Universitäts HNO Klinik Mannheim

Diffusion-weighted MRI (DWI) and perfusion MRI (PI) have been mainly applied in acute stroke, but may provide information in the peri-ictal phase in epilepsy patients. Both transient reductions of brain water diffusion, namely a low apparent diffusion coefficient (ADC), and signs of hyperperfusion have been reported in experimental and human epilepsy case studies. We studied 10 patients with complex partial status epilepticus (CPSE) with serial MRI including DWI and PI. All patients showed regional hyperintensity on DWI, and a reduction of the ADC in (i) the hippocampal formation and the pulvinar region of the thalamus (six out of 10 patients), (ii) the pulvinar and cortical regions (two out of 10), (iii) the hippocampal formation only (one out of 10), and (iv) the hippocampal formation, the pulvinar and the cortex (one out of 10). In all patients a close spatial correlation of focal hyperperfusion with areas of ADC/DWI change was present. In two patients hyperperfusion was confirmed in additional SPECT (single photon emission computed tomography) studies. All patients received follow-up MRI examinations showing partial or complete resolution of diffusion and perfusion abnormalities depending on the length of the follow-up interval. The clinical course, EEG and SPECT results all indicate that MRI detected changes related to prolonged epileptic activity. Combined PI and DWI can visualize haemodynamic and tissue changes after CPSE in the hippocampus, thalamus and affected cortical regions.

OBJECTIVE: The risk for symptomatic intracerebral hemorrhage (sICH) associated with thrombolytic treatment has not been evaluated in large studies using diffusion-weighted imaging (DWI). Here, we investigated the relation between pretreatment DWI lesion size and the risk for sICH after thrombolysis. METHODS: In this retrospective multicenter study, prospectively collected data from 645 patients with anterior circulation stroke treated with intravenous or intraarterial thrombolysis within 6 hours (<3 hours: n = 320) after symptom onset were pooled. Patients were categorized according to the pretreatment DWI lesion size into three prespecified groups: small (< or =10 ml; n = 218), moderate (10-100 ml; n = 371), and large (>100 ml; n = 56) DWI lesions. RESULTS: In total, 44 (6.8%) patients experienced development of sICH. The sICH rate was significantly different between subgroups: 2.8, 7.8, and 16.1% in patients with small, moderate, and large DWI lesions, respectively (p < 0.05). This translates to a 5.8 (2.8)-fold greater sICH risk for patients with large DWI lesions as compared with patients with small (or moderate) DWI lesions. The results were similar in the large subgroup (n = 536) of patients treated with intravenous tissue plasminogen activator. DWI lesion size remained an independent risk factor when including National Institutes of Health Stroke Scale, age, time to thrombolysis, and leukoariosis in a logistic regression analysis. INTERPRETATION: This multicenter study provides estimates of sICH risk in potential candidates for thrombolysis. The sICH risk increases gradually with increasing DWI lesion size, indicating that the potential benefit of therapy needs to be balanced carefully against the risk for sICH, especially in patients with large DWI lesions.

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma.

Skin tests in patients with IgE-mediated immediate type allergy are performed with the intention to establish a contact between allergens and skin mast cells. The latter carry specific IgE antibodies on their surface. If mast cells get activated, mediators (mainly histamine) are released which induce a visible skin reaction (wheal and erythema).[nl]Skin tests are indicated, if an immediate type allergic disease is suspected. Systemic anaphylactic reactions at skin testing are very rare. However, it is necessary to take them into account and to provide emergency treatment. Relative contraindications comprise skin diseases in the test area, poor general condition and insufficiently treated severe asthma. If tests are used, which have a higher risk for a systemic anaphylactic reaction, pregnancy or beta-blocker therapy, are further contraindications.[nl]Skin test application does not depend on patient age. However, in pre-school age tests are reluctantly performed. It is essential to consider the half-life of drugs which may interfere with the test result, and which have to be discontinued early enough before testing. After anaphylactic reactions there may be a refractory period. Therefore, tests should not be done within the first week after such reactions. Skin prick tests are the procedures of first choice, intradermal tests are more sensitive than prick tests. Skin tests are performed at the flexor side of the forearm. As intradermal tests are more inconvenient, testing can be also done at a less susceptible site of the body (upper back).[nl]It is recommended to use standardized test extracts. However, if standardised extracts are not available or do not yield suitable test results, one may switch to other preparations. If the patient shows a positive reaction to a non-standardized substance, control tests should be performed in healthy subjects in order to exclude an unspecific reaction.[nl]The reaction is read after 15 to 20 min. Skin tests are regarded positive if the mean wheal diameter is ≥ 3 mm at the prick test, and ≥ 5 mm at the intradermal test.[nl]Skin test results may be negative although patients are allergic. If a skin test is positive, one will have to distinguish reactions, which are clinically relevant, from those, which are not. History and/or challenge tests help to clarify the relevance of a sensitization. Usually, a clinically irrelevant sensitization does not lead to practical consequences.

BACKGROUND: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far. METHODS: We report on 7 patients with metastatic anal cancer treated with cetuximab - a chimeric antibody against EGFR - on a compassionate use basis along with the results of KRAS mutational analysis. RESULTS: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting > or =6 months after previous rapid tumor progression. CONCLUSION: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy.

BACKGROUND: Air-conducted (ACS) cervical VEMP (cVEMP) reflect both saccular and inferior vestibular nerve function. Ocular VEMP (oVEMP) to air and bone-conducted vibration (BCV) are critically discussed, whether they reflect predominantly utricular and superior vestibular nerve function. The video head impulse test (vHIT) accurately detects changes in the high frequency range (5-7 Hz) of the vestibular ocular reflex (VOR) in all 3 planes and can be used to assess semicircular canals (SCC) impairment. OBJECTIVES: To evaluate oVEMP and cVEMP in response to 500 Hz ACS stimulation and to compare these with vHIT results in acute unilateral vestibular neuritis (VN) to classify the probable involvement of SCC and otolith organs. MATERIALS AND METHODS: Patients with VN were studied. ACS oVEMP and ACS cVEMP (100 dB nHL 500 Hz tone burst stimulation) were recorded. The vHIT for the 3 SCC were performed simultaneously. RESULTS: ACS oVEMP and ACS cVEMP in combination with vHIT allows the differentiation of 4 types of VN: entire VN (EVN), superior VN (SVN), inferior VN (IVN), and ampullary VN (AVN). Lesions of EVN, SVN, and IVN may be either complete or partial. CONCLUSION: ACS oVEMP and ACS cVEMP to 500 Hz stimulation together with the vHIT allows a better differentiation of receptor involvement in VN. Results suggest a different origin of AC oVEMP and AC cVEMP to 500 Hz in complete SVN and IVN. Partial SVN and IVN may indicate a role of saccular fibers in oVEMP.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

Abnormalities of the short arm of chromosome 12 (12p) are found in about 5% of acute nonlymphocytic leukaemias (ANLL) and myelodysplastic syndromes (MDS). They are described to be characteristic of secondary leukaemias, especially after prior mutagenic exposure, and to be associated with a poor prognosis. In our series of 59 patients with 12p abnormalities and ANLL or MDS, exposure to genotoxic agents was proven only in five patients, but in 13/44 patients ANLL evolved from an MDS. Patients with a small deletion del(12)(p11.2p13) having a mild clinical course were distinguished from those with a large del(12)(p11.2), additional chromosomal anomalies, and a poor clinical course. Among the 31 patients with translocations or dicentric chromosomes involving 12p, a group of eight with t/dic(12;13) was the most frequent and was associated with a poor prognosis. The clinical outcome was adverse in the majority of patients with complex karyotype abnormalities, but in some patients a milder clinical course seems likely. A new, hitherto undescribed, abnormality in an MDS case with a duplication dup(12)(p11.2p13) was the amplification of the signal of the yeast artificial chromosome (YAC) clone 964c10 (D12S736). In 38 cases with deletions or unbalanced translocations/dicentrics one YAC signal was lost. Five patients with balanced translocations demonstrated breakpoints within the YAC, containing the ETV6 (TEL) gene. The breakpoints were telomeric to the YAC 964c10 in seven cases and centromeric in one patient.

INTRODUCTION: Tonsillectomy is one of the most frequently performed surgical interventions in children. In the following, indications, preoperative evaluation, surgical techniques and postoperative complications will be discussed. METHODS: Literature search in PubMed (National Library of Medicine) focusing on publications in German or English up to June 2008. RESULTS: Indications are selected infectious diseases, upper airway obstruction for example due to tonsillar hypertrophy, and a suspected malignancy. Viral infections of the tonsils without upper airway obstruction are not an indication for surgery; in the case of acute bacterial tonsillitis, tonsillectomy is no longer recommended. In recurrent tonsillitis, tonsillectomy is only effective in specific and narrow indications. The indication for tonsillectomy in sleep-disordered breathing due to adenotonsillar hypertrophy has to be based on clinical assessment, medical history, and a sleep history. The most relevant risk factors are obstructive sleep apnea and coagulation disorders. A standardized history regarding hemostasis and bleeding is mandatory, and is superior to routine coagulation tests. Postoperative bleeding is still the most relevant complication of tonsillectomy and is always an emergency situation. CONCLUSION: Tonsillectomy is one of the most frequently performed interventions in children but should be considered with care, as life-threatening complications can occur.

: The acute vestibular syndrome is a clinically defined entity consisting of vertigo or dizziness that develops acutely over minutes to hours and is accompanied by nausea/vomiting, gait instability, head motion intolerance, and nystagmus, while persisting over a day or more. When it is caused by a peripheral vestibular lesion and is not associated with clinically manifest auditory deficits, it is mostly labeled vestibular neuritis/neuronitis/neuropathy or sometimes peripheral vestibulopathy. Here, we propose hypotheses and discuss current research advances on viral or vascular factors in the pathogenesis, the recurrence, the site of lesion, old and new treatment options, contraindicated measures, the differential diagnosis, and the prognosis of vestibular neuritis/neuronitis/neuropathy or vestibulopathy. Possibly, other structures than the vestibular nerve are also involved in the pathogenetic process and the label peripheral vestibulopathy would be more apt.

Tissue engineering represents a promising method for generating chondrogenic grafts for reconstructive surgery. In cultured chondrocytes, the dedifferentiation of cells seems unavoidable for multiplication. Stem cells, however, displaying unlimited self-renewal and the capacity to differentiate towards chondrocytes, might be usable after further characterization. As the interactions between the extracellular matrix and the cellular compartment can alter the cellular behaviour, we investigated the expression of integrins using microarray analysis during chondrogenic differentiation of human mesenchymal stem cells (MSC) in comparison with de-differentiating human chondrocytes (HC) harvested during septoplasty. During chondrogenic differentiation of MSC, the fibronectin-receptor (Integrin beta1alpha5), fibronectin and the GPIIb/IIIa-receptor were downregulated. The components of the vitronectin-receptor (Integrin alphavbeta3) and CD47 were constantly expressed and ILK was downregulated. Vitronectin and osteopontin were not expressed by the cells. In HC, Integrin beta1alpha5 in conjunction with the ligand fibronectin were upregulated during dedifferentiation, Integrin alphavbeta3 as well as the GBIIb/IIIa-receptor were activated on day 21 but neither vitronectin nor osteopontin were expressed by the cells. The integrins, beta2, beta4, beta6, beta8 and alpha2, alpha4, alpha6, alpha7, alpha11, were not expressed at any time. ILK, CD47, and ICAP were activated with ongoing dedifferentiation. In conclusion, a candidate for signal-transmission is the fibronectin receptor (integrin alpha5beta1) in conjunction with its ligand fibronectin. Other receptors, e.g. for vitronectin and osteopontin (alphavbeta3), or their ligands do not seem to be involved in signal transmission for dedifferentiation. The GPIIb/IIIa-receptor might assist the process of dedifferentiation. Intracellularly, ILK, ICAP1 and CD47 might be involved in the transduction of integrin-dependent signals.

Inverted papilloma (IP) is a benign sinonasal lesion that has a known propensity for recurrence, local aggressiveness and an association with transformation to squamous cell carcinoma. Due to the high rate of recurrence, association with malignancy and a tendency of multicentricity, the surgical approaches to treatment are controversial. Over the years there has been a slow evolution from aggressive (en bloc) resection by lateral rhinotomy to endoscopic techniques. This progress corresponds to the advances that have been made in endoscopic sinus surgery over the past 15 years. Technological advances have allowed the detection of sinonasal IP before its extension beyond the sinonasal region, thus enabling minimally invasive techniques to be used in the treatment of selected cases of IP. Differences in recurrence rates were not observed for endoscopic management as compared with lateral rhinotomy or sublabial degloving approaches. In terms of aetiology there is certain evidence that the presence of HPV in IP could be predictive of malignant transformation. Although IPs are monoclonal proliferations, they do not fit the profile of a prototypic precursor lesion. In contrast, an increased EGFR and TGF-alpha expression is associated with early events in IP carcinogenesis. Parameters such as hyperkeratosis, squamous epithelial hyperplasia and a high mitotic index are negative prognostic indicators, which could be useful in the future follow-up of patients with IP. Present literature should encourage us to recommend the use of a uniformly accepted staging system. The propensity for delayed recurrences and the maximal 13% incidence of malignant transformation mandates careful, long-term follow-up.

Leiomyosarcomas comprise a group of malignant soft-tissue tumors with smooth-muscle differentiation. In this study, 14 cases of leiomyosarcoma were screened for changes in relative chromosome copy number by comparative genomic hybridization. A high number of imbalances (mean, 16.3; range, 6-26) was detected, with chromosomal gains occurring about twice as much as losses. The most frequent gains were found in 5p15, 8q24, 15q25-->q26, 17p, and Xp (43% to 50%), whereas the most frequent losses were found in 10q and 13q (50% and 78%, respectively). Twenty high-level amplifications affecting 15 different chromosomal subregions were detected in nine different tumors. In three leiomyosarcomas, sequences on chromosome arm 17p were found to be highly amplified, with a minimal overlapping region on subbands 17p12-->p11. We further discovered that the Smith-Magenis syndrome critical region on 17p11.2 is included in the 17p amplicons of two leiomyosarcoma cases. Using probes flanking this genetically unstable region, a mean of 14 and 22 signals per nucleus, respectively, was detected in both leiomyosarcomas by fluorescence in situ hybridization. In conclusion, this analysis identifies a number of characteristic chromosomal imbalances in leiomyosarcomas and provides evidence for the localization of potential oncogenes and tumor suppressor genes active in leiomyosarcoma genomes.

Tissue engineering represents a promising method for the construction of autologous chondrogenic grafts for reconstructive surgery. The destruction or malformation of organs such as nasal cartilage, pinna and trachea in otorhinology-head and neck surgery can be caused by both: primary disease or treatment modalities. A large part of modern medical practice is aimed to repair, replace, maintain or enhance the function of damaged or diseased tissues and organs. Replacement or repair is by either artificial implants or transplantation of tissues. Such interventions are hindered by factors such as rejection by the immune system, limited blood supply or morbidity of the donor site. Reconstruction of an injured face using plastic surgery is a prime example of when the limitations of materials, science and reconstructive techniques become apparent. This review aims to briefly outline the use of chondrocytes for tissue engineering with special regard to the function of the extracellular matrix for the signalling between the chondrocytes.

Chondrocytes surrounded by extracellular matrix are responsible for the maintenance of the cartilage as a functional entity. It is well accepted that chondrocytes cultivated for tissue engineering dedifferentiate in cell culture. We characterized the expression of different collagens and collagen related proteins in differentiated (primary) and cultured nasal chondrocytes by using microarray gene expression analysis and immunohistochemical staining. The genes for collagen subunits 1alpha1 (Col1alpha1) and 1alpha2 (Col1alpha2) were activated during a cell culture period of 5 and 20 days whereas Col2alpha1 could be detected both in differentiated and dedifferentiated chondrocytes. The long-term cell culture revealed a late activation of the Col3alpha1, Col4alpha1 and Col11alpha1 genes as well as biglycan, fibromodulin and lumican. In addition, short- and long-term cell culture resulted in down-regulation of Col9alpha1, Col9alpha2, Col9alpha3, Col10alpha1, Col18alpha1, ColQ and chondroadherin. The decorin gene showed up-regulation in short-term cell culture, but down-regulation in long-term culture. Immunohistochemical staining of the different cell populations confirmed the mRNA data for collagen type 1, 2, 3, 4, 9alpha2, 9alpha3, 18 and decorin. Because of their up-regulation in cultured chrondrocytes the collagen types 1, 3, 4 and 11 as well as biglycan, fibromodulin and lumican may be markers for dedifferentiation. The collagen types 9, 18 and Q as well as decorin and chondro-adherin revealed down-regulation and, presumably, represent markers for the differentiation of chondrocytes.

The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing and currently they account for 5% of all malignancies worldwide. Inspite of ongoing developments in diagnostic imaging and new therapeutic facilities, HNSCC still represents a multidisciplinary challenge. One of the most important prognostic factors in HNSCC is the presence of lymph node metastases. Patients with confirmed nodal involvement have a considerable reduction of their 5-year overall survival rate. In the era of individually optimised surgery, chemotherapy and intensity modulated radiotherapy, the main role of pre- and posttherapeutic imaging remains cancer detection at an early stage and accurate follow-up. The combined effort of early diagnosis and close patient monitoring after surgery and/or radio-chemotherapy influences disease progression and outcome prediction in patients with HNSCC. This review article focuses on currrent oncologic concepts and emerging tools in imaging of head and neck squamous cell cancer. Besides the diagnostic spectrum of the individual imaging modalities, their limitations are also discussed. One main part of this article is dedicated to PET-CT which combines functional and morphological imaging. Furthermore latest developments in MRT are presented with regard to lymph node staging and response prediction. Last but not least, a clinical contribution in this review explains, which information the head and neck surgeon requires from the multimodality imaging and its impact on operation planning.

BACKGROUND: In intra-arterial (IA) thrombolysis trials, higher rates of symptomatic intracerebral haemorrhage (sICH) were found than in trials with intravenous (IV) recombinant tissue plasminogen activator (tPA); this observation could have been due to the inclusion of more severely affected patients in IA thrombolysis trials. In the present study, we investigated the rate of sICH in IA and combined IV + IA thrombolysis versus IV thrombolysis after adjusting for differences in clinical and MRI parameters. METHODS: In this multicenter study, we systematically analyzed data from 645 patients with anterior-circulation strokes treated with either IV or IA thrombolysis within 6 h following symptom onset. Thrombolytic regimens included (1) IV tPA treatment (n = 536) and (2) IA treatment with either tPA or urokinase (n = 74) or (3) combined IV + IA treatment with either tPA or urokinase (n = 35). RESULTS: 44 (6.8%) patients developed sICH. sICH patients had significantly higher scores on the National Institutes of Health Stroke Scale (NIHSS) at admission and pretreatment DWI lesions. The sICH risk was 5.2% (n = 28) in IV thrombolysis, which is significantly lower than in IA (12.5%, n = 9) or IV + IA thrombolysis (20%, n = 7). In a binary logistic regression analysis including age, NIHSS score, time to thrombolysis, initial diffusion weighted imaging lesion size, mode of thrombolytic treatment and thrombolytic agent, the mode of thrombolytic treatment remained an independent predictor for sICH. The odds ratio for IA or IV + IA versus IV treatment was 3.466 (1.19-10.01, 95% CI, p < 0.05). CONCLUSION: In this series, IA and IV + IA thrombolysis is associated with an increased sICH risk as compared to IV thrombolysis, and this risk is independent of differences in baseline parameters such as age, initial NIHSS score or pretreatment lesion size.

In a former study, taste disturbances after tonsillectomy seemed to be more frequent than expected. Eight percent of patients reported subjective taste disorders 6 months after tonsillectomy. Fifteen patients from the initial trial, who reported taste disorders after tonsillectomy, were contacted again for this long-term follow-up. A telephone interview using the same questionnaire addressing the current self-estimate of taste function was performed. At 32 ± 10 months following surgery, two (0.9%) patients still reported suffering from taste disturbance. This long-term follow-up study shows that dysgeusia following tonsillectomy occurs in approximately 1% of patients. These data should be considered when patients are informed about complications after tonsillectomy.

Tissue engineering is a multidisciplinary field combining biology and engineering along with clinical application to design, manufacture, modify, grow and maintain living tissue. This field has enjoyed tremendous growth in the past 10 years fueled by its potential role in regenerating new tissues and naturally healing injured or diseased organs. Many approaches to tissue engineering have been explored, including ex vivo de novo construction of tissues and strategies of in vivo induction of tissue regeneration. Interventions are hindered by factors such as rejection by the immune system, limited blood supply or morbidity of the donor site. Regardless of the approach, most researchers and clinicians agree that any successful tissue engineering construct will derive from a single unit, the cell. Because the engineering of tissue necessitates a sufficient number of tissue-specific cells with minimal donor site morbidity, a great deal of scientific effort has been directed towards stem cell research and the use of stem cells as a source of cells for new tissues. This review aims at outlining the role of stem cells in tissue engineering, focusing on the use of adult-derived stem cells as applied to the research and practice of plastic surgery.