Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience.

BACKGROUND: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. METHODS: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. RESULTS: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. CONCLUSION: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.

Apolipoprotein E ε4-positive multiple sclerosis patients develop more gray-matter and whole-brain atrophy: a 15-year disease history model based on a 4-year longitudinal study.

Multiple sclerosis is a disease with considerable individual variation, and genetic background plays a key role in disease susceptibility and severity. The objective of the study was to evaluate the relationship between apolipoprotein E (APOE) genotype and the evolution of different clinical and MRI parameters. We investigated a group of 150 relapsingremitting patients that completed 4-year follow-up. The mean age was 30.2 years, disease duration 56.8 months, and baseline Expanded Disability Status Scale (EDSS) 1.8. The changes in brain parenchymal volume (BPV), gray matter (GMV), white matter (WMV) and peripheral gray volume (PGMV) were measured by SIENA/X. T2-lesion volume was assessed by semi-automated methods. The mixed-effect model analysis was used to investigate evolution of clinical and MRI parameters in relation to the APOE ε4 genotype considering two different time models: 4-year follow-up and 15-year period from disease onset. We identified 36 APOE ε4-positive patients. Decline of GMV (P = 0.017), and BPV (P = 0.029) were significantly faster in APOE ε4-positive than in APOE ε4-negative patients in the 15-year model. In the 4- year model, a trend for faster decrease of GMV was found in APOE ε4-positive patients (P = 0.067). No differences in other MRI parameters or EDSS were found between the APOE groups. The results of the study suggest that APOE ε4-positive patients experience faster rate of gray matter atrophy.

Influence of chemotherapy to hormonal levels in postmenopausal breast cancer patients.

Targeting and tailoring of therapy is the latest trend in breast cancer treatment. The efficacy of the available treatment must be estimated and the probable benefit for the patient determined. The aim of this project was to find out wether also in postmenopausal women chemotherapy can affect hormonal levels in serum and if even the levels of IGF-1 and IGFBP-3 can be changed. In the group of 72 postmenopausal breast cancer patients blood samples were taken before, during and after adjuvant chemotherapy and levels of estradiol, progesterone, LH, FSH, IGF-1 and IGFBP-3 were evaluated. We did not find any statistically significant dependence on tumor stage, expression of hormonal receptors or HER-2 and treatment regimen with studied hormones. Serum levels before treatment in comparison with status during treatment were significantly different in LH, FSH and progesterone value. Hormone levels after the treatment in comparison with status during treatment were significantly different only in levels of estradiol. Significant differences in all parameters were found except IGF-1. There was not any statistical dependence on the menopausal gap, age, weight or type of chemotherapy. We can conclude, that also in postmenopausal women hormonal changes can take part in the final effect of adjuvant treatment.

Haemolytic anaemia and acute liver failure--the initial manifestations of Wilson's disease.

We describe a case of a 16-year-old girl with Wilson disease, which was initially presented as Coombs-negative haemolytic anaemia and acute liver failure. The diagnosis was based on the findings of low ceruloplasmin serum level and high copper levels both in serum and 24-hour urinary excretion. The patient underwent orthotopic liver transplantation. A DNA-based diagnostic tool confirmed Wilson's disease: the patient was p.H1069Q homozygote. Based on further molecular-genetic examinations in the family, Wilson disease was diagnosed seven days later in one of the patient's asymptomatic brothers. The proband's cousin was confirmed as a carrier of the p.H1069Q mutation (Fig. 1, Ref. 24).

[Comparison of dendritic cells antigens in healthy volunteers and monoclonal gammopathy of undetermined significance and/or multiple myeloma patients]. / Srovnání vybraných markeru dendritických bunek u zdravých darcu a pacientu s monoklonální gamapatií nejasného významu ci mnohocetným myelomem.

BACKGROUND: Dendritic cells (DCs) are highly specialized antigen-presenting cells, which can be used for immunotherapy trials. Functionally normal DCs play a critical role in the activation and potentiation of antitumor antigen-specific responses. DESIGN AND SUBJECTS: Maturation of DCs from 10 healthy donors, 14 monoclonal gammopathy of undetermined significance patients and 14 multiple myeloma patients was tested in an in vitro study. METHODS AND RESULTS: DCs were generated from adherent mononuclear precursors of peripheral blood and cultured in presence of IL-4 and GM-CSF with human CD40Ligand stimulation. Serum-free or autologous serum conditions were used and expression of significant surface antigens, chemokines receptors and production of IL-12p70, were compared. We found no difference between groups under serum-free conditions with or without CD40L stimulation. Under autologous conditions we found negative effect on patients DCs manifested by reduction of some markers. The production of IL-12p70 was low and no difference in serum IL-6 levels between individual groups was found. CONCLUSION: Under serum free conditions there was no difference between healthy volunteers, MGUS and patients, but CD40L stimulation did not lead to the full maturation ofDCs. Autologous patient serum had negative influence on DCs, with no definite dependance on the IL-6 level.

[Analysis of circadian rhythm influence to heart rate turbulence in patients post myocardial infarction with left ventricular dysfunction]. / Analýza vlivu cirkadiánního rytmu na turbulenci srdecní frekvence u pacientu s poinfarktovou dysfunkcí levé srdecní komory.

BACKGROUND: Some study reported circadian occurence of sudden cardiac death, ventricle ectopic activity, acute coronary syndromes and heart rate variability. Heart rate turbulence (HRT) is one of a new markers of noninvasive stratification of sudden cardiac death. METHODS AND RESULTS: We have evaluated HRT in 120 consecutive patiens post myocardial infarction in mean age 62.7+/-12.4 years (90 M, 30 W), indicated for ecg Holter monitoring with LVEF 0.45+/-0.12 in 2hours interval during 24 hours. We have analysed circadian variation of the HRT. CONCLUSIONS: The statistically significant circadian patterns were found in turbulence slope parameter of HRT. No significant changes for turbulence onset parameter were described.

Morphological evidence of collateral sprouting of intact afferent and motor axons of the rat ulnar nerve demonstrated by one type of tracer molecule.

In our experimental paradigm we sutured the distal stump of a transected musculocutaneous nerve to an intact ulnar nerve of the rat in an end-to-side fashion. We demonstrated the formation of collateral sprouts from intact afferent and motor axons by application of one type of molecule conjugated by two different fluorophores (Fluoro-Ruby and Fluoro-Emerald). Fluoro-Ruby and Fluoro-Emerald were applied distal to end-to-side suture into fresh cut ends of the ulnar and musculocutaneous nerves, respectively. Formation of collateral sprouts was evidenced by findings of mixed (a yellow to orange color) fluorescence labeling of spinal motoneurons and dorsal root ganglia neurons. Colocalization of two different tracers retrogradely transported to the neurons was verified by the individual green and red fluorescence profiles analyzed by means of the computer-assisted image-analyzing system. Our results unequivocally demonstrate that a nerve stump attached to an intact nerve can induce collateral sprouting of both afferent and motor axons.

Immune regulatory T cells in siblings of children suffering from type 1 diabetes mellitus.

Patients with type 1 diabetes are suffering from defects in immune regulatory cells. Their siblings may be at increased risk of type 1 diabetes especially if they are carriers of certain human leucocyte antigen (HLA) alleles. In a prospective non-randomized study, we intended to evaluate 31 healthy siblings of paediatric patients with type 1 diabetes and explore immune regulatory populations of CD4+CD25+ T cells and natural killer (NK) T cells. Tested siblings of type 1 diabetes patients were stratified according to the HLA-associated risk of possible diabetes development. Immune regulatory function of CD4+CD25+ T cells was tested in vitro. Significant differences in CD4+CD25+ but not in NK T cells have been identified. Siblings of type 1 diabetes patients carrying high risk HLA alleles (DQA1*05, DQB1*0201, DQB1*0302) had significantly lower number of immune regulatory CD4+CD25+ T cells than the age-matched healthy controls or siblings carrying low-risk HLA alleles (DQB1*0301, DQB1*0603, DQB1*0602). Regulatory function of CD4+CD25+ T cells demonstrated a dose-escalation effect. In siblings of type 1 diabetes patients, the defect in immune regulatory CD4+CD25+ T cells exists in association with genetic HLA-linked risk for type 1 diabetes.