RESUMEN
Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Japón , Paclitaxel , Compuestos de Fenilurea , QuinolinasRESUMEN
BACKGROUND: We investigated whether multiple food allergies could be safely prevented by simultaneously administering very small amounts of multiple foods. METHODS: Infants 3-4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing egg, milk, wheat, soybean, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4, and continued until week 12. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000027837). RESULTS: A total of 163 participants were randomly allocated to either the MP group (n = 83) or the PP group (n = 80). The incidence of food allergy episodes by 18 months was significantly different between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116-0.784]; P = 0.0066). Egg allergies were reduced in the MP group. In addition, food allergy episodes from any of the other five foods were significantly reduced, although the reductions in those due to individual foods were not significant. CONCLUSIONS: Gradually increasing the intake of very small amounts of multiple foods in early infancy can safely reduce the incidence of egg allergies. Other foods may also suppress food allergies, but no definitive conclusions could be reached.
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Hipersensibilidad al Huevo , Hipersensibilidad a los Alimentos , Alérgenos , Arachis , Niño , Hipersensibilidad al Huevo/prevención & control , Emolientes , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/prevención & control , Humanos , Lactante , PolvosRESUMEN
In order to elucidate the roles of ChiP, ChiQ, and ChiX in chitin utilization by Serratia marcescens 2170, the construction of single-gene deletion mutants of the chiP, chiQ, and chiX genes was attempted by allelic exchange mutagenesis. ΔchiP formed smaller clearing zones and ΔchiX formed larger ones than wild-type 2170 on an agar plate containing colloidal chitin. ΔchiP grew slowly on the lower concentration of (GlcNAc)2, and there was essentially no growth on chitin oligosaccharides larger than (GlcNAc)3. The gene product of chiP was detected in the outer membrane fraction, consistently with the hypothesis that chiP encodes outer membrane chitoporin. Deletion of chiQ decreased and that of chiX increased the growth rates on chitin oligosaccharides. These observations strongly suggest that all three genes are involved in chitin utilization and that the deletion mutants obtained in this study might prove useful tools to clarify the details of the chitin utilization system of this bacterium.
Asunto(s)
Quitina/metabolismo , Quitinasas/genética , Serratia marcescens/genética , Quitina/química , Oligosacáridos/metabolismo , Eliminación de Secuencia , Serratia marcescens/enzimologíaRESUMEN
OBJECTIVE: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician's choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. METHODS: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. RESULTS: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1-43.0) months. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49-1.10) and 0.64 (0.44-0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45-1.02) and 0.61 (0.41-0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3-5, 74% and 72%), respectively. CONCLUSION: Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03517449.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Compuestos de Fenilurea , Médicos , Quinolinas , Humanos , Femenino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Asia Oriental/epidemiología , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
PURPOSE: Combination treatment using lenvatinib (a multikinase inhibitor) plus pembrolizumab (a programmed death-1 immune checkpoint inhibitor) has shown efficacy in the treatment of endometrial and renal cell cancers. This phase 1b study investigated the tolerability and safety of lenvatinib plus pembrolizumab in Japanese patients with metastatic selected solid tumors. METHODS: Patients received a starting dose of 20 mg oral lenvatinib per day plus 200 mg intravenous pembrolizumab every 3 weeks in 21-day cycles. Dose-limiting toxicities were evaluated during the first cycle. Tumor assessments were performed by investigators based on modified RECIST v1.1. Pharmacokinetic parameters and serum biomarkers were assessed. RESULTS: Among enrolled patients (N = 6), 3 had non-small cell lung cancer, and 3 had urothelial cancer. No patients experienced a dose-limiting toxicity. All patients experienced at least 1 treatment-related treatment-emergent adverse event. The objective response rate was 33.3% (95% confidence interval 4.3-77.7); both responses (1 complete, 1 partial) were observed in patients with urothelial cancer. Pharmacokinetics were consistent with previous studies. Serum angiopoietin-2 levels tended to decrease, and serum fibroblast growth factor-23 levels tended to increase from baseline to Cycle 2 Day 1. CONCLUSIONS: This study supports the tolerability of 20 mg lenvatinib/day plus 200 mg pembrolizumab every 3 weeks in Japanese patients, consistent with the results from a global study of lenvatinib plus pembrolizumab combination therapy in patients with selected solid tumors. Favorable antitumor activity was observed and there were no new safety signals identified. TRIAL REGISTRATION: Clinical Trials.gov number: NCT03006887.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Estudios de Factibilidad , Japón , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVE: The aim was to identify the characteristics and treatment patterns of early and advanced stage endometrial cancer patients using real-world data. METHODS: Patients' data extracted from a Japanese health insurance claims database were analyzed. RESULTS: Of the 12,449 endometrial cancer patients, 74.4% were in stage I, 5.1% in stage II, 12.0% in stage III, and 8.4% in stage IV. Their median age was 60.5 years, higher in advanced stages (III/IV) than in early stages (I/II). Overall, 11,055 patients (88.8%) underwent surgery, and 4977 patients (40.0%) received post-surgery treatment, including chemotherapy (4441: 35.7%), chemoradiation therapy (379: 3.0%), and radiation therapy (157 patients: 1.3%); 1394 patients (11.2%) were not treated by surgery, and 742 patients (6.0%) received other treatment, with chemotherapy (548: 4.4%), radiation therapy (105: 0.8%), and chemoradiation therapy (89: 0.7%). The rate of patients undergoing surgery decreased, and that receiving chemotherapy increased significantly as cancer stage progressed. Paclitaxel/carboplatin was the most frequent first-line regimen (85.4% of patients), whereas various combination and monotherapy regimens were used as second- and third-line regimens. The most frequent second-line monotherapy was paclitaxel. The rate of monotherapy increased as the treatment line progressed (first-line 3.5%, second-line 22.0%, and third-line 36.4%). CONCLUSIONS: The characteristics and treatment patterns of endometrial cancer patients differed between early and advanced stages, as did the chemotherapy regimens among first-, second-, and third-lines. Since various regimens were used for second- and third-line chemotherapies, development of appropriate second- and third-line chemotherapy regimens is warranted. A real-world analysis of cancer patients using a nationwide claims database may be a valuable approach to identifying unmet medical needs.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Carboplatino , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/terapia , Femenino , Humanos , Japón/epidemiología , Persona de Mediana Edad , Paclitaxel , Estudios RetrospectivosRESUMEN
PURPOSE: MORAb-202, an antibody-drug conjugate containing farletuzumab and eribulin with a cathepsin-B cleavable linker, targets folate receptor α (FRα)-expressing tumor cells. The primary objective of this first-in-human study was to evaluate the safety and tolerability of MORAb-202 in patients with solid tumors. PATIENTS AND METHODS: Patients ≥20 years with adequate organ function and FRα-positive solid tumors who failed to respond to standard therapy were eligible. Patients received MORAb-202 intravenously at doses of 0.3 to 1.2 mg/kg once every three weeks. Endpoints included dose-limiting toxicities, safety, tumor responses, pharmacokinetics, and pharmacodynamics. TRIAL REGISTRATION NUMBER: NCT03386942 (ClinicalTrials.gov). RESULTS: Between November 28, 2017 and June 4, 2019, 22 patients (median age, 58.0 years) with advanced solid tumors were enrolled. Treatment-emergent adverse events occurred in 21 (95%) patients, with leukopenia and neutropenia in 10 (45%) patients each. One patient (0.9 mg/kg cohort) experienced two grade 3 dose-limiting toxicities: serum alanine aminotransferase and γ-glutamyl transferase increases. Following review by an independent adjudication committee, grade 1/2 interstitial lung disease thought to be related to MORAb-202 was identified in five (23%) patients. Complete response, partial response, and stable disease were observed in one, nine, and eight patients, respectively. The normalized predose serum FRα tended to be positively correlated with the maximum tumor shrinkage (R 2 = 0.2379; P = 0.0291). CONCLUSIONS: The MTD of MORAb-202 was not reached. MORAb-202 demonstrated promising antitumor activity in FRα-positive solid tumors and was generally well-tolerated at the tested doses. Further investigations are required to establish appropriate dosage and clinical utility of MORAb-202.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Furanos/uso terapéutico , Cetonas/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Femenino , Receptor 1 de Folato/análisis , Furanos/efectos adversos , Humanos , Inmunoconjugados/uso terapéutico , Cetonas/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/química , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.
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Enfermedades Renales/etiología , Proteínas Motoras Moleculares/genética , Mutación , Cadenas Pesadas de Miosina/genética , Proteinuria/etiología , Adolescente , Adulto , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Pérdida Auditiva Sensorineural/genética , Humanos , Masculino , Nefritis Hereditaria/genética , Trombocitopenia/genética , Adulto JovenRESUMEN
BACKGROUND: We evaluated the clinical pictures, outcome for childhood idiopathic thrombocytopenic purpura (ITP) and the trends of the choice of management for childhood ITP in Japan. METHOD: Every year, questionnaires were sent to all institutions that employ the active members of the Japanese Society of Pediatric Hematology. The questionnaires included age, sex, date of diagnosis, platelet count at diagnosis, the presence or absence of antecedent infection, hemorrhagic symptoms, initial management, and the outcome of all patients newly diagnosed with ITP. RESULTS: A total of 986 newly diagnosed as ITP patients were reported between January 2000 and December 2005. The occurrence of ITP peaked in boys less than 1 year of age, and at 1 year of age in girls. The male-to-female ratio was 1.24:1. Wet purpura was observed in more than half of the patients with platelet counts of <10,000/microL. The initial treatment varied among the patients with different platelet counts at diagnosis; most of the patients with platelet counts <20,000/microL received intravenous immunoglobulin or oral corticosteroids. Conversely, cases without any aggressive treatment increased to a larger degree in patients with > or =20,000/microL of platelet. CONCLUSIONS: These findings indicate that overall compliance to the Japanese guideline is considered to be relatively good in Japan.
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Encuestas Epidemiológicas , Púrpura Trombocitopénica Idiopática/diagnóstico , Adolescente , Niño , Femenino , Humanos , Japón , Masculino , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/terapia , Encuestas y CuestionariosRESUMEN
Approximately 30% of patients with hemophilia in Japan were infected with human immunodeficiency virus (HIV) in early 1980s through contaminated blood products. In 1995, a cohort of HIV-infected, asymptomatic patients with hemophilia was set up for follow-up study. Although the patients met the criteria for long-term non-progressor (LTNP) at the entry to the cohort, some of them later developed lymphopenia during five more years of observation. We collected blood samples from 80 long-term survivors; 42 of them did not require antiviral therapy, but the rest were under treatment. Analysis of HLA-B genotype revealed that carriers of known HIV-resistant alleles such as HLA-B*5701, B*5801, and alleles of B27 antigenic group were not increased in frequency, but that HLA-B*1507 was increased in the cohort (6.25% vs. 1.03%, OR = 6.40, p = 0.039). We also observed the decrease in carriers of HLA-B*5401 (3.75% vs. 14.95%, OR = 0.22, p = 0.016). HLAB* 5401 is a relatively common allele in East Asian populations and belongs to the same B22 antigenic group as B55 and B56 which were reported to associate with rapid progression. Our data indicated that HLA class I is one of the host factors involved in the retardation of HIV disease progression as also reported in the previous studies; however, the alleles associated with this resistance were not the same because of divergent host genetic background.
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Infecciones por VIH/genética , Infecciones por VIH/inmunología , Antígenos HLA-B/genética , Hemofilia A/genética , Hemofilia A/inmunología , Alelos , Estudios de Cohortes , Infecciones por VIH/complicaciones , Sobrevivientes de VIH a Largo Plazo , VIH-1 , Hemofilia A/complicaciones , Humanos , Japón , Masculino , Polimorfismo Genético , PronósticoRESUMEN
BACKGROUND: In Japan, the inoculation dosage of inactivated influenza vaccine for children under 1 year old is 0.1 mL per dose. The dosage is not half as much as that in Europe and the U.S.A. We considered that low efficacy fate of influenza vaccine in children under 1 year old results from its less dosage. So we designed this study to verify this hypothesis. MATERIALS AND METHODS: This study was prospective in design. Subjects were divided into two groups by age: 8 to 11 months old (n = 26) and 12 to 16 months old (n = 22). Infants received 0.1 mL of inactivated influenza vaccine and over 1 year, 0.2 mL. Forty-eight children were inoculated twice at intervals of over 4 weeks. Serum samples were drawn before the first inoculation and 1 month after the second vaccination. Pre- and post-immunization antibody titers were measured. The titers of hemaglutinatinin inhibiting antibodies to the 3 viral strains were assayed. Antibody titers were determined using HAI. RESULTS: The post-vaccination proportions of children with protective HAI antibody titers were significantly smaller in infants than those in children over 1 year old (A/H1N1; 23% vs. 77%, A/H3N2; 39% vs. 73%, B; 0% vs. 32%). The number of children with >four-fold increased antibodies were significantly smaller in infants than that in 1 year old (A/H1N1; 74% vs. 91%, B; 0% vs. 39%). In the mean antibody titer, there were signficant differences between infants and children over 1 year old (A/H1N1; 19 times vs. 56 times, B; 8 times vs. 14 times). CONCLUSION: We consider that significant differences in antibody titers between infants and children over 1 year old were caused by the difference of dosage in influenza vaccines. To obtain protective levels of antibodies by influenza vaccines in infants, they must be inoculated with enough dosage.
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Vacunas contra la Influenza/administración & dosificación , Anticuerpos Antivirales/sangre , Humanos , Esquemas de Inmunización , Lactante , Estudios Prospectivos , Vacunas de Productos Inactivados/administración & dosificaciónAsunto(s)
Anticonvulsivantes/toxicidad , Obstrucción Intestinal/complicaciones , Fenitoína/toxicidad , Estado Epiléptico/inducido químicamente , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Comorbilidad , Epilepsia/epidemiología , Femenino , Semivida , Humanos , Absorción Intestinal/fisiología , Obstrucción Intestinal/epidemiología , Obstrucción Intestinal/metabolismo , Fenitoína/administración & dosificación , Fenitoína/sangre , Fenitoína/farmacocinética , Adulto JovenRESUMEN
OBJECTIVE: MYH9 disorders are characterised by giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, the gene for non-muscle myosin heavy chain-IIA (NMMHC-IIA). MYH9 R702 mutations are highly associated with Alport manifestations and result in Epstein syndrome. The aim of our study was to determine the haematological characteristics of MYH9 disorders as a result of R702 mutations to aid in making a proper diagnosis. PATIENTS AND METHODS: Platelet size of patients with MYH9 disorders was determined as platelet diameter by microscopic observation of 200 platelets on stained peripheral blood smears. Double in situ hybridisation using a biotinylated oligo(dT) probe and immunofluorescence analysis of neutrophil NMMHC-IIA was performed on peripheral blood smears. RESULTS: Patients carrying R702 mutations had significantly larger platelets than those with other MYH9 mutations. Although granulocyte inclusion bodies were mostly invisible on stained blood smears, immunofluorescence analysis for NMMHC-IIA showed an abnormal type II localisation in all neutrophils. We first showed that poly(A)+ RNA coincided with accumulated NMMHC-IIA at inclusion bodies in patients with MYH9 disorders. However, no condensation of poly(A)+ RNA at inclusion bodies was observed in patients with R702 mutations. CONCLUSION: Our study shows that R702 mutations result in especially large platelets and inclusion bodies being faint and mostly invisible on conventionally stained blood smears. We further demonstrated that poly(A)+ RNA content but not NMMHC-IIA accumulation is responsible for the morphological appearance/stainability of inclusion bodies on stained blood smears and the amount of poly(A)+ RNA is decreased in those with R702 mutations.
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Arginina/genética , Plaquetas/patología , Proteínas Motoras Moleculares/genética , Proteínas Motoras Moleculares/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Trombocitosis/genética , Trombocitosis/patología , Arginina/metabolismo , Trastornos de las Plaquetas Sanguíneas/genética , Trastornos de las Plaquetas Sanguíneas/patología , Tamaño de la Célula , Niño , Preescolar , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Lactante , Masculino , Mutación , Neutrófilos/metabolismo , Neutrófilos/patología , Poli A/genéticaRESUMEN
Central nervous system (CNS) involvement in cases of anaplastic large cell lymphoma (ALCL) has been described only rarely. The authors describe an 11-year-old girl with ALCL who developed isolated CNS relapse but had no CNS disease at initial diagnosis and had received CNS-prophylactic treatment. The patient achieved a second remission following intensive treatment of the relapse and continues to be in remission at the time of writing. This case serves to emphasize that isolated CNS relapse without detectable initial CNS involvement can arise even after CNS-prophylactic treatment in pediatric ALCL cases.