RESUMO
Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis. However, its prevalence has increased significantly the past few years due to increased awareness about the disorder, and 1500 cases have been reported worldwide. It is often a multisystemic disease with skeletal, cardiovascular, urologic, renal, retroperitoneal, pulmonary, endocrine, cutaneous, and neurologic involvement. MAPK pathway mutations, such as BRAF activating and MAP2K1 mutations, play a key role in its pathogenesis. In addition to the characteristic clinical, radiological, and histopathological findings, identifying underlying mutations helps diagnose and treat patients with highly effective targeted therapies such as BRAF and MEK inhibitors. We report a case of a man, aged 55 years, with an extensive and prolonged course of an unexplained multisystemic disease, later diagnosed with BRAF V600E-negative and MAP2K1-positive ECD on cell-free DNA testing. Additionally, we review common clinical manifestations, mutations, diagnoses, and targeted therapies for ECD.
Assuntos
Doença de Erdheim-Chester , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/genética , Sequenciamento de Nucleotídeos em Larga Escala , MAP Quinase Quinase 1/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Glioblastoma (GBM), the most common primary brain tumor, is a highly aggressive malignancy for which the median survival is about 13 months, and 5-year survival is well under 5%. These tumors usually occur in the brain and enlarge and infiltrate through white matter, including crossing through the corpus callosum to the opposite cerebral hemisphere. They may spread to distant parts of the central nervous system (CNS) via cerebrospinal fluid pathways. Extraneural metastases from primary brain tumors are quite rare, for 2 probable reasons: because most patients survive less than 2 years, and because of the absence of true lymphatics in the CNS. Typical sites for distant extraneural metastasis of GBM are lungs and pleura, followed by lymph nodes and bones; spread to the liver is exceptional. Most of the reported cases with liver metastases had either single or only a few such metastatic lesions. We report a probably unique case of GBM with extensive liver metastases along with a review of previous cases of liver metastasis from GBM, and we discuss the possible mechanisms of metastasis.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Glioblastoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Neoplasias Encefálicas/terapia , Glioblastoma/secundário , Glioblastoma/terapia , Humanos , Neoplasias Hepáticas/terapiaRESUMO
Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Leucemia Mieloide de Fase Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
Leukemic-stem-cell-specific targeting may improve the survival of patients with acute myeloid leukemia (AML) by avoiding the ablative effects of standard regimens on normal hematopoiesis. Herein, we perform an unbiased screening of compounds targeting cell surface proteins and identify clinically used DPP4 inhibitors as strong suppressors of AML development in both murine AML models and primary human AML cells xenograft model. We find in retrovirus-induced AML mouse models that DPP4-deficient AML cell-transplanted mice exhibit delay and reversal of AML development, whereas deletion of DPP4 has no significant effect on normal hematopoiesis. DPP4 activates and sustains survival of AML stem cells that are critical for AML development in both human and animal models via binding with Src kinase and activation of nuclear factor κB (NF-κB) signaling. Thus, inhibition of DPP4 is a potential therapeutic strategy against AML development through suppression of survival and stemness of AML cells.
Assuntos
Dipeptidil Peptidase 4 , Leucemia Mieloide Aguda , Animais , Humanos , Camundongos , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Leucemia Mieloide Aguda/metabolismo , Transdução de Sinais , Células-Tronco/metabolismoAssuntos
Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/patologia , Ruptura Esplênica/etiologia , Genes bcl-1 , Humanos , Leucemia Linfoide/complicações , Leucemia Linfoide/genética , Leucemia Linfoide/patologia , Linfoma de Célula do Manto/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Esplênicas/complicações , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia , Ruptura Esplênica/patologia , Translocação GenéticaRESUMO
Cardiac metastasis from head and neck cancer is an extremely rare and devastating condition with an abysmal prognosis. Most of our knowledge about this condition is from case reports and series. We present a case of squamous cell carcinoma of the tonsils that was complicated by embolic stroke and critical limb ischemia that were found to be secondary to intracardiac metastasis. We believe that this condition is under-reported; hence, we conducted a thorough review of the literature to highlight the characteristics and previous therapeutic experiences with various presentations of cardiac metastasis from head and neck carcinoma. Clinicians are encouraged to report their experience with evaluating and managing this type of metastasis.
Assuntos
AVC Embólico , Neoplasias Cardíacas , Esvaziamento Cervical/métodos , Nivolumabe/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tonsilectomia/métodos , Quimiorradioterapia Adjuvante/métodos , Diagnóstico Diferencial , AVC Embólico/diagnóstico , AVC Embólico/etiologia , AVC Embólico/fisiopatologia , Evolução Fatal , Neoplasias Cardíacas/patologia , Neoplasias Cardíacas/fisiopatologia , Neoplasias Cardíacas/secundário , Neoplasias Cardíacas/cirurgia , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tonsila Palatina/diagnóstico por imagem , Tonsila Palatina/patologia , Tonsila Palatina/cirurgia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/fisiopatologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgiaAssuntos
Anemia Hemolítica/diagnóstico , Anemia Hemolítica/etiologia , Aranha Marrom Reclusa , Citofagocitose , Picada de Aranha/complicações , Anemia Hemolítica/terapia , Animais , Transfusão de Eritrócitos , Feminino , Humanos , Índice de Gravidade de Doença , Pele/patologia , Resultado do Tratamento , Adulto JovemAssuntos
Artefatos , Erros de Diagnóstico , Adesividade Plaquetária , Contagem de Plaquetas , Trombocitopenia/diagnóstico , Idoso , Autoanticorpos/imunologia , Plaquetas/imunologia , Ácido Edético/farmacologia , Granulócitos/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Adesividade Plaquetária/imunologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Receptores de IgG/imunologiaRESUMO
The US FDA has recently approved an updated nivolumab dosing schedule, a single 480 mg iv. dose every 4 weeks [1], across all its previously approved indications, including second-line therapy for metastatic renal cell carcinoma. As this regimen is still in its infancy, we have not yet observed significant differences in immune-related toxicities and have not yet identified clinical characteristics which would predict intolerance and increased risk for complications. Herein, we present a patient with metastatic renal cell carcinoma who developed bullous pemphigoid after a single 480 mg iv. dose of nivolumab after previously tolerating a 240 mg biweekly dose for 2 years.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Nivolumabe , Penfigoide Bolhoso , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/patologiaRESUMO
Merkel cell carcinoma (MCC), a rare skin cancer, is associated with high mortality, especially in a metastatic setting. Though conventional chemotherapy with platinum and etoposide has had high response rates, many of the patients have had early relapse without any effective therapy thereafter. Recently, immune check point inhibitors have shown very good durable responses, leading to the approval of a programmed death-ligand 1 inhibitor Avelumab for these patients. We briefly review the epidemiology and immune basis of the pathogenesis of MCC, which therefore explains the excellent response to check point inhibitors, and throw light on future directions of immunotherapy for this cancer.
RESUMO
The relevance of this case lies in the extensive diagnostic workup that can be avoided with proper laboratory evaluation of relatively unsophisticated tests.
RESUMO
BACKGROUND: Visual heuristics of pathology diagnosis is a largely unexplored area where reported studies only provided a qualitative insight into the subject. Uncovering and quantifying pathology visual and nonvisual diagnostic patterns have great potential to improve clinical outcomes and avoid diagnostic pitfalls. METHODS: Here, we present PathEdEx, an informatics computational framework that incorporates whole-slide digital pathology imaging with multiscale gaze-tracking technology to create web-based interactive pathology educational atlases and to datamine visual and nonvisual diagnostic heuristics. RESULTS: We demonstrate the capabilities of PathEdEx for mining visual and nonvisual diagnostic heuristics using the first PathEdEx volume of a hematopathology atlas. We conducted a quantitative study on the time dynamics of zooming and panning operations utilized by experts and novices to come to the correct diagnosis. We then performed association rule mining to determine sets of diagnostic factors that consistently result in a correct diagnosis, and studied differences in diagnostic strategies across different levels of pathology expertise using Markov chain (MC) modeling and MC Monte Carlo simulations. To perform these studies, we translated raw gaze points to high-explanatory semantic labels that represent pathology diagnostic clues. Therefore, the outcome of these studies is readily transformed into narrative descriptors for direct use in pathology education and practice. CONCLUSION: PathEdEx framework can be used to capture best practices of pathology visual and nonvisual diagnostic heuristics that can be passed over to the next generation of pathologists and have potential to streamline implementation of precision diagnostics in precision medicine settings.
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Because cancer is a leading cause of mortality in the United States, the number of therapeutic modalities available for the treatment of neoplastic processes has increased. This has resulted in a large number of patients being exposed to a wide variety of cancer therapy. Historically, it has been well recognized that antineoplastic agents may have adverse effects on multiple organs and normal tissues. The most commonly associated toxicities occur in tissues composed of rapidly dividing cells and may spontaneously reverse with minimal long-term toxicity. However, the myocardium consists of cells that have limited regenerative capability, which may render the heart susceptible to permanent or transient adverse effects from chemotherapeutic agents. Such toxicity encompasses a heterogeneous group of disorders, ranging from relatively benign arrhythmias to potentially lethal conditions such as myocardial ischemia/infarction and cardiomyopathy. In some instances, the pathogenesis of these toxic effects has been elucidated, whereas in others the precise etiology remains unknown. We review herein the various syndromes of cardiac toxicity that are reported to be associated with antineoplastic agents and discuss their putative mechanisms and treatment.
Assuntos
Antineoplásicos/efeitos adversos , Cardiopatias/induzido quimicamente , Neoplasias/complicações , Neoplasias/tratamento farmacológico , HumanosRESUMO
Among the various deleterious effects of cancer chemotherapy, vascular toxicity is the least well recognized. This lack of recognition may be because the vasculotoxic phenomena are not unique to antineoplastic agents, can occur in patients without exposure to these agents, and the fact cancer itself may produce a hypercoagulable state. As a result, many vascular events either go unnoticed, are ignored, and/or are attributed to the underlying malignancy. Many antineoplastic therapies are associated with various vascular phenomena that range from simple phelibitis to lethal microangiopathy. Recognition of these events is important to minimize the morbidity and even prevent unnecessary deaths. Herein we review the vascular syndromes that have been reported in association with antineoplastic agents.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Vasculares/induzido quimicamente , Animais , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Recently, immunotherapeutic drugs, including PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, avelumab), and CTLA4 inhibitors (ipiliumumab), have emerged as important additions to the armamentarium against certain malignancies and have been incorporated into therapeutic protocols for first-, second-, or third-line agents for these metastatic cancers. Immune checkpoint inhibitor nivolumab is currently FDA approved for the treatment of patients with metastatic malignant melanoma [Redman et al.: BMC Med 2016;14: 20], metastatic non-small cell lung cancer [Guibert and Mazières: Expert Opin Biol Ther 2015;15: 1789-1797], metastatic renal cell cancer [Farolfi et al.: Expert Opin Drug Metab Toxicol 2016;12: 1089-1096], and relapsed or refractory classic Hodgkin's lymphoma [Villasboas and Ansell: Expert Rev Anticancer Ther 2016;16: 5-12]. Given the current and increasing indications for these drugs, it is essential for all physicians to become well versed with their common adverse effects and to be observant for other less documented clinical conditions that could be unmasked with the use of such medications. A definite association between autoimmune hemolytic anemia and the immune checkpoint inhibitor nivolumab has not been clearly documented, although a few cases have been reported recently [Kong et al.: Melanoma Res 2016;26: 202-204; Schwab et al.: Case Rep Oncol 2016;9: 373-378; Tardy et al.: Hematol Oncol 2016, DOI: 10.1002/hon.2338]. We report a case of fatal autoimmune hemolytic anemia refractory to steroids in a patient treated with nivolumab for metastatic lung cancer, and reflect on the other reported cases of autoimmune hemolytic anemia after the use of nivolumab.
RESUMO
Total hip replacement (THR) and total knee arthroplasty (TKA) carry a high risk of postoperative venous thromboembolism (VTE); therefore, anticoagulation prophylaxis is recommended in these patients. Unfortunately, there are no guidelines about VTE prophylaxis in patients with hemophilia who underwent these high-risk surgeries. To determine whether these patients have high risk of VTE, we conducted a retrospective study on patients with hemophilia who underwent elective THR/TKA at our institute from 2004 to 2012. Postoperatively, we collected information on duration and method of factor VIII/IX infusion, VTE-prophylaxis, and complications. There were 23 patients with hemophilia, 18 (78%) with hemophilia A and 5 (22%) with hemophilia B, who underwent high-risk surgeries (39% THR and 61% TKA). The VTE prophylaxis included sequential compression device, 12 (52%), and prophylactic enoxaparin, 1 (4%). Ten (43%) patients did not receive VTE prophylaxis. At 1-year follow-up, we did not find any evidence of clinical VTE in our patients. Better risk stratification is needed to identify patients who would benefit from pharmacological prophylaxis.
Assuntos
Artroplastia de Quadril/efeitos adversos , Bandagens Compressivas , Enoxaparina/administração & dosagem , Fator IX/administração & dosagem , Fator VIII/administração & dosagem , Hemofilia A/cirurgia , Hemofilia B/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tromboembolia Venosa/etiologiaRESUMO
BACKGROUND: The purpose of this study is to determine prognostic factors and survival in patients who present with combined small-cell lung cancer (SCLC). METHODS: A retrospective review of combined SCLC histology in patients treated between1995-2010 was undertaken. Demographics, diagnostic information, disease characteristics, treatment modality, and survival were captured. Survival estimates were performed using Kaplan Meier analysis. Statistical significance was defined as P < 0.05. RESULTS: Forty-one patients were identified, and 35 records were available for analysis. Median age at diagnosis was 68 (range 50-85). The study included 20 (57%) women and 15 (43%) men; and 94% had a current or former history of smoking. Histology was SCLC/large cell carcinoma not otherwise specified in 28 (80%), and SCLC/adenocarcinoma or SCLC/squamous cell carcinoma in seven (20%). Cardiac or pulmonary comorbidities were present in 80% of patients, and 24 patients had metastatic disease at presentation. Twenty-eight patients received treatment of chemotherapy (n = 24), cranial radiotherapy (n = 5), or thoracic radiotherapy (n = 7). Staging was as follows: stage I-III (n = 11), stage IV (n = 24). Median survival was 15.4 months (range <1-53 months) and 3.4 months (range <1-21.9 months) for American Joint Committee on Cancer (AJCC) stage I-III and stage IV, respectively. Estimated overall six and 12 month survival was 82%, 55%, 37%, and 17% for stage I-III and stage IV, respectively. An improved overall survival rate was found for patients with an Eastern Cooperative Oncology Group performance status of <2, and no weight loss (P < 0.05). CONCLUSION: Akin to SCLC, advanced stage combined SCLC portends a poor prognosis. Perhaps novel chemotherapeutic drugs or targeted agents may improve outcomes for future patient populations.