RESUMO
Anaplastic lymphoma kinase ( ALK )-fusion sarcomas are rare part of the emerging theoretically targetable tyrosine kinase RAS::MAPK pathway fusion myopericytic-ovoid sarcomas. We report our clinicopathologic and treatment experience with an ALK fusion sarcoma. A novel ELKS/RAB6-interacting/CAST family member 1 - unaligned ALK fusion infiltrative nonmetastatic low-grade sarcoma of the right hand of a 15-month-old male was treated with crizotinib, an ALK tyrosine kinase inhibitor as oral monotherapy, inducing complete radiographic and clinical resolution by 10 months and sustained response now over 12 months after elective discontinuation. Crizotinib can successfully be used to treat unresectable novel ALK fusion sarcomas.
Assuntos
Neoplasias Pulmonares , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Masculino , Criança , Lactente , Crizotinibe/uso terapêutico , Quinase do Linfoma Anaplásico/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Sarcoma/tratamento farmacológico , Sarcoma/genética , Proteínas Tirosina Quinases/uso terapêutico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias Pulmonares/patologiaRESUMO
Immune thrombocytopenia (ITP) is an autoimmune disease causing platelet destruction, and is a common cause of symptomatic thrombocytopenia in children. Intravenous immune globulin (IVIG) is a treatment for ITP that increases the platelet counts of most patients within 24 to 48 hours. This study aimed to calculate the rate of rise in pediatric ITP after a dose of IVIG and to analyze if patient characteristics affected the rate. For 116 children treated for ITP with IVIG at Hershey Medical Center, the rate of rise of the platelet count for all patients was calculated. The rate of rise ranged from -0.1 to +4.2 K/µL/hour (average 1.3, median 1.2). 78% of patients had a rate of rise of over 0.5 K/µL/hour. There was a statistically significant correlation between the rate rise of the platelet count and the initial platelet count (P=0.0197), but rate was not affected by age or sex. This study was able to demonstrate that IVIG is effective in most patients and that demographic features do not affect the rate of rise. By providing a nomogram showing when to expect a meaningful rise in the platelet count after IVIG, we give guidance for timing of the postinfusion platelet count to avoid administering a second dose. Future studies are needed to test this nomogram prospectively.
Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Criança , Humanos , Imunoglobulinas Intravenosas , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/tratamento farmacológicoRESUMO
Over the course of medical school, students' optimism and hopefulness often devolve into a cynical view of medicine that continues throughout clinical rotations and beyond (Neumann et al., Acad Med 86(8):996-1009, 2011). Here, we present a qualitative evaluation of a novel immersive elective in pediatric psycho-oncology coupled with narrative medicine and its impact on students. Participants were third- and fourth-year medical students who were relieved of traditional clinical duties. Alternatively, they shadowed pediatric cancer patients, keeping narrative journals of their observations and insights. A trained team of pre-clinical medical students and faculty conducted a retrospective analysis of 120 journals written between 2008 and 2019. They compared recurring concepts to assess how blending experiential learning and reflective writing influenced the attitudes and behaviors of students. Consistent themes emerged related to developing a rich understanding of patient experiences, a humanistic appreciation of the context of illness, the ability to meaningfully reflect on insights to critically ill children, and an appreciation for the unique learning opportunity. Additionally, families expressed gratitude for the students' attentiveness to their emotional needs. By the conclusion of the elective, most students discovered that they had reignited their intrinsic empathic behaviors and were provided with beneficial insights that they believed would continue into future rotations. Experiential teaching methods paired with narrative reflection may be a valuable and therapeutic tool to learn the intricacies of the patient perspective, with the potential to enhance humanism in students during a critical time in their medical training when empathy tends to drift. Longitudinal and quantitative studies are warranted to better understand the degree and duration of specific benefits.
Assuntos
Medicina Narrativa , Estudantes de Medicina , Criança , Humanos , Estudantes de Medicina/psicologia , Humanismo , Estudos Retrospectivos , Psico-OncologiaRESUMO
BACKGROUND: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. METHODS: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). RESULTS: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18â¯years. Sizes ranged 5.3-25.0, median 9.1â¯cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). CONCLUSIONS: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Femorais/genética , Fusão Gênica , Neoplasias de Cabeça e Pescoço/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Neoplasias Torácicas/genética , Adolescente , Adulto , Idoso , Algoritmos , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Extremidades/patologia , Feminino , Neoplasias Femorais/diagnóstico , Neoplasias Femorais/tratamento farmacológico , Neoplasias Femorais/patologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fenótipo , Prognóstico , Sarcoma/diagnóstico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologia , Neoplasias Torácicas/diagnóstico , Neoplasias Torácicas/tratamento farmacológico , Neoplasias Torácicas/patologia , Parede Torácica/patologia , Adulto JovemRESUMO
Although sleep is ubiquitous, its evolutionary purpose remains elusive. Though every species of animal, as well as many plants sleep, theories of its origin are purely physiological, e.g. to conserve energy, make repairs or to consolidate learning. An evolutionary reason for sleep would answer one of biology's fundamental unanswered questions. When environmental conditions change on a periodic basis (winter/summer, day/night) organisms must somehow confront the change or else be less able to compete in either niche. Seasonal adaptation includes the migration of birds, changes in honeybee physiology and winter abscission in plants. Diurnal adaptation must be more rapid, forcing changes in behavior in addition to physiology. Since organisms must exist in both environments, evolution has created a way to force a change in behavior, in effect creating "different" organisms (one awake, one asleep) adapted separately to two distinct niches. We sleep to allow evolving into two competing niches. The physiology of sleep forces a change to a different state for the second niche. The physiological needs for sleep are mechanisms that have evolved to achieve this goal.
Assuntos
Linfoma de Células B , Linfoma Folicular , Neoplasias Cutâneas , Humanos , Adolescente , Rituximab/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B(12) as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at www.clinicaltrials.gov as NCT00069680 and NCT00369421.
Assuntos
Cromossomos Humanos Par 3/genética , Síndrome da Plaqueta Cinza/genética , Síndrome da Plaqueta Cinza/fisiopatologia , Adolescente , Adulto , Plaquetas/ultraestrutura , Separação Celular , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Citometria de Fluxo , Ligação Genética , Estudo de Associação Genômica Ampla , Síndrome da Plaqueta Cinza/sangue , Humanos , Masculino , Repetições de Microssatélites , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/ultraestrutura , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Vitamina B 12/sangue , Adulto JovemRESUMO
BACKGROUND: It is common practice to hold anthracycline induction chemotherapy in children with high-risk acute lymphoblastic leukemia (HR-ALL) until an echocardiogram is performed and interpreted. It is unclear whether withholding therapy in HR-ALL children is justified by echocardiogram findings. We reviewed the initial echocardiograms in a cohort of children with HR-ALL to determine the incidence of contraindications for anthracycline treatment. PROCEDURE: We identified 50 consecutive children (<21 years old) with HR-ALL presenting at our institution over a 10-year period. One didn't have an initial echocardiogram, 39 had pre-therapy studies, and 10 were studied within 6 days of beginning chemotherapy. These 49 studies were reviewed to determine the incidence and clinical significance of abnormalities. RESULTS: All 49 patients had normal cardiac function. Initial echocardiogram findings had no impact on induction chemotherapy administration in any patient. However, only 22(45%) of the studies were completely normal. Echocardiographic abnormalities included pericardial effusion (17/49), trivial or mild mitral or aortic insufficiency (13/49), left ventricular enlargement (3/49), and structural heart disease (4/49). Twelve percent of the children had a patent foramen ovale. None of the cardiac findings required therapeutic intervention other than repositioning of indwelling lines (6/49) due to intracardiac positioning. CONCLUSIONS: In our experience, findings on echocardiograms in childhood HR-ALL did not impact anthracycline administration. This study suggests that induction chemotherapy should not be delayed for an echocardiogram. However, whenever possible, a pre-therapy echocardiogram is still recommended for determining baseline function and to identify associated problems like pericardial effusions which were common in this study.
Assuntos
Antraciclinas , Antibióticos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ecocardiografia , Cardiopatias/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Contraindicações , Feminino , Cardiopatias/induzido quimicamente , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
With the advent of commercial human spaceflight, it is important to analyze the historical safety of humans traveling to, in, and from space. We break down the fatality rates of human spaceflight and compare them to those of several terrestrial transportation modes. We created a database of human space travel, containing the vehicles, launches, and the total time and distance traveled. For the 4 fatal space missions and 18 fatalities, we determined the fatality rates, calculated by several methods, including rates per trip, person, and distance traveled, stratified by the mission segment affected. Two of the 326 launches did not reach space, and 8 others were suborbital. There have been 1285 person-launches to space; the total time in space is estimated to be 55,939 person-days; and the total distance traveled is approximately 23.5 billion person-miles. One fatal trip occurred on the way to orbit and the other 3 during the return. There has yet to be a fatality in orbit, and there have been none on any space flight since 2003. The per-trip and per-person fatality rates are 1.2% and 1.4%, respectively, but the per mile rate is much lower, depending on the flight segment.
Assuntos
Acidentes Aeronáuticos/mortalidade , Acidentes de Trânsito/mortalidade , Aviação , Veículos Automotores , Ferrovias , Voo Espacial , Automóveis , Humanos , Motocicletas , Meios de Transporte , ViagemRESUMO
Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder that is characterized by large platelets that lack α-granules. Here we show that mutations in NBEAL2 (neurobeachin-like 2), which encodes a BEACH/ARM/WD40 domain protein, cause GPS and that megakaryocytes and platelets from individuals with GPS express a unique combination of NBEAL2 transcripts. Proteomic analysis of sucrose-gradient subcellular fractions of platelets indicated that NBEAL2 localizes to the dense tubular system (endoplasmic reticulum) in platelets.
Assuntos
Plaquetas/metabolismo , Proteínas Sanguíneas/genética , Grânulos Citoplasmáticos/metabolismo , Retículo Endoplasmático/metabolismo , Síndrome da Plaqueta Cinza/genética , Megacariócitos/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/genética , Vesículas Secretórias/metabolismo , Humanos , Megacariócitos/citologia , Biogênese de Organelas , Agregação Plaquetária , Estrutura Terciária de Proteína , Proteômica , Frações SubcelularesRESUMO
Idiopathic thrombocytopenic purpura (ITP) is a disorder of rapid destruction of antibody-coated platelets. Anti-D immune globulin has been used for treatment of ITP in the United States since 1995. Initial studies identified no significant side effects of treatment. However, a recent report highlighted occasional episodes of intravascular hemolysis after anti-D immune globulin. We describe two children with ITP who developed acute renal failure (ARF) after treatment with anti-D immune globulin and also analyze ten additional cases of ARF reported to the manufacturer, Cangene Corporation, through postmarketing surveillance. All episodes of ARF were associated with intravascular hemolysis. Four patients required dialysis. Patient age ranged from 1 to 82 years, but those requiring dialysis were all under age 15 years. Several patients with ARF had preexisting creatinine elevation. Three of the patients with ARF had serologic evidence of acute Epstein-Barr virus (EBV) infection. Renal biopsy in one patient showed acute tubular necrosis, with findings consistent with pigment nephropathy. Anti-D immune globulin, used to treat ITP, may be associated with intravascular hemolysis and resultant ARF. Renal function should be monitored in patients with evidence of intravascular hemolysis. Children and adolescents may have increased risk of ARF requiring dialysis.