[Medication therapy during pregnancy]. / Medikamentöse Therapie während der Schwangerschaft.

Approximately 85% of pregnant women receive at least one medical prescription during their gestation. One percent of major congenital malformations of the fetus are attributed to embryotoxic medication. Because ENT surgeons and pregnant women are often uncertain about proper medication, treatment of specific ENT problems is often provided by the obstetrician. Based on the current knowledge, PubMed research, and recommendations of the Red List (Rote Liste) of the German Pharmaceutical Industry and the FDA, medical treatment of ENT-specific diseases is discussed.

[Examiner variability of clinical findings in patients with sleep related breathing disorders]. / Variabilität klinischer Befunde bei Patienten mit schlafbezogenen Atmungsstörungen in Abhängigkeit vom Untersucher.

BACKGROUND: Clinical findings in sleep related breathing disorders (SRBD) and primary snoring are not only of diagnostic but also of therapeutic relevance because clinical findings may be used for the selection of surgical interventions such as uvulopalatopharyngoplasty (UPPP), maxillofacial surgery or radiofrequency induced surgical alternatives. We developed a standardized protocol for clinical examination of the upper airway using pictograms. MATERIAL AND METHODS: To determine the interinvestigators variability various parameters such as length of the uvula, position of tongue base, Angle-classification, webbing of posterior pillar and tonsil size were assessed by a number of residents and an assistant professor for Otorhinolaryngology and sleep medicine simultaneously. RESULTS: 95 patients (81 male and 14 female) with a mean age of 47.0 +/- 1.21 years, a Body-Mass-Index (BMI) of 27.2 +/- 0.46 kg/m2, and an Apnea-Hypopnea-Index (AHI) of 17.7 +/- 2.4 were examined. The appearance of the uvula has only little variations between different investigators (corr.: 0.943). The interinvestigator variability is also low for position of tongue base (corr.: 0.931) and Angle-classification (corr.: 0.893). The results of tonsil size and webbing assessment seems to have a higher variability (corr.: 0.880 and 0.693). Statistical significance for all parameters was p=<0.0001. CONCLUSION: As to our knowledge, this is the first controlled study to record intraobserver variations of clinical findings of the upper airway. Standardized protocols are mandatory, and the variability of the measurements must be taken into account if results of different investigations must be compared or if changes after therapeutic interventions are to be investigated.

[New substances in the therapy of head and neck cancer]. / Neue Substanzen in der Therapie von Kopf-Hals-Tumoren.

During the last 3 years the FDA approved numerous innovative drugs for cancer therapy. Drugs relevant to the otolaryngologist are presented and discussed. These new therapeutic tools may play a future part also in the therapy of head and neck cancer.

[The ASA-score as a comorbidity index in patients with cancer of the oral cavity and oropharynx]. / Der ASA-Score als Komorbiditätsindex bei Mundhöhlen- und Mundrachenkarzinomen.

BACKGROUND: The American Society of Anesthesiologists Physical Status Scores (ASA-Score) may serve as a valuable indicator of comorbidity in head and neck cancer patients. METHODS: In 135 patients with squamous cell carcinoma of the oral cavity and/or oropharynx, the relation of disease free and overall survival and the ASA-score was evaluated in a univariate (logrank-test) and a Cox regression model. In the Cox model, age, tumor site and stage, and therapeutic modality served as covariates. RESULTS: In the univariate model, overall 5 year survival in ASA I and II patients was 44 %, and in ASA III and IV patients, it was 16 % (p < 0.005). The ASA-score also significantly influenced survival in the multivariate model. The hazard ratio (ASA I and II vs. ASA III and IV) was 2.1 (95 % confidence interval 1.3 to 3.4; p < 0,005). This corresponds to a 8 times higher risk to die, even when the effects of age, tumor site and stage, and therapeutic modalities are compensated for. CONCLUSION: The ASA-score is a valuable indicator of comorbidity in patients with oral cavity and oropharyngeal tumors. An essential advantage is its easy availability in most clinical settings.

An autologous system for culturing head and neck squamous cell carcinomas for the assessment of cellular therapies on the chorioallantois membrane.

The evaluation of novel immunotherapeutic anti-cancer strategies requires target and effector cells from the autologous host to avoid false positive results because of allo-reactivity. Head and neck squamous cell carcinoma cells (HNSCC) do not proliferate under standard culture conditions in plastic ware. To create an autologous model, the chorioallantois membrane (CAM) of chicken embryos was employed to culture HNSCC and peripheral blood mononuclear cells (PBMC). Separated tumor cells were co-incubated with a cytostatic agent, PBMC, or mere cell culture medium as a control. Tumor cell lysis was assessed by acridine orange staining or by flow cytometry analysis of iodide marked cells after 24 and 48 h of co-incubation. Incubation with cisplatin resulted in a decrease of viable cells by 49% after 24 h and 48 h. In contrast, incubation with mere culture medium resulted in an increase of viable tumor cells by 5% after 24 h and a decrease of 4% after 48 h; the incubation of tumor cells and PBMC led to a non-significant decrease by 14% after 24 h and 16% after 48 h. Taken together, the CAM supports a favorable environment for the co-culture of HNSCC and PBMC, thus providing an approximated in vivo autologous model to assess the efficacy of new cell-therapeutical approaches.

[Secondarily accelerated foreign bodies as a source of danger from airbag deployment]. / Sekundär beschleunigte Fremdkörper als Gefahrenquelle bei Airbagauslösung.

BACKGROUND: The use of airbag systems in motor vehicle construction has led to a significant reduction in both the frequency and intensity of injuries during traffic accidents. However, recent reports have shown numerous cases in which it is assumed that the airbag was the major cause of serious injury. CASE REPORT: In a collision with a wild boar, both airbags in the automobile deployed. The driver suffered facial abrasion and belt contusion to the left shoulder. The passenger held a glass bottle in her hands during the impact that, secondarily accelerated through the airbag, hit both eyes and the bridge of her nose. On clinical admission, the patient showed fractures of the nasal bridge, of both medial orbital walls on both sides and a massive periocular haematoma which required direct examination under narcosis. Both eyes showed an orbital contusion, a large area of corneal abrasion, traumatic mydriasis with sphincter tears such as bilateral 90% hyphema. During surveillance, a progressive reduction in visual acuity occurred. After posterior chamber vitrectomy with epiretinal peeling and posterior chamber lens implantation in the left eye, visual acuity was 0.05 in the left eye and 0.01 in the right. CONCLUSIONS: A considerable danger emanates from objects which are situated between head and airbag in the moment of airbag deployment. This requires public education and, in addition, airbag systems which are adapted to the drivers height and weight, as well as to objects in its immediate vicinity.

[T-cells activated with a trifunctional bi-specific antibody in head and neck cancer]. / Removab aktivierte Lymphozyten bei Plattenepithelkarzinomen des oberen Aerodigestivtraktes.

BACKGROUND: The trifunctional bi-specific antibody Removab bridges and activates CD3 positive T cells to EpCAM on carcinoma cells and simultaneously binds to an accessory immune cell, thus inducing tumor cell lysis. Following intravenous application, Removab may induce cytokine-related side effects resulting in a sepsis like syndrom. It was questioned, if peripheral mononuclear blood cells (PBMN) already opsonized with Removab could retain antitumor activity and induce less cytokine release than the mere antibody. METHODS: PBMN of patients with head and neck cancer were incubated with Removab and the released cytokines were washed out. Then the Removab-opsonized PBMN were coincubated with genuine tumor cells of the same patient on a chorioallantois membrane for 24 h (T 24) and 48 h (T 48). Tumor cells coincubated with Cisplatin or solely cell culture medium served as control. RESULTS: Coincubation of tumor cells with opsonized PBMN resulted in a 32 % decrease of viable cells at T 24 and a 37 % decrease at T 48, whereas viable cells increased by 10 % at T 24 or 3 % at T 48 when incubated with medium alone (p < 0.05). This tumor cytotoxicity was similar to that of Cisplatin (35 % at T 24/37 % at T 48). CONCLUSION: In an autologous human ex vivo tumor system, Removab-opsonized PBMN induce tumor cell lysis with significantly reduced cytokine release after i. v. application.

Opsonization with a trifunctional bispecific (alphaCD3 x alphaEpCAM) antibody results in efficient lysis in vitro and in vivo of EpCAM positive tumor cells by cytotoxic T lymphocytes.

Removab is a trifunctional bispecific antibody which can bridge CD3+ T cells and epithelial cell adhesion molecule positive (EpCAM+) tumor cells, and binds with its Fc fragment to antigen presenting cells. To explore a new approach for the treatment of patients with carcinoma of the upper aerodigestive tract, we investigated whether Removab can induce specific cellular responses to the EpCAM+ carcinoma cell line BHY. Particular emphasis was put on the opsonization of peripheral blood mononuclear cells (PBMN) with respect to clinical application. Tumor cells and allogeneic PBMN of healthy volunteers were incubated with or without Removab. In a third group, PBMN were opsonized with Removab and washed before incubation with tumor cells. Inverse microscopy, ELISPOT, flow cytometry analysis and cytotoxicity assays on the chorioallantois membrane (CAM) were performed. In comparison with PBMN alone, opsonization with Removab resulted in: a) activation of CD83+ antigen presenting cells, b) secretion of interferon gamma, and c) granzyme B mediated lysis of targeted BHY cells by EpCAM specific CD8+ T cells. The secretion of tumor necrosis factor alpha, interferon gamma and interleukin-2 by opsonized PBMN was significantly reduced after 24 h. Washed opsonized PBMN maintained their lytic activity against tumor cells as tested on the CAM. Removab is an appropriate agent for the therapeutic amplification of T cell responses against EpCAM+ tumor cells by opsonization of PBMN without putting patients at risk for severe adverse events caused by a cytokine storm.

Gene polymorphisms in detoxification enzymes as susceptibility factor for head and neck cancer?

OBJECTIVE: Impaired detoxification of carcinogens found in tobacco smoke appears to increase the risk for tobacco associated cancer. The objective of this study was to investigate concomitant polymorphisms in genes encoding for various detoxification enzymes in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: In 187 patients with HNSCC and in 139 healthy control subjects, the polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), and glutathione S-transferase mu1 and Theta (GSTM1, GSTT1) were detected by polymerase chain reaction. RESULTS: No significant association were identified between CYP1A1 and CYP2D6 gene polymorphisms and HNSCC. Patients with laryngeal cancer revealed the GSTM1 null genotype more frequently than did the control subjects (P < 0.05). The coincidence of GSTM1 and GSTT1 null genotype was found twice as great in patients as in control subjects (P < 0.05). CONCLUSIONS: It is assumed that detoxification enzymes are functionally redundant and only the simultaneous deficiency of several detoxification enzymes increase the risk for HNSCC in alcohol- and tobacco-exposed individuals.

GSTM1 enzyme concentration and enzyme activity in correlation to the genotype of detoxification enzymes in squamous cell carcinoma of the oral cavity.

BACKGROUND: Differences in genotype and phenotype of detoxification genes could be one reason for conflicting results in studies dealing with gene polymorphisms as susceptibility factors for tobacco associated cancer. OBJECTIVES: The objective of this study was to investigate gene polymorphisms of detoxification enzymes and to determine whether the enzyme concentration and activity of glutathione S transferase microliter 1 correlates with the genotype in patients with cancer of the oral cavity. MATERIAL AND METHODS: In 73 cancer patients and 136 matched healthy controls, the polymorphisms of glutathione S-transferase mu1 and theta (GSTM/GSTT), cytochrome p450 1A1 and CYP2D6 were detected. Simultaneously, GSTM1 protein concentration and total GSTM1-activity were determined. RESULTS: Only the coincidence of GSTM1 and GSTT null genotype was associated with oral cavity cancer. GSTM1 protein concentration and enzyme activity in null-genotype patients was significantly lower than in GSTM1-allele-carrier. But the enzyme concentration did not correlate with the activity. CONCLUSION: We assume that detoxification enzymes are functionally redundant and that only the simultaneous deficiency of several detoxification enzymes increases the risk for oral cancer.

11Beta-hydroxysteroid dehydrogenase 1 expression in squamous cell carcinomas of the head and neck.

11Beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) has been identified as a major detoxification enzyme of one of the most potent tobacco smoke-derived carcinogens, NNK. If not metabolized by 11beta-HSD1, activation of NNK by cytochrome p450 mono-oxidase 2D6 (CYP2D6) results in an electrophile intermediate responsible for DNA damage. Interindividual variability in the expression of 11beta-HSD1 and CYP2D6 has been found to influence the susceptibility to lung cancer. The aim of this study was to compare 11beta-HSD1 mRNA expression and CYP2D6 metabolizer status in pharyngeal tissues of patients with oropharyngeal carcinoma and controls. In 20 patients with oropharyngeal cancer and 15 non-smoking controls, the 11beta-HSD1 mRNA expression was assessed with RT-PCR. The frequency of genetic polymorphisms of the CYP2D6 gene was assessed using RFLP. It was found that 11beta-HSD1 mRNA is expressed in human pharyngeal mucosa. It is upregulated in mucosa exposed to tobacco smoke. In tumour tissues, 11beta-HSD1 expression was significantly lower than in non-affected mucosa. The frequency distribution of CYP2D6 gene polymorphisms was similar in patients and controls. Chronic tobacco abuse results in 11beta-HSD1 enzyme induction. A reduction of 11beta-HSD1 expression in tumour tissues could be a consequence of malignantly transformed cells. It remains unclear if the lower 11beta-HSD1 expression gives rise to an increased rate of additional mutations.

[GSTM1 gene polymorphism in patients with head and neck tumors]. / GSTM1-Genpolymorphismus bei Patienten mit Kopf-Hals-Tumoren.

BACKGROUND: Glutathione S-Transferase mu (GSTM) is a phase II detoxification enzyme, which rapidly detoxifies carcinogens found in tobacco smoke. The prevalence of this polymorphism is about 50% in the caucasian population. The lack of GSTM1 has been linked with an increased susceptibility of smoking related cancers. A homozygote deletion of the GSTM-gene results in a missing gene product. The objective of this study was to investigate the frequency of the GSTM1 null genotype in squamous cell carcinoma of head and neck, especially the larynx and hypopharynx and to analyse the occurrence with respect to certain anatomical sites of cancer. MATERIAL AND METHODS: The GSTM1 genotypes of 83 patients with head and neck cancers and 60 healthy controls were determined by polymerase chain reaction (PCR) using blood leukocyte DNA. The presence or absence of the PCR-product after electrophoretic separation in an 2.0% agarose gel revealed the positive or negative genotype. RESULTS: The absence of the GSTM1 gene (null genotype) was found in 64% of all head and neck cancer patients and in 48% of the healthy controls (p < 0.05). Separating for cancer site, the null genotype was found in 44% of patients with hypopharyngeal cancer and in 78% of patients with laryngeal cancer (p < 0.05). The protein concentration of GSTM-enzyme correlated with the genotype. CONCLUSIONS: The results suggest that GSTM1 deficiency predisposes to head and neck cancer, especially to cancer of the larynx, which is particularly exposed to tobacco smoke carcinogens.

The three-dimensional structure of halorhodopsin to 5 A by electron crystallography: A new unbending procedure for two-dimensional crystals by using a global reference structure.

Electron microscopy does not, in principle, require highly ordered crystals to determine a high-resolution structure. Nevertheless, crystals of any type help to constrain the molecules into a more limited range of orientations and positions, from which it is easier to carry out structure determination. We describe an improved procedure for determination of crystalline disorder, which we have applied to poorly ordered two-dimensional crystals of the chloride pump halorhodopsin from Halobacterium salinarum. The new image analysis procedure involves the use of a reference projection calculated from a global three-dimensional map to carry out the initial cross-correlation analysis. Coupled with a greater number of images taken with field emission gun microscopes, this has allowed us to calculate a three-dimensional structure for halorhodopsin, in which the seven transmembrane helices and certain molecular features, such as the beta-ionone ring of retinal, are now resolved.

Concentration of cefamandole in plasma and tissues of patients undergoing cardiac surgery: the influence of different cefamandole dosage.

OBJECTIVE: To develop an improved regimen of antibiotic prophylaxis in cardiac surgery, three antibiotic prophylactic regimens for patients scheduled to have elective cardiothoracic surgery involving a median sternotomy were evaluated. DESIGN: A prospective, randomized, unblinded study. SETTING: A university teaching hospital. PARTICIPANTS: Sixty-nine men scheduled for elective coronary artery bypass grafting (CABG) with extracorporeal circulation (ECC) were included in the study. INTERVENTIONS: The patients were selected at random to receive 2 g of cefamandole (CM) at induction of anesthesia (group 1, n = 24), or 2 g of CM at the beginning of anesthesia followed by an additional dose (2 g) immediately after onset of cardiopulmonary bypass (CPB) (group 2, n = 22), or 4 g of CM just at the initiation of anesthesia (group 3, n = 23). Samples from the mammary artery, sternum, and plasma were obtained at various intervals after injection of the antibiotic (10 minutes intravenously) to compare antibiotic levels, assayed for CM concentrations, with high-pressure liquid chromatography (HPLC) and plasma bactericidal activity as well as infectious complications in these sites as a function of time for the three groups. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in biometric data, duration of hospitalization, or management of cardiopulmonary bypass, including urinary tract drainage and infusion volume. The mean plasma t1/2 (distributive or alpha-phase) before bypass was 51.7 +/- 16.7 minutes for group 1 and 2 patients and 54.9 +/- 15.9 minutes for group 3 patients. CM plasma values were significantly higher in group 2 (170.3 +/- 105.8 micrograms/mL) than in groups 1 and 3 (111.8 +/- 42.2 micrograms/mL, 101.2 +/- 57.2 micrograms/mL) at the end of bypass periods (p < 0.05). The antibiotic contents of mammary artery and sternum samples of group 2 (15.6 +/- 4.7 micrograms/mL, 9.5 +/- 4.7 micrograms/mL) were significantly higher after completion of CPB compared with group 1 (5.7 +/- 1.9 micrograms/mL, 3.8 +/- 2.9 micrograms/mL) and group 3 (6.3 +/- 3.5 micrograms/mL, 3.6 +/- 1.8 micrograms/mL) (p < 0.05). There were no significant differences in distribution of micro-organisms among the three groups, but two patients of groups 1 and 3 with plasma and tissue CM levels below minimal inhibitor concentration (MIC90) for Hemophilus influencea, E coli, Proteus ssp and Klebsiella ssp after completion of CPB, respectively, developed a pneumonia postoperatively caused by Hemophilus influencea (1), E coli (1) and Klebsiella ssp (2) (p < 0.05). CONCLUSIONS: It would be preferable to infuse the antibiotic shortly before the operative procedure. However, to keep tissue and plasma CM values more than MIC90 for common pathogens during the time period studied, a second infusion of 2 g of CM administered after onset of CPB suggests better protection against the risk of microbial infections. Therefore, the findings might be important for the choice of antibiotic prophylaxis, particularly for high-risk patients.