ABSTRACT
BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.
Subject(s)
Castleman Disease , Interleukin-6/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/metabolism , Adolescent , Adult , Castleman Disease/drug therapy , Castleman Disease/metabolism , Castleman Disease/pathology , Female , Humans , Male , Middle Aged , ProteomicsABSTRACT
RATIONALE: This is the report of the first case of TAFRO syndrome (Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction, Organomegaly) in Latin America. PATIENT CONCERNS: The patient was a 61-year-old white woman of Ashkenazi Jewish descent, who presented with a history of 8 days of nausea, vomiting, and fever; severe pitting edema in both legs, ascites, splenomegaly, and palpable axillary lymph nodes. DIAGNOSES: Abdominal computed tomography (CT) showed bilateral pleural effusion and retroperitoneal lymph node enlargement. INTERVENTIONS: Anasarca and worsening of renal function led to admission to the intensive care unit (ICU) with multiple organ failure, requiring mechanical ventilation, vasopressor medications, and continuous renal replacement therapy (CRRT). Diagnosis of TAFRO syndrome was made on day 18 after admission, based on clinical findings and results of bone marrow and lymph node biopsies. She was treated with methylprednisolone, tocilizumab, and rituximab. One week after the first tocilizumab dose, she had dramatic improvements in respiratory and hemodynamic status, and was weaned from ventilator support and vasopressor medications. OUTCOMES: After 2 weeks of therapy, CRRT was switched to intermittent hemodialysis. On day 46, the patient was discharged from the ICU to the general ward, and 3 months after admission, she went home. LESSONS: Provided the interleukin-6 measurement is available, this approach is suggested in cases of TAFRO syndrome, in order to customize the treatment.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Castleman Disease/drug therapy , Immunologic Factors/administration & dosage , Methylprednisolone/administration & dosage , Rituximab/administration & dosage , Drug Therapy, Combination , Female , Humans , Middle AgedSubject(s)
Adenocarcinoma/diagnosis , Carcinoma, Ovarian Epithelial/diagnosis , Muscular Diseases/diagnosis , Necrosis/pathology , Paraneoplastic Syndromes/diagnosis , Sepsis/diagnosis , Adenocarcinoma/physiopathology , Adenocarcinoma/therapy , Carcinoma, Ovarian Epithelial/physiopathology , Carcinoma, Ovarian Epithelial/therapy , Deglutition Disorders , Dysphonia , Edema , Fatal Outcome , Female , Humans , Lower Extremity , Middle Aged , Muscular Diseases/pathology , Paraneoplastic Syndromes/physiopathology , Paraneoplastic Syndromes/therapy , Sepsis/physiopathology , Weight LossSubject(s)
Humans , Female , Paraneoplastic Syndromes/diagnosis , Adenocarcinoma/diagnosis , Sepsis/diagnosis , Carcinoma, Ovarian Epithelial/diagnosis , Muscular Diseases/diagnosis , Necrosis/pathology , Paraneoplastic Syndromes/physiopathology , Paraneoplastic Syndromes/therapy , Weight Loss , Adenocarcinoma/physiopathology , Adenocarcinoma/therapy , Deglutition Disorders , Fatal Outcome , Sepsis/physiopathology , Lower Extremity , Edema , Dysphonia , Carcinoma, Ovarian Epithelial/physiopathology , Carcinoma, Ovarian Epithelial/therapy , Middle Aged , Muscular Diseases/pathologyABSTRACT
The vitamin K antagonists are the most widely used oral anticoagulant. Although bleedings are common side effect, development of hemothorax is rare. Most cases are associated with impairment in pleura or parenchyma structural alteration in the presence of INR values outside therapeutic range. We report the case of a patient with rheumatoid arthritis presenting with massive hemothorax under anticoagulation with warfarin and present an overview of the main aspects related to warfarin overdose. A 58-year-old woman was evaluated due to transvaginal bleeding and dry cough. In her past medical history, rheumatoid arthritis, smoking and deep venous thrombosis was reported. She had clinical signs of anemia and pulmonary auscultation revealed no lung sounds in the lower third of the right hemithorax. The hemoglobin was 7,2g/dL and the international normalized ratio (INR) was greater than 9. The tomographic study showed pleural effusion and pulmonary embolism in the left pulmonary artery with chronic characteristics, but was negative for pulmonary infarct. The patient received crystalloids, vitamin K and transfusions of blood products. Thoracentesis demonstrated presence of hemothorax. After recovery and hospital discharge, an elective pleural biopsy reveals pleural tissue without histological changes and no signs of malignancy. Despite the fact that hemothorax is a rare complication in patients on oral anticoagulants, this occurrence can be life threatening. The evidence of pleural effusion in these patients should always raise the suspicion of hemothorax. Comorbidities that may affect the lung may be predisposing factors for the occurrence of hemothorax, but the roll of pleural and parenchymal diseases of the lung is not fully clarified and investigation of such conditions should be encouraged.
Os antagonistas da vitamina K são os anticoagulantes orais mais utilizados. Embora sangramentos sejam efeitos colaterais comuns, o desenvolvimento de hemotórax é raro. A maioria dos casos está associada ao comprometimento da pleura ou alteração estrutural do parênquima na presença de valores de INR fora da faixa terapêutica. Relatamos o caso de uma paciente com artrite reumatóide e em anticoagulação com varfarina que apresentou-se com hemotórax maciço. Apresentamos também uma visão geral sobre os principais aspectos relacionados à intoxicação varfarínica. Uma mulher de 58 anos de idade foi avaliada devido a sangramento transvaginal e tosse seca. Em seu histórico médico, artrite reumatóide, tabagismo e trombose venosa profunda foram relatados. Ela tinha sinais clínicos de anemia e a ausculta pulmonar revelou ruídos abolidos no terço inferior do hemitórax direito. A hemoglobina era de 7,2g/dL e a relação normatizada internacional (RNI) maior do que 9. O estudo tomográfico mostrou derrame pleural e embolia na artéria pulmonar esquerda com características crônicas, mas foi negativo para infarto pulmonar. O paciente recebeu cristalóides, vitamina K e transfusões de hemocomponentes. A toracocentese demonstrou presença de hemotórax. Após a recuperação e alta hospitalar, uma biópsia pleural eletiva revelou tecido pleural sem alterações histológicas e sem sinais de malignidade. Apesar do fato de que hemotórax é uma complicação rara em pacientes que tomam anticoagulantes orais, esta ocorrência pode ser fatal. A evidência de derrame pleural nesses pacientes deve sempre levantara suspeita de hemotórax. Co-morbidades que podem afetar o pulmão podem ser fatores predisponentes para a ocorrência de hemotórax, mas o papel de doenças pleurais e parenquimatosas do pulmão não está totalmente esclarecido e a investigação de tais condições deve ser incentivada.
Subject(s)
Humans , Female , Middle Aged , Anticoagulants/adverse effects , Hemothorax/etiology , Warfarin/adverse effects , Vitamin K/antagonists & inhibitorsABSTRACT
Os anti-inflamatórios não esteroides (AINEs) estão entre os medicamentos mais comumente prescritos em todo o mundo e são responsáveis por cerca de um quarto de todas as notificações de reações adversas. Têm sido amplamente indicados em pacientes com doença reumática e outras doenças musculoesqueléticas - população de maior risco de graves complicações gastrintestinais (GI). Os AINEs tópicos são administrados para o tratamento de diversas condições: lesões musculoesqueléticas, dor pós-operatória, neuralgia pós-herpética, periodontite, úlceras aftosas e ceratoses actínicas. Dados mostram que metade dos AINEs é indicada para osteoartrite (OA). Sua administração tópica oferece como benefício menor incidência de efeitos adversos sistêmicos, como úlcera péptica e hemorragia GI, na metabolização do medicamento nos tecidos afetados...
Nonsteroidal anti-inflammatory are among the drugs more usually prescribed in all over the world which is responsible for about a fourth of all notifications of adverse reactions. It has been widely indicated in patients with rheumatic disease and others musculoskeletal disease - high risk population of severe gastrointestinal complications (GI). The topic AINEs are managed for the treatment of many conditions: musculoskeletal injury, postoperative pain, postherpetic neuralgy, periodontic, mouth ulcer and actinic keratosis. Data show that half of AINEs are indicated for osteoarthritis (OA). Its topic administration provides benefits like less incidence of systemic adverse effects like peptic ulcer and GI bleeding in drug-metabolizing in affected tissues...
Subject(s)
Humans , Male , Female , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Musculoskeletal Pain/drug therapy , Administration, Topical , Diclofenac/therapeutic use , Rheumatic Diseases/drug therapy , Pain, Postoperative/drug therapy , Stomatitis, Aphthous/drug therapy , /therapeutic use , Neuralgia, Postherpetic/drug therapy , Osteoarthritis/drug therapy , Musculoskeletal System/injuriesABSTRACT
KEY CLINICAL MESSAGE: A 74-year-old female patient underwent a Roux-en-Y cystjejunostomy for pancreatic pseudocyst developed several melena episodes and she was surgically reappraised. The main diagnostic concern was a pancreatic cystic neoplasm. A 12 × 8.0 × 5.0 cm retro-gastric lesion was resected and pathology report indicated an unsuspected gastrointestinal stromal tumor (GIST). The report aimed to describe an atypical presentation of GIST.
ABSTRACT
Em pacientes sob ventilação mecânica, a equipe assistente, não raro, defronta-se com um subgrupo particular de indivíduos que apresenta repetidos episódios de apneia, quando em modo de suporte ventilatório. Realizou-se uma busca na literatura com o objetivo de avaliar a melhor estratégia de desmame ventilatório nesses pacientes e discutir o papel da polissonografia nesse contexto. Paciente do gênero feminino, 71 anos, internada por um quadro de insuficiência cardíaca congestiva descompensada e pé diabético infectado, evoluiu com parada cardiorrespiratória. Foi reanimada e admitida em unidade de terapia intensiva, onde apresentou melhora clínica gradual. Os fármacos vasoativos foram suspensos e iniciou desmame ventilatório. Nesse momento, passou a apresentar repetidos episódios de apneia quando em modo de pressão de suporte e quadro clínico de delirium. Extubou-se por duas vezes e, finalmente, obteve compensação clínica, a ponto de ter alta para enfermaria e, dentro de 1 mês, alta hospitalar. O número de artigos encontrados, o pequeno número de pacientes avaliados, o delineamento inadequado, dentre outros fatores, não permitem conclusão isenta de incertezas, quando se trata de avaliar a melhor estratégia de retirada da assistência ventilatória nesses pacientes. A presença de apneia per se não parece contraindicar a progressão do desmame ventilatório, decanulação ou extubação. A polissonografia, se disponível, está indicada, mesmo no contexto de unidade de terapia intensiva. O desmame em modo neurally adjusted ventilatory assist parece ser promissor em pacientes com apneia do sono suspeita ou confirmada...
In patients requiring mechanical ventilation, staff assistant is frequently confronted with a particular subgroup of individuals who have repeated episodes of apnea when in pressure support mode. We performed a literature search to define the best approach to ventilator weaning in these patients, and discuss the proper role of polysomnography in this context. Female patient, 71 years old, admitted for decompensated heart failure and infected diabetic foot, had a heart arrest. She was resuscitated and admitted thereafter in the intensive care unit, where she presented with clinical improvement; vasoactive drugs were discontinued, and ventilator weaning was initiated. In that moment, the patient developed multiple apnea episodes during pressure support mode ventilation, and delirium. Despite endotracheal tube self-extubation twice, the patient got better and finally was transferred to the clinical ward, and discharged within a month. The number of studies found, the small number of patients enrolled, and the inappropriate study designs do not guarantee an unflawed conclusion. The presence of apnea per se does not seem to contraindicate the progression of ventilator weaning, decannulation, or extubation. Polysomnography, if available, should be indicated, even in the intensive care unit environment. Ventilator weaning in neurally adjusted ventilatory assisted mode seems to be very promising in patients with suspected or confirmed sleep apnea syndromes...
Subject(s)
Humans , Female , Aged , Polysomnography , Respiration, Artificial , Respiratory Care Units , Sleep Apnea Syndromes , Ventilator WeaningABSTRACT
A osteoartrite (OA) é a causa mais frequente de doença crônica musculoesquelética, sendo sem dúvida a maior causa de limitação das atividades diárias entre os idosos. Atualmente, cerca de 40% dos adultos com idade superior a 70 anos sofrem de OA do joelho; destes, 80% apresentam limitações de movimento e em 25% as atividades diárias estão comprometidas. Nas últimas décadas têm ocorrido avanços na terapêutica da osteoartrite
Osteoarthritis (OA) is the most common cause of chronic musculoskeletal disease and the most prevalent reason for the limitation of daily activities of the elderly population. Currently, about 40% of adults aged over 70 suffer from OA of the knee. Of these, 80% suffer from limitations in motion and 25% are engaged to carry out their daily activities. In recent decades there have been advances in the treatment of osteoarthritis
Subject(s)
Humans , Male , Female , Osteoarthritis, Knee/physiopathology , Osteoarthritis, Knee/drug therapy , Osteoarthritis, Hip/physiopathology , Osteoarthritis, Hip/drug therapy , Anti-Inflammatory Agents , Acetaminophen/therapeutic use , Knee Joint , Glucosamine/administration & dosage , Osteoarthritis/rehabilitation , Patient Education as Topic , Viscosupplementation , Weight LossABSTRACT
OBJECTIVE: To evaluate the magnitude of effects of sildenafil on respiratory parameters and heart rate variability (HRV) in slow wave sleep (SWS) and REM sleep of patients with severe obstructive sleep apnea (OSA). METHODS: Thirteen male patients with untreated severe OSA (aged 43+/-10 years, body mass index of 26.7+/-1.9 kg/m(2)) were studied on two nights, one with sildenafil 50mg and one with a placebo, in a double-blind, randomized fashion. All-night polysomnography and HRV were simultaneously recorded. Short-term HRV measures were performed in apnea-free intervals. Respiratory parameters were separately assessed in non-REM and REM sleep and compared to total sleep time (TST). Short-term HRV analysis was conducted in samples with regular respiration obtained in SWS and REM sleep. RESULTS: Comparing to placebo, during sildenafil night there was an increase in apnea-hypopnea index (AHI) in TST and also in non-REM and REM sleep. Increase in central AHI occurred in non-REM sleep; increase in obstructive AHI and decrease in oxyhemoglobin saturation occurred in both non-REM and REM sleep. Additionally, an increase in arousal index and in low/high frequency component of HRV ratio (LF/HF) was significant only in REM sleep. Correlation between sleep architecture and respiratory parameters were more frequent in non-REM sleep for placebo and in REM sleep for sildenafil. CONCLUSION: In severe OSA, the use of sildenafil 50mg at bedtime plays a detrimental role on respiratory parameters in both non-REM and REM sleep, fragmentation in REM sleep, and a prolonged increase in LH/HF component of HRV after resumption of ventilation.
Subject(s)
Heart Rate/drug effects , Piperazines/adverse effects , Polysomnography/drug effects , Sleep Apnea, Obstructive/chemically induced , Sleep Stages/drug effects , Sleep, REM/drug effects , Sulfones/adverse effects , Vasodilator Agents/adverse effects , Adult , Aged , Arousal/drug effects , Arousal/physiology , Double-Blind Method , Drug Administration Schedule , Electrocardiography, Ambulatory , Heart Rate/physiology , Humans , Hypoxia/chemically induced , Hypoxia/physiopathology , Male , Middle Aged , Oxygen/blood , Oxyhemoglobins/metabolism , Piperazines/administration & dosage , Purines/administration & dosage , Purines/adverse effects , Sildenafil Citrate , Sleep Apnea, Obstructive/physiopathology , Sleep Stages/physiology , Sleep, REM/physiology , Sulfones/administration & dosage , Vasodilator Agents/administration & dosageABSTRACT
O uso do propiltiouracil (PTU) está associado ao desenvolvimento de diferentes auto-anticorpos, entre eles anticorpos anticitoplasma de neutrófilos (ANCA), que estão envolvidos na patogênese das vasculites sistêmicas ANCA-associadas (VSAA). Será relatado o caso de um paciente do sexo feminino, de 46 anos, que apresentou vasculite cutânea durante o uso de PTU como terapêutica para doença de Graves. O ANCA com padrão perinuclear (p-ANCA) foi positivo em títulos maior ou igual 1/320, porém anticorpos antimielo-peroxidase (MPO) não foram detectados. A biópsia de pele revelou uma vasculite leucocitoclástica. Houve melhora clínica em dez dias após a retirada do PTU e optou-se pelo iodo radioativo (I131) para o tratamento do hipertireoidismo. O p-ANCA manteve-se positivo em títulos maior ou igual 1/320 em duas medidas, realizadas oito meses e quatro anos após a suspensão do PTU.
The use of propylthiouracil (PTU) is associated with the development of different auto-antibodies, amongst them are antineutrophil cytoplasmic antibodies (ANCA) that are involved in the pathogenesis of ANCA associated systemic vasculitis. The case of a 46-years old woman who presented cutaneous vasculitis when taking PTU for Graves' disease is reported. Perinuclear ANCA (p-ANCA) was positive with titer > 1/320, but anti-myeloperoxidase antibodies were not detected. Skin biopsy showed leucocytoclastic vasculitis. The patient improved within ten days after withdrawing PTU and the resolution of hyperthyroidism was achieved with radioiodine (131I). The p-ANCA test remained positive > 1/320 eight months and four years after PTU withdrawal.
Subject(s)
Humans , Female , Middle Aged , Antibodies, Antineutrophil Cytoplasmic , Endocrine System Diseases , Hyperthyroidism , Propylthiouracil , Vasculitis , Vasculitis, Leukocytoclastic, CutaneousABSTRACT
A doença de Paget óssea é uma doença osteometabólica focal comforte componente genético caracterizada por aumento da remodelaçãoóssea que afeta um ou mais sítios do esqueleto. A doença de Pagetóssea pode ser assintomática, porém, freqüentemente, se associa ador óssea, deformidades, fratura patológica, osteoartrite secundária esurdez. A prevalência parece estar diminuindo em algumas regiões domundo. O diagnóstico é realizado habitualmente por meio de achadosradiológicos e laboratoriais. No tratamento medicamentoso, é feitauma terapia padrão utilizando bifosfonatos de última geração, como,por exemplo, o ácido zoledrônico; porém, na avaliação rotineira destespacientes, freqüentemente, não são contemplados itens de qualidadede vida e, além disso, não há reversão de complicações.
