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.     

Studies for estimating the biologic behavior and prognosis of paragangliomas in the head and neck

Despite a large number of histopathologic and immunohistochemical studies, the biologic behavior and prognosis of paragangliomas (glomus tumors) of the head and neck still remain uncertain. In the present study 36 specimens from 32 patients who underwent surgery for a paraganglioma were examined. The examinations included routine histology, quantitative DNA analysis based on image cytometry, immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) along with visualization of nucleolar organizer regions (AgNOR). According to LeCompte, the paragangliomas were histologically divided into three subcategories: 16 patients had a paragangliomatous tumor. 14 patients had an adenomatous tumor, and 6 patients had an angiomatous tumor. Quantitative DNA analysis revealed three categories of tumors with characteristical DNA pattern; DNA type I tumors were pure diploid, DNA type II tumors had stemlines at 2c and 4c and were therefore recognized as diploid-tetraploid. Aneuploid cells were not apparent in these two groups. DNA type III tumors had stemline ploidies exceeding 2c and 4c. Aneuploid cells were present in all of these tumors. The biologic behavior of these lesions therefore must be recognized as suspicious. DNA type III tumors and adenomatous tumors showed the highest values for the PCNA scores, indicating a higher proliferation rate and a more rapid growth pattern in these lesions. Twenty patients could be followed over a period of up to 110 months. Five of these patients developed a recurrent tumor. All of them had DNA type III tumors. The DNA indices showed significantly higher values in the recurrent tumor group. The 2c deviation index (DI) and the entropy value had the highest prognostic significance. No correlation to clinical follow-up was found for the AgNOR score. Based on these results, prognostic indices for paragangliomas were developed: patients with a tumor having a 2c DI exceeding 2.0, entropy value of more than 4.0. 5c exceeding rate more than 8.0, and a PCNA score more than 20.0% can be recognized as being at high-risk for developing recurrent disease.     

Prognostic Indicators for Squamous Cell Carcinoma of the Oral Cavity: A Clinicopathologic Correlation

Fifty-three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into “aggressive” and “nonaggressive” groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin-embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying “aggressive” behavior, although possibly an evaluation of composite factors might show promise in the future.     

Characteristic expression profiles induced by genotoxic carcinogens in rat liver.

When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound's mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens dimethylnitrosamine (4 mg/kg/day), 2-nitrofluorene (44 mg/kg/day), aflatoxin B1 (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 20 mg/kg/day). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and, therefore, confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-nitrofluorene and aflatoxin B1; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. For dimethylnitrosamine and aflatoxin B1, which caused observable inflammation in vivo, we found a corresponding upregulation of inflammatory genes at the same time points. Thus, by the toxicogenomic analysis of short-term in vivo studies, we identified genes and pathways commonly deregulated by genotoxic carcinogens, which may be indicative for the early events in tumorigenesis and, thus, predictive of later tumor development.     

Auditory-evoked brain-stem responses and auditory disorders in patients with Bell's palsy

Summary Out of 121 patients examined with acute unilateral facial paralysis, 93 were determined to have idiopathic facial palsy (Bell's palsy). The examination included pure-tone and speech audiometry, stapedial reflex recordings, temporal bone radiography and auditory-evoked brain-stem response testing (ABR). If a retrocochlear lesion was suspected, computed tomography or magnetic resonance imaging was performed. Patients with sensorineural hearing loss affecting all frequencies were compared to one group with hearing loss affecting only high frequencies and to another group with ABR findings suggesting a cochlear lesion. No association could be made between the etiology of these pathological results and the concurrent facial paresis. Most of them were probably caused by unrelated disorders of the auditory system. In cases with prolonged inter-peak latencies representing brain-stem responses, abnormal ABRs could be caused by the same pathology as the paralysis. This might well suggest the presence of a neuropathy in both the central auditory system and the facial tracts.     

Evaluation of the performance of general emergency physicians in pediatric emergencies: Obstructive airway diseases,seizures, and trauma

BACKGROUND: In the Lübeck region, as is usual in Germany, hospital-based emergency physicians are called for outside emergencies. They evaluate and stabilize patients and transfer them to hospital facilities of their choice (no emergency department system). These physicians are mainly anesthesiologists, surgeons, and internists-not pediatricians. Numerous quality management studies have shown an overall excellent performance of this system, but it has not been evaluated for pediatric emergencies. PATIENTS AND METHODS: In a prospective, observational study conducted over a 1-year period, all pediatric emergencies (patient age < 15 y) treated by the emergency physician service were studied. A syllabus with standards of care for children with trauma, obstructive airway disease, and seizures was distributed. In accordance with this syllabus, the actions taken were documented by the emergency physicians, and the cases were documented as life threatening or not and were classified as "trauma," "obstructive airway disease," "seizures," or "other" by the admitting pediatric intensivists and surgeons. The admitting attending physician compared these data and evaluated whether the standard management required by the syllabus was followed. RESULTS: A total of 422 pediatric cases out of 11,605 emergencies (3.5%) were recorded (147 [34.8%] trauma patients, 41 [9.7%] patients with obstructive airway disease, and 108 [25.6%] patients with seizures). Of the pediatric patients, 20.5% had life-threatening conditions; three children died before arrival, and the others required treatment in the intensive care unit. In 25% of trauma patients, deficiencies in primary treatment were observed: no documentation of neurologic status in 10.6%, no cervical immobilization in 15% of head trauma patients, and no adequate analgesia in 7%. In 25% of seizure patients, neurologic status was not documented, although treatment was in accordance with the standard of care. The worst results were observed in infants with obstructive airway disease: no documentation of oxygen saturation in 71.4%, no oxygen therapy despite hypoxemia in seven of 12 patients, and overall therapy not in accordance with the standard of care in 50%. CONCLUSIONS: The high quality of the emergency physician service documented for adults is not reproduced in the pediatric population. Trauma and seizures with similarities to adult cases are handled in a fair manner. However, the most important pediatric diagnostic entity of obstructive airway disease is often not treated adequately. Intensified educational programs for emergency physicians are warranted.     

Patterns of chromosomal aberrations in metastasizing and nonmetastasizing squamous cell carcinomas of the oropharynx and hypopharynx

Although several cytogenetic events of the tumor progression cascade have been identified in the past, the specific types of chromosomal alterations that lead to the development of lymph node metastases are still unknown. Operative specimens of 20 patients (10 patients with metastasizing tumors, 10 patients with nonmetastasizing tumors) with squamous cell carcinomas of the oropharynx and hypopharynx, along with the corresponding lymph node metastases, were investigated by quantitative DNA measurements and comparative genomic hybridization (CGH). Nonmetastasizing tumors (N0) displayed overrepresentations on chromosomes 10q (8 cases); 5p (7 cases); 3q and 20q (6 cases each); 8q (5 cases); 1p and 21q (4 cases each); 7p and 20p (3 cases each); and 2p, 15q, and 19q (2 cases each). Loss of chromosomal material was found on 5q, 9p, and 14q (2 cases each). Metastasizing tumors (N+) demonstrated overrepresentations on chromosomes 5p, 15q, and 22q (6 cases each); 3q and 11q13 (5 cases each); 20p and 21q (4 cases each); and 10q (3 cases). In 2 cases, an overrepresentation of the chromosomal arm 3q was accompanied by a loss of chromosomal arm 3p. Less frequent overrepresentations were observed on chromosomes 1q and 17q. Deletions were found on chromosomes 18q (3 cases), 3p, 4q, 5q, and 19p (2 cases each); and sporadic deletions occurred on 2q, 6q, 8p, 9p, 10p, 13q, 14q, 15q, and 16q. Whereas overrepresentations on chromosomes 1p and 7p occurred exclusively in N0 tumors, overrepresentations on chromosomes 1q, 11q, and 22q, along with deletions on 18q, were only observed in N+ tumors. Quantitative DNA measurements revealed a significantly higher percentage of aneuploid cells and a higher degree of DNA entropy in the N+ tumors. Chromosomal overrepresentations on chromosomes 1q, 8q, 11q, 18q, and 19q occurred more frequently in the metastases than in the corresponding primary tumors. Pairwise analysis of chromosomal alterations in the primary tumors and associated lymph node metastases revealed a genetic relationship, although a greater number of chromosomes on average were affected in the lymph node metastases. Quantitative DNA measurements demonstrated greater aneuploid values in the metastases. Recurring patterns of chromosomal alterations in N0 and N+ tumors were demonstrated in this study. In general, metastasizing tumors are characterized by overrepresentations on chromosomes 11q13 and 22q, and deletions on 18q. These aberrations suggest an elevation along the tumor progression cascade.     

Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient

We describe the first case of sirolimus-induced drug fever in a female liver transplant recipient, with a history of hepatitis C-induced end-stage liver cirrhosis in 1999. In 2005, six years after transplantation, she developed calcineurin inhibitor-induced renal function impairment. Immunosuppression was switched from tacrolimus to sirolimus. Two days after the intake of sirolimus, she developed daily fever spikes, but no infectious focus was found. Antibiotic therapy had no influence on the fever. After fourteen days, sirolimus was switched back to tacrolimus and the fever disappeared. In history, the patient developed ciclosporin-induced generalized seizures eleven days after liver transplantation, followed by the development of a motoric speech disorder. Magnetic resonance imaging （MRI） findings were consistent with leucoencephalopathy, therefore immunosuppressive therapy was changed from ciclosporin to tacrolimus and the neurologic symptoms improved significantly. Our case is the first reported case of sirolimus-induced drug fever. In addition, the patient showed the rare occurrence of ciclosporin-induced leukencephalopathy with seizures.