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1.
Artigo em Inglês | MEDLINE | ID: mdl-32178607

RESUMO

This report summarises Australian spontaneous surveillance data for adverse events following immunisation (AEFI) for 2018 reported to the Therapeutic Goods Administration and describes reporting trends over the 19-year period 1 January 2000 to 31 December 2018. There were 4221 AEFI records for vaccines administered in 2018, an annual AEFI reporting rate of 16.9 per 100,000 population. There was a 2.9% increase in the overall AEFI reporting rate in 2018 compared to 2017. This slight increase in reported adverse events in 2018 was likely due to new additions to the National Immunisation Program schedule, namely meningococcal ACWY vaccination for children aged 12 months, enhanced immunogenicity trivalent influenza vaccines for adults aged ≥65 years, and state- and territory-funded seasonal influenza vaccination programs for children aged 6 months to <5 years. AEFI reporting rates for most individual vaccines in 2018 were similar to 2017. The most commonly reported adverse events were injection site reaction (34%), pyrexia (15%), rash (15%), vomiting (8%), headache (6%) and pain (6%). Two deaths were reported to the TGA but no clear causal relationship with vaccination was found.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Programas de Imunização , Vacinação/efeitos adversos , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Criança , Pré-Escolar , Exantema/induzido quimicamente , Febre/induzido quimicamente , Humanos , Esquemas de Imunização , Lactente , Vacinas contra Influenza , Reação no Local da Injeção , Masculino , Adulto Jovem
2.
BMC Health Serv Res ; 19(1): 704, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619221

RESUMO

BACKGROUND: Skin rash remains one of the most prevalent and troublesome clinical problems experienced by patients on chemotherapy and targeted therapy. To ensure high-quality care, guidelines are seen as the best guidance. Considering the quality of guidelines varies greatly, a systematical appraisal of the methodological quality of guidelines for the management of skin rash in patients on chemotherapeutic drugs and targeted anticancer therapies was undertaken, in order to identify appropriate ones for healthcare professionals. METHODS: A systematic search of databases and Internet was conducted to obtain pertinent guidelines. Two reviewers independently assessed the eligibility of guidelines according to the inclusion criteria. Then the guidelines included were appraised by three researchers with the methodological quality of eligible guideline using Appraisal of Guidelines for Research and Evaluation II (AGREEII). RESULTS: Totally nineteen guidelines met the inclusion criteria. The quality ranged from good to acceptable in scope and purpose (mean: 78.80%, range: 66.67-94.44%) and clarity of presentation domains (mean: 85.38%, 75.00-91.67%), but not in stakeholder involvement (mean: 50.15%, range: 36.11-75.00%), rigor of development (mean: 23.65%, range: 6.25-70.83%), applicability (mean: 23.96%, range: 4.17-52.08%), and editorial independence domains (mean: 45.18%, range: 0.00-87.50%). Overall, two guidelines were classified as "recommended". CONCLUSIONS: Only two guidelines were recommended to manage skin rash in patients on chemotherapy and targeted therapies, most guidelines issued were of low to moderate quality. Thus, more attention should be paid to the methodological quality of guideline development in this field.


Assuntos
Antineoplásicos/efeitos adversos , Erupção por Droga/terapia , Exantema/terapia , Terapia de Alvo Molecular/efeitos adversos , Guias de Prática Clínica como Assunto/normas , Bases de Dados Factuais , Erupção por Droga/etiologia , Exantema/induzido quimicamente , Humanos
5.
J Toxicol Sci ; 44(8): 559-563, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31378767

RESUMO

Acetaminophen (Paracetamol, APAP) has been widely used for many decades as an analgesic and antipyretic agent but APAP overdose often causes acute adverse reactions, particularly liver damage. The metabolically oxidized form of APAP, N-acetyl-p-benzoquinone imine (NAPQI), is chemically reactive and binds covalently to proteins. Therefore, NAPQI is believed to be the key metabolite that causes hepatotoxicity, especially under conditions of glutathione depletion. Other APAP-induced adverse reactions, such as skin damage, are rare and remain poorly studied. Here, we report a case study of a male patient who presented with an acute swelling skin rash (without hepatotoxicity) caused by therapeutic doses of APAP. Plasma samples were collected at 17 hr after dosing (during the manifestation of symptoms) and at one month (after recovery) and were subjected to LC-MS analysis of NAPQI-adducts. A significant concentration of NAPQI-cysteine adduct (33 pmol/mL) was found together with low concentrations of NAPQI-N-acetylcysteine adduct (2.0 pmol/mL) and NAPQI-glutathione adduct (0.13 pmol/mL). However, the NAPQI-albumin adduct was below the detection limit (below 0.001% modification on albumin) despite a previous report of high concentrations of NAPQI-albumin adduct following acute liver injury. Therefore, the observed APAP-induced skin damage may have had a different cause from APAP-induced liver injury.


Assuntos
Acetaminofen/efeitos adversos , Acetilcisteína/sangue , Benzoquinonas/efeitos adversos , Benzoquinonas/sangue , Cisteína/sangue , Edema/induzido quimicamente , Exantema/induzido quimicamente , Glutationa/sangue , Iminas/efeitos adversos , Iminas/sangue , Dermatopatias/induzido quimicamente , Acetilcisteína/metabolismo , Doença Aguda , Adulto , Benzoquinonas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Cromatografia Líquida , Cisteína/metabolismo , Glutationa/metabolismo , Humanos , Iminas/metabolismo , Masculino , Ligação Proteica , Albumina Sérica/metabolismo , Espectrometria de Massas em Tandem
6.
BMJ Case Rep ; 12(8)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31377719

RESUMO

Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.


Assuntos
Clindamicina/efeitos adversos , Erupção por Droga/diagnóstico , Exantema/induzido quimicamente , Intertrigo/induzido quimicamente , Administração Oral , Biópsia , Erupção por Droga/tratamento farmacológico , Erupção por Droga/patologia , Exantema/tratamento farmacológico , Exantema/patologia , Feminino , Humanos , Intertrigo/tratamento farmacológico , Intertrigo/patologia , Pessoa de Meia-Idade , Esteroides/administração & dosagem , Esteroides/uso terapêutico , Resultado do Tratamento
7.
Muscle Nerve ; 60(5): 528-537, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31443119

RESUMO

INTRODUCTION: Although intravenous immune globulin (IVIg) is used to treat patients in the outpatient setting, there is limited documentation addressing the safety of this practice. METHODS: Retrospective analysis of 438 patients with neuromuscular diseases receiving IVIg in an outpatient setting. RESULTS: Adverse events (AE) overall occurred in 16.9% of patients. Headache was the most common AE, noted in 11.6% of patients. Serious AEs occurred in 0.91% of patients; aseptic meningitis was the only one noted. Multivariate analyses identified the following risk factors for AEs: first-lifetime course of IVIg, higher dose per course of IVIg, diagnosis of myasthenia gravis, women, and younger age. DISCUSSION: Intravenous immune globulin is generally safe to administer in an outpatient setting. Women, myasthenia gravis patients, and those receiving their first course or a higher total dose of IVIg are at an increased risk of experiencing an AE.


Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Doenças Neuromusculares/terapia , Adulto , Fatores Etários , Idoso , Assistência Ambulatorial , Exantema/induzido quimicamente , Feminino , Cefaleia/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Infusões Intravenosas , Masculino , Meningite Asséptica/induzido quimicamente , Pessoa de Meia-Idade , Análise Multivariada , Miastenia Gravis/terapia , Miosite/terapia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
8.
Int J Clin Oncol ; 24(12): 1596-1604, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446511

RESUMO

BACKGROUND: Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC. METHODS: In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1. RESULTS: All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC0-24. Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92-310.11) ng/mL at baseline to 11.70 (0.37-47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients. CONCLUSION: Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02162836.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Tioidantoínas/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Exantema/induzido quimicamente , Humanos , Japão , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Tioidantoínas/efeitos adversos , Tioidantoínas/farmacocinética
9.
J Nippon Med Sch ; 86(3): 187-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31292332

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that targets the low-density lipoprotein (LDL) receptor for lysosomal degradation. PCSK9 impedes the receptor-mediated clearance of LDL-cholesterol, thereby increasing serum LDL-cholesterol levels. Evolocumab, a human monoclonal antibody against PCSK9, effectively reduces serum LDL-cholesterol levels. We report the first known case of a patient who developed an atopic dermatitis (AD)-like rash during evolocumab therapy. A 43-year-old Japanese man with heterozygous familial hypercholesterolemia was treated with subcutaneous injection of 140 mg evolocumab biweekly, for 16 months. The therapy was then changed to subcutaneous injection of 420 mg evolocumab monthly. A few days after the first dose, the patient experienced pruritus and rash on his extremities. The rash worsened, while the pruritus subsided, then relapsed after the second and third doses. He had erythema and excoriation on his legs, lichenification over his popliteal fossa, xerosis on his forearms, an increased serum IgE level, and a family history of AD in his siblings. We made a provisional diagnosis of AD characterized by enhanced type 2 helper T (Th2) activity and treated him with topical corticosteroids and oral anti-histamines. His rash improved and did not relapse after the fifth dose; however, his LDL-cholesterol level increased. PCSK9 or oxidized LDL activates macrophages or dendritic cells, respectively, and enhances their activity to induce Th1 cells antagonizing Th2 cells. We hypothesized that high-dose evolocumab may suppress Th1 activity to antagonize Th2, and unmask Th2 disposition based on the patient's atopic diathesis, triggering the rash mimicking AD. Clinicians should be aware of rash development during evolocumab therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Dermatite Atópica/induzido quimicamente , Exantema/induzido quimicamente , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Adulto , Dermatite Atópica/imunologia , Exantema/imunologia , Humanos , Hiperlipoproteinemia Tipo II/imunologia , Injeções Subcutâneas , Masculino , Terapia de Alvo Molecular , Pró-Proteína Convertase 9/imunologia , Pró-Proteína Convertase 9/fisiologia , Células Th1/imunologia , Células Th2/imunologia
10.
Clin Drug Investig ; 39(9): 825-834, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264159

RESUMO

The use of targeted therapies, when added to conventional chemotherapy, has significantly improved clinical outcomes and survival of cancer patients. While targeted therapies do not have the systemic adverse reactions of chemotherapy, they are associated with toxicities that can be severe and impair patient quality of life and adherence to anti-cancer treatment. Panitumumab and cetuximab, two monoclonal antibodies against epidermal growth factor receptor (EGFR), are recommended for the treatment of metastatic colorectal cancer (mCRC). The majority of patients with mCRC who are treated with anti-EGFR therapy develop skin toxicities, including papulopustular rash (the most common), xerosis, painful cracks and fissures on the palms and soles of the feet, paronychia, pruritus, and abnormal hair and eyelash growth; they are also more prone to skin infections. Given the involvement of EGFR in normal epidermis physiology, development and function, skin toxicities caused by anti-EGFR therapy are not unexpected. In recent years, recommendations have been formulated for the prevention and treatment of anti-EGFR therapy-related skin toxicities. Indeed, proper and timely management of these toxicities is important for ensuring uninterrupted anti-cancer treatment and optimal outcomes. Here, we review the current knowledge of anti-EGFR therapy-related skin toxicities and the latest recommendations for their management. We also present a treatment approach for papulopustular rash based on the combination of fusidic acid plus betamethasone in a lipid-enriched topical formulation. The effectiveness of this approach is documented by the presentation of five cases successfully treated in clinical practice for anti-EGFR therapy-related rash.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Metástase Neoplásica , Panitumumabe/uso terapêutico , Guias de Prática Clínica como Assunto , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/imunologia , Cetuximab/efeitos adversos , Cetuximab/imunologia , Receptores ErbB/imunologia , Exantema/induzido quimicamente , Humanos , Panitumumabe/efeitos adversos , Panitumumabe/imunologia , Cooperação do Paciente , Qualidade de Vida
11.
Cancer Sci ; 110(9): 2884-2893, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31265163

RESUMO

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.


Assuntos
Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Acrilamidas/efeitos adversos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Exantema/induzido quimicamente , Exantema/epidemiologia , Humanos , Japão/epidemiologia , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Paroniquia/induzido quimicamente , Paroniquia/epidemiologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Análise de Sobrevida , Taxa de Sobrevida
12.
Artigo em Inglês | MEDLINE | ID: mdl-31315166

RESUMO

This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2017 reported to the Therapeutic Goods Administration and describes reporting trends over the 18-year period 1 January 2000 to 31 December 2017. There were 3,878 AEFI records for vaccines administered in 2017; an annual AEFI reporting rate of 15.8 per 100,000 population. There was a 12% increase in the overall AEFI reporting rate in 2017 compared with 2016. This increase in reported adverse events in 2017 compared to the previous year was likely due to the introduction of the zoster vaccine (Zostavax®) provided free for people aged 70­79 years under the National Immunisation Program (NIP) and also the state- and territory-based meningococcal ACWY conjugate vaccination programs. AEFI reporting rates for most other individual vaccines in 2017 were similar to 2016. The most commonly reported reactions were injection site reaction (34%), pyrexia (17%), rash (15%), vomiting (8%) and pain (7%). The majority of AEFI reports (88%) described non-serious events. Two deaths were reported that were determined to have a causal relationship with vaccination; they occurred in immunocompromised people contraindicated to receive the vaccines.


Assuntos
Doenças do Sistema Imunitário/epidemiologia , Vacinação/efeitos adversos , Vacinas/efeitos adversos , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Austrália/epidemiologia , Criança , Pré-Escolar , Exantema/induzido quimicamente , Exantema/epidemiologia , Feminino , Febre/induzido quimicamente , Febre/epidemiologia , Vacina contra Herpes Zoster , Humanos , Programas de Imunização , Lactente , Reação no Local da Injeção/epidemiologia , Masculino , Pessoa de Meia-Idade , Dor/induzido quimicamente , Dor/epidemiologia , Vigilância da População , Vacinação/normas , Vacinação/estatística & dados numéricos , Vacinas/administração & dosagem , Vômito/induzido quimicamente , Vômito/epidemiologia , Adulto Jovem
13.
Cancer Invest ; 37(6): 253-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303065

RESUMO

We fully investigate the skin toxicities of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in cancer patients. The studies about randomized controlled trials in cancer treatment with EGFR-TKIs were retrieved and the systematic evaluation was conducted. The results suggest that EGFR-TKIs significantly increase the risk of skin toxicities including all-grade rash, pruritus, dry skin, and high-grade rash, pruritus. However, the risk of high-grade dry skin did not increase. Rash was the most common toxicity. Physicians should be aware of skin toxicities and should monitor cancer patients when receiving EGFR-TKIs.


Assuntos
Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pele/efeitos dos fármacos , Exantema/induzido quimicamente , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
N Engl J Med ; 381(7): 603-613, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31180194

RESUMO

BACKGROUND: Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS: We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS: A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS: Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complexo CD3/antagonistas & inibidores , Diabetes Mellitus Tipo 1/prevenção & controle , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Método Duplo-Cego , Exantema/induzido quimicamente , Feminino , Teste de Tolerância a Glucose , Antígeno HLA-DR3 , Antígeno HLA-DR4 , Humanos , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Adulto Jovem
15.
N Engl J Med ; 381(1): 13-24, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31150574

RESUMO

BACKGROUND: Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined. METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival. RESULTS: A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group. CONCLUSIONS: In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).


Assuntos
Adenocarcinoma/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Tioidantoínas/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Receptores de Andrógenos/efeitos adversos , Método Duplo-Cego , Exantema/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Intervalo Livre de Progressão , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Qualidade de Vida , Radiografia , Tioidantoínas/efeitos adversos
16.
BMJ Case Rep ; 12(6)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167767

RESUMO

Immune checkpoint inhibitors, such as pembrolizumab, have significantly improved cancer patient outcome. Toxicities are usually moderate and manageable. However, some adverse events, if not early recognised, could be life-threatening. We report a patient with non-small cell lung cancer who received treatment with pembrolizumab and developed multiple immune-related adverse events both during and after completing treatment, including rash, pericarditis, colitis and myasthenia gravis.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Miastenia Gravis/induzido quimicamente , Miastenia Gravis/tratamento farmacológico , Pericardite/induzido quimicamente , Pericardite/tratamento farmacológico , Plasmaferese/métodos , Resultado do Tratamento
17.
Medicine (Baltimore) ; 98(20): e15731, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31096532

RESUMO

BACKGROUND: Programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors are promising cancer immunotherapy. Their dermatologic safety profiles are still poorly understood. The purpose of this article is to evaluate the incidence of selected dermatologic and mucosal adverse effects (AEs) and determine the risk of developing these adverse events associated with PD-1/PD-L1 inhibitors, compared with chemotherapy or ipilimumab. METHODS: PubMed was searched for eligible studies (up to February 21, 2019). Only phase II and phase III randomized controlled trials (RCTs) compared with chemotherapy or ipilimumab monotherapy were included in this meta-analysis. RESULTS: A total 11,465 patients from 18 clinical trials were included in this meta-analysis. Rash and pruritus were the most frequently reported dermatologic AE, with incidence 11.8% and 12.2% respectively. Compared with patients receiving chemotherapy, PD-1/PD-L1 inhibitor treated patients had higher risk of developing rash (RR = 1.84), pruritus (RR = 3.74) and vitiligo (RR = 9.54), and also lower risk in developing mucosal inflammation (RR = 0.26), stomatitis (RR = 0.26), and alopecia (RR = 0.03). Additionally, anti-PD1/PD-L1 drugs had similar risk of developing rash and lower risk of inducing pruritus compared to ipilimumab. In the subgroup analysis, PD-L1 inhibitor demonstrated better safety than PD-1 inhibitor in developing rash, with RR = 1.38 and RR = 2.11, respectively. CONCLUSION: Our meta-analysis concluded that anti PD-1/PD-L1 drugs have different dermatological and mucosal safety profile compared to conventional therapy, and differences of dermatological toxicity between PD-1 and PD-L1 inhibitor warrant further investigation.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Ipilimumab/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Alopecia/induzido quimicamente , Tratamento Farmacológico , Exantema/induzido quimicamente , Humanos , Incidência , Mucosite/induzido quimicamente , Prurido/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Estomatite/induzido quimicamente , Vitiligo/induzido quimicamente
19.
Cutan Ocul Toxicol ; 38(3): 261-266, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31010330

RESUMO

Background: Papulopustular rash is the most common cutaneous adverse effect during targeted tumour therapy particularly with epidermal growth factor receptor inhibitors (EGFRIs). Objective: To evaluate the adverse skin reactions, mainly papulopustular rash, caused by targeted tumour therapy. Materials and methods: We retrospectively analysed the data of patients who were diagnosed papulopustular rash due to targeted chemotherapeutic agents between January 2016 and August 2018. Demographic characteristics of the patients, the type of malignancy, chemotherapeutic agents causing papulopustular rash, clinical features and grade of the rash, treatment modalities used for the rash, other associated cutaneous adverse reactions, and the need for dose-modification or discontinuation of the chemotherapy were recorded. Results: A total of 39 patients (26 males, 13 females) with a median age of 60 (range 32-86) years were included in the study. EGFRIs such as erlotinib, lapatinib, cetuximab, and panitumumab were the main drugs causing papulopustular rash in 2 (5.1%), 3 (7.6%), 18 (46.1%), and 13 (33.3%) patients, respectively. Imatinib, bevacizumab in combination with oxaliplatin, and everolimus in combination with exemestane and goserelin were responsible in three patients. The most commonly affected area was the face (87.1%) followed by the trunk (56.4%), scalp (25.6%), and extremities (23%). The rash was recorded as grade 1, 2, and 3 in 18, 13, and 6 of the patients, respectively. Grade 3 rash was lead to dose interruptions in 5 (12.8%) patients with subsequent reintroduction at a lower dose in 4 (10.2%) of them and discontinuation of the therapy in 1 (2.5%) patient. Pruritus, xerosis, paronychia, increased growth of the eyelashes, mucositis, hand-foot syndrome (HSF), and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) are other skin toxicities associated with the targeted tumour therapy. Conclusions: With the increasing use of targeted therapies, dermatologists are now confronted with extensive spectrum of skin toxicities. Therefore, it is critical for dermatologists to be aware of these toxicities so as to develop the best approach without discontinuation of cancer therapy.


Assuntos
Antineoplásicos/efeitos adversos , Exantema/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cetuximab/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Lapatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Panitumumabe/efeitos adversos , Prurido/induzido quimicamente , Estudos Retrospectivos
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