RESUMO
BACKGROUND: Diffuse midline glioma (DMG) is the most common malignant glioma in early childhood with median survival of only eleven months. This retrospective interview study investigates specific coping strategies and needs of affected parents. PATIENTS: 13 interviews with parents of seven children who died from DMG at the age of five to 16 years were conducted in 2016. METHOD: The used method is a problem-oriented guided interview with consecutive content and evaluating structuring analysis according to Mayring. RESULTS: Major inductive category was whether the parents had talked to their children about their upcoming death. All parents stated overall satisfaction and comfort regarding their palliative care. Lack of psycho-social support in families was successfully addressed by involving palliative care. CONCLUSIONS: Retrospective interview studies in this context are feasible. Early involvement of the palliative care team may relieve burden from affected parents. Open communication about death proved helpful for all involved parties, it may facilitate acceptance of terminal illness and alleviate guilt in parents.Concepts for an open and empowering communication within families and between treatment site and families need continuing adjustment. The Palliative care team may also have a key role regarding early phase trials and molecular studies.
Assuntos
Glioma Pontino Intrínseco Difuso , Glioma , Assistência Terminal , Criança , Pré-Escolar , Humanos , Adolescente , Assistência Terminal/métodos , Estudos Retrospectivos , Pais , Cuidados Paliativos , Adaptação Psicológica , Glioma/terapia , Pesquisa QualitativaRESUMO
For patients with myeloid malignancies who relapse after allogeneic stem cell transplantation (allo-SCT), one salvage option is a second SCT. We retrospectively analyzed outcomes of the second allo-SCT in 25 patients who received at least 2 allografts from related/unrelated donors due to relapse of acute myeloid leukemia, myelodysplastic syndrome or myelofibrosis after the first SCT. A minority of the acute myeloid leukemia/myelodysplastic syndrome patients had reached complete hematological remission before the second SCT (6/25, 24%). Reduced conditioning strategies were performed in the majority (n = 23). Complete remission was achieved in all 21 cases with available data after the second SCT, but relapse was seen in 11/25 patients (44%). After a median follow-up of 18 months (range 6-47), 8/25 patients (32%) were still alive, and of those, 6 (24%) were in stable remission. In 9 cases mortality was associated to relapse and in 8 cases to transplant-related causes (treatment-related mortality; 8/25, 32%). In conclusion, a second SCT offers the chance of stable remission for some patients relapsing with a myeloid malignancy after a first allo-SCT, although high treatment-related mortality and relapse rates remain a problem. Efforts should concentrate on an optimization of conditioning strategies, immunosuppression and post-transplant surveillance for this specific situation.
Assuntos
Leucemia Mieloide Aguda/cirurgia , Síndromes Mielodisplásicas/cirurgia , Transplante de Células-Tronco de Sangue Periférico , Mielofibrose Primária/cirurgia , Adolescente , Adulto , Transplante de Medula Óssea , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mielomonocítica Juvenil/cirurgia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Policitemia/complicações , Mielofibrose Primária/etiologia , Recidiva , Reoperação , Estudos Retrospectivos , Terapia de Salvação , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: To evaluate optimal therapy and potential risk factors. METHODS: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed. RESULTS: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse. CONCLUSION: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
Assuntos
Neoplasias Abdominais/terapia , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Neoplasias Abdominais/patologia , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína C-Reativa/análise , Criança , Terapia Combinada , Tumor Desmoplásico de Pequenas Células Redondas/patologia , Feminino , Humanos , Masculino , Derrame Pleural/diagnóstico , Prognóstico , Fatores de Risco , Transplante de Células-Tronco , Trombose Venosa/diagnóstico , Adulto JovemRESUMO
PURPOSE: The present in vitro study was conducted to evaluate the effects of the histone deacetylase inhibitors (HDIs) suberoyl anilide hydroxamic acid (SAHA), sodium butyrate (NaB) and MS-275 applied as single agents or in combination with TRAIL in Ewing's sarcoma. METHODS: Cytotoxic activities were assessed by cytofluorometric analysis of propidium iodide uptake, DNA fragmentation and mitochondrial depolarisation as well as by measuring caspase-9 and -3 activities. Cell-surface expression of TRAIL receptors was determined by cytofluorometry, and histone H4 acetylation was assessed by western blot. RESULTS: All three HDIs potently induced cell death in the two cell lines explored, SK-ES-1 and WE-68. However, they seemed to differ in their modes of action. SAHA and NaB induced mitochondrial depolarisation as well as caspase-9 and -3 activities, and their cytotoxic effects could be significantly reduced by the pan-caspase inhibitor z-VAD-fmk. MS-275 was a much weaker inducer of caspase-9 and -3 activities as well as mitochondrial injury; consistently, z-VAD-fmk had little effect on MS-275-mediated activities. Combined treatment of HDIs and TRAIL led to an additive effect in SK-ES-1 cells and a supra-additive effect in WE-68 cells. Yet, HDIs did not increase cell-surface expression of TRAIL receptor 2, but rather decreased it. Selective inhibition of caspase-8 in WE-68 cells and HDI treatment of CADO-ES-1 cells, a Ewing's sarcoma cell line deficient in caspase-8 expression, revealed that caspase-8 was not required for HDI-mediated apoptosis. CONCLUSIONS: These results suggest that HDIs may be considered as a novel treatment strategy for Ewing's sarcoma either applied as monotherapy or in combination with TRAIL.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Sarcoma de Ewing/patologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Butiratos/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Piridinas/farmacologia , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/metabolismo , VorinostatRESUMO
Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, their precise mechanism of action is uncertain; particularly, the role of caspases in the apoptotic response to HDIs is controversial. Here, we show that the HDIs explored, suberoylanilide hydroxamic acid, sodium butyrate and trichostatin A, activated caspase-3 in A549 and PC-3 carcinoma cells. Additionally, the poly-caspase inhibitor z-VAD-fmk prevented HDI-induced apoptosis, as judged by determining mitochondrial membrane potential and by quantifying internucleosomal DNA fragmentation. Importantly, z-VAD-fmk also significantly inhibited HDI-elicited cell death, as assessed by measuring propidium iodide uptake. As an accessory finding, with the inhibition of caspases, a HDI-induced G2-M arrest became evident. Taken together, these results provide evidence that HDIs require activated caspases to induce apoptosis of carcinoma cells.
Assuntos
Apoptose/efeitos dos fármacos , Caspases/fisiologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Neoplasias da Próstata/patologiaRESUMO
Juvenile xanthogranuloma (JXG), one of the most common forms of Langerhans-dendritic cell proliferation in young children, usually presents as spontaneously regressing cutaneous lesions. JXG with systemic (extracutaneous) involvement is a rare histiocytic disorder in which significant morbidity and death may occur. The systemic type, especially combined with multiple central nervous system lesions in young children, has a very poor prognosis. The patient described here presented with disseminated disease including lungs, liver, kidneys, ribs, scalp, and central nervous system. The patient was treated with multiagent chemotherapy based on the Langerhans cell histiocytosis II treatment protocol. The regimen used included an additional intrathecal therapy with methotrexate and prednisolone to control central nervous system lesions. The patient was treated for 28 months and has been in remission for almost 5 years.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Vimblastina/uso terapêutico , Xantogranuloma Juvenil/tratamento farmacológico , Doenças do Sistema Nervoso Central/cirurgia , Terapia Combinada , Craniotomia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Injeções Espinhais , Hepatopatias/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Paresia/etiologia , Prednisolona/administração & dosagem , Dermatopatias/tratamento farmacológico , Vimblastina/administração & dosagem , Xantogranuloma Juvenil/cirurgiaRESUMO
We recently cloned six human importin a proteins that transport specific substrates in complex with importin beta into the nucleus. We now compared their absolute expression levels in different human cell lines. We examined their expression regulation during human cell proliferation and differentiation by means of specific antibodies. Proliferation inhibition by starvation of HeLa and HaCaT cells led to a marked decrease in the expression of various nuclear transport factors. In contrast, re-addition of serum increased alpha-importin expression. We analyzed two models for cell differentiation and found differential importin regulation. Stimulation of rat pancreatic AR42J cell differentiation towards a neuroendocrine phenotype with activin A or towards an acinar phenotype with dexamethasone, caused strong upregulation of importin alpha3 and alpha4 expression. Phorbol ester-induced differentiation of human leukemia (HL60) cells towards a macrophage phenotype led to downregulation of importin alpha1 and alpha4 expression after 72 hours. Similarly, importins alpha1 and alpha4 displayed a strong downregulation when HL60 cells were directed towards a neutrophil phenotype by DMSO treatment. This study is the first to assess all the human importin alpha isoforms in documenting differential nuclear transport factor regulation during cell proliferation and differentiation.