Aktivierung von c-Jun-N-terminalen Kinasen (SAPK,JNK) als Teil der späten Cisplatin abhängigen DNA-Schadensantwort

Stress-aktivierte-Protein-Kinasen (c-Jun-N-terminal kinases) SAPK/JNK werden sehr schnell nach Exposition von Zellen mit verschiedensten Noxen, wie beispielsweise Genotoxinen, aktiviert. Sie sind allerdings noch nicht als Teil der DNA-Schadensantwort etabliert. In dieser Arbeit sollte gezeigt werden, das SAPK/JNK einen wichtigen Teil innerhalb der DNA-Schadensantwort spielen. Aus diesem Grund wurde zu frühen (z.B.: 4 h) als auch zu späten Zeiten (z.B.: 24 h) die Bildung von DNA-Addukten nach Cisplatin Exposition untersucht und überprüft, ob diese mit dem Aktivierungsstatus der SAPK/JNK nach Cisplatinbehandlung korreliert. Menschliche Fibroblasten, die einen Defekt in der Transkription gekoppelten Nukleotid-Exzisionsreparatur (TC-NER) aufwiesen, wie beispielsweise CSB-Zellen (Cockayne Syndrom B) oder XPA-Zellen (Xeroderma Pigmentosum A), sind charakterisiert durch einen erhöhten Phosphorylierungsstatus der SAPK/JNK, 16 h nach Cisplatingabe, im Vergleich zu normalen Wildtyp-Fibroblasten. Die nach Cisplatin Exposition beobachtete Aktivierung der SAPK/JNK ist quantitativ jedoch nicht vergleichbar mit dem Level an gebildeten Cisplatin-DNA-Addukten, wie in den Southwestern- und Massenspektrometrischen Untersuchungen gezeigt werden konnte. Es konnten jedoch Parallelen zwischen der Aktivierung der SAPK/JNK, sowie den gezeigten γ-H2AX-Foci als auch der Aktivierung von Check-Point Kinasen gefunden werden. Dies lässt darauf schließen, dass DNA-Doppelstrangbrüche (DSB) an der späten Aktivierung des SAPK/JNK Signalweges beteiligt sind. Dementsprechend lässt sich ebenfalls in Zellen, die einen Defekt in der Reparatur von Doppelstrangsbrüchen aufweisen, wie beispielsweise DNA-PKcs Zellen, eine erhöhte, durch Cisplatin hervorgerufene späte Phosphorylierung der SAPK/JNK als auch eine vermehrte γ-H2AX-Foci Bildung und Check-Point Kinasen Aktivierung nachweisen. Vergleichend dazu zeigten Zellen mit einem Defekt in ATM (Ataxia telegiectasia mutated protein) oder XPC keine erhöhte Phosphorylierung zu späten Zeiten nach Cisplatin Behandlung. Weiterhin bleibt festzuhalten, dass die späte, durch Cisplatin hervorgerufene Schadensantwort unabhängig von p53, ER-Stress oder MKP-1 ist. Die SAPK/JNK Aktivierung nach Cisplatin Exposition erfordert funktionsfähige Rho-GTPasen und kann durch pharmakologische Hemmung der Tyrosin-Kinasen und durch N-Acetylcystein gehemmt werden. Es lässt sich zusammenfassend sagen, dass die durch Cisplatin induzierte späte SAPK/JNK Aktivierung durch die Formation von DSB initiiert wird und XPC, Rho-Proteine sowie Tyrosin Kinasen an der Signalweiterleitung beteiligt sind.

Einfluss von Uracil in der DNA auf die Genexpression : die Rolle der Basen-Exzisions-Reparatur

Uracil ist eine der am häufigsten vorkommenden DNA-Basenmodifikationen, die über den Mechanismus der Basen-Exzisions-Reparatur (BER) aus dem Genom entfernt wird. Im Verlauf der Reparatur dieser Läsion durch monofunktionelle Uracil-DNA-Glykosylasen (UNG1/2, SMUG1, TDG und MBD4) entstehen AP-Läsionen und Einzelstrangbrüche. Da von beiden bekannt ist, eine Blockade der Transkription verursachen zu können, wurde in dieser Arbeit der Einfluss von Uracil und dessen Exzision auf die Expression eines Gens untersucht. Dafür wurde eine effiziente Methode entwickelt, die DNA-Basenmodifikation spezifisch in den transkribierten oder nicht-transkribierten DNA-Strang eines Reporter-Vektors einzufügen. rnIn Host cell reactivation Assays konnte gezeigt werden, dass Uracil unabhängig davon, ob es mit Adenin gepaart (U:A) oder mit Guanin (U:G) eine Fehlpaarung bildet, keine direkte Blockade der Transkriptions-Maschinerie in menschlichen Zellen auszulösen vermag. Dies kann daraus geschlossen werden, dass die Expression des Reportergens der Uracil-enthaltenen Vektoren im Vergleich zu unmodifizierten Referenz-Vektoren kurze Zeit nach der Transfektion unverändert ist. Die erst mit zunehmender Inkubationszeit in den Wirtszellen progressiv abnehmende Transkription ließ vermuten, dass die intrazelluläre Prozessierung der Läsion über die BER für die verringerte Genexpression verantwortlich ist. In der Tat bewirkte der Knockdown der BER-initiierenden UNG1/2, die Uracil aus der DNA herausschneidet und damit eine AP-Läsion generiert, eine Verringerung des negativen Effektes eines U:A-Basenpaares auf die Genexpression. Dass der Knockdown der SMUG1- oder TDG-Glykosylase hingegen keine Auswirkungen zeigte, beweist, dass UNG1/2 die Hauptglykosylase für die Exzision dieser Läsion und der Auslöser der inhibierten Transkription in HeLa-Zellen darstellt. Der Zusammenhang zwischen dem Maß des Ausschnitts einer DNA-Basenmodifikation im Verlauf der BER und einer verringerten Expression des Reportergens konnte zudem am Beispiel von 5-Hydroxymethyluracil und der für diese Läsion spezifischen SMUG1-Glykosylase nachgewiesen werden. Im Falle einer U:G-Fehlpaarung besaß weder UNG1/2 noch SMUG1 oder TDG einen Einfluss auf die Rate oder das Ausmaß der mit der Zeit abnehmenden Genexpression, was die Beteiligung einer anderen Glykosylase oder eines anderen Reparatur-Mechanismus vermuten lässt. rnDie Tatsache, dass die Stärke der Gen-Suppression unabhängig davon war, ob Uracil im transkribierten oder nicht-transkribierten DNA-Strang positioniert wurde, lässt die Mutmaßung zu, dass keine Blockade der elongierenden RNA-Polymerase, sondern vielmehr ein indirekter Mechanismus der Auslöser für die verringerte Transkription ist. Dieser Mechanismus muss unabhängig von der gut untersuchten transkriptionsgekoppelten Nukleotid-Exzisions-Reparatur erfolgen, da der Knockdown des hierfür benötigten CSB-Gens keine Auswirkungen auf die Inhibition der Genexpression der Uracil-enthaltenen Vektoren hatte. Insgesamt liefert diese Arbeit neue Erkenntnisse über den Beitrag der einzelnen Uracil-DNA-Glykosylasen zur Reparatur der DNA-Basenmodifikation Uracil in humanen Zellen und zeigt, dass die BER über einen indirekten Mechanismus die Hemmung der Genexpression verursacht.

On-table reconstruction of comminuted fractures of the radial head

The most widely accepted treatment for comminuted fractures of the radial head is either the excision or open reduction and internal fixation. The purpose of the present study is to evaluate the value of an 'on-table' reconstruction technique in severely comminuted fractures of the radial head. In this study, two patients with a Mason type-III and four patients with a Mason type-IV radial-head fracture were treated with 'on-table' reconstruction and fixation using low-profile mini-plates. After a mean follow-up of 112 months (47-154 months), the mean elbow motion was 0-6-141 degrees extension flexion with 79 degrees of pronation and 70 degrees of supination. The mean Broberg and Morrey functional rating score was 97.0 points, the Mayo Elbow Performance Index was 99.2 points and the mean Disabilities of the Arm, Shoulder, and Hand (DASH) Outcome Measure score was 1.94 points. One patient had symptoms of degenerative changes, with a slight joint-space narrowing. There were no radiographic signs of devitalisation at final examination. Comminuted fractures of the radial head, which would otherwise require excision, can be successfully treated with an 'on-table' reconstruction technique.

Rapidly excised and cryofixed rat tissue

All preparation efforts of biological samples in electron microscopy are focused to preserve structures as close as possible to the native state. To achieve this goal with tissues, it is of advantage to have a very short time between excision and fixation. The most common approach is chemical fixation: cross-linking of the tissue samples with aldehydes followed by postfixation with osmium tetroxide. Here, the fastest approach for tissue samples is perfusion. However, the diffusion of the fixation solution from blood vessels into the depth of the tissue is still slow and does not allow an overall instant fixation of a single cell. As a result, osmotic effects become evident (swelling or shrinkage of cell organelles). Another possibility is to take a tissue sample from the experimental animal. Excision of tissue can last quite some time, which results in even more pronounced autolytic induced osmotic effects. Furthermore, the animal does not survive the procedure in most cases. Alternatively, microbiopsies are an elegant technique to rapidly excise small quantities of tissue. Some tissues, such as liver and muscle, may be obtained using a non-lethal approach. To avoid the artifacts introduced by chemical fixation, high-pressure freezing of microbiopsies (brain, liver, kidney, and muscle) is a powerful alternative to chemical fixation. Here, we describe the microbiopsy method, and high-pressure freezing/freeze-substitution (HPF/FS) as a follow-up procedure. Cryosectioning of high-pressure frozen samples is optimally preserving the ultrastructure; however, it is not considered to be a routine approach yet.

On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations

Abstract Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER), which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH) and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs). The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer. The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools.

Atypical presentation of a hormonally active adrenocortical tumor in an adolescent leading to delayed diagnosis

Adrenocortical tumors are rare in children and present with variable signs depending on the type of hormone excess. We herein describe the unusual presentation of a child with adrenocortical tumor and introduce the concept of in vitro chemosensitivity testing. CASE REPORT: A 10.5-year-old girl presented with hypertrichosis/hirsutism and weight loss. The weight loss and behavioral problems, associated with halted puberty and growth, led to the initial diagnosis of anorexia nervosa. However, subsequent weight gain but persisting arrest in growth and puberty and the appearance of central fat distribution prompted further evaluation. RESULTS AND FOLLOW-UP: 24h-urine free cortisol was elevated. Morning plasma ACTH was undetectable, while cortisol was elevated and circadian rhythmicity was absent. Thus a hormonally active adrenal cortical tumor (ACT) was suspected. On magnetic resonance imaging (MRI) a unilateral, encapsulated tumor was found which was subsequently removed surgically. Tissue was investigated histologically and for chemosensitivity in primary cell cultures. Although there were some risk factors for malignancy, the tumor was found to be a typical adenoma. Despite this histology, tumor cells survived in culture and were sensitive to cisplatin in combination with gemcitabine or paclitaxel. At surgery, the patient was started on hydrocortisone replacement which was unsuccessfully tapered over 3 months. Full recovery of the hypothalamus-pituitary-adrenal axis occurred only after 3 years. CONCLUSIONS: The diagnosis of a hormonally active adrenocortical tumor is often delayed because of atypical presentation. Cortisol replacement following unilateral tumor excision is mandatory and may be required for months or years. Individualized chemosensitivity studies carried out on primary cultures established from the tumor tissue itself may provide a tool in evaluating the effectiveness of chemotherapeutic drugs in the event that the adrenocortical tumor may prove to be carcinoma.

Advantages of preoperative hybrid SPECT/CT in detection of sentinel lymph nodes in cutaneous head and neck malignancies

There is some controversy around the value of sentinel lymph node excision (SLNE). Especially SLNE of cutaneous head and neck malignancies has been debated intensively, in part because of the complexity of the lymphatic drainage in this region associated with potential high morbidity. In order to improve preoperative three-dimensional mapping of sentinel lymph nodes (SLN), in the head and neck region, by means of hybrid single photon emission computed tomography/computed tomography (SPECT/CT) is gaining significance. Our study seeks to identify the potential medical and economic advantages of preoperative SPECT/CT in direct comparison to standard SLNE without SPECT/CT in patients with cutaneous head and neck malignancies.

Recent developments for surgical aortic valve replacement: the concept of sutureless valve technology

Aortic stenosis has become the most frequent type of valvular heart disease in Europe and North America and presents in the large majority of patients as calcified aortic stenosis in adults of advanced age. Surgical aortic valve replacement has been recognized to be the definitive therapy which improves considerably survival for severe aortic stenosis since more than 40 years. In the most recent period, operative mortality of isolated aortic valve replacement for aortic stenosis varies between 1–3% in low-risk patients younger than 70 years and between 4 and 8% in selected older adults. Long-term survival following aortic valve replacement is close to that observed in a control population of similar age. Numerous observational studies have consistently demonstrated that corrective surgery in symptomatic patients is invariably followed by a subjective improvement in quality of life and a substantial increase in survival rates. More recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to be feasible in patients with high surgical risk using either a retrograde transfemoral or transsubclavian approach or an antegrade, transapical access. Reported 30-day mortality ranges between 5 and 15%) and is acceptable when compared to the risk predicted by the logistic EuroSCORE (varying between 20 and 35%) and the STS Score, although the EuroScore has been shown to markedly overestimate the effective operative risk. One major concern remains the high rate of paravalvular regurgitation which is observed in up to 85% of the patients and which requires further follow-up and critical evaluation. In addition, long-term durability of these valves with a focus on the effects of crimping remains to be addressed, although 3-5 year results are promising. Sutureless biological valves were designed to simplify and significantly accelerate the surgical replacement of a diseased valve and allow complete excision of the calcified native valve. Until now, there are 3 different sutureless prostheses that have been approved. The 3f Enable valve from ATS-Medtronic received CE market approval in 2010, the Perceval S from Sorin during Q1 of 2011 and the intuity sutureless prosthesis from Edwards in 2012. All these devices aim to facilitate valve surgery and therefore have the potential to decrease the invasivness and to shorten the conventional procedure without compromise in term of excision of the diseased valve. This review summarizes the history and the current knowledge of sutureless valve technology.

Advanced nail surgery

Six techniques not yet widely known or used in the dermatologic surgery of the nails are briefly described. Small-to-medium-sized tumours of the proximal nail fold (PNF) can be excised and the defect repaired with advancement or rotation flaps. A superficial biopsy technique of the matrix for the diagnosis of longitudinal brown streaks in the nail, which allows rapid histological diagnosis of the melanocyte focus to be performed, is described here. Because the excision is very shallow and leaves the morphogenetic connective tissue of the matrix intact, the defect heals without scarring. Laterally positioned nail tumours can be excised in the manner of a wide lateral longitudinal nail biopsy. The defect repair is performed with a bipedicled flap from the lateral aspect of the distal phalanx. Malignant tumours of the nail organ often require its complete ablation. These defects can be covered by a full-thickness skin graft, reversed dermal graft, or cross-finger flap. The surgical correction of a split nail is often difficult. The cicatricial tissue of the matrix and PNF have to be excised and the re-attachment of these wounds prevented. The matrix defect has to be excised and sutured or covered with a free matrix graft taken either from the neighbouring area or from the big toe nail.

Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome

Background DNA polymerase γ (POLG) is the only known mitochondrial DNA (mtDNA) polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions) and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS). Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. Methods mtDNA content in various tissues (fibroblasts, muscle and liver) was quantified using quantitative PCR (qPCR). OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. Results We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome). These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. Conclusions mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment.

Presentation, microsurgical therapy, and clinical outcomes in three cases of expanding melanonychia of the nail unit in children

The management of expanding melanonychia in childhood is controversial. Here, we present three cases and discuss their operating indications and reconstruction. Between January 1, 1995 and December 31, 2007, one boy and two girls, were operated for expanding melanonychia, involving the thumb, index finger or the middle finger. They were 2, 4, and 7 years at the time of surgery. A complete resection of the nail plate was performed followed by a direct finger reconstruction using a free short-pedicle vascularized nail flap of the toe. Histology showed a junctional nevus in all cases. The follow-ups were after 2, 3, and 5 years and without any complications or recurrence. Regarding reconstruction, the mean Foucher and Leclère score were, respectively, 17 and 16 points. It is concluded that for expanding melanonychia, in case of doubt, an examination of the entire lesion is necessary. Reconstruction of the nail unit after wide excision with nail plate ablation can be performed using microsurgery as discussed below. However, new guidelines on shave biopsy can make this microsurgical procedure obsolete.

Consensus Document of the International Union of Angiology (IUA)-2013. Current concept on the management of arterio-venous management

Arterio-venous malformations (AVMs) are congenital vascular malformations (CVMs) that result from birth defects involving the vessels of both arterial and venous origins, resulting in direct communications between the different size vessels or a meshwork of primitive reticular networks of dysplastic minute vessels which have failed to mature to become 'capillary' vessels termed "nidus". These lesions are defined by shunting of high velocity, low resistance flow from the arterial vasculature into the venous system in a variety of fistulous conditions. A systematic classification system developed by various groups of experts (Hamburg classification, ISSVA classification, Schobinger classification, angiographic classification of AVMs,) has resulted in a better understanding of the biology and natural history of these lesions and improved management of CVMs and AVMs. The Hamburg classification, based on the embryological differentiation between extratruncular and truncular type of lesions, allows the determination of the potential of progression and recurrence of these lesions. The majority of all AVMs are extra-truncular lesions with persistent proliferative potential, whereas truncular AVM lesions are exceedingly rare. Regardless of the type, AV shunting may ultimately result in significant anatomical, pathophysiological and hemodynamic consequences. Therefore, despite their relative rarity (10-20% of all CVMs), AVMs remain the most challenging and potentially limb or life-threatening form of vascular anomalies. The initial diagnosis and assessment may be facilitated by non- to minimally invasive investigations such as duplex ultrasound, magnetic resonance imaging (MRI), MR angiography (MRA), computerized tomography (CT) and CT angiography (CTA). Arteriography remains the diagnostic gold standard, and is required for planning subsequent treatment. A multidisciplinary team approach should be utilized to integrate surgical and non-surgical interventions for optimum care. Currently available treatments are associated with significant risk of complications and morbidity. However, an early aggressive approach to elimiate the nidus (if present) may be undertaken if the benefits exceed the risks. Trans-arterial coil embolization or ligation of feeding arteries where the nidus is left intact, are incorrect approaches and may result in proliferation of the lesion. Furthermore, such procedures would prevent future endovascular access to the lesions via the arterial route. Surgically inaccessible, infiltrating, extra-truncular AVMs can be treated with endovascular therapy as an independent modality. Among various embolo-sclerotherapy agents, ethanol sclerotherapy produces the best long term outcomes with minimum recurrence. However, this procedure requires extensive training and sufficient experience to minimize complications and associated morbidity. For the surgically accessible lesions, surgical resection may be the treatment of choice with a chance of optimal control. Preoperative sclerotherapy or embolization may supplement the subsequent surgical excision by reducing the morbidity (e.g. operative bleeding) and defining the lesion borders. Such a combined approach may provide an excellent potential for a curative result. Conclusion. AVMs are high flow congenital vascular malformations that may occur in any part of the body. The clinical presentation depends on the extent and size of the lesion and can range from an asymptomatic birthmark to congestive heart failure. Detailed investigations including duplex ultrasound, MRI/MRA and CT/CTA are required to develop an appropriate treatment plan. Appropriate management is best achieved via a multi-disciplinary approach and interventions should be undertaken by appropriately trained physicians.

Treatment of clinically diagnosed equine sarcoid with a mistletoe extract (Viscum album austriacus)

BACKGROUND: Equine sarcoids (ES) are common, difficult to treat, and have high recurrence rates. Viscum album extracts (VAE) are used in human cancer treatment. HYPOTHESIS: That therapy with VAE (Iscador P) is effective in the treatment of ES. ANIMALS: Fifty-three horses (444 ES); 42 were treated with VAE or placebo as monotherapy; 11 were treated with VAE or placebo after selective excision of ES. METHODS: Prospective, randomised, blinded, clinical trial. Horses were randomly assigned to treatment (VAE; n=32) or control group (Placebo; n=21). One milliliter of VAE (Iscador P) in increasing concentrations from 0.1 to 20 mg/mL or physiological NaCl solution was given SC 3 times a week over 105 days. Number, localization, and type of the ES were documented over 12 months. A subset of 163 clinically diagnosed equine sarcoid (CDES) lesions (95 VAE, 68 Placebo) was evaluated in detail, considering clinical findings and tumor volume. RESULTS: No undesired adverse effects were observed except for mild edema at the injection site in 5 of 32 horses (16%). Complete or partial regression was observed in 13 horses of the VAE group (41%) and in 3 of the control horses (14%; P<.05). After VAE treatment, 48 of 95 CDES (67%) showed an improvement compared with 17 of 68 CDES in the control group (40%; P<.01). Twenty-seven CDES had disappeared completely in the VAE group (38%) compared with 9 CDES in the control group (13% NS). CONCLUSIONS AND CLINICAL IMPORTANCE: VAE (Iscador P) represents a safe and effective treatment for CDES.

[Mucormycosis due to Mycocladus corymbiferus in a fattening pig]

A fattening pig with enlarged head and abdominal lymph nodes was examined. An aspirate of the abscesses did not produce a conclusive diagnosis. Only an excision with subsequent histological and bacteriological examination showed the mould Mycocladus corymbiferus (syn. Absidia corymbifera) to be present. Similar abscesses should be examined as actinomycosis and leucosis are the main differential diagnoses.

Microsurgical management of large intra-and extracranial calvarial meningiomas

Objective: Based on the largest series reported of giant intra- and extracranial calvarial meningiomas (GIECM) the purpose of the present study was to characterize the treatment and outcome data associated with patients operated on GIECM and to describe our experience in the management of this rare and therapeutically demanding tumour entity. Methods: The data of 12 patients (7/12 males, 5/12 females) with surgically treated GIECM at the University Hospitals Aachen and Bern between 1994 and 2011 were retrospectively analyzed. The mean patient age was 58 years (range, 22 to 78 years). Symptom distribution included extracranial swelling (12/12), seizures (5/12), headache (4/12), gait disturbance (3/12), dizziness (2/12), and impaired vision (1/12). GIECM were located frontal (6/12), temporal (3/12), parietal, fronto-parietal, and parieto-occipital (1/12 each). Microsurgical resection with acrylic-augmented cranioplasty was performed in all patients and 11/12 patients received dural repair with synthetic (7/11) or autologous (4/11) patch grafts. Surgical excision in two stages with primary removal of the extracranial meningioma component was undertaken in 2/12 patients, whereas preoperative embolization and postoperative radiotherapy were applied in 1/12 patient each. Results: In contrast to intradural meningiomas GIECM mainly affect male patients at a comparatively younger age. GIECM could be completely (9/12) or subtotally (3/12) resected. Surgical-associated complications included minor CSF leak (6/12), wound healing disturbance (3/12), venous engorgement, and haemorrhage (2/12 each), requiring reoperation in 3/12 cases. Histopathological examination revealed meningothelial (6/12), atypical (4/12), and transitional (1/12) GIECM. 10/12 patients exhibited excellent postoperative clinical outcome, 1/12 patient each deteriorated or died of pulmonary embolism. Conclusions: The operative management of GIECM is challenging, carries a substantial risk, and demands special strategies because of the large tumour size, anatomical involvement of scalp, calvaria, meninges, brain or vascular structures, and more frequent atypical histology. Although microsurgical resection with cranioplasty and mostly dural grafting usually results in a good clinical outcome, the potential complication rate is markedly higher when compared to smaller meningiomas without extracranial component. Preoperative embolization and staging of surgical resection are possible additional therapeutic options.