Analysis of cytogenetic aberrations in esthesioneuroblastomas by comparative genomic hybridization

Esthesioneuroblastoma (ENB) are rare tumors originating from the olfactory epithelium of the superior nasal cavity. This lesion is morphologically closely related to Ewing sarcoma and other peripheral primitive neuroectodermal tumors (pPNET). The affiliation of ENB to the pPNET family is still under discussion. Only very limited and contradictory cytogenetic data are available on ENB and only one patient has been analyzed by comparative genomic hybridization (CGH), so far. In the present study, genomic imbalances of three ENB were analyzed by CGH to evaluate (1) a recurrent pattern of imbalances, and (2) its relation to the pPNET family. The CGH analysis of three ENB revealed multiple recurrent aberrations including DNA overrepresentations of chromosomal material of the entire chromosome 19, partial gains of the long arms of chromosomes 8, 15, and 22, and deletions of the entire long arm of chromosome 4. Beside these common aberrations, several single gains and losses occurred, that is, gains on 6p, 10q, 1p, 9q, and 13q. We confirmed the former observation of amplified genetic material on chromosome 8 and found several new, currently not described recurrent genetic aberrations distinct from those described for pPNET. Our findings give evidence that ENB is not part of the pPNET family. We suggest that the combined gain of genetic material on 15q, 22q, and chromosome 8 might be indicative for ENB. To verify our findings and to define prognosis-related aberrations, a larger number of cases needs to be studied.     

Diagnosis of mold allergy

Conclusion The problems of elucidating the role of mold spores in allergy are related to both an absence of detailed information about allergen exposure, and lack of standardized allergen extracts. Provided qualitatively and quantitatively optimal extracts are available, the IgE-diagnostic tests are of equal value in diagnosing mold sensitization, as with other aeroallergens. In the opinion of the author, the specific diagnosis represents the combination of demonstrated IgE reactivity (using diagnostic tests) and clinical symptoms related to exposure to the causative allergen. In order to diagnose organ-specific disease, an unequivocally positive challenge in the relevant shock organ is essential. The rational approach to diagnosing mold allergy is, based on the clinical history, to use skin test as the primary screening test. SPT has the highest sensitivity (few false negative reactions) and, compared to ICT, few irrelevant positive reactions, and should consequently be used to screen for IgE sensitization in the diagnostic workup. Because of the lower sensitivity, RAST is not optimal as the initial test, but as a result of high specificity (few false positive reactions) it is optimal as a confirmatory test for the presence of specific IgE. The clinical relevance of the IgE sensitization should be confirmed by reevaluating the history to ensure that the patients do in fact have symptoms caused by the allergen (Table 2). Challenge tests are normally indicated only if the diagnosis of allergen sensitization implies therapeutic interventions, such as allergen-specific immunotherapy.     

Molecular characterization and determination of the coding capacity of the genome of equine herpesvirus type 2 between the genome coordinates 0.235 and 0.258 (theEcoRI DNA fragment N; 4.2 kbp)

The complete DNA nucleotide sequence of theEcoRI DNA fragment N (0.235 to 0.258 viral map units) of equine herpes virus type 2 (EHV-2) strain T400/3 was determined. This DNA fragment comprises 4237 bp with a base composition of 55.23% G+C and 44.77% A+T. Nineteen open reading frames (ORFs) of 50-287 amino acid (aa) residues were detected. ORF number 10 is located between the nucleotide position 2220 and 2756 coding for a protein of 179 amino acid residues. This protein shows significant homology to the cytokine synthesis inhibitory factor (CSIF; interleukin 10) of human (76.4%) and mouse (68.5%), and to the Epstein-Barr virus (EBV) protein BCRF1 (70.6%). The existence of an interleukin 10 (IL-10) analogous gene within the genome of the EHV-2 was confirmed by screening the genome of nine EHV-2 strains using specific oligonucleotide primers corresponding to the 5 and 3 region of this particular gene by polymerase chain reaction. In all experiments an 870 bp DNA product was amplified. The specifity of the amplified DNA fragments obtained from individual EHV-2 strains was confirmed by DNA-DNA hybridization experiments. The DNA sequence analysis of the amplified DNA products of the EHV-2 strain LK was carried out. This analysis revealed the identity of the corresponding IL-10 gene (540 bp) of this strain to the IL-10 gene of EHV-2 strain T400/3. The presented data indicate that the EHV-2 genome harbors a viral interleukin 10-like gene. This is further evidence that the IL-10 gene can be present in the genomes of members of the Herpesviridae family.     

Dipole Localization and Test-Retest Reliability of Frequency and Duration Mismatch Negativity Generator Processes

The mismatch negativity (MMN) is an event related potential component elicited by changes in duration, frequency or intensity of the stimuli during repetitive series of equal standard stimuli. In the present study we compared duration and frequency MMN using dipole source analysis concerning both the test-retest reliability of MMN-amplitudes and the locations of the potential sources. Furthermore, the influence of attention for test-retest-reliability was studied. Therefore, two groups of healthy subjects were investigated with different attentional manipulations. Twenty-one healthy subjects had to perform a visual attention task during the recording and 21 healthy subjects had no additional task to perform. All subjects were studied twice with a time interval of 3 weeks. Test-retest reliability was sufficiently high for the frequency but slightly lower for the duration MMN. The locations of the frequency and duration MMN-dipoles were in the auditory cortex with a more anterior and caudal location for the frequency MMN-dipoles. The latter finding supports the hypothesis that the frequency and duration MMNs have separate neuronal generators.     

Cerebral blood flow in autogenic training and hypnosis

In 12 healthy volunteers with at least an experience of six months in autogenic training (AT), the cerebral blood flow (CBF) was measured at rest, in AT and in hypnosis (H). The results were correlated with individual test profiles. The cortical flow pattern at rest of our AT trained volunteers did not show the hyperfrontality which is described in the literature. This may be interpreted as an effect of better and habitualized relaxation in long trained AT practitioners. This flow pattern corresponds to the low grades of neuroticism and aggressivity found in the tests. Furthermore an activation in central cortical areas and a deactivation in regions which are associated with acoustic and autonomous functions occur.Possible explanations for these phenomena as well as for the relatively low perfusion of the left hemisphere at rest and activation in AT are discussed. The global rise of CBF in H may be an activation effect caused by resistance against the hypnotizer: the deeper the trance, the smaller the CBF increase in the motor cortical area needed for maintaining catalepsy of the right arm and in temporal cortical fields processing acoustic inputs.     

Therapy of primary breast cancer in the 21st century: A prediction

Biology

New treatment selection criteria will arise from molecular biology parameters of growth and treatment response, most probably coupled with the increasing use of initial chemotherapy and repeated minimally invasive surgery.

Prevention

Secondary and hopefully also primary prevention of breast cancer will become more and more successful in the era of molecular genetics, and such interventions will be more directed to individuals and groups at defined higher risk.

Surgery

Surgery will increasingly tend towards “minimally invasive surgery,” which favors not only cosmetics and quality of life, but also more appropriate imaging follow-up.

Chemotherapy

Primary (preoperative) chemo- and endocrine therapy will become the standard initial form of breast cancer treatment, with the intent of down-staging of the tumors to allow later breast-conserving procedures, but also to use the tumor as a biological response parameter and hopefully also for better clinical outcome.

Cost — Effectiveness

Economical parameters might become more and more decisive, as we will have to live with much more “evidence based medicine” and with much more restricted allocation of resources in the future. This might mean, that we will have to diligently develop more simple and cheaper, but not prognostically worse treatment strategies in years to come. More specifically: Do we still need all of the traditional steps in diagnosis and treatment of breast cancer in order to achieve the same results?

Gain of Life

Finally in all of this, we have to make clearcut assumptions, supported also by society and people involved: How do we value “gained years of life” in breast cancer adjuvant and prevention trials? This certainly is not predominantly a medical or economical, but rather an ethical, social and political problem, which has to be finally answered by our socio-cultural environment, and not by doctors alone.     

Proliferative response of cultured human tenon's capsule fibroblasts to platelet-derived growth factor isoforms

Background: Although platelet-derived growth factor (PDGF) has been thought to be critical in the wound-healing response of Tenon's capsule fibroblasts after glaucoma filtration surgery, no information is currently available concerning the proliferative effect of PDGF isoforms on this cell type. The aim of the present study was to evaluate the proliferative effect of PDGF-AB heterodimer and PDGF-AA and -BB homodimers on cultured human Tenon's capsule fibroblasts. Methods: Human Tenon's capsule fibroblasts, cultured under serum-free conditions, were stimulated with PDGF-AA, -AB and -BB isoforms in concentrations ranging from 1 to 100 ng/ml. Cell numbers were determined on days 1, 3, 5 and 7, using a cell counter. Results: Addition of PDGF-AB and -BB led to a dosedependent increase in cell proliferation. A maximal response (79.9% over control) was obtained after 7 days with 30 ng/ml of PDGF-BB, with an EC₅₀ of 8.9 ng/ml. The maximal increase in cell proliferation caused by PDGF-AB (30 ng/ml) was 54.9%, with an EC₅₀ of 12.5 ng/ml. Stimulation with PDGF-AA revealed a significant effect only with concentrations higher than 30 ng/ml. Conclusion: Our results indicate that PDGF-AB and -BB isoforms are potent stimulators of proliferation of human Tenon's capsule fibroblasts, suggesting that PDGF-AB and -BB isoforms play an important role in the wound-healing response after glaucoma filtration surgery.Presented in part at the annual meeting of the Deutsche Ophthalmologische Gesellschaft, Mannheim, September 1996     

Fluorine-18 fluorodeoxyglucose positron emission tomography in the follow-up of differentiated thyroid cancer

Whole-body fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging was performed during the follow-up of 33 patients suffering from differentiated thyroid cancer. Among them there were 26 patients with papillary and seven with follicular tumours. Primary tumour stage (pT) was pT1 in six cases, pT2 in eight cases, pT3 in three cases and pT4 in 14 cases. FDG PET was normal in 18 patients. In three patients a slightly increased metabolism was observed in the thyroid bed, assumed to be related to remnant tissue. In one case local recurrence, in ten cases lymph node metastases (one false-positive, caused by sarcoidosis) and in three cases distant metastases were found with FDG PET. In comparison with whole-body scintigraphy using iodine-131 (WBS) there were a lot of discrepancies in imaging results. Whereas three patients had distant metastases (proven with¹³¹I) and a negative FDG PET, in four cases¹³¹I-negative lymph node metastases were detectable with PET. Even in the patients with concordant staging, differences between¹³¹I and FDG were observed as to the exact lesion localization. Therefore, a coexistence of¹³¹I-positive/FDG-negative,¹³¹I-negative/FDG-positive and¹³¹I-positive/FDG-positive malignant tissue can be assumed in these patients. A higher correlation of FDG PET was observed with hexakis (2-methoxyisobutylisonitrile) technetium-99m (I) (MIBI) scintigraphy (performed in 20 cases) than with WBS. In highly differentiated tumours¹³¹I scintigraphy had a high sensitivity, whereas in poorly differentiated carcinomas FDG PET was superior. The clinical use of FDG PET can be recommended in all cases of suspected or proven recurrence and/or metastases of differentiated thyroid cancer and is particularly useful in cases with elevated serum thyroglobulin levels and negative WBS.     

Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer.

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer-both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers.     

Prognostic factors in malignant glioma: Influence of the overexpression of oncogene and tumor-suppressor gene products on survival

Despite the use of multimodal therapy, higher-grade glioma is stilluniformly fatal in the adult population. There is a considerable differencebetween the length of survival in each given patient, even within the sametumor type and malignancy grade group, suggesting that there are factorsthat might differentially influence outcome. To identify such factors, 107patients with anaplastic or malignant glioma were retrospectivelyinvestigated. Clinical parameters and paraclinical data on the p53, mdm2,and EGFR genes at the DNA or protein level were evaluated by univariateanalysis and Cox proportional hazards regression modeling. Kaplan-Meiersurvival estimation demonstrated that immunohistochemical positivity formdm2 protein in patients with anaplastic astrocytoma or with glioblastomamultiforme was associated with a shorter survival time (p = 0.02).P53 gene mutations and immunopositivity for the epidermal growth factorreceptor (EGFR) protein were not significantly related to poor prognosis.The Cox proportional hazards model revealed immunohistochemical positivityfor p53, mdm2, or for both of them, the presence of postoperativeirradiation, and the extent of surgical resection of tumor to be variablessignificantly associated with prolonged survival. EGFR overexpression, ageover 60 years, and Karnofsky performance score below 40 points did notsignificantly shorten survival time. In conclusion, the present studyidentified immunohistochemically detected mdm2-protein overexpression as astatistically significant negative prognostic parameter in patients bearinganaplastic or malignant glioma. Association analysis of variables revealed apossible correlation between mdm2 and p53, which is also consistent with thebiological interaction mode of both proteins in vivo.