Marie Hladíková

Pediatric Intracranial Ependymomas: Prognostic Relevance of Histological, Immunohistochemical, and Flow Cytometric Factors

The correlation between the histological features and clinical outcome remains poor in pediatric intracranial ependymomas. We performed a retrospective study of a group of 31 patients (diagnosed from 1985 to 1995) to assess prognostic implications of the current grading system, of histological and immunohistochemical features, and of ploidy status estimated by flow cytometry. Immunoexpression of a broad spectrum of antigens was evaluated, including MIB-1, topoisomerase-IIα, cyclin D1, glial and epithelial proteins (GFAP, EMA, cytokeratins), molecules involved in controlling apoptosis (bcl-2, caspase-3/CPP32), and p53 oncoprotein. Univariate and multivariate statistical analyses were performed to evaluate the influence of each variable on both the progression free survival (PFS) and the overall survival (OS) with at least 7-year follow up. Although we showed a significant correlation between histological grade and prognosis, the current grading system failed in predicting outcome in nearly one third of individual cases. Problems with interpathologist reproducibility were also demonstrated. The extent of surgical resection was the only clinical factor that was associated with survival. Both the PFS and the OS were significantly decreased for the following pathological variables: increased cellularity (>300 nuclei per HPF), mitotic activity of >7 per 10 HPF, increased MIB-1 labeling index (LI), topoisomerase-IIα LI, S-phase fraction, and p53 and bcl-2 positivity. Increased cyclin D1 LI was demonstrated to have only a marginally significant impact on PFS. A flow chart modeling was further performed to formulate a scheme for discriminating of prognostic subgroups. Based on that, p53 immunopositivity and/or MIB-1 LI of >5% (after subtotal resection) or MIB-1 LI of >15% (after complete resection) were the strongest indicators of the tumors aggressive behavior and of a poor prognosis of the disease. Foci of hypercellularity should be specifically looked for in ependymomas for assessing the immunohistochemical studies.

Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin’s disease

PurposeThe aim of this study was to perform a prospective, blinded comparison of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and conventional staging methods (CSMs) for initial staging of children and adolescents with Hodgkin’s disease (HD).MethodsOver a period of 4 years, 55 children and adolescents with HD (mean age 15.5 years, range 3.9–18.9 years) were prospectively recruited into the study. They underwent 61 FDG-PET studies using a dedicated whole-body PET scanner as a part of their initial staging work-up. PET findings were correlated with the results of CSMs, including computed tomography (CT), ultrasound, bone scanning and bone marrow examination. Discordant findings were resolved by magnetic resonance imaging or clinical follow-up (range 2–47 months).ResultsPET correctly changed the staging in 15% of patients (seven upstagings, two downstagings). Only two out of 61 patients (3%) were not accurately staged by PET; in these children, PET missed small lymphoma nodules detected on lung CT. The sensitivity of PET and CSMs for pretreatment staging was 96.5% and 87.5%, respectively; specificity was 100% and 60%, and accuracy, 96.7% and 85.2%, respectively. Upon combination of FDG-PET and lung CT, the diagnostic accuracy reached 100% in our series.ConclusionOur study showed that whole-body FDG-PET is an efficient and useful method for the initial staging of children with HD. FDG-PET in combination with lung CT should be recommended as a screening method prior to other conventional imaging modalities to plan a rational staging protocol. Large multicentre prospective studies are necessary to verify this conclusion.

Regulatory T cells and their prognostic value for patients with squamous cell carcinoma of the head and neck

Regulatory T cells (Treg) are important regulators of anti‐cancer immune responses, and an increase in Treg frequency was observed in the blood of cancer patients. Blood samples from 112 patients with head and neck squamous cell carcinoma antigen (HNSCC) were obtained at the time of tumour diagnosis, and lymphocyte subpopulations (CD3+; CD3−CD16+CD56+; CD4+; CD8+; CD19+; CD4+CD45RA+) with emphasis on Treg counts (CD3+CD4+CD25+), complete blood count and tumour markers (squamous cell carcinoma [SCC]; CEA; α‐1‐antitrypsin [AAT]; Cyfra 21–1; C‐reactive protein [CRP]) were analysed. The data were grouped according to TNM classification, and their significance for the course of the disease at an interval of 1 year after the end of the therapy was determined. The percentage of CD8+ cells increased and the CD/D8 ratio decreased with tumour grade. The ratio of B lymphocytes decreased in patients with locoregional metastases (11.25%versus 9.22%). Treg (15.2%) and CD4+ cells (45.3%) increased, while NK cells (11.8%) decreased in HNSCC patients compared to controls (9.0%, 38.1% and 15.8%, respectively). The data obtained at time of diagnosis were used to assess the significance of tumour markers (SCC, Cyfra 21–1 and AAT) for evaluation of prognosis. The erythrocyte counts (4.64 × 1012/l versus 4.45 × 1012/l) and haemoglobin levels (14.58 g/dl versus 14.05 g/dl) decreased, while Treg counts (8.91%versus 15.70%) increased in patients with early recurrence. Our results show that examination of these parameters could be helpful for prognostication in HNSCC patients and aid improvement of treatment strategy.

Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome?

AbstractAnticipation in the age at onset of cancer in successive generations was described in several familial cancer syndromes. Based on multiple statistical analyses of a database of families with germline TP53 mutations, and using several different approaches and measures to eliminate possible biases, we show that anticipation may be a feature of the Li-Fraumeni syndrome. Definitive proof of anticipation in pedigrees with germline TP53 mutations will require more family data and further analysis, as well as research on the role of the p53 protein in processes like genome stability, which may represent the biological basis of anticipation in these families. This should have important practical implications for genetic testing, counselling, and preventative care for individuals at risk.

Asbestos exposure and antineutrophil cytoplasmic antibody (ANCA) positivity

The authors used indirect immunofluorescence to examine the association of antineutrophil cytoplasmic antibodies (ANCAs) with exposure to asbestos among 61 asbestos-exposed patients (mean exposure = 24.6 yr) and 39 nonexposed controls. ANCA positivity was detected significantly more frequently (p = 0.034) in the asbestos-exposed group (21.3%) than in the control group (5.1%). ANCA-associated diseases did not occur more frequently among subjects exposed previously to asbestos than among unexposed controls. These findings confirmed that exposure to asbestos is another occupational factor, as is silica exposure, that is associated with ANCA positivity. The influence of asbestos appears stronger than that of silica because ANCA positivity was found among subjects who had histories of exposure to asbestos but who did not exhibit typical radiographic signs of asbestosis on their chest x-rays. Additional stimuli may be necessary to induce systemic vasculitis in asbestos-exposed persons.

Topical symphytum herb concentrate cream against myalgia: a randomized controlled double-blind clinical study.

The effectiveness and tolerability of the topicalSymphytum product Traumaplant® (Harras Pharma Curarina, München, Germany) (10% active ingredient of a 2.5:1 aqueous-ethanolic pressed concentrate of freshly harvested, cultivated comfrey herb [Symphytum uplandicum Nyman], corresponding to 25 g of fresh herb per 100 g of cream) in the treatment of patients with myalgia (n=104) were tested against a 1% reference product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n=111). The primary efficacy parameter in this double-blind, reference-controlled, randomized, multicenter study of 215 patients with pain in the lower and upper back was pain in motion, assessed with the aid of a visual analogue scale. Secondary efficacy parameters included pain at rest, pain on palpation, and functional impairment. With high concentrations of the treatment product, amelioration of pain on active motion (P > 5×10-9), pain at rest (P > .001), and pain on palpation (P=5×10-5) was significantly more pronounced than that attained with the reference product and was clinically highly relevant. A number needed to treat of 3.2 was calculated from the study results. Global efficacy was significantly better (P = 1 × 10-8) and onset of effects was faster (P = 4 × 10-7) with the high-concentration product. Tolerability of the highly concentrated study product was good to excellent in all patients. Study results confirm the known anti-inflammatory and analgesic effects of topicalSymphytum cream. As a new finding, applicability in certain forms of back pain can be concluded.

Effect of topical heparin and levomenol on atopic dermatitis: a randomized four‐arm, placebo‐controlled, double‐blind clinical study

Background  The aim of the controlled double‐blind trial was to demonstrate the superiority of a topical combination product over its single constituents.

Arnica/Hydroxyethyl Salicylate Combination Spray for Ankle Distortion: A Four-Arm Randomised Double-Blind Study

570 patients with acute ankle joint distortion were randomized to four treatment groups: a combination spray of arnica tincture and hydroxyethyl salicylate (HES; group A, n = 228), arnica (B, n = 57), HES (C, n = 228), and placebo (D, n = 57). The medication was applied 4-5 times daily for 10 days. Efficacy was assessed on day 3-4 by evaluating pain on motion on a visual analogue scale (VAS). Pain improvement in group A was significantly superior over groups B–D (t-test with unadjusted baseline values, P < 4 × 10−7 and ANCOVA after adjustment, P < 5 × 10−11) and approximately corresponded to the cumulative effect of the single constituents (12.1, 7.5, and 18.7 mm VAS for A versus B, A versus C, and A versus D; 95% CI 8.0–16.2, 4.7–10.4, and 14.8–22.5 mm). The combination is justified by the additive effects of the single active constituents.

Protein microarray analysis as a tool for monitoring cellular autoreactivity in type 1 diabetes patients and their relatives

Background:  Autoreactive T cells have a crucial role in type 1 diabetes (T1D) pathogenesis.

Influence of concomitant heparin administration on pregnancy-associated plasma protein-A levels in acute coronary syndrome with ST segment elevation.

Introduction The time course of pregnancy-associated plasma protein-A (PAPP-A) levels was studied at admission, immediately after percutaneous coronary intervention (PCI) and 1, 2, 4, 6, 12, 24 and 48 h after PCI in acute coronary syndrome with ST segment elevation (ACS-STE) to determine the impact of PCI, concomitant clinical complications and heparin administration. Material and methods Pregnancy-associated plasma protein-A serum levels, examined by the KryptorTM system, were studied in 30 heparinized PCI ACS-STE patients, in 10 elective PCIs and 12 coronary angiographies with heparin, and in 5 patients with normal coronary angiogram without heparin. Results Heparin caused a high PAPP-A increase in ACS-STE patients, in all patients with heparin without ACS and angiographic signs of significant atherosclerosis. This increase was directly associated with heparin dosage and activated clotting time (ACT) (r = 0.71, p = 0.0001) and inversely with the interval between heparin applications and time of serum sampling. It was followed by a rapid decrease within 1 to 2 h and return to normal levels in 10 to 12 h. In ACS-STE patients the decrease was significantly slower than in heparinized elective PCI and angiography patients. The PAPP-A increase was not significantly dependent on the length of PCI. Persistent increase after 24 h was associated in 4/7 patients with concomitant clinical complications. Conclusions The diagnostic validity of PAPP-A can be verified only within the 1st h after clinical onset of ACS before heparin administration, the prognostic value in heparinized patients not earlier than 12 h after the last heparin application, if ACT is normal and serious clinical concomitant complications are eliminated.