouse model. BP-GMC mixed with white petrolatum was intranasally administered to 10 healthy individuals (active drugs, 8; placebo, 2) for 14 days. RESULTS: In electrophoresis and WB, no 17-kDa band was observed. In ELISA and BAT, BP-GMC did not react to specific IgE but was bound to IgA and IgG. In the mouse model, BP-GMC was detected in nasopharyngeal-associated lymphoid tissues. In the active drug group, the salivary-specific IgA level significantly increased on day 15 (p = 0.0299), while the serum-specific IgG level significantly increased on day 85 (p = 0.0006). CONCLUSIONS: The BP-GMC ointment rapidly produced antagonistic antibodies against IgE; it is safe and easy to use and might serve as a therapeutic antigen for hay fever and PFAS.
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Fluorocarbonos , Hipersensibilidade Alimentar , Galactose/análogos & derivados , Mananas , Rinite Alérgica Sazonal , Humanos , Animais , Camundongos , Rinite Alérgica Sazonal/terapia , Alérgenos , Betula , Antígenos de Plantas , Pomadas , Pólen , Imunoglobulina E , Dessensibilização Imunológica , Imunoglobulina G , Imunoglobulina ARESUMO
Zolbetuximab is a chimeric monoclonal antibody that targets claudin-18.2, a candidate biomarker in patients with advanced gastric/gastroesophageal cancer. This nonrandomized phase 1 study (NCT03528629) enrolled previously treated Japanese patients with claudin-18.2-positive locally advanced/metastatic gastric/gastroesophageal cancer in two parts: Safety (Arms A and B, n = 3 each) and Expansion (n = 12). Patients received intravenous zolbetuximab 800 mg/m2 on cycle 1, day 1 followed by 600 mg/m2 every 3 weeks (Q3W; Safety Part Arm A and Expansion) or 1000 mg/m2 Q3W (Safety Part Arm B). For the Safety Part, the primary endpoint was safety (i.e., dose-limiting toxicities [DLTs]) and a secondary endpoint was objective response rate (ORR) by investigator. For the Expansion Part, the primary endpoint was ORR by investigator and secondary endpoints included ORR by central review and safety. Additional secondary endpoints for both the Safety and Expansion Parts were disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response, pharmacokinetics, and immunogenicity. In 18 patients, no DLTs (Safety Part) or drug-related treatment-emergent adverse events (TEAEs) grade ≥3 were observed. Most TEAEs were gastrointestinal. In 17 patients with measurable lesions, best overall response was stable disease (64.7%) or progressive disease (35.3%). The DCR was 64.7% (95% confidence interval 38.3-85.8). In Arm A and Expansion combined (n = 15), median OS was 4.4 months (2.6-11.4) and median PFS was 2.6 months (0.9-2.8). In Arm B (n = 3), median OS was 6.4 months (2.9-6.8) and median PFS was 1.7 months (1.2-2.1). Zolbetuximab exhibited no new safety signals with limited single-agent activity in Japanese patients.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , População do Leste Asiático , Junção Esofagogástrica/patologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Neoplasias Gástricas/patologia , Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Claudinas , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
INTRODUCTION: Leucine-rich alpha-2 glycoprotein (LRG) is a newly studied biomarker for inflammatory diseases. This study aimed to investigate whether LRG can be used for evaluating transmural activity in patients with Crohn's disease (CD). METHODS: We performed magnetic resonance enterography (MRE) in 227 consecutive patients with CD from June 2020 to August 2021. We prospectively compared MRE findings with clinical and laboratory data including LRG. MRE was evaluated using 2 validated scoring systems, and transmural inflammation was defined as having a maximum simplified magnetic resonance index of activity (sMaRIA) score of ≥4 and a 5-point classification score of ≥9, respectively. RESULTS: The correlation between LRG and the total MRE score showed a positive correlation ( r = 0.576 for the sMaRIA score, P < 0.01, and r = 0.633 for the 5-point score, P < 0.01). Serum concentrations of LRG significantly increased as MRE scores increased ( P < 0.01). The area under the curve of LRG for a sMaRIA score of ≥4 and a 5-point score of ≥9 was 0.845 and 0.869, respectively, which was significantly higher than that of CDAI ( P < 0.01) or C-reactive protein ( P < 0.01). LRG levels of ≥14 µg/mL had a 67% sensitivity and 90% specificity for a sMaRIA score of ≥4 and a 73% sensitivity and 89% specificity for a 5-point score of ≥9. Patients with high LRG levels were also strongly associated with CD-related hospitalization, surgery, and clinical relapse compared with those with low LRG levels ( P < 0.01 for all). DISCUSSION: LRG is a highly accurate serum biomarker for detecting transmural activity in patients with CD. Results need to be validated in further multicenter studies.
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Doença de Crohn , Humanos , Doença de Crohn/diagnóstico por imagem , Leucina , Biomarcadores , Inflamação , Glicoproteínas/metabolismo , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.
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Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , População do Leste Asiático , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Neurônios Motores/patologiaRESUMO
BACKGROUND: A basket trial is a type of clinical trial in which eligibility is based on the presence of specific molecular characteristics across subpopulations with different cancer types. The existing basket designs with Bayesian hierarchical models often improve the efficiency of evaluating therapeutic effects; however, these models calibrate the type I error rate based on the results of simulation studies under various selected scenarios. The theoretical control of family-wise error rate (FWER) is important for decision-making regarding drug approval. METHODS: In this study, we propose a new Bayesian two-stage design with one interim analysis for controlling FWER at the target level, along with the formulations of type I and II error rates. Since the difficulty lies in the complexity of the theoretical formulation of the type I error rate, we devised the simulation-based method to approximate the type I error rate. RESULTS: The proposed design enabled adjustment of the cutoff value to control the FWER at the target value in the final analysis. The simulation studies demonstrated that the proposed design can be used to control the well-approximated FWER below the target value even in situations where the number of enrolled patients differed among subpopulations. CONCLUSIONS: The accrual number of patients is sometimes unable to reach the pre-defined value; therefore, existing basket designs may not ensure defined operating characteristics before beginning the trial. The proposed design that enables adjustment of the cutoff value to control FWER at the target value based on the results in the final analysis would be a better alternative.
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Aprovação de Drogas , Humanos , Teorema de Bayes , Simulação por ComputadorRESUMO
BACKGROUND: Angiographic fractional flow reserve (angioFFR) is a novel artificial intelligence (AI)-based angiography-derived fractional flow reserve (FFR) application. We investigated the diagnostic accuracy of angioFFR to detect hemodynamically relevant coronary artery disease.MethodsâandâResults: Consecutive patients with 30-90% angiographic stenoses and invasive FFR measurements were included in this prospective, single-center study conducted between November 2018 and February 2020. Diagnostic accuracy was assessed using invasive FFR as the reference standard. In patients undergoing percutaneous coronary intervention, gradients of invasive FFR and angioFFR in the pre-senting segments were compared. We assessed 253 vessels (200 patients). The accuracy of angioFFR was 87.7% (95% confidence interval [CI] 83.1-91.5%), with a sensitivity of 76.8% (95% CI 67.1-84.9%), specificity of 94.3% (95% CI 89.5-97.4%), and area under the curve of 0.90 (95% CI 0.86-0.93%). AngioFFR was well correlated with invasive FFR (r=0.76; 95% CI 0.71-0.81; P<0.001). The agreement was 0.003 (limits of agreement: -0.13, 0.14). The FFR gradients of angioFFR and invasive FFR were comparable (n=51; mean [±SD] 0.22±0.10 vs. 0.22±0.11, respectively; P=0.87). CONCLUSIONS: AI-based angioFFR showed good diagnostic accuracy for detecting hemodynamically relevant stenosis using invasive FFR as the reference standard. The gradients of invasive FFR and angioFFR in the pre-stenting segments were comparable.