RESUMO
Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations.
Assuntos
Ataxia Telangiectasia , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Sulfonamidas , Humanos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Ataxia Telangiectasia/tratamento farmacológico , Ataxia Telangiectasia/complicações , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações , Masculino , Antineoplásicos/uso terapêutico , Feminino , CriançaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotin , Doença de Hodgkin , Nivolumabe , Humanos , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/terapia , Doença de Hodgkin/patologia , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Criança , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Antineoplásicos Imunológicos/uso terapêutico , Adolescente , Imunoterapia/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Vimblastina/administração & dosagem , Vimblastina/uso terapêuticoAssuntos
Anticorpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Histona-Lisina N-Metiltransferase , Imunoterapia Adotiva , Proteína de Leucina Linfoide-Mieloide , Piperazinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridinas , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Proteína de Leucina Linfoide-Mieloide/genética , Histona-Lisina N-Metiltransferase/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Feminino , Rearranjo Gênico , Acrilamidas/uso terapêutico , Criança , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/etiologiaRESUMO
Childhood acute lymphoblastic leukemia (ALL) has witnessed substantial improvements in prognosis; however, a subset of patients classified as high-risk continues to face higher rates of relapse and increased mortality. While the National Cancer Institute (NCI) criteria have traditionally guided risk stratification based on initial clinical information, recent advances highlight the pivotal role of biological markers in shaping the prognosis of childhood ALL. This review delves into the emerging understanding of high-risk childhood ALL, focusing on molecular, cytogenetic, and immunophenotypic markers. These markers not only contribute to unraveling the underlying mechanisms of the disease, but also shed light on specific clinical patterns that dictate prognosis. The paradigm shift in treatment strategies, exemplified by the success of tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemia, underscores the importance of recognizing and targeting precise risk factors. Through a comprehensive exploration of high-risk childhood ALL characteristics, this review aims to enhance our comprehension of the disease, offering insights into its molecular landscape and clinical intricacies in the hope of contributing to future targeted and tailored therapies.
RESUMO
Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.
Assuntos
Interferon gama , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Interferon gama/farmacologia , Prognóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Microambiente TumoralRESUMO
BACKGROUND: Stenotrophomonas maltophilia is a bacterial pathogen that can be fatal in hospitalized and immunocompromised patients with mortality as high as 69%. Pediatric cancer patients often have risk factors that are common for this infection, making them particularly susceptible. Managing S. maltophilia is especially challenging as it has inherent resistance to several antibiotics. Furthermore, soft tissue infections in neutropenic patients may deviate from the typical clinical presentation of S. maltophilia. CASE DETAILS: This case series describes an in-depth examination of three cases involving immunocompromised pediatric patients with S. maltophilia infections. Each case exhibited a distinct clinical presentation, encompassing infection of the blood, lung, and skin, which highlights the variability in which S. maltophilia manifests in immunocompromised pediatric patients. These patients were treated at MD Anderson Cancer Center (MDACC) from 2020 to 2023, unfortunately resulting in fatality. CONCLUSIONS: The study aims to provide valuable insights and guidance for the management of patients with S. maltophilia infections. Emphasizing a heightened clinical suspicion will potentially lead to early initiation of directed therapy against S. maltophilia. Timely intervention may play a pivotal role in improving patient outcomes and reduce further burden to the healthcare system.
Assuntos
Neoplasias , Stenotrophomonas maltophilia , Humanos , Criança , Antibacterianos/uso terapêutico , Neoplasias/tratamento farmacológico , Fatores de RiscoRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy, especially in pediatrics, that can involve the bone marrow, skin, lymph nodes, and central nervous system (CNS). Given its variable clinical presentation, coupled with an immunohistochemistry pattern (CD4, CD56, TCF4, TCL-1, and CD123 positivity) that differs from other myeloid neoplasms, the diagnosis of BPDCN can be missed. Limited data are available to guide the treatment of pediatric BPDCN. Herein, we report a case of a pediatric patient who had BPDCN with central nervous system, orbital, and skin involvement. This patient achieved complete remission after receiving modified hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with venetoclax and intrathecal chemotherapy. He remains disease-free 200 days after receiving a stem cell transplant. This represents the first known published pediatric case using a modified hyper-CVAD plus venetoclax regimen for treating a pediatric BPDCN patient in the frontline setting.
Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Masculino , Humanos , Criança , Células Dendríticas/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neoplasias Hematológicas/patologiaRESUMO
Energy balance accounts for an individual's energy intake, expenditure, and storage. Each aspect of energy balance has implications for the pharmacokinetics of cancer treatments and may impact an individual's drug exposure and subsequently its tolerance and efficacy. However, the integrated effects of diet, physical activity, and body composition on drug absorption, metabolism, distribution, and excretion are not yet fully understood. This review examines the existing literature on energy balance, specifically the role of dietary intake and nutritional status, physical activity and energy expenditure, and body composition on the pharmacokinetics of cancer therapeutics. As energy balance and pharmacokinetic factors can be influenced by age-related states of metabolism and comorbidities, this review also explores the age-related impact of body composition and physiologic changes on pharmacokinetics among pediatric and older adult populations with cancer.
Assuntos
Ingestão de Alimentos , Neoplasias , Humanos , Criança , Idoso , Dieta , Metabolismo Energético , Ingestão de Energia , Composição Corporal , Neoplasias/tratamento farmacológicoAssuntos
Síndrome de Down , Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Nitrilas , PirimidinasRESUMO
Advances in energy balance and cancer research to date have largely occurred in siloed work in rodents or patients. However, substantial benefit can be derived from parallel studies in which animal models inform the design of clinical and population studies or in which clinical observations become the basis for animal studies. The conference Translating Energy Balance from Bench to Communities: Application of Parallel Animal-Human Studies in Cancer, held in July 2021, convened investigators from basic, translational/clinical, and population science research to share knowledge, examples of successful parallel studies, and strong research to move the field of energy balance and cancer toward practice changes. This review summarizes key topics discussed to advance research on the role of energy balance, including physical activity, body composition, and dietary intake, on cancer development, cancer outcomes, and healthy survivorship.
Assuntos
Neoplasias , Animais , Humanos , Exercício FísicoRESUMO
Exercise has the potential to positively affect patients with osteosarcoma by improvement of function, mitigation of disability, and maintenance of independence and quality of life. Exercise may also directly impact cancer treatment efficacy. This chapter examines the feasibility and use of exercise or physical activity as therapy in the treatment of osteosarcoma and its survivors. It additionally presents the benefits of physical activity as treatment and rehabilitation both preoperatively (prehabilitation) and postoperatively. This chapter will also discuss barriers to exercise and physical activity for patients with osteosarcoma and its survivors, emphasizing the need for a comprehensive and cohesive support system to promote its incorporation into patient treatment plans and ensure compliance.