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CONTEXT.: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.
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Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls (p < .001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients (p < .001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC = 0.782, p < .001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.
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Histiocitose de Células de Langerhans , Receptor de Fator Estimulador de Colônias de Macrófagos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Humanos , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/sangue , Masculino , Feminino , Criança , Prognóstico , Pré-Escolar , Lactente , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/sangue , Adolescente , Estudos Prospectivos , SeguimentosRESUMO
Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm mainly affecting young children. This study aimed to evaluate the outcomes of 449 pediatric patients enrolled in the BCH-LCH 2014 study. 52.6% of patients were classified with single-system (SS) LCH, 28.1% with multisystem (MS) risk organ negative (RO-) LCH, and 19.4% with MS RO+ LCH. Three hundred ninety-six patients (88.2%) were initially treated with first-line therapy based on the vindesine-prednisone combination. One hundred thirty-nine patients who lacked a response to initial treatment were shifted to second-line therapy, 72 to intensive treatment Arm S1 (a combination of cytarabine, cladribine, vindesine, and dexamethasone), and 67 to Arm S2 (without cladribine). The 5-year overall survival (OS), progression-free survival (PFS), and relapse rates were 98.2% (median: 97.6 months), 54.6% (median: 58.3 months), and 29.9%, respectively. MS RO+ patients had the worst prognosis among the three clinical subtypes. For the patients initially treated with first-line therapy, the 5-year OS, PFS, and relapse rates were 99.2%, 54.5%, and 29.3%, respectively. Patients in Arm S1 had a significantly better prognosis than patients in Arm S2 (5-year PFS: 69.2% vs. 46.5%, p = .042; relapse rate: 23.4% vs. 44.2%, p = .031). Multivariate analysis revealed that early treatment response, the involvement of RO, skin, and oral mucosa, as well as laboratory parameters, including CRP and γ-GT, were independent risk factors for the PFS of LCH. Thus, the prognosis of LCH in children has been improved significantly with stratified chemotherapy, and progression and relapse remained the challenges, especially for RO+ patients.
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Cladribina , Histiocitose de Células de Langerhans , Criança , Humanos , Pré-Escolar , Prognóstico , Resultado do Tratamento , Cladribina/uso terapêutico , Vindesina/uso terapêutico , Fatores de Risco , Histiocitose de Células de Langerhans/terapia , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients. RESULTS: LCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034). CONCLUSIONS: LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH.
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Histiocitose de Células de Langerhans , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Criança , Pré-Escolar , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Síndrome de Ativação Macrofágica/tratamento farmacológico , Mutação , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the characteristics and treatment outcomes of patients with pediatric Langerhans cell histiocytosis (LCH) with thymic involvement. STUDY DESIGN: We retrospectively described the clinical, biological, and imaging characteristics of a series of 19 patients with pediatric LCH with thymic involvement in our center between September 2016 and December 2019. We further analyzed the treatment response and outcomes of patients treated with chemotherapy or targeted therapy. RESULTS: Thymic involvement was found in 4.4% of a 433-consecutive pediatric LCH cohort; all LCH-thymic involvement presented with multisystem disease. Patients with thymic involvement were typically younger, harboring more lung and thyroid involvement and less bone involvement than those without thymic involvement. Most patients with thymic involvement had alteration of immunocompetence with decreased numbers of T-lymphocyte subsets and immunoglobulin G levels. Overall, 47.1% of patients demonstrated a response after 6 weeks of induction therapy, and 92.3% of the patients who did not respond to the first-line treatment had resolution of thymus after the second-line and/or targeted therapy. The progression/relapse rate showed no difference between patients who shifted to second-line therapy and those to dabrafenib (33.3% vs 25%, P = 1.000). The survival for patients with thymic involvement did not differ from those without thymic involvement. More patients treated with second-line chemotherapy had severe adverse events than those given dabrafenib (88.9% vs 0, P < .001). CONCLUSIONS: Thymic involvement was observed rarely in LCH and had specific clinical characteristics. Chemotherapy could resolve most thymic lesions, and BRAF inhibitors might provide a promising treatment option with less toxicity for infants with BRAF-V600E mutation. TRIAL REGISTRATION: http://www.chictr.org.cn, identifier: ChiCTR2000030457 (BCH-LCH 2014 study); ChiCTR2000032844 (dabrafenib study).
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Histiocitose de Células de Langerhans , Proteínas Proto-Oncogênicas B-raf , Criança , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/tratamento farmacológico , Humanos , Lactente , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECT: Goal of this research was to investigate values of serum cytokines in childhood HLH with different triggers, with the expectation to find secretion spectrum of 5 main types of underlying diseases. METHOD: 118 newly diagnosed HLH were included, and serum concentrations of 6 cytokines were tested before treatment began. Absolute cytokine levels and ratios between them were then studied in the HLH groups collectively and separately RESULTS: In general, IFN-γ, IL-10 and IL-6 showed differences among 5 HLH groups. Specifically, relative levels of these three cytokines to each other were meaningful in distinguishing 4 types of HLH. Level of IL-6 was higher than those of IFN-γ or IL-10 in HLH driven by Systemic auto-inflammatory disorders (SAIDs) or Langerhans Cell Histiocytosis (LCH), while primary HLH and EBV-HLH shared elevated ratio of IL-10 to IL-6. Although more than one distinctive ratios were found in 3 HLH groups, combination of these parameters didn't offer optimal balance between sensitivity and specificity. CONCLUSION: As a group of easily gained laboratory findings, cytokine levels were reliable in the procedure of roughly classifying HLH cases with the help of patients' clinical phenotype. However, adequate data is still needed to explore the significance of these indicators in identifying one particular underlying disease accurately.
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Citocinas/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Células Th1/metabolismo , Células Th2/metabolismo , Adolescente , Contagem de Células Sanguíneas/métodos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Masculino , Sensibilidade e Especificidade , Equilíbrio Th1-Th2/fisiologiaRESUMO
The aim of this study was to investigate the prognostic significance of BRAFV600E in cell-free (cf) DNA (cfBRAFV600E) and lesion tissues (ltBRAFV600E) in pediatric Langerhans cell histiocytosis (LCH). This study included a total of 140 patients with successfully detected cfBRAFV600E and ltBRAFV600E at diagnosis. Treatment response at week 6 was correlated with both cfBRAFV600E and ltBRAFV600E Moreover, the patients with positive cfBRAFV600E had a much lower 3-year progression-free survival (PFS) rate and a higher progression/reactivation rate than those with negative cfBRAFV600E (47.1% ± 7.6% vs. 78.4% ± 5.1%, P < 0.0001; 44.6% vs. 19.0%, P = 0.001, respectively). However, no significant difference was found in the 3-year PFS rate or progression/reactivation rate between patients with positive and negative ltBRAFV600E (P = 0.348 and 0.596, respectively). In addition, after patients were divided into group A (both cfBRAFV600E and ltBRAFV600E positive, n = 56), group B (ltBRAFV600E positive and cfBRAFV600E negative, n = 28), and group C (both cfBRAFV600E and ltBRAFV600E negative, n = 56), there was a significant difference in the 3-year PFS rate and progression/reactivation rate among the three groups (47.1% ± 7.6%, 92.9% ± 6.1%, and 72.2% ± 6.1%, P < 0.001; 44.6%, 3.6%, and 26.8%, P < 0.001, respectively). In the multivariate analysis, cfBRAFV600E and age at diagnosis remained independent prognostic factors for 3-year PFS in childhood LCH. Therefore, cfBRAFV600E was more closely associated with important clinical characteristics, treatment response at week 6, and prognosis than ltBRAFV600E.
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Alelos , Biomarcadores Tumorais , DNA Tumoral Circulante , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Fatores Etários , Substituição de Aminoácidos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is an immune-regulatory disorder characterized by excessive production of inflammatory cytokines. The treatment recommendations of the HLH-1994 and HLH-2004 protocols have long been used in HLH therapy, but some patients still do not respond well to or have unacceptable side effects from conventional therapies. It is believed that cytokine-targeted strategies that directly target disease-driving pathways will be promising options for HLH. This prospective study aimed to investigate the efficacy and safety of ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, as a front-line therapy in children with secondary HLH. Twelve newly diagnosed patients without previous treatment were enrolled in this study with a median follow-up of 8.2 (7.1-12.0) months, including 8 cases of Epstein-Barr virus associated HLH (EBV-HLH), 2 cases of autoinflammatory disorder (AID)- associated HLH, and 2 cases of unknown etiology. Patients received oral ruxolitinib dosed on 2.5 mg, 5 mg or 10 mg twice daily depending on the body weight for 28 consecutive days. The overall response rate at the end of treatment (day 28) was 83.3% (10/12), with 66.7% (8/12) in complete response (CR), 8.3% (1/12) in partial response (PR), and 8.3% (1/12) in HLH improvement. Among the patients achieving CR, 87.5% (7/8) maintained CR condition for>6 months, and one patient with EBV-HLH relapsed following CR. For the EBV-HLH subgroup, all 8 patients responded to ruxolitinib, with a CR rate of 75% and a PR rate of 25%. Two patients with AID-associated HLH had quite different responses, with one showing reversal of the HLH abnormalities soon and the other showing no improvement, as did the two cases of unknown etiology. Patients who had no response or discontinued ruxolitinib all responded well to the subsequent HLH-1994 regimen. The expected 6-month event-free survival (EFS) rate was 58.3%±10.2%. No serious adverse effects were reported. Our study provides further support for the possibility of ruxolitinib targeted therapy for secondary HLH in children. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR2000029977.
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Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Criança , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Humanos , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Nitrilas , Projetos Piloto , Estudos Prospectivos , Pirazóis , PirimidinasRESUMO
PURPOSE: We sought to investigate the effectiveness and safety of dabrafenib in children with BRAFV600E-mutated Langerhans cell histiocytosis (LCH). MATERIALS AND METHODS: A retrospective analysis was performed on 20 children with BRAFV600E-mutated LCH who were treated with dabrafenib. RESULTS: The median age at which the patients started taking dabrafenib was 2.3 years old (range, 0.6 to 6.5 years). The ratio of boys to girls was 2.3:1. The median follow-up time was 30.8 months (range, 18.9 to 43.6 months). There were 14 patients (70%) in the risk organ (RO)+ group and six patients (30%) in the RO- group. All patients were initially treated with traditional chemotherapy and then shifted to targeted therapy due to poor control of LCH or intolerance to chemotherapy. The overall objective response rate and the overall disease control rate were 65% and 75%, respectively. During treatment, circulating levels of cell-free BRAFV600E (cfBRAFV600E) became negative in 60% of the patients within a median period of 3.0 months (range, 1.0 to 9.0 months). Grade 2 or 3 adverse effects occurred in five patients. CONCLUSION: Some children with BRAFV600E-mutated LCH may benefit from monotherapy with dabrafenib, especially high-risk patients with concomitant hemophagocytic lymphohistiocytosis and intolerance to chemotherapy. The safety of dabrafenib is notable. A prospective study with a larger sample size is required to determine the optimal dosage and treatment duration.
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Histiocitose de Células de Langerhans/tratamento farmacológico , Imidazóis/uso terapêutico , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/uso terapêutico , Criança , Pré-Escolar , China , Feminino , Histiocitose de Células de Langerhans/patologia , Humanos , Imidazóis/farmacologia , Lactente , Recém-Nascido , Masculino , Oximas/farmacologia , Proteínas Proto-Oncogênicas B-raf/farmacologia , Estudos RetrospectivosRESUMO
INTRODUCTION: The threshold of serum ferritin (SF) level listed in diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH) of HLH-2004 has a low specificity. The goal of this research was to evaluate the role of admission SF in HLH diagnostic procedure and to find an appropriate threshold for a HLH suspected cohort with fever. METHODS: All patients admitted to Beijing Children's Hospital during the period of September 1, 2015 and July 31, 2016 with fever and SF tested at admission were included in this study. The significance of SF in HLH diagnosis and its relationships with HLH-relevant clinical characteristics were studied. RESULTS: Among 357 patients, 39 HLH cases were diagnosed (24 EBV-related HLH, 13 unknown etiologies triggered HLH, and two familial HLH). The best cutoff value of admission SF was 934 ng/mL, with sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) being 87.2%, 88.4%, 47.9%, and 98.3%, respectively. Compared to 500 ng/mL, specificity and PPV of the new SF standard in HLH diagnose increased by 11.7% and 14.0%, which indicated improvements in diagnostic ability of "non-HLH" and in veracity of "HLH" identification. Among four HLH patients whose admission SF was between 500 ng/mL and 934 ng/mL, HLH diagnosis was guaranteed by other laboratory results in two patients; however, possible misdiagnosis was made in the rest two patients. CONCLUSION: Elevated cutoff value of admission SF level seems to be more appropriate for distinguishing HLH in patients with fever. The exact cutoff value of SF level at diagnosis needs to be determined.
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Ferritinas/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
BACKGROUND: Central nervous system (CNS) involvement is found in many patients with hemophagocytic lymphohistiocytosis (HLH). In this study, we mainly analyzed neurological symptoms, imaging findings, cerebrospinal fluid (CSF), and their relationship with outcomes of HLH children. METHODS: Related data of 179 Chinese pediatric patients with HLH admitted to our center from January 2010 to December 2015 were analyzed retrospectively. Diagnosis and treatment were based on the HLH-2004 protocol. Two-tailed Chi-squared test was used to compare between different groups, and Kaplan-Meier survival curves were used to analyze the overall survival (OS) of patients with HLH. RESULTS: In the present study, 21.2% (38/179) of total patients had neurological symptoms including seizure, irritability, somnolence, and unconsciousness. There were 80 (50.0%, excluding 19 patients without imaging data) patients with cranial imaging abnormalities. There were 14.7% (17/116, excluding 63 patients who did not accept lumbar puncture) of patients with abnormal CSF results. CNS involvement is defined as abnormalities in one or more of CNS symptoms, radiological findings, and CSF. Thus, 60.3% of them had CNS involvement. As for the prognosis, the median follow-up time was 3.2 years (17 lost to follow-up). The probable 3-year OS of children was higher without CNS involvement (86.0% ± 4.6%) than those with CNS involvement (68.9% ± 4.9%, hazard ratio [HR] = 2.286, P = 0.019). Among them, the probable 3-year OS of children without CNS symptoms was 76.0% ± 3.8%, higher than with CNS symptoms (59.5% ± 8.1%, HR = 2.147, P = 0.047). The 3-year OS of children with abnormal CSF was 64.7% ± 11.6%, compared with normal CSF (85.1% ± 3.7%, HR = 0.255, P = 0.038). CONCLUSIONS: HLH patients with CNS involvement might have worse outcomes compared with those without CNS involvement, and CNS symptoms and CSF changes are more important to access the prognosis than imaging abnormality.
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Doenças do Sistema Nervoso Central/etiologia , Linfo-Histiocitose Hemofagocítica/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , ConvulsõesRESUMO
BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is an interstitial primary pulmonary disease, characterized by Langerhans cell proliferation. It is easily misdiagnosed in children. This study aimed to characterize the clinical manifestations and features of PLCH by retrospective analysis. METHODS: A retrospective analysis was performed in 117 PLCH patients out of 338 LCH patients who were admitted in our center from November 2006 to October 2013. Variables between two groups were compared by Mann-Whitney U-test and Chi-square test. Kaplan-Meier curves were constructed to compare the survival rates and Cox regression to evaluate the effect of risk factors. RESULTS: The median age of PLCH group was significantly lower than that of non-PLCH group (18.63 months vs. 43.4 months, P < 0.001). All PLCH children had other organ involvement and only 11 cases (9.4%) had respiratory symptoms. The most common radiologic finding was cystic lesions (29 cases, 24.8%). Pulmonary function abnormalities were dominated by obstructive ventilatory dysfunction (63 cases, 82.9%). The 5-year overall survival (OS) of PLCH children was 93.6% ± 2.3% and the event-free survival (EFS) was 55.7% ± 5.2%. Among the 38 cases with progressed or relapsed disease, five cases (13.2%) were due to progression or recurrence of lung damage. The 5-year OS of PLCH children with "risk organ" involvement was significantly lower than those without "risk organ" involvement (86.0% ± 4.9% vs. 100%, χ2 = 8.793, P = 0.003). The difference of EFS between two groups was also significant (43.7% ± 7.7% vs. 66.3% ± 6.5%, χ2 = 5.399, P = 0.020). The "risk organ" involvement had a significant impact on survival (hazard ratio = 1.9, P = 0.039). CONCLUSIONS: PLCH mainly occurs in young children, and only a small percentage of patients have respiratory symptoms. They generally have other organ involvement. Most of PLCH children have a good prognosis and most lung lesions could have improved or stabilized. Management of "risk organ" involvement is the key point to improving EFS.
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Histiocitose de Células de Langerhans/diagnóstico , Pneumopatias/etiologia , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/complicações , Humanos , Lactente , Células de Langerhans , Pulmão/fisiopatologia , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND & OBJECTIVE: The therapeutic effect on melanoma metastasizing to liver is poor. Researches have demonstrated that hepatic intra-arterial bio-chemotherapy can improve the treatment efficacy of metastatic melanoma. This study was to investigate hepatic intra-arterial bio-chemotherapy for the treatment and survival of patients with liver metastasis from melanoma. METHODS: Twenty-one patients with liver metastasis from melanoma were treated with hepatic intra-arterial infusion of dacarbazine (250 mg/m(2)) from the first to the fifth day, and fotemustine (100 mg/m(2)) at the sixth and fourteenth day, followed by adoptive transfer of autologous cytokine-induced killer cells and administration of interleukin-2 and 150 ug granulocyte/macrophage colony stimulating factor for 10-12 days. The treatment was repeated every 28 days. The overall survival, response and toxicity were analyzed. RESULTS: Seventeen of twenty-one patients were evaluable. One achieved complete remission (CR), one achieved partial remission (PR), six had stable disease (SD) and nine had progression disease (PD).The disease control rate was 47.06% (8/17), with a median progression free survival (PFS) of 3.76 months and a medium overall survival (OS) of 6 months. Treatment related complications were mainly myelosuppression (grade III-IV), occurring in 38.1% (8/21) patients. CONCLUSIONS: Hepatic intra-arterial chemotherapy can improve the disease control rate of progressive melanoma. It tends to prolong the PFS and OS with tolerable toxicity in patients with liver metastasis from melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Melanoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Células Matadoras Induzidas por Citocinas/transplante , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Interleucina-2/uso terapêutico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Compostos de Nitrosoureia/efeitos adversos , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Proteínas Recombinantes , Indução de Remissão , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND & OBJECTIVE: Gemcitabine combined with cisplatin has been taken as the front-line regimen for patients with advanced non-small-cell lung cancer (NSCLC). The routine use of gemcitabine is intravenous injection of a dose of 1,000 mg/m(2) within 30 minutes on days 1 and 8, and the treatment is repeated every 3 weeks. This study was to evaluate the efficacy and safety of 6-hour continuous infusion of low dose of gemcitabine plus cisplatin for patients with advanced NSCLC. METHODS: Forty-eight patients with measurable stage III B/IV NSCLC and without chemotherapy were enrolled. All of them received 6-hour continuous infusion of gemcitabine 250 mg/m(2) on day 1 and 8 plus cisplatin 75 mg/m(2) on day 2-4 for more than 2 cycles. The cycle was repeated every 3 weeks. RESULTS: All 48 patients were evaluated for toxicity and 46 for response. The overall response rate was 32.5% (completed and partial response rates were 2.2% and 30.3%, respectively). The median time to progression was 5.1 months, median survival time was 10.2 months; and 1-year survival rate was 36.6%. The main hematologic toxicity consisted of 60.4% neutropenia, 39.5% thrombocytopenia. Grade III-IV neutropenia and thrombocytopenia were 20.8% and 12.5%, respectively. CONCLUSION: Six-hour prolonged infusion of low dose gemcitabine combined with cisplatin is a relatively safe and effective regimen for patients with advanced NSCLC.