RESUMEN
OBJECTIVE: Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. METHODS: To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis. RESULTS: Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1-2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2 cycles, a lower proportion of patients receiving 3-10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. CONCLUSIONS: Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.
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Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Resultado del Tratamiento , Duración de la Terapia , Vigilancia de Productos ComercializadosRESUMEN
OBJECTIVES: To evaluate the maximum tolerated dose/maximum administered dose, safety, pharmacokinetic, and efficacy profiles of ombrabulin combined with paclitaxel and carboplatin in Japanese patients with solid tumors. METHODS: Ombrabulin (25, 30, or 35 mg/m2) combined with paclitaxel (175 or 200 mg/m2) and carboplatin (AUC5 or AUC6) was administered by intravenous infusion once every 3 weeks to patients with advanced solid tumors, including cervical, ovarian, and uterine cancers. The maximum tolerated dose/maximum administered dose was defined based on the dose-limiting toxicity at cycle 1. Efficacy was assessed based on Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: In total, 18 patients were recruited for this dose escalation study. One out of six patients treated with the highest doses of combination of ombrabulin (35 mg/m2), paclitaxel (200 mg/m2), and carboplatin (AUC6) presented a dose-limiting toxicity consisting of grade 3 Escherichia urinary tract infection. This dose was defined as the maximum tolerated dose of ombrabulin. The most frequent treatment-emergent adverse events were alopecia (83.3%), neutropenia and fatigue (72.2% each), decreased appetite, nausea, diarrhea, arthralgia, and myalgia (66.7% each). The grade 3-4 treatment-emergent adverse events included neutropenia (61.1%), Escherichia urinary tract infection, drug hypersensitivity, syncope, pulmonary embolism, and hydronephrosis (one patient each). In efficacy evaluation, seven patients achieved partial response or better (38.9%), including one complete response, and seven of 18 patients had stable disease (38.9%). Pharmacokinetic profiles in this Japanese study were comparable with those observed in the previous study without Japanese patients. CONCLUSIONS: Although the maximum tolerated dose/maximum administered dose of ombrabulin (35 mg/m2) with taxane-platinum combination may be tolerable in Japanese patients in the first cycle, the dosages in the repeated treatment should be carefully selected for further study. TRIAL REGISTRATION NUMBER: NCT01293630.
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Neoplasias , Neutropenia , Serina/análogos & derivados , Infecciones Urinarias , Humanos , Carboplatino , Paclitaxel/efectos adversos , Japón , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/etiología , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Infecciones Urinarias/etiología , Dosis Máxima ToleradaRESUMEN
BACKGROUND: The CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial. METHODS: This was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS). RESULTS: Of the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8-10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94-128) days for cabazitaxel and 58 (57-66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279-0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258-0.402) favouring cabazitaxel. CONCLUSIONS: Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.
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Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Docetaxel , Japón , Vigilancia de Productos ComercializadosRESUMEN
Advancing the understanding of the relationship between perinatal nicotine addiction and the reward mechanism of the brain is crucial for uncovering and implementing new treatments for addiction control and prevention. The mesolimbic pathway of the brain, also known as the reward pathway, consists of two main areas that regulate dopamine (DA) and addiction-related behaviors. The ventral tegmental area (VTA) releases DA when stimulated, causing the propagation of neuronal firing along the pathway. This ends in the release of DA into the extracellular space of the nucleus accumbens (NAc), which is directly modulated by the uptake of DA. Much research has been conducted on the effects of nicotine addiction, but little research has been conducted concerning nicotine addiction and the mesolimbic pathway regarding maturation due to the small brain size. In this study, we apply our novel microstimulation experimental system to rat pups that have been perinatally exposed to nicotine. By using our self-fabricated photo-stimulation (PS) device, we can stimulate the VTA and collect dialysate, which is then used to estimate DA released into the NAc. The proposed platform has demonstrated the potential to monitor neural pathways as the pups mature.
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Nicotina , Tabaquismo , Ratas , Animales , Nicotina/farmacología , Nicotina/metabolismo , Área Tegmental Ventral/metabolismo , Tabaquismo/metabolismo , Optogenética , Núcleo Accumbens/metabolismo , Neuronas/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismoRESUMEN
Dopamine (DA)'s relationship with addiction is complex, and the related pathways in the mesocorticolimbic system are used to deliver DA, regulating both behavioral and perceptual actions. Specifically, the mesolimbic pathway connecting the ventral tegmental area (VTA) and the nucleus accumbens (NAc) is crucial in regulating memory, emotion, motivation, and behavior due to its responsibility to modulate dopamine. To better investigate the relationship between DA and addiction, more advanced mapping methods are necessary to monitor its production and propagation accurately and efficiently. In this study, we incorporate dLight1.2 adeno-associated virus (AAV) into our latest CMOS (complementary metal-oxide semiconductor) imaging platform to investigate the effects of two pharmacological substances, morphine and cocaine, in the NAc using adult mice. By implanting our self-fabricated CMOS imaging device into the deep brain, fluorescence imaging of the NAc using the dLight1.2 AAV allows for the visualization of DA molecules delivered from the VTA in real time. Our results suggest that changes in extracellular DA can be observed with this adapted system, showing potential for new applications and methods for approaching addiction studies. Additionally, we can identify the unique characteristic trend of DA release for both morphine and cocaine, further validating the underlying biochemical mechanisms used to modulate dopaminergic activation.
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Cocaína , Ratones , Animales , Dopamina/metabolismo , Morfina/farmacología , Morfina/metabolismo , Núcleo Accumbens/metabolismo , Área Tegmental Ventral/metabolismoRESUMEN
BACKGROUND: Dupilumab, a human monoclonal anti-interleukin (IL)-4Ra antibody blocks the shared receptor component of IL-4 and IL-13, drivers of type 2 inflammation. Dupilumab is approved for severe/refractory asthma inadequately controlled by existing therapies, but knowledge of its effect on real-world disease burden is lacking. This study investigates real-world effects of dupilumab on asthma exacerbation risk and oral corticosteroid (OCS) use in Japanese individuals with asthma. METHODS: This retrospective, cohort study used a Japanese insurance claims database to identify patients who started dupilumab between 26 March 2019-31 May 2020. Patients were followed for ±365 days from dupilumab initiation. The study primarily assessed the annual incidence rate of severe asthma exacerbations occurring simultaneously with hospitalizations or OCS bursts. Secondary and exploratory endpoints assessed OCS dosage and duration, and healthcare resource utilization (HRU), respectively. RESULTS: At dupilumab initiation (N = 215), mean age was 57.2 years, 41.9% of patients were aged ≥65 years, and 59.5% were female. Dupilumab significantly reduced the annual incidence of severe asthma exacerbations from 1.29 to 0.74 (95% confidence interval, 0.44-0.76) per patient per year. Mean OCS dosage decreased from 10.4 to 7.2 mg/day in chronic OCS users; median frequency of OCS bursts decreased from 3 to 0. Both unscheduled outpatient visits (35.8% vs 29.8%) and hospitalizations (21.9% vs 12.1%) decreased. Mean (standard deviation) duration of hospitalization also decreased from 6.7 (27.6) to 2.2 (8.1) days. CONCLUSIONS: Japanese patients with asthma who received dupilumab had reduced incidence rates of severe asthma exacerbations, OCS use, and HRU over 12 months.
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Antiasmáticos , Asma , Humanos , Femenino , Persona de Mediana Edad , Masculino , Antiasmáticos/uso terapéutico , Estudios Retrospectivos , Estudios de Cohortes , Japón/epidemiología , Asma/tratamiento farmacológico , Asma/epidemiología , Costo de Enfermedad , Corticoesteroides/uso terapéuticoRESUMEN
Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression-free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5-fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%-15.3%), and the disease control rate (DCR) was 80.0% (69.9%-90.1%). The median progression-free survival was 5.42 months (4.14-6.70 months) and the median overall survival was 15.59 months (11.20-19.81 months). No treatment-related deaths were observed, and no significant drug-drug interactions were found. The most common treatment-emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 µg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5-fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5-fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well-tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Pueblo Asiatico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/metabolismo , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Estudios Prospectivos , Receptores de Factores de Crecimiento Endotelial Vascular/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Cabazitaxel is an efficacious treatment for patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel, but febrile neutropenia during the first cycle is a frequent complication. Asian patients are at increased risk of febrile neutropenia. Although primary prophylaxis with granulocyte colony-stimulating factor can reduce the incidence, its efficacy has not been prospectively demonstrated in Japanese patients with cabazitaxel treatment. METHODS: PEGAZUS, a prospective, single-arm study conducted at eight clinical sites in Japan, enrolled 21 heavily pretreated patients with metastatic castration-resistant prostate cancer. Patients received cabazitaxel 25 mg/m2 every 3 weeks, up to 10 cycles. Oral prednisolone 10 mg was taken daily. Pegfilgrastim 3.6 mg was administered at least 24 h after the cabazitaxel infusion. The primary endpoint was the incidence of febrile neutropenia in the first cycle. RESULTS: The median number of treatment cycles was seven. The relative dose intensity of cabazitaxel was 67.4% (range, 53.2-91.3%). Two of 21 patients (9.5%) experienced febrile neutropenia in the first cycle. This rate was lower than the rate (43%) previously observed without prophylactic granulocyte colony-stimulating factor in a similar patient population. Six patients showed a prostate-specific antigen response (28.6%). Three of four patients evaluable for tumor response had stable disease and one had progressive disease. Grade ≥3 diarrhea was not observed. Primary prophylaxis with granulocyte colony-stimulating factor significantly reduced the incidence of febrile neutropenia in this study. CONCLUSIONS: Cabazitaxel plus granulocyte colony-stimulating factor is safe and effective for Japanese patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel. Clinical trial registration: ClinicalTrials.gov (NCT02441894).
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Filgrastim/uso terapéutico , Polietilenglicoles/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/uso terapéutico , Anciano , Anciano de 80 o más Años , Humanos , Japón , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , Antígeno Prostático Específico/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models. METHODS: In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated. RESULTS: Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2). CONCLUSION: A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level. CLINICAL TRIAL REGISTRATION ID: ClinicalTrials.gov number, NCT01095302.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Serina/análogos & derivados , Taxoides/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Serina/efectos adversos , Serina/sangre , Serina/farmacocinética , Serina/uso terapéutico , Taxoides/efectos adversos , Taxoides/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the safety, efficacy and pharmacokinetics of alemtuzumab in Japanese patients, we conducted a phase I study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia. METHODS: Six patients received alemtuzumab by intravenous infusion every other day three times a week for 12 weeks. The dose was gradually escalated on daily basis (3, 10 and then 30 mg) until the patient tolerated. The primary objective was to evaluate the safety of alemtuzumab in Japanese patients and the secondary objectives were to evaluate the overall response rate and the pharmacokinetics. RESULTS: The major treatment-emergent adverse events were anemia, neutropenia (6/6 patients each) and thrombocytopenia (5/6 patients) in hematologic adverse events, and nausea, vomiting, decreased appetite, cytomegalovirus test positive and pyrexia (4/6 patients) in non-hematologic adverse events. As serious adverse events, cytomegalovirus infection, pulmonary tuberculosis and diffuse large B-cell lymphoma were reported in 1/6 patient each. The overall response rate was 33% (95% confidence interval: 4-78) (1/6 patient each achieved complete response and partial response, respectively) and 3/6 patients had stable disease and 1/6 patient had progressive disease. The median time to response was 2.9 months. After last intravenous dosing (Week 12) of alemtuzumab 30 mg every other day three times a week, Cmax, tmax, AUC0-τ and t1/2 were higher and CL and Vss were lower than the values observed after the first dose. CONCLUSIONS: The efficacy, safety and pharmacokinetics results observed with alemtuzumab in Japanese patients were generally similar to those reported in overseas clinical studies. Alemtuzumab at 30 mg by intravenous infusion every other day three times a week for 12 weeks should be safe and effective similarly in Japanese B-cell chronic lymphocytic leukemia patients. CLINICAL TRIAL REGISTRATION NO: NCT00923182.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/inmunología , Antígenos de Neoplasias/inmunología , Glicoproteínas/inmunología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Área Bajo la Curva , Pueblo Asiatico , Antígeno CD52 , Esquema de Medicación , Femenino , Fiebre/etiología , Semivida , Humanos , Japón , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neutropenia/etiología , Curva ROC , Inducción de Remisión , Resultado del TratamientoRESUMEN
OBJECTIVE: In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m2 ombrabulin with 75 mg/m2 cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors. METHODS: This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m2 combined with cisplatin 75 mg/m2. The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities. RESULTS: Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients. CONCLUSIONS: Ombrabulin 25 mg/m2 with cisplatin 75 mg/m2 once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.
RESUMEN
Objectives: Chronic rhinosinusitis (CRS) is a heterogeneous disease, which can be subdivided into CRS with (CRSwNP) or without (CRSsNP) nasal polyps. An intractable form of CRSwNP that is associated with an eosinophil-dominant inflammatory cell infiltration (eosinophilic CRS) has become more prevalent in Japan. There is currently limited information on the burden of CRS in Japan and treatment approaches used in real-world practice. Methods: This retrospective, observational, comparative cohort study used information from the Japanese JMDC insurance claims database (study period April 1, 2015, to March 31, 2020). A CRS cohort was identified and matched with a control group without CRS. The primary objective was to clarify disease burden and treatment approaches by comparing comorbidities, healthcare resource utilization (HRU), and drug prescriptions in the CRS and non-CRS groups. Results: In total, 23,256 individuals with CRS (1762 with CRSwNP and 21,494 with CRSsNP) were matched with 23,256 controls. The mean age was 45 years and the majority of individuals were male (57%). Individuals with CRS had a higher disease burden than controls, with more frequent comorbidities (particularly, type 2 inflammatory disease [e.g., allergic rhinitis and asthma], and those caused by systemic corticosteroids [SCS]), and higher HRU (including outpatient visits, laboratory examinations and surgical procedures). Further, individuals with CRS were prescribed more medications, both for CRS (including SCS) and non-CRS conditions, than controls. Conclusion: In Japan, CRS is associated with a high disease burden, and multiple treatment approaches are used in affected individuals, including long-term SCS, which is generally not recommended. Level of Evidence: 3.
RESUMEN
Brain growth occurs during the first 2 weeks of postnatal development in rats. This developmental period is equivalent to the third trimester of human gestation. Dendritic arborization, axonal growth, and gliogenesis are observed along with a strong maturation of neurotransmission during this critical development period. Furthermore, nicotine exposure during early development causes deficiencies in sensory and cognitive processing in adults. In this study, we further investigated the gene expression of neuron groups and the influence of perinatal nicotine exposure on gene expressions of neurons within the sub-regions of the ventral tegmental area (VTA) in 1 week, 2 week and 3-week-old rat pups. We exposed pregnant rats to nicotine perinatally on gestational day 7 through postnatal day 14. Pups are exposed to nicotine during pregnancy and through breastfeeding to investigate its effect in rat pups during early neuronal development. Real time PCR was used to find the relative expressions of gamma-aminobutyric acid (GABA), dopamine, and glutamate neuron markers within the three sub-regions of the VTA including the parabrachial pigmented nucleus (PBP), parainterfascicular (PIF), and paranigral nucleus (PN). Our results indicated that during early maturation, the dopamine marker tyrosine hydroxylase (TH) showed a consistently increased significance in PN sub-region compared to PIF and PBP. These results suggest that following perinatal nicotine exposure, VTA dopamine neurons, especially within the PN sub-region, are significantly excited starting from birth.
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Nicotina , Efectos Tardíos de la Exposición Prenatal , Embarazo , Humanos , Femenino , Ratas , Animales , Nicotina/efectos adversos , Nicotina/metabolismo , Área Tegmental Ventral/metabolismo , Transcriptoma , Dopamina/metabolismo , Ratas Sprague-Dawley , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Neuronas Dopaminérgicas/metabolismoRESUMEN
The affiliation of the last author, Kenshi Suzuki has been incorrectly published in the original publication of the article. The correct affiliation is provided in this correction.
RESUMEN
The present study (ClinicalTrials.gov Identifier: NCT02221492) was conducted to assess the efficacy and safety of plerixafor for the mobilization and collection of haematopoietic stem cells (HSCs) for autologous transplantation in Japanese non-Hodgkin lymphoma (NHL) patients. In this randomized phase 2 study, patients received granulocyte-colony stimulating factor (G-CSF, filgrastim) 400 µg/m²/day for up to 8 days. Starting on the evening of day 4, patients received, for up to 4 days, either plerixafor (240 µg/kg/day) in the G-CSF+ plerixafor arm (GP arm) or G-CSF alone arm (G arm). On day 5, daily apheresis started and was continued for up to 4 days, or until ≥ 5 × 106 CD34+ cells/kg was collected. A total of 32 patients were randomized to either the GP or G arm. In the GP arm, 9/16 patients (56.3%) achieved collection of ≥ 5 × 106 CD34+ cells/kg in ≤ 4 days of apheresis, while 1/16 patient (6.3%) achieved this target in the G arm. The most common treatment-emergent adverse events in the GP arm were back pain (56.3%), platelet count decreased (25.0%), headache, diarrhoea, and nausea (18.8% each). We found that plerixafor was well tolerated and effective for the mobilization and collection of peripheral HSCs for autologous transplantation in Japanese NHL patients.
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Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas , Compuestos Heterocíclicos/administración & dosificación , Linfoma no Hodgkin/terapia , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Autoinjertos , Bencilaminas , Ciclamas , Femenino , Compuestos Heterocíclicos/efectos adversos , Humanos , Linfoma no Hodgkin/sangre , Masculino , Persona de Mediana EdadRESUMEN
To evaluate the efficacy and safety of plerixafor for the mobilization/collection of peripheral hematopoietic stem cells (HSCs) for autologous transplantation in Japanese patients with multiple myeloma (MM). In a randomized study, patients received G-CSF (filgrastim, 400 µg/m2/day) for 4 days prior to the first dose of plerixafor. Starting on Day 4 evening and for up to 4 days, patients received either plerixafor (240 µg/kg/day) + G-CSF group (PG group) or G-CSF alone (G group). Daily apheresis started on Day 5 for up to 4 days, or until ≥6 × 106 CD34+ cells/kg were collected. A total of 7 patients were randomized in each treatment group. Five patients in PG group and no patients in G group achieved a collection of ≥6 × 106 CD34+ cells/kg in ≤2 days of apheresis [difference of 71.4% (90%CI 29-100%)]. These results were supported by the shorter median time to collect ≥6 × 106 CD34+ cells/kg (2 days in PG group; no patient in G group). The incidence of treatment emergent adverse events (TEAEs) was higher in PG group than in G group. Plerixafor was well tolerated, and effective for the mobilization/collection of peripheral HSCs for autologous transplantation in Japanese patients with MM.