Biomedical subjects
V Jahnke
Publications and source records attributed to V Jahnke.
[First results on the influence of polymorphisms at glutathione S-transferase, cytochrome P450, and tumor necrosis factor gene loci on the development of multiple head and neck cancer].
BACKGROUND: The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for single head and neck cancer. In patients with multiple cancer development a cumulation of genetic risk factors can be assumed. METHODS: Accordingly, we have examined genotype frequencies at GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and TNF loci, in patients with single and multiple squamous cell carcinoma (SCC) of the head and neck, and controls. RESULTS: GSTT1 0 was increased in multiple SCC patients (36.8 %) compared with single SCC patients (21.2 %) and controls (22.2 %). GSTM3 AA was more frequent in the single SCC patients (76.6 %) and multiple SCC patients (82.1 %) compared with controls (66.5 %) but lacked significance. The TNF allele B3 was significantly increased in the single SCC group (B3-allele: 22.5 %, B3/B3 : 10.8 %) and showed a further cumulation in the multiple SCC group (B3 : 30.3 %, B3/B3 : 15.8 %). CONCLUSIONS: Patients suffering from multiple SCC development showed a cumulation of high risk genotypes at GST and TNF gene loci. Specific genetic variations could not be determined.
[Bilateral spontaneous development of a frontal sinus pyocele--a rare diagnosis].
Due to the length and the narrowing of the sinus draining passage, mucoceles are typically located within the frontal sinus. This case report describes the pathology of a patient with bilateral formation of pyoceles of the frontal sinus without the history of trauma, sinus operation or nasal pathology. The patient visited an ophthalmologist and reported a slowly increasing visual loss and protrusion of the left bulbus in the course of one year. Coronal CT scan showed bilateral soft tissue densities within the frontal sinus with arrosion of the floor on the left side. Extranasal frontal sinus surgery with ethmoidectomy (Ritter-Jansen and Uffenorde mucosal plasty) was performed. Intraoperative view demonstrated bony defects of the floor and the posterior wall of the frontal sinus.
[Influence of glutathione s-transferase and cytochrome p450 polymorphisms on prognosis of head and neck cancer].
BACKGROUND: The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for head and neck cancer. Recently, they have been associated with outcome in several cancers. METHODS: Accordingly, we have examined, in patients with squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1 and CYP2E1 genotypes and outcome parameters, tumor extension, histological grade, presence of lymph nodes, and recurrence free survival over 5 years. Genotypes were determined by PCR; logistic regression and a step-wise model were used to investigate the influence of the individual genes. RESULTS: GSTT1 0 was associated with T3/T4 tumor lesions in the pharynx and oral cavity (p = 0.029), but not laryngeal SCC cases. GSTT1 0 was also associated with histological differentiation (G3) in the oral cavity /pharynx, but not laryngeal SCC cases, although this association only approached significance (p = 0.069). CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal SCC cases. CONCLUSIONS: The data demonstrate site-dependent associations between GSTT1 null and CYP2D6 PM and tumor extension and lymph node involvement in SCC of the head and neck.
Cyclin D1 polymorphism and expression in patients with squamous cell carcinoma of the head and neck.
We have previously reported that the cyclin D1 (CCND1) GG870 genotype was associated with poorly differentiated tumors and reduced disease-free interval in patients with squamous cell carcinoma of the head and neck (SCCHN). We have now examined the association of this and a second CCND1 polymorphism with gene expression and outcome in SCCHN patients. Analysis of a CCND1 G/C1722 polymorphism revealed that CCND1 CC1722 genotype was associated with poorly differentiated tumors [P = 0.005; odds ratio (OR), 5.7; 95% CI, 1.7 to 19.2), and reduced disease-free interval (P = 0.003; Hazard Ratio (HR), 7.3; 95% CI, 1.1 to 27.2.) independently from the influence of CCND1 GG870 genotype. Patients whose tumors were negative for cyclin D1 were associated with reduced disease-free interval (P = 0.028; HR, 4.1; 95% CI, 1.4 to 14.2). Although G/C1722 genotypes were not associated with expression, we found a significant trend between reduced expression of cyclin D1 in patients with the CCND1 GG870 genotype (P = 0.04). Splicing of CCND1 mRNA in head and neck tissues was modulated by CCND1 A/G870 alleles, thus CCND1 transcript a was spliced equally from CCND1 A870 and G870 alleles, whereas CCND1 transcript b was spliced mainly from the CCND1 A870 allele. Our analysis has also identified differences in cyclin D1 genotype and protein expression and the pathogenesis of SCCHN in males and females. Thus, CCND1 CC1722 genotype was more common in female patients (P = 0.019; OR, 3.3; 95% CI, 1.3 to 10) and cyclin D1 expression was more frequent (chi-square1, 3.96; P = 0.046) and at higher levels (P = 0.004) in tumors from female patients. In summary, our data show that the two CCND1 polymorphic sites are independently associated with tumor biology and clinical outcome. CCND1 A/G870 alleles affect gene expression in head and neck tissues. We also provide preliminary evidence that the molecular genetics of SCCHN development may be influenced by patient gender.
[Electron microscopic studies of the rabbit nasal mucosa after short-term application of naphzoline nitrate].
BACKGROUND: Vasoconstricting nasal drops are applied frequently. Especially early ultrastructural alterations of the vessels were not examined up to now in animal models. Our goal was the systematic investigation of the submucosal vessels and the epithelium after topic application of naphazoline nitrate (Privin) in an animal model. METHODS: Three times daily over 6 days 3 ml of 0.1% naphazoline nitrate solution (Privin) were instilled into the right nasal cavity of 5 rabbits. At the 7th and 14th day an incisional biopsy of the lower nasal turbinate was carried out in ketamine/rompun anesthesia. RESULTS: In the naphazoline group the capillaries showed an edematous endothelium with narrowed lumina. Thrombosis of the arterioles were frequently observed. The more cubic epithelial cells had deciliated areas with microvilli. Venules, submucosal glands and the surrounding connective tissue was normally configurated. Analogous findings were also observed after 2 weeks. CONCLUSIONS: The disturbance of the microcirculation shows impressive endothelial alterations. These structural changes can result in nonreversible mucosal damages. A regeneration time of more than 1 week is assumable. Our results should be considered critically in order to prevent damages of the nasal mucosa.
[Influence of genetic variation in the major histocompatibility complex on head and neck cancer susceptibility].
BACKGROUND: While cigarette smoking and alcohol consumption are risk factors for squamous cell carcinomas (SCC) of the head and neck, genetic factors are also significant. The gene of tumor necrosis factor (TNF) is located in the major histocompatibility complex class III and the cytokine has pleiotropic actions some of which are anticarcinogenic. As this gene complex is polymorphic with microsatellite markers identified it is a further candidate for head and neck cancer susceptibility. METHODS: We used a case-control approach to study the influence of polymorphism at the A-D markers on susceptibility in 113 controls, 265 laryngeal and 123 oral cavity/pharyngeal SCC cases. Genotypes were identified on polyacrylamide gels in an automated DNA sequencer after amplification with fluorescently-labeled primers. RESULTS: We found no differences in allele frequencies between controls and oral cavity/pharyngeal SCC cases but the frequency of B3 was greater in the laryngeal SCC cases than controls (p = 0.004, odds ratio 2.8). Homozygosity for B3 conferred an increased risk of laryngeal cancer compared with controls (p = 0.021, odds ratio 10.8). CONCLUSIONS: The data provide the first evidence that allelism at MHC class III microsatellite markers is associated with risk to laryngeal SCC.
[Protection of autogenous cartilage transplants from resorption using membrane encapsulation].
In reconstruction of cartilage defects, autogenous transplantation is known as a reliable and experienced method. Although a clinical application has not been reported until now, tissue engineering permits in vitro production of autogenous cartilage transplants. Nevertheless, in both methods the cartilage is exposed to individually varying resorptive mechanisms. Among other methods for in vivo tissue protection, the encapsulation with a semipermeable polyelectrolytecomplex membrane could guarantee sufficient protection against resorptive influences. Human septal cartilage was encapsulated (group 1) with polyelectrolytecomplex membranes and subcutaneously implanted on the back of thymusaplastic nude mice. Cartilage implants without encapsulation (group 2) were used as control. Scanning electron microscopy and histochemical investigations were performed 1, 4, 8, 12 and 16 weeks after implantation. Group 1 showed no signs of resorption and chronic inflammation at all. In contrast, group 2 presented, correlating to the time of implanta-tion, increasing signs of cell death and fibrotic transformation, representing an increased activity of resorption. In conclusion, tissue encapsulation with a polyelectrolytecomplex membrane could ensure a sufficient protection of human cartilage transplants from resorptive influences. For the plastic-reconstructive surgeon the desired result becomes more calculable.
Macroencapsulation of human cartilage implants: pilot study with polyelectrolyte complex membrane encapsulation.
Autogenous cartilage transplantation is a generally accepted method in reconstructive surgery. A promising alternative to this established method could be represented by in vitro engineering of cartilage tissue. In both methods of autogenous transplantation, host response induces reduction of transplant size and transplant instability to an unforeseeable extent. To investigate if polyelectrolyte complex (PEC) membranes were able to avoid host-induced effects on implanted tissues without neglecting the tissue metabolism, human septal cartilage was encapsulated with polyelectrolyte complex membranes and subcutaneously implanted on the back of nude mice. Septal cartilage implants, without encapsulation served as control group. Histochemical and electron microscopic investigations were performed 1, 4, 8 and 16 weeks after implantation. In the case of an intact PEC-membrane no interactions between the host and the implant could be observed. In some implants, the capsule was torn in several areas and signs of chronic inflammation with the cartilage having been affected mildly could be observed. Implanted cartilage protected with PEC-encapsulation showed no signs of degeneration and significantly lower level of after effects of chronic inflammation than implanted cartilage without PEC-encapsulation. Therefore, it could be expected, that PEC membrane encapsulation offers a novel approach to protect cartilage implants from host response after autogenous transplantation.
Genetic polymorphism and clinical outcome: identification of individuals at risk of a poor clinical outcome.
Susceptibility and outcome in complex disorders such as asthma and cancer appear to be determined, at least in part, by genetic polymorphism. However, while our ability to identify new allelic variants and study them in case and control populations has greatly improved, considerable difficulties remain in elucidating how many genes determine particular clinical phenotypes. This is because most studies have concentrated on study of single genes in relatively small study groups. The important issues of gene-gene interactions (epistasis) and high-risk subgroups have not yet been adequately addressed. We now describe a general approach, using patients with head and neck cancers as an example. Our purpose is to demonstrate candidate gene selection, statistical approaches, and identification of patient subgroups.
[Genetic predisposition for the development of head and neck carcinomas].
BACKGROUND: While cigarette smoking and chronic alcohol consumption are the major risk factors for the development of head and neck cancer, it is assumed that genetic factors contribute to risk. Glutathione-S-transferase GSTM1 AB, GSTM3 BB and GSTP1 AA as well as TNF genotypes were determined from leucocyte DNA in 392 patients with head and neck carcinoma and 216 controls, with added immunohistochemical studies. Comparative genomic hybridization was used to screen for genetic alterations in the tumor tissue. RESULTS: While the frequency of GSTM1 AB was significantly lower in all head and neck carcinomas compared with controls, GSTM3 BB was significantly lower in the laryngeal and GSTP1 AA in the oral cavity/pharyngeal carcinoma cases; the frequency of the TNFb3 allele was higher in the laryngeal cases. Chromosomal alterations were specific for head and neck carcinomas, differing both in well differentiated and undifferentiated and in metastasizing and non-metastasizing tumors. CONCLUSIONS: Allelism at GST gene loci mediates susceptibility to head and neck carcinomas: GSTM1 AB is associated with a lower risk for all head and neck carcinomas, GSTM3 BB only for laryngeal carcinomas and GSTP1 AA only for oral cavity/pharyngeal carcinomas. The TNFb3 allele was significantly more frequent in laryngeal cancer patients. The genetic alterations in the tumor tissue are in line with the "tumor progression model". Genetic conditions are important from the first exposure with carcinogens up to late genetic events in the tumor tissue.
[Immunohistologic and molecular genetic studies of the effect of glutathione-S-transferases on the development of squamous epithelial carcinomas in the area of the head-neck].
BACKGROUND: While cigarette smoking and alcohol consumption are the major risk factors for the development of head and neck carcinomas, it is assumed that genetic factors contribute to risk. The aim of this study was to characterize the influence of the carcinogen metabolizing glutathione-S-transferases on susceptibility to head and neck carcinomas. PATIENTS AND METHODS: Polymorphisms at GSTM1, M3, T1 and P1 gene loci were determined in 398 head and neck cancer patients and 216 controls using polymerase chain reaction and restriction enzyme digestion. The epithelial distribution of the GSTs was determined by immunohistochemical methods. RESULTS: The GSTM1 A/B genotype was less frequent in all tumor groups compared with controls. The GSTM3 B/B genotype was reduced only in the laryngeal cancer group whereas GSTP1 A/A showed significant differences between pharyngeal cancer patients and controls. Accordingly, GSTM3 was expressed only in the cilia of the laryngeal respiratory epithelium. In contrast, GSTP1 was distributed throughout all outer layers of the squamous cell epithelium. CONCLUSIONS: While GSTM1 seems to influence susceptibility to all head and neck cancers, GSTM3 and P1 reflected site-specific differences. Thus GSTM3 appears to be associated with altered risk only to laryngeal cancer whereas GSTP1 is likely to influence pharyngeal cancer risk.
Association of arylamine N-acetyltransferases NAT1 and NAT2 genotypes to laryngeal cancer risk.
Genetically polymorphic xenobiotic metabolizing enzymes are supposed to be host factors for an individual's cancer susceptibility. A total of 255 laryngeal cancer patients was genotyped for NAT1 and NAT2 and compared with 510 reference individuals, matched by age and gender. NAT1 genotypes (NAT1*3, *4, *10, and *11 ) were found equally distributed between cases and control individuals. However, there was a significant overrepresentation of 20 (7.8%) homozygous NAT2 genotypes coding for rapid acetylation (NAT2*4/*4 and NAT2*4/*12A) amongst laryngeal cancer patients versus 19 (3.7%) such individuals in the control group (odds ratio 2.18, 95% confidence limits 1.13, 4.22; P = 0.018). Furthermore, an increasing NAT2*4/*4 frequency in cases with strong cigarette consumption was observed, but also in non-smokers. Heterozygous genotypes of NAT2*4/slow were not overrepresented. These results correspond with earlier findings in lung cancer. Analysis of NAT1 and NAT2 combinations revealed a linkage disequilibrium between NAT1*10 and NAT2*4; NAT1*10 frequency was twofold higher in NAT2*4/*4 carriers than in slow NAT2 coding genotypes. In conclusion, the distinct genotype NAT2*4/*4 proved to be a rare, but powerful host risk factor for larynx carcinoma. These data support the notion that an individual's specific NAT2 genotype may be decisive for the organ of his smoking-initiated cancer.
Cyclin D1, glutathione S-transferase, and cytochrome P450 genotypes and outcome in patients with upper aerodigestive tract cancers: assessment of the importance of individual genes using multivariate analysis.
GST, CYP, and CCND1 genotypes have been associated with outcome in several cancers. Accordingly, we have examined, in patients with one squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and CCND1 genotypes and the outcome parameters, tumor extension, histological grade, and presence of nodes. We used logistic regression to study, first, each gene individually and, second, in a step-wise model that included all of the genes. Different genes were associated with each outcome parameter. Thus, GSTT1 null was associated with T3/T4 lesions in the oral cavity/pharyngeal (P = 0.029), but not laryngeal, SCC cases. GSTT1 null was also associated with histological differentiation (G3) in the oral cavity/pharyngeal, but not laryngeal, SCC cases, although this association only approached significance (P = 0.069). CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases. The combination of GSTT1 null/CCND1 GG was also associated with G3 tumors. CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal, but not oral/pharynx, SCC cases. Genes that were individually associated with outcome were also associated with the parameter in the step-wise routine. The GSTT1 null frequency was greater in 39 patients with second primary tumors than in those with one lesion (P = 0.014). The data demonstrate site-dependent associations between GSTT1 null, CCND1 GG, and CYP2D6 PM and tumor extension, differentiation, and nodes.
Genomic alterations associated with malignancy in head and neck cancer.
BACKGROUND: Comparative genomic hybridization (CGH) was performed on 50 primary head and neck squamous cell carcinomas (HNSCC) to discover molecular genetic alterations underlying the progression of these tumors. METHODS: In CGH, equal amounts of differently labeled tumor deoxyribonucleic acid (DNA) and normal reference DNA were hybridized simultaneously to normal metaphase chromosomes. They were visualized by different fluorochromes, and the signal intensities were quantitated separately as gray levels along the single chromosomes. The over- and underrepresented DNA segments were determined by computation of ratio images and average ratio profiles. RESULTS: Prevalent changes observed in more than 50% of the HNSCC included deletions of chromosomes 1p, 4, 5q, 6q, 8p, 9p, 11, 13q, 18q, and 21q and DNA overrepresentations of 11q13 as well as 3q, 8q, 16p, 17q, 19, 20q, and 22q. The calculation of ratio profiles of tumor subgroups revealed that well differentiated carcinomas (G1) were defined by the deletions of chromosomes 3p, 5q, and 9p together with the overrepresentation of 3q, suggesting the association with early tumor development. Accordingly, the undifferentiated tumors (G3) were characterized by additional deletions of chromosomes 4q, 8p, 11q, 13q, 18q, 21q, and overrepresentations of 1p, 11q13, 19, and 22q. CONCLUSION: Our data indicate that the CGH patterns of chromosomal imbalances may help to define the malignant potential of head and neck squamous cell carcinomas.
[Electron microscopy studies of the human vomeronasal organ].
The vomeronasal organ, or Jacobson's organ, is essential for pheromone detection and reproductive behavior in most mammals. In humans, it has been described as a blind diverticulum in the anterior nasal septum, but without a documented function. The purpose of this study is to describe the fine structure of the human adult vomeronasal organ in 14 specimens. Our studies showed a duct-like invagination of the epithelium that was surrounded by numerous exocrine glands with short ducts. The fine structure of these glands suggested a serous secretion. In the depth of the invagination, pseudostratified columnar epithelial cells were seen that had plump processes, kinocilia and microvilli at the apical cell membrane. Several cell types were seen that differed regarding their organelles and electron density, with light sensory cells exhibiting neurofilaments. Underneath the typical basement membrane, numerous myelinated and unmyelinated axons were present in the very vascular lamina proprion. These morphological findings are unique in the human body and suggest that a chemosensory epithelium corresponding to a vomeronasal organ may exist. Its central connections and the possible functional significance of this tubed organ for pheromone detection are unknown and need further study.
[Effect of gene polymorphism on detoxifying glutathione-S-transferase enzymes on chromosomal stability of squamous epithelial carcinomas in the area of the head-neck].
BACKGROUND: While cigarette smoking and chronic alcohol consumption are the major risk factors for the development of head and neck cancer, it is assumed that genetic factors contribute to risk. MATERIAL AND METHODS: We examined genotype frequencies from leukocyte DNA of 269 laryngeal cancer patients, 123 pharyngeal cancer patients and 216 controls. Polymorphisms at different glutathione-S-transferase (GST) gene loci were investigated. Losses of heterozygosity (LOH) at 12 different chromosomal gene loci were determined in 37 of the study patients by comparing blood and tumor cell DNA. The relationship between high risk genotypes and the occurrence of LOH was investigated. RESULTS: Glutathione-S-transferase high risk genotypes were identified at the first and third genes of the M family (GSTM1, GSTM3) and the first gene of the P family (GSTP1). These high risk genotypes are seen to have a statistically significant influence on the occurrence of LOH in the tumor tissue. CONCLUSION: There is evidence that the polymorphisms studied play a role in the carcinogenic process by influencing the chromosomal fragility which may lead to the inactivation of tumor suppressor genes or the activation of oncogenes.
[Glands of the human nasal mucosa--electron microscopy and immunohistochemical studies].
BACKGROUND: Ultrastructural characteristics of the nasal glands are presented and possible changes concerning different diseases of the nasal mucosa are investigated. METHODS AND PATIENTS: Specimens from 23 patients suffering from primary ciliary dyskinesia, allergic rhinopathy, and chronic inflammatory hyperplasia were the subject of electron microscopic and immunohistochemical studies. RESULTS: All preparations exclusively showed glands of the serous type. The end segments of the glands were surrounded by contractile myoepithelial cells in a basket-like fashion. Distinct differences in the fine structure of the glands were not observed between the individual groups. The epithelial cells of the efferent ducts consisted of numerous rows forming one layer with pronounced interlockings. These cells in particular showed a high content of mitochondria. This segment of the duct probably has the function of changing the content of water and ions in the nasal secretion. CONCLUSIONS: Our immunofluorescence and electronmicroscopic investigations present the ultrastructure of the nasal glands in detail. We assume an influence of the efferent ducts on the composition of the nasal secretion.