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Signal transducer and activator of transcription 3 (STAT3) plays key roles in cancer cell proliferation, invasion, and immunosuppression. In many human cancer cells, STAT3 is hyperactivated, which leads to tumor progression and drug resistance, and therefore STAT3 and its modulators are considered effective drug targets. However, the complex regulatory mechanisms of STAT3 have made it difficult to develop potent anticancer drugs that suppress its activity. Here, we report serum and glucocorticoid-regulated kinase 1 (SGK1) as a novel regulator of STAT3 signaling and an effective target for combination therapy with Janus kinase (JAK) inhibitors. We screened small molecules using a gain-of-function mutant of STAT3 resistant to JAK inhibition and found that an SGK1 inhibitor suppressed the constitutive activation of STAT3. Importantly, our results revealed that SGK1 also mediated the activation of wild-type STAT3. Further examination suggested that the tuberous sclerosis complex 2 and mammalian target of rapamycin signaling pathway were involved in STAT3 activation by SGK1. Finally, we demonstrated that SGK1 inhibition enhanced the inhibitory effect of a JAK inhibitor on STAT3 phosphorylation and cancer cell proliferation. Our findings provide new insights into the molecular mechanisms of STAT3 activation and suggest SGK1 as a potential target for STAT3-targeted combination cancer therapy.
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Proteínas Imediatamente Precoces , Neoplasias , Proteínas Serina-Treonina Quinases , Fator de Transcrição STAT3 , Linhagem Celular Tumoral , Humanos , Proteínas Imediatamente Precoces/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
PURPOSE: According to the revised Japanese medical service fees aimed at reducing irrational psychotropic polypharmacy, medical service fees are reduced if the number of simultaneously prescribed psychotropic drugs exceeds the standard. This study primarily aims to examine the effect of the 2018 revision. METHODS: Using a large Japanese administrative claims database, we retrospectively identified five groups (April 2013-September 2018) prescribed at least one drug from the following drug groups: anxiolytics, hypnotics, sum of anxiolytics and hypnotics, antipsychotics, and antidepressants (study population in each group: 547,511, 406,524, 759,137, 112,929, and 201,046, respectively). We used an interrupted time-series design to evaluate changes in the proportion of patients prescribed more than the standard number of drugs. RESULTS: After the 2018 revision, the proportion of patients prescribed more than the standard number of drugs significantly decreased only for the sum of anxiolytics and hypnotics; estimated changes in level and trend were - 0.60% [- 0.69%, - 0.52%] and - 0.04% [- 0.06%, - 0.02%] per month, respectively. The proportion of patients exhibiting a decrease in the number of prescribed drugs from more than the standard to within the standard increased when the revision was enforced (April 2018); this proportion in April 2018 was 36.3%, while all other proportions were in the range of 12.1-22.3%. CONCLUSION: The 2018 revision promoted a reduction in the number of prescribed drugs, which served as an important factor in the decrease in the proportion of patients prescribed more than the standard number of drugs for the sum of anxiolytics and hypnotics.
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Antipsicóticos , Polimedicação , Antipsicóticos/uso terapêutico , Humanos , Japão , Psicotrópicos/uso terapêutico , Estudos RetrospectivosRESUMO
OBJECTIVES: There are patients who do not undergo colonoscopy even if the fecal immunochemistry test (FIT) results are positive and even with repeated positive test results the following year. We aimed to investigate colorectal cancer (CRC) risk in examinees with positive FIT results in our annual screening program. METHODS: We analyzed patients who underwent initial colonoscopy from April 2010 to March 2017 because of positive FIT results using an endoscopy database in our hospital. We investigated the difference in the risk of advanced colorectal neoplasia as a surrogate marker of CRC between those who had an initial positive test and those who had repeated positive tests. RESULTS: A total of 748 patients were included in this analysis. The advanced neoplasia detection rates were 7.6% (50/656) and 18.5% (17/92) for the initial and repeated positive test groups, respectively. Subgroup analysis of those with repeated positive tests revealed that the detection rates in examinees with positive tests 1-2 and >2 years ago were 16.7% (6/36) and 19.6% (11/56), respectively. The odds ratios for advanced neoplasia detection in patients with positive tests 1-2 and >2 years ago compared with those in the initial positive test group were 2.72 (95% confidence interval [CI], 1.04-7.10) and 3.09 (95% CI, 1.47-6.48), respectively. CONCLUSIONS: The risk of CRC appears more than doubled in patients with a repeated positive FIT result. Prompt colonoscopy is recommended for FIT-positive cases.
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We report a case of polyangiitis overlap syndrome of giant cell arteritis (GCA) and granulomatosis with polyangiitis (GPA) and conduct a literature review of polyangiitis overlap syndrome. The patient was 73-year-old male who developed cranial-type GCA and GPA simultaneously and was successfully treated with rituximab. Rituximab might be effective for not only GPA but also GCA.
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Arterite de Células Gigantes , Granulomatose com Poliangiite , Rituximab , Idoso , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/tratamento farmacológico , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , Masculino , Rituximab/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. METHODS: A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. RESULTS: Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. CONCLUSIONS: B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.
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Genes myc/genética , Linfoma Folicular , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Biópsia , Medula Óssea/patologia , Diagnóstico Diferencial , Humanos , Hibridização in Situ Fluorescente , Linfoma Folicular/complicações , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , Proteínas de Fusão Oncogênica/genética , Pâncreas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Testículo/patologia , Translocação GenéticaRESUMO
BACKGROUND AND AIM: As the significance of the quantitative fecal immunochemical test (FIT) in patients who previously underwent a colonoscopy is unknown, this study aimed at investigating the association between fecal hemoglobin concentration and the risk of colorectal cancer (CRC). METHODS AND RESULTS: We retrospectively analyzed FIT-positive patients who underwent a colonoscopy through our opportunistic annual screening program from April 2010 to March 2017 at the Kyoto Second Red Cross Hospital. We stratified them into no colonoscopy and past colonoscopy (>5 years or ≤5 years) groups based on whether they had a history of undergoing a colonoscopy and analyzed the correlation between fecal hemoglobin concentration and advanced neoplasia or invasive cancer detection in each group. We analyzed 1248 patients with positive FIT results. There were 748 (59.9%), 198 (15.9%), and 302 (24.2%) patients in the no colonoscopy, past colonoscopy (>5 years), and past colonoscopy (≤5 years) groups, respectively. In the no colonoscopy group, the advanced neoplasia detection rate significantly increased with the fecal hemoglobin concentration (P < 0.001). However, no significant trend was observed in the past colonoscopy (both >5 years and ≤5 years) group (P = 0.982). No invasive cancer was detected in the past colonoscopy (≤5 years) group. CONCLUSION: The risk of CRC might be low even if fecal hemoglobin concentration was high, especially in those who underwent colonoscopy within 5 years.
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We present aptamer-based sensing using a coupled acoustic-gravitational (CAG) field, which transduces a change in the density of a microparticle (MP) to a change in the levitation coordinate. A large density of the MP is initially induced by the binding of gold nanoparticles (AuNPs) on the MP through sandwich hybridization with aptamer DNA molecules. Targets added to the system interact with the aptamer DNA molecules to form complexes, and the duplex between the aptamer and the probe DNA molecules is dissociated. This leads to the release of AuNPs from the MP and a decrease in its density. As the target concentration increases, the levitation coordinate of the MP increases. From the levitation coordinate shift, we can determine the target concentration. The detection limits for adenosine triphosphate, dopamine, and ampicillin as test targets are 9.8 nM, 17 nM, and 160 pM, respectively. The dissociation constants for the aptamer-target complexes are quantitatively determined from the dependence of the levitation coordinate on the target concentration. This scheme is a useful analytical tool not only for the trace analyses of targets but also for the evaluation of aptamer-target interactions.
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OBJECTIVES: Polymyalgia rheumatica (PMR) is a systemic inflammatory disease in the elderly of unknown etiology. While glucocorticoids are the mainstay of treatment for PMR, various glucocorticoid-related adverse events are common. Recently, several studies have reported the efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, for PMR treatment in addition to an accompanying reduction, or even tapering-off, of glucocorticoids in some cases. The objective of this study was to elucidate the efficacy of TCZ monotherapy in the absence of glucocorticoids for PMR. METHOD: We conducted a 2-year, prospective, single-center, open-label pilot study of TCZ monotherapy in patients with PMR. TCZ (8 mg/kg) was administered at fortnightly intervals for the first 2 months and monthly over the next 10 months. Subsequently, patients were observed for another year without any treatment. The primary endpoints were the remission rates at weeks 12 and 52, and the secondary endpoints were the relapse rate and safety over the total 104 weeks. RESULTS: Thirteen patients were included in this study. Four of these patients achieved remission at week 12 (remission rate 31%). Four patients withdrew from the study due to adverse events (n = 2) and inefficacy (n = 2). At week 52, all 9 patients who had completed the first year achieved remission. Eight patients completed the drug-free second year, with 7 maintaining remission. CONCLUSIONS: TCZ monotherapy is well tolerated and can lead to remission in most patients with PMR in the absence of glucocorticoids.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Polimialgia Reumática/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Interleucina-6/sangue , Japão , Masculino , Pessoa de Meia-Idade , Polimialgia Reumática/diagnóstico , Polimialgia Reumática/imunologia , Estudos Prospectivos , Recidiva , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011. METHODS: We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital. RESULTS: Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%). CONCLUSION: Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.
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Procedimentos Clínicos , Fator Estimulador de Colônias de Granulócitos , Neutropenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Neutropenia/prevenção & controle , Estudos Retrospectivos , Adulto JovemRESUMO
We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.
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Eritema Nodoso/diagnóstico , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Neoplasias Cutâneas/diagnóstico , Pré-Escolar , Diagnóstico Diferencial , Eritema Nodoso/diagnóstico por imagem , Feminino , Humanos , Síndrome de Linfonodos Mucocutâneos/diagnóstico por imagem , Gravidez , Neoplasias Cutâneas/diagnóstico por imagemRESUMO
BACKGROUND AND AIM: Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic. METHODS: This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago (> 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis. RESULTS: Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and > 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and > 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively. CONCLUSION: Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.
Assuntos
Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Fezes/química , Imunoquímica , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Japão/epidemiologia , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Estudos Prospectivos , Risco , Fatores de TempoRESUMO
BACKGROUND: Underwater endoscopic mucosal resection (U-EMR) has emerged as an alternative technique for the resection of colorectal lesions. This study aimed to evaluate our initial experience using U-EMR. METHODS: This is a single-center, retrospective case series study. We analyzed the clinical outcomes of consecutive patients who underwent U-EMR in our endoscopy center, from December 2015 to February 2017. RESULTS: Our analysis included 64 lesions, contributed by 38 patients, with a mean age of 68.6 years (range, 25 to 90 years). The study sample included 33 right-sided and 25 left-sided colon lesions, and seven rectal lesions, with an average size of 16.2 mm (6 - 40 mm). Of these, 46 lesions were polypoid and 18 ones non-polypoid. Histologically, 31 lesions were low-grade adenomas, eight ones were high-grade adenomas, 11 were mucosal cancers, four were submucosal cancers, and 10 were classified as "others". En bloc resection was achieved in 52 (81%) lesions, with an en bloc resection rate of 95% for lesions < 20 mm and 55% for lesions ≥ 20 mm. Complete resection of neoplastic epithelial lesions, defined by a negative pathological margin, was achieved in 32 of 59 neoplastic epithelial lesions (54%). We identified three cases (5%) of post-procedural bleeding and one case of perforation (2%). CONCLUSIONS: U-EMR can be feasibly used for resection of colonic lesions, including lesions ≥ 20 mm, although the en bloc resection rate for these lesions was lower than for lesions < 20 mm.
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Dimerization in signal transduction is a dynamically regulated process and a key regulatory mechanism. Signal transducer and activator of transcription 3 (STAT3) dimerizes after tyrosine phosphorylation upon cytokine stimulation. Because only the STAT3 dimer possesses the trans-activation activity, dimerization is an indispensable process for cytokine signaling. Here we report the detection of dynamic STAT3 dimerization in living cells using the homoFluoppi system. This method allowed us to validate the presence of an intact Src homology 2 domain and STAT3 Tyr705 phosphorylation, which facilitate puncta formation and homodimerization. Puncta formation was reversible, as determined by a decreased punctate signal after washout of oncostatin M. We analyzed STAT3 mutants, which have been reported in patients with hyper IgE syndrome and inflammatory hepatocellular adenoma (IHCA). Analysis of the IHCA mutants using homoFluoppi revealed constitutive activity independent of cytokine stimulation and novel insight into kinetics of dimer dissociation process. Next, we used homoFluoppi to screen for inhibitors of STAT3 dimerization, and identified 3,4-methylenedioxy-ß-nitrostyrene as a novel inhibitor. The results of this study show that homoFluoppi is a useful research tool for the analysis of proteins like STAT3 that dynamically dimerize, and is applicable for the screening of dimerization modulators.
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Técnicas Citológicas/métodos , Imagem Óptica/métodos , Multimerização Proteica , Fator de Transcrição STAT3/metabolismo , Coloração e Rotulagem/métodos , Análise Mutacional de DNA , Células Epiteliais/metabolismo , Células HEK293 , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
OBJECTIVES: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. RESULTS: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. CONCLUSION: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a troublesome issue in chemotherapy for cancer patients. A second-generation 5HT3 receptor antagonist (5HT3RA), palonosetron, is effective and safe for the prevention of CINV in breast cancer patients treated with cyclophosphamide and anthracycline, but there is little data for malignant lymphoma. We conducted a prospective phase 2 study at a single institution to clarify the efficacy and safety of palonosetron in lymphoma patients. METHODS: Chemotherapy-naïve lymphoma patients who were treated with highly emetogenic chemotherapy (HEC) received a single intravenous bolus of palonosetron, 0.75 mg/body, before chemotherapy on day 1 during the first course of chemotherapy. The occurrence of CINV was assessed using the Multinational Association for Supportive Care in Cancer (MASCC) antiemesis tool, which was recorded by patients during the first course of chemotherapy. RESULTS: A total of 59 patients were enrolled, and 49 patients were eligible and evaluated. The complete response (CR) rate was 93.9% (95% confidence interval 83.1-98.7%) at 0-120 h post-chemotherapy. The proportion of patients who developed nausea of any grade and vomiting at 0-120 h post-chemotherapy was 34.7 and 6.1%, respectively. Although treatment-related adverse events were observed in 36 (73.5%) patients, these were mild and they recovered by the next cycle of chemotherapy. CONCLUSION: The present study demonstrated that a single dose of palonosetron was highly effective and safe for the prevention of CINV in lymphoma patients.
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Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Isoquinolinas/uso terapêutico , Linfoma/tratamento farmacológico , Náusea/prevenção & controle , Quinuclidinas/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Isoquinolinas/administração & dosagem , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Palonossetrom , Estudos Prospectivos , Quinuclidinas/administração & dosagem , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
The purpose of this study is to report the efficacy and safety of a combination of tocilizumab (TCZ) and high-dose corticosteroid (CS) in two patients with microscopic polyangiitis (MPA) and review the published current clinical evidence on TCZ in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), except for large vessel vasculitis (LVV) and polymyalgia rheumatica (PMR). Two MPA patients were treated with TCZ at 8 mg/kg every month for 1 year and CS (prednisolone 1 mg/kg/day for 2 weeks, followed by tapering) in a prospective single-arm, single-center, cohort, open-label pilot study (UMIN clinical trials: 000012072). We performed a systematic literature search (PubMed and ICHUSHI [Japan Medical Abstracts Society] until June 30, 2017) to identify published reports on patients with all vasculitis other than LVV/PMR, who were treated with TCZ. We successfully treated the first patient. However, the other patient had serious infection probably associated with the combination of TCZ and high-dose CS. The literature review identified 22 reports with a total of 34 patients who received TCZ for AAV, rheumatoid vasculitis, and other types of vasculitis, in addition to our patients. In 15 of 17 patients (88.2%) with primary and secondary AAV, especially MPA, TCZ induced clinical remission, although TCZ use for rheumatoid vasculitis and vasculitis with mucocutaneous lesions is controversial. This study suggested that TCZ therapy is a potential treatment strategy for patients with AAV. However, TCZ combined with high-dose of CS might not be an appropriate treatment. Future studies are needed to confirm our findings.
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Corticosteroides/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Poliangiite Microscópica/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto , Estudos de Coortes , Feminino , Arterite de Células Gigantes/tratamento farmacológico , Humanos , Interleucina-6/metabolismo , Japão , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polimialgia Reumática/tratamento farmacológico , Estudos Prospectivos , Resultado do Tratamento , Vasculite/sangueRESUMO
BACKGROUND AND AIM: The significance of examination time of esophagogastroduodenoscopy (EGD) for asymptomatic examinees is yet to be established. We aimed to clarify whether endoscopists who allot more examination time can detect higher numbers of neoplastic lesions among asymptomatic examinees. METHODS: We reviewed a database of consecutive examinees who underwent EGD in our hospital from April 2010 to September 2015. Staff endoscopists were classified into fast, moderate, and slow groups based on the mean examination time of EGD without a biopsy. Neoplastic lesion detection rate among these groups was compared using multiple logistic regression. RESULTS: Of the 55 786 consecutive examinees who underwent EGD, 15 763 asymptomatic examinees who were screened by staff doctors were analyzed. Mean examination time of 13 661 EGD without biopsy was 6.2 min (range, 2-18 min). When cut-off times of 5 and 7 min were used, four endoscopists were classified into the fast (mean duration, 4.4 ± 1.0 min), 12 into the moderate (6.1 ± 1.4 min), and four into the slow (7.8 ± 1.9 min) groups. Neoplastic lesion detection rates in the fast, moderate, and slow groups were 0.57% (13/2288), 0.97% (99/10 180), and 0.94% (31/3295), respectively. Compared with that in the fast group, odds ratios for the neoplastic lesion detection rate in the moderate and slow groups were 1.90 (95% confidence interval [CI], 1.06-3.40) and 1.89 (95% CI, 0.98-3.64), respectively. CONCLUSION: Endoscopists who do not allot adequate examination time may overlook neoplastic lesions in the upper gastrointestinal tract.
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Endoscopia Gastrointestinal , Neoplasias Gastrointestinais/diagnóstico por imagem , Indicadores de Qualidade em Assistência à Saúde , Trato Gastrointestinal Superior , Idoso , Doenças Assintomáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Físico , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND AND STUDY AIMS: An iincreasing number of reports describe endoscopic ultrasound-guided hepaticogastrostomy for malignant biliary obstruction in patients with endoscopic retrograde cholangiopancreatography failure. However, this procedure has not yet been standardized; as a result, the rate of adverse events, including bile leakage and stent migration, is relatively high. Here, we report our experience with four cases of endoscopic ultrasound-guided hepaticogastrostomy performed according to our institutional procedure.
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OBJECTIVE: We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy. PARTICIPANTS AND METHODS: The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy. The associations of these polymorphisms with the disposition, clinical efficacy, and incidence of adverse effects of carbamazepine treatment were retrospectively investigated in 104 patients treated with carbamazepine alone. The associations with disposition were also assessed in 64 patients treated with carbamazepine and other antiepileptic drugs, which constituted the internal replication group, and in the combined 168 patients. RESULTS: Neither polymorphism alone affected the carbamazepine disposition, but a significant interactive effect of PXR*1B and HNF4α rs2071197 polymorphisms on the concentration-to-dose (C/D) ratios was observed (P=0.027). The C/D ratios among patients with the HNF4α G/G genotype were higher in PXR*1B carriers than in PXR*1B noncarriers, which was confirmed in the internal replication and combined groups. In patients with the HNF4α G/G genotype, the rate of freedom from seizures until 3 months after starting carbamazepine therapy was significantly greater and the time required to reach the dose required for seizure freedom was shorter in PXR*1B carriers than in PXR*1B noncarriers. CONCLUSION: These results suggest that PXR*1B, in combination with HNF4α rs2071197, might be associated with the C/D ratios and the duration to reach the maintenance dose of carbamazepine therapy, thus indicating an influence upon the autoinduction of the carbamazepine metabolism.
Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Fator 4 Nuclear de Hepatócito/genética , Receptores de Esteroides/genética , Adolescente , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Criança , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptor de Pregnano X , Estudos Retrospectivos , Adulto JovemRESUMO
(R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reductase in bacterial membranes) also catalyzed (R)-thalidomide 5-hydroxylation. Purified human P450s 2C19, 3A4, and 3A5 mediated (R)-thalidomide 5-hydroxylation at similar rates in reconstituted systems. P450 2C19 showed a rather nonsaturable substrate-velocity curve; however, P450s 3A4 and 3A5 showed sigmoidal curves. P450 also oxidized 5-hydroxythalidomide to an epoxide or dihydroxy compound. Liquid chromatography-mass spectrometry analysis revealed the formation of a glutathione conjugate from (R)- and (S)-5-hydroxythalidomide, catalyzed by liver microsomal P450s 3A4 and 3A5 in the presence of glutathione (assigned as a conjugate of 5-hydroxythalidomide formed on the phenyl ring). These results indicate that human P450s 3A4 and 3A5 mediate thalidomide 5-hydroxylation and further oxidation leading to a glutathione conjugate, which may be of relevance in the pharmacological and toxicological actions of thalidomide.