Ramin Naim

Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures

ZusammenfassungDie hereditäre hämorrhagische Teleangiektasie (HHT), auch als Morbus Rendu-Osler-Weber bekannt, ist eine autosomal-dominant vererbte Erkrankung des Gefäßbindegewebes. Die Erkrankung wird charakterisiert durch die klassische Trias bestehend aus (muko-)kutanen Teleangiektasien, arteriovenösen Malformationen mit rezidivierender Epistaxis und Hämorrhagien sowie der Heredität. Eine Vielzahl unterschiedlicher klinischer Manifestationsformen der HHT sind beschrieben worden. In mehr als 90% der Fälle stellt die Epistaxis das klinische Erstsymptom dar, wodurch Hals-Nasen-Ohrenärzten eine wichtige Schlüsselrolle in der Diagnosestellung und der Behandlung der HHT zukommt. Trotz neuester diagnostischer und therapeutischer Entwicklungen ist eine Heilung dieser, den Betreffenden in seiner Lebensqualität oft einschränkenden Erkrankung nicht möglich. Außer der Nase sind vor allem die Haut, die Lunge, das Hirn, die Leber und der Gastrointestinaltrakt von arterio-venösen Malformationen (AVM) befallen. Die Entstehung der HHT wird im wesentlichen Mutationen zweier Gene zugeschrieben. Zum einen handelt es sich hierbei um Endoglin (ENG) auf Chromosom 9q33-q34 und activin-receptor like kinase (ALK1) auf Chromosom 12q13. Mutationen von Endoglin werden dem HHT Typ 1 zugeschrieben mit einer Inzidenz von bis zu 40% für pulmonale arteriovenöse Malformationen (AVM). Mutationen von ALK1 entsprechen dem HHT Typ 2 mit einer Inzidenz von bis zu 14% für pulmonale AVM. Diese Arbeit dient zum besseren Verständnis der Komplexität der HHT-Erkrankung, wobei anhand einer Übersicht zur aktuellen Literatur vor allem ein Schwerpunkt auf die klinischen Manifestationsformen, die Molekulargenetik und die Diagnosemöglichkeiten gelegt werden soll. Therapeutische Optionen in der Behandlung der HHT sind hier bewusst nicht erwähnt worden, da sie Gegenstand einer weiteren Arbeit sind. Dadurch, dass die HHT häufiger vorkommt als vermutet und eine weite Bandbreite klinischer Manifestationen aufweisen kann, stellt sie für viele Subspezialisierungen eine enorme Herausforderung dar, die ein eingehendes interdisziplinäres diagnostisches Screening in der Behandlung verlangt.SummaryHereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomal dominant disorder of the fibrovascular tissue. It is characterized by the classic triad of (muco-)cutaneous telangiectases, arteriovenous malformations with recurrent epistaxis and hemorrhages, and inheritance. A wide variety of clinical manifestations in HHT have been described. In more than 90% of the patients, nosebleeds are the first predominant symptom, therefore ENT physicians often play a key role as far as diagnosis and management of the disease are concerned. In spite of recent diagnostic and therapeutic progress, a cure for this often burdening and handicapping disease is still not available. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract. The two known genes that are implicated in HHT are endoglin (ENG) located on chromosome 9q33-q34 and activin-receptor-like kinase (ALK1) located on chromosome 12q13. Mutations of ENG are observed in HHT type 1 with an incidence up to 40% for pulmonary AVMs, whereas mutations of ALK1 are observed in HHT type 2 with an incidence of only 14% for pulmonary AVMs, which clinically distinguishes these two types of mutation. The emphasis of this paper is mainly on the clinical manifestation, molecular genetics and diagnosis of HHT, taking account of current literature on HHT in order to better understand the complexity of the disease. Recent therapeutic options in the treatment of HHT have been omitted from this paper as they are subject of a following paper. HHT is more common than previously thought and shows a broad range of different clinical organ manifestations that can be sources of substantial morbidity and mortality, making HHT a continuing challenge for many sub-specialties where interdisciplinary diagnostic screening is mandatory in the management of the disease.

Classification of the external auditory canal cholesteatoma.

Objectives/Hypothesis: The external auditory canal cholesteatoma (EACC) is a rare disease in the field of otolaryngology. Only 1 in 1,000 new otologic patients present with this entity, which was first described by Toynbee. The aim of this article is to classify EACC by different histopathologic and clinical findings of patients presenting to the Department of Otolaryngology at the University of Mannheim, Germany.

Radiotherapy and wound healing: Principles, management and prospects (Review)

Radiation therapy is a major therapeutic modality in the management of cancer patients. Over 60% of these patients receive radiotherapy at some point during their course of treatment and over 90% will develop skin reactions after therapy. Problematic wound healing in radiation-damaged tissue constitutes a major surgical difficulty and despite all efforts, irradiated skin remains a therapeutic challenge. This review provides an overview of the fundamental principles of radiation therapy with regards to the wound healing in normal and irradiated skin. Furthermore, it presents techniques that describe how to prevent and manage skin side effects as well as prospects that may improve cutaneous wound repair in general and in irradiated skin.

Co-expression of different angiogenic factors in external auditory canal cholesteatoma.

Objective Although external auditory canal cholesteatoma (EACC) was first described in 1850, its cause remains surprisingly unclear. Angiogenesis, the formation of new blood vessels, is essential to normal development and wound healing in adults. Abnormal regulation of angiogenesis has been implicated in the pathogenesis of several disorders. The aim of this study was to analyse angiogenesis regulator expression in EACC. Materials and Methods Cryostat sections of 13 investigated EACC tissue samples and normal control tissue were immunostained for angiogenic hepatocyte growth factor (HGF)/scatter factor (SF), its c-Met receptor and vascular endothelial growth factor (VEGF) using a standard streptavidin–biotin complex procedure. Staining against von Willebrand factor (vWF) served as an endothelial marker. Statistical analysis was performed semiquantitatively. Results The assayed angiogenic factors were all present in the EACC tissue, and partly overexpressed. vWF was detected in the apical layers of the matrix epithelium. Positive immunoreactivity for c-Met and VEGF was detectable in all layers of the EACC epithelium; however, adjacent tissue did not express c-Met and VEGF. HGF/SF was predominantly expressed in the adjacent perimatrix tissue and fibroblasts in particular were stained positive. Conclusions The presence of vWF in the apical part of the matrix depicted the attempt at angiogenesis in this part of the EACC. The detection of VEGF and c-Met in the epithelial part of the EACC implied that their origin may be epithelial, while HGF/SF may be secreted or stored in the adjacent mesenchymal EACC tissue. The angiogenic factors investigated seem to play an important role in establishing that EACC occurs by modulation of angiogenesis.

Regulation of Apoptosis in External Auditory Canal Cholesteatoma by Hepatocyte Growth Factor/Scatter Factor

Objectives: External auditory canal cholesteatomas (EACC) are characterized by focal invasion of squamous cell epithelium and accumulation of keratin debris in the apical part of the matrix. Apoptosis appears to be important in understanding the pathogenesis of EACC. Here the possible regulatory effect of the apoptosis mediated by hepatocyte growth factor (HGF)/scatter factor (SF)-c-Met-Fas in EACC is dicussed. Methods: We examined 17 EACC specimens for immunohistochemical expression of HGF/SF, c-Met, caspase 3 and Fas. The staining reaction was evaluated semiquantitatively. Results: HGF/SF was detected in mesenchymal tissue below the EACC epithelium. c-Met was expressed throughout the epithelium. Fas and caspase 3 were detected at increasing levels towards the apical layers of the EACC matrix. Conclusions: High levels of HGF/SF result in binding of HGF/SF to c-Met, releasing Fas to aggregate and bind to its death-inducing signaling complex. The result is apoptosis, marked by formation of dead squamous cells and sequestered keratin debris on the apical side of the cholesteatoma.

Benign Mixed Tumor of the Lacrimal Gland

The accurate clinical diagnosis of benign mixed tumors of the lacrimal gland is important for the proper therapeutic management. We present an adult case with a benign mixed tumor of the orbital lobe of the lacrimal gland, 8 years after periorbital blunt injury. The tumor lesion was diagnosed later in the persisting traumatic tumefaction region. Clinical examination, ultrasonography and MRI revealed a soft-tissue mass with high density and peripheral enhancement over the superior lateral portion of the right eye with expansion to and invasion of the orbital roof and lateral wall. Lateral orbitotomy was performed to resect the tumor. Histopathology disclosed a pleomorphic adenoma of the orbital lobe of the lacrimal gland. Pleomorphic adenomas of the lacrimal gland are seen rarely. The awareness of the clinical and diagnostic features of benign mixed tumors of the orbital lobe should help to avoid complications arising from an incisional biopsy or incomplete tumor resection.

Ossifying haemangioma of the frontal sinus

First described by Natali, the ossifying haemangioma is a rare entity. Although cases of ossifying haemangioma have been described in the literature, no involvement of the frontal sinus has been presented yet. We present a 46-year-old female patient who complained of recurrent cephalalgia and pressure in her forehead for 3 months. A computerized tomography scan demonstrated a compact radiopaque density arising from the floor of the middle cavity of her frontal sinus. Surgery was performed using the coronal approach. A rhomboid-shaped ossified tumour in the middle cavity of the frontal sinus was found with no signs of bleeding, partially obstructing the right sinus ostium. The small tumour was removed at the very base showing slight bleeding. Two weeks later, during the clinical follow-up, the patient did not complain of any of her previous symptoms. Previous studies have presented ossifying haemangioma of the temporal bone as an extremely aggressive entity affecting the 7th cranial nerve. In our case, the frontal sinus showed no signs of destruction of the adjacent tissue, and the only associated symptom was frontal cephalalgia. Because no critical surgical complications have been observed, no further changes to the surgical procedure appear necessary. We recommend performing a computerized tomography 6–12 months after surgery for follow-up to detect possible tumour regrowth.

Keloids: Fundamental principles and prospects (Review).

Wound healing is a very complex process of interactions between different cells, growth factors, blood elements and extracellular matrix. Keloids represent one of the possible complications in the fundamental process of cutaneous wound repair. Despite all efforts, keloids remain a therapeutic challenge since no treatment is as yet considered 100% effective. Growth factors, discovered in the late 1970s, have been shown to influence dermal regeneration. However, the exogenous application of growth factors to chronic wounds has not proven to be effective in healing them. Additionally, genetic analysis has not revealed any single gene that might cause keloids; as such, classic gene therapy is not a feasible option for the treatment of keloids. A new approach is so-called somatic gene therapy. This review provides an overview of the fundamentals of wound healing and of keloids, and presents new possibilities that may improve cutaneous wound repair.

TGF-β1 Modulates HGF/SF in Keloid Fibroblast Cell Culture

Objective Abnormal wound healing processes can result in hypertrophic scars and keloids. TGF-β1 and HGF/SF are biphasic growth factor cytokines in physiological and pathophysiological conditions. TGF-β1 has been found to be pivotal in the formation of keloid tissue and therefore neutralising antibodies may allow wound healing without keloid formation. TGF-β1 has been reported to be antagonised by HGF/SF. Some authors have reported that exogenous administration of HGF/SF prevented scar formation. Hence in this study, we targeted TGF-β1 and determined the levels of HGF/SF in fibroblast cell culture. Methods Keloid tissue was taken from 7 patients while another 7 patients with mature non-hypertrophic scar served as controls. All tissues were cultured and fibroblast cultures were used for further experiments. TGF-β1 antisense was administered at 3 and 6 μmol/ml and HGF/SF levels were determined after 16, 24 and 48 hours of incubation. Results The levels of HGF/SF showed significant differences after incubation with antisense oligonucleotides. The increasing antisense levels resulted in increased HGF/SF levels (up to 87.66pg/ml after 48 hours of incubation). Conclusions In conclusion, targeting TGF-β1 resulted in significantly increased levels of HGF/SF. The clinical relevance could include the use of locally administered HGF/SF in protein or gene form to minimise keloid formation. Nevertheless, wound healing is the result of many interacting cytokines and therefore neutralising or targeting one protein could result in no significant effect.

Targeting TGF-β1 increases hepatocyte growth factor (HGF/SF) levels in external auditory canal cholesteatoma (EACC) epithelial cell culture

OBJECTIVE The transforming growth factor (TGF)-beta 1 is known to have pro- and anti-angiogenic actions. Hepatocyte growth factor/scatter factor (HGF/SF) antagonizes TGF-beta1 by stabilizing SMAD transcriptional co-repressor TGIF. HGF/SF is a multifunctional polypeptide with morphogenic, motogenic, angiogenic, and proliferative capabilities. We assume HGF to be a pivotal factor during the pathogenesis of the external auditory canal cholesteatoma (EACC). In this study, we investigate the effect of antisense targeting TGF-beta1 on HGF/SF levels in the epithelial EACC-culture. MATERIALS For 48 h, epithelial EACC cell culture was incubated with 3 and 6 mumol antisense targeting TGF-beta1, respectively. Levels of HGF/SF were determined and normalized to cellular protein. Untreated EACC cell culture and scrambled TGF-beta1-antisense served as control. In the second experiment, EACC cells were incubated with rh TGF-beta1 (2 and 4 ng/ml) for 48 h and HGF/SF was determined. RESULTS After incubation with 3 mumol TGF-beta1-antisense, the average level of HGF/SF was measured at 43.68 pg/ml. Incubation with 6 micromol TGF-beta1-antisense showed 64.95 pg/ml. In untreated EACC (control), the average level of HGF/SF after 48 was 34.55 pg/ml. Incubation with scrambled TGF-beta1 oligonucleotide showed an average HGF/SF level of 34.41 (3 micromol) and 35.66 (6 micromol), respectively. The difference between the scrambled antisense and the targeting antisense TGF-beta1 was significant (p<0.05). After incubation with 2 ng/ml TGF-beta1, the HGF/SF levels were at 22.16 pg/ml. TGF-beta1, 4 ng/ml, resulted in 15.33 pg/ml of HGF/SF. The difference of the levels of HGF/SF after incubation with exogenous TGF-beta1 was significant (p<0.05). CONCLUSION In this study, levels of HGF/SF increased in the epithelial EACC cell culture after incubation with 3 and 6 mumol antisense TGF-beta1 oligonucleotides depending on the concentration of the antisense. In reverse, TGF-beta1 acted as inhibiting cytokine on HGF/SF levels. In conclusion, TGF-beta1 may be a useful therapeutic agent for managing EACC.