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Most antitumour therapies damage tumour cell DNA either directly or indirectly. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum, ataxia-telangiectasia and Fanconi anemia. Notably, DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Unexpectedly, a paradoxical relationship between DNA mismatch repair and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between DNA repair mechanism efficiency and tumour therapy might be more complex. Here, we review the evidence for the contribution of carcinogenic properties of several drugs as well as of alterations in specific mechanisms involved in drug-induced DNA damage response and repair in the pathogenesis of therapy-related cancers.

The WRN protein belongs to the RecQ family of DNA helicases and is implicated in replication fork restart, but how its function is regulated remains unknown. We show that WRN interacts with the 9.1.1 complex, one of the central factors of the replication checkpoint. This interaction is mediated by the binding of the RAD1 subunit to the N-terminal region of WRN and is instrumental for WRN relocalization in nuclear foci and its phosphorylation in response to replication arrest. We also find that ATR-dependent WRN phosphorylation depends on TopBP1, which is recruited by the 9.1.1 complex in response to replication arrest. Finally, we provide evidence for a cooperation between WRN and 9.1.1 complex in preventing accumulation of DNA breakage and maintaining genome integrity at naturally occurring replication fork stalling sites. Taken together, our data unveil a novel functional interplay between WRN helicase and the replication checkpoint, contributing to shed light into the molecular mechanism underlying the response to replication fork arrest.

The surgical treatment of sinonasal malignancies is in continuous evolution. In selected patients, endoscopic resection has become a sound alternative to traditional external approaches. Further improvements are necessary to enhance the possibilities of endoscopic transnasal resection of sinonasal malignancies. We present a case of intestinal-type adenocarcinoma of the left nasal fossa eroding the skull base that affected a 56-year-old male. The patient was surgically-treated by means of a four-hand binarial endoscopic transnasal resection using a 3D endoscopic system and neuronavigation. Surgery was completed in 5 hours without significant complications. Surgeons were able to recognize and manage anatomical structures, and to control bleeding easily thanks to the bimanual technique and 3D visualization. The new 3D scopes and the bimanual technique under the guidance of a navigation system represent an interesting solution that can overcome the traditional limits of the traditional set up currently used.

Conclusion: The ENT magnetic navigation system is potentially useful and offers the most accurate technique for harvesting frontal osteoplastic flaps. It represents a valid tool in the wide range of instruments available to rhinologists., Objective: Precise delineation of the boundaries of the frontal sinus is a crucial step when harvesting a frontal osteoplastic flap. We present a novel technique using the ENT magnetic navigation system., Methods: Nineteen patients affected by different pathologies involving the frontal sinus underwent an osteoplastic flap procedure using the ENT magnetic navigation system between January 2009 and April 2011., Results: The ENT magnetic navigation system was found to be a safe and accurate tool for delineating the frontal sinus boundaries. No intraoperative complications occurred during the osteoplastic procedures.

Objective: To review our experience with the surgical treatment of frontoethmoidal osteomas, focusing on the osteomas that were either localized laterally in the frontal sinus or showing intraorbital involvement., Design: Retrospective evaluation., Setting: Tertiary care center., Patients: Patients with symptomatic frontoethmoidal or intraorbital osteomas who had been treated surgically from 1996 through 2011., Intervention: Sixty frontoethmoidal osteomas were treated surgically. The lesion involved the far lateral portion of the frontal sinus in 23 cases and the orbital region in 6 cases. In 31 cases, a purely endoscopic approach was performed while a combined procedure was used in 25 patients. In 4 patients, an exclusively external approach was required., Main Outcome Measure: No recurrence of osteoma., Results: Radical resection was obtained, except in the case of 2 lesions. No osteoma recurrence was observed during a mean follow-up of 72.6 months., Conclusions: The size of the osteoma, far lateral extension of the tumor in the frontal sinus beyond the lamina papyracea, and intraorbital involvement are no longer absolute contraindications for purely transnasal endoscopic resection. What is important is that the surgeon should not be dogmatic but rather be ready to change his or her mind during surgery, shifting to an external approach when required.

Nowadays endoscopic skull base reconstruction is safely and effectively performed by means of two-dimensional (2-D) endoscopic technique. The aim of our study is to compare our 2-D experience with the novel 3-D technology in the field of skull base reconstruction techniques. In this study four patients treated with various kinds of planned duraplasty are included. The new 3-D technology was compared with the high-definition 2-D scopes during the different steps of the procedures. The 3-D endoscopic skull base reconstruction obtained primary closure without complications in all cases. According to the subjective opinion of experienced endosurgeons, this novel technique improved depth perception, distance and size estimation, ability to identify specific anatomic structures, and hand-eye coordination. The main drawbacks detected were inferior sharpness, contrast and lighting that impaired the application of the technique in narrow sinonasal spaces. According to our preliminary impressions, 3-D endoscopic skull base reconstruction is an effective and safe procedure and could represent a significant advantage for accurate managing of the skull base region.

We report a case of a left fronto-temporo-parietal subdural haematoma that emerged as a complication of an endonasal endoscopic resection of a sinonasal adenocarcinoma of the left ethmoidal region. During the first surgical intervention, following oncological principles, the dura mater above the ethmoidal plate was removed and a skull base plasty was performed. In the post-operative phase a massive cerebrospinal fluid leak was observed and a revision duraplasty was performed the following day. Subsequently the patient was discharged on day 8 with no signs of CSF leakage. At the three month follow-up MR examination a subdural haematoma was observed and then treated by the neurosurgeon in a standard fashion. The collection was quite asymptomatic and discovered accidentally. We strongly advise the role of early post-op neuroimaging in every patient undergoing skull base procedures. We maintain that a massive CSF leak, that causes a significant reduction of intracranial pressure, should be managed as a surgical emergency, in order to reduce the risk of subdural haematoma., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Fungal rhinosinusitis is a common disease of the paranasal sinuses. The fungus ball (FB) is defined as an extramucosal mycotic proliferation that fills one or more paranasal sinuses. Sphenoid sinus is an uncommon localization of this disease, as reported in the literature. This study describes our experience in the diagnosis and treatment of sphenoid sinus FB (SSFB), with a particular focus on the surgical approach to the sphenoid sinus., Methods: We retrospectively analyzed the clinical records of patients affected by FB of the sphenoid sinus, who underwent endoscopic sinus surgery (ESS) in our institutions between 1995 and 2009. We described the surgical technique, the methods of mycological and histopathological evaluation, as well as the perioperative and postoperative management., Results: From 1995 to 2009, 226 patients affected by sinonasal FB underwent ESS in our institutions. A sphenoid localization was found in 56 patients (24.78%; mean age, 62 years). Cephalea was the most common symptom, and 14.3% of patients complained of ocular symptoms. We performed a direct paraseptal sphenoidotomy in 31 patients (55.4%) and a transethmoidal sphenoidotomy in 25 patients (44.6%). Histology unveiled fungal hyphae with absent mucosal invasion in all cases. Cultural results revealed positivity for mycotic colonization in 26 cases (46.4%, most commonly Aspergillus fumigatus). Follow-up ranged from 12 to 181 months with a mean of 70.7 months., Conclusion: The description of our experience in the diagnosis and treatment of SSFB underlines the importance of a precise diagnostic pathway in case of sphenoidal disease. Nowadays, in our opinion, the paraseptal direct sphenoidotomy represents the less invasive, fastest and most anatomically conservative approach to the sphenoid sinus in case of SSFB.

During the last years, multiple methods and a wide set of materials for skull base reconstruction have been described. In our experience, the ideal graft for duraplasty is the iliotibial tract due to its favorable characteristics in terms of thickness, pliability, and strength. In this report, we show the iliotibial tract-harvesting technique under endoscopic guidance with a minimally invasive approach using a cadaveric model. Two longitudinal incisions of 1 cm each were made at 4 cm down a line drawn between the anterior-superior iliac spine and the lateral margin of patella at the extremities of the middle third of the thigh. By using a set of instruments for endoscopic face-lifting, the graft was easily set up and harvested. The endoscopic approach is associated with less visible scars, but longer operative time in comparison with open traditional procedure. The pros and cons in terms of morbidity need to be evaluated by further studies on actual cases.

Background: Surgical approaches to the parapharyngeal spaces are challenging. Little is known about the transoral perspective of the anatomy of the parapharyngeal space. Thus, transoral approaches are seldom performed, and only for small-sized tumors., Methods: Six freshly injected cadaver heads were dissected to illustrate the transoral surgical anatomy of the parapharyngeal space., Results: The transoral window dominates the parapharyngeal space from the medial pterygoid muscle laterally to the superior constrictor muscle medially. The stylopharyngeus and styloglossus muscles seem to be critical landmarks in this approach. Posterior to these muscles and laterally to the superior constrictor muscle, the internal carotid artery, internal jugular vein, and lower cranial nerves are identifiable., Conclusion: This anatomic study emphasizes the critical role of the superior constrictor, styloglossus, and stylopharyngeus muscles and highlights the concept of a logical step by step technique that allows the identification of important structures and the creation of safe surgical corridors., (Copyright © 2010 Wiley Periodicals, Inc.)

The Werner syndrome protein (WRN) is a member of the human RecQ family DNA helicases implicated in the maintenance of genome stability. Loss of WRN gives rise to the Werner syndrome, a genetic disease characterised by premature aging and cancer predisposition. WRN plays a crucial role in the response to replication stress and significantly contributes to the recovery of stalled replication forks, although how this function is regulated is not fully appreciated. There is a growing body of evidence that WRN accomplishes its task in close connection with the replication checkpoint. In eukaryotic cells, the replication checkpoint response, which involves both the ATR and ATM kinase activities, is deputed to the maintenance of fork integrity and re-establishment of fork progression. Our recent findings indicate that ATR and ATM modulate WRN function at defined steps of the response to replication fork arrest. This review focuses on the novel evidence of a functional relationship between WRN and the replication checkpoint and how this cross-talk might contribute to prevent genome instability, a common feature of senescent and cancer cells.

Oxidative DNA damage can be the consequence of endogenous metabolic processes and exogenous insults and several DNA repair enzymes provide protection against the toxic effects of oxidized DNA bases. Here we review the increasing knowledge on the relationship between an oxidized dNTPs pool and genome instability. The review also describes some important progress toward understanding the role of oxidative DNA damage and its repair in neurodegenerative diseases. In particular the hMTH1 hydrolase destroys oxidized nucleic acid precursors to prevent their harmful incorporation into DNA and RNA. Based on results obtained in our transgenic mouse overexpressing hMTH1 in the brain we discussed the mechanisms by which this hydrolase protects against neurodegeneration in Huntington disease models., (2010 Elsevier B.V. All rights reserved.)

Aim: To report our experience with endoscopic, endonasal management of sinonasal haemangiopericytoma., Materials and Methods: Retrospective review of the medical records of 10 patients undergoing endoscopic, endonasal surgery for sinonasal haemangiopericytoma of the nose and paranasal sinuses, between 1997 and 2008., Results: Five men and five women were included. Their mean age at surgery was 59 years. All patients underwent endoscopic, endonasal resection of their tumour. Major post-operative complications were encountered in only one patient (stroke). Local recurrence was diagnosed in only one patient (10 per cent), who subsequently underwent a combined resection (endoscopic and external) with orbital exenteration., Conclusions: Sinonasal haemangiopericytomas are rare tumours that are usually benign. The mainstay of treatment is wide surgical excision with free resection margins. Nowadays, the great majority of patients can be treated using a purely endoscopic, endonasal approach.

Background: The aim of this study was to illustrate the endoscopic surgical anatomy of the infratemporal fossa (ITF) and upper parapharyngeal space and to provide useful landmarks by comparing transnasal perspectives with external ones., Materials and Methods: 6 fresh double injected heads were dissected. External lateral dissection was performed through a pre-auricular skin incision while external anterior dissection started with a modified Weber-Ferguson incision. External medial to lateral dissection was performed starting from the rhinopharyngeal and pterygoid regions, after cutting the specimen in 2 halves passing through the nose. Endoscopic dissection was performed through an endonasal approach (0° and 45° scopes)., Results: Among all the structures identified during the dissection, the most useful landmark when dissecting the ITF in a lateral to medial direction is the lateral pterygoid muscle. In anterior approaches (mostly endoscopic) the role of the lateral pterygoid muscle is less important and the Eustachian tube (ET) represents the most important landmark to point out the upper portion of the parapharyngeal internal carotid artery (ICA). The role of the ET, in lateral dissection is, on the contrary, by far less important given the fact that it is very deep in the surgical field and that the ICA is encountered earlier during surgical approaches. Another crucial landmark during anterior endoscopic surgery is the vidian nerve because it points to the anterior genu of the internal carotid artery., Conclusion: The complex 3-dimensionality of the ITF and the upper parapharyngeal space needs a sound knowledge of the surgical anatomy. The role of the same landmarks changed in different approaches. The ability to orientate oneself in this complex area is related to an accurate knowledge of its anatomy through comparison of endoscopic and external perspectives., (© Georg Thieme Verlag KG Stuttgart · New York.)

Accurate response to replication arrest is crucial to preserve genome stability and requires both the ATR and ATM functions. The Werner syndrome protein (WRN) is implicated in the recovery of stalled replication forks, and although an ATR/ATM-dependent phosphorylation of WRN was observed after replication arrest, the function of such modifications during the response to perturbed replication is not yet appreciated. Here, we report that WRN is directly phosphorylated by ATR at multiple C-terminal S/TQ residues. Suppression of ATR-mediated phosphorylation of WRN prevents proper accumulation of WRN in nuclear foci, co-localisation with RPA and causes breakage of stalled forks. On the other hand, inhibition of ATM kinase activity or expression of an ATM-unphosphorylable WRN allele leads to retention of WRN in nuclear foci and impaired recruitment of RAD51 recombinase resulting in reduced viability after fork collapse. Altogether, our findings indicate that ATR and ATM promote recovery from perturbed replication by differently regulating WRN at defined moments of the response to replication fork arrest.

Background and Importance: To describe a transnasal endoscopic route to the jugular foramen and the endoscopic anatomy of the infratemporal fossa., Clinical Presentation: Endoscopic transnasal dissection of the infratemporal fossa was performed in 3 injected fresh heads (1 head only in arteries and 2 heads in arteries and veins). Two other double-injected specimens were dissected externally (2 of them side laterally and 1 anteriorly) to compare the different views and better understand the 3-dimensionality of the region.Detailed endoscopic anatomy of the infratemporal fossa was clearly observed. The realization of a septal and posterior maxillary window allows surgeons to gain space to the jugular foramen. The ability to manage the vessels, especially the veins, and identify the muscles is mandatory. The fundamental role of the vidian canal in targeting the anterior genu of the internal carotid artery is confirmed. The role of the maxillary and mandibular branches of the trigeminal nerve and the eustachian tube in this kind of approach is critical., Conclusion: A fully transnasal endoscopic route to the jugular foramen is feasible. The most important landmark for this kind of approach is the eustachian tube.

Background: The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh(-/-) mice to oxidative stress., Methodology/principal Findings: The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh(-/-) phenotype was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh(-/-) mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh(-/-) mice. Lymphoid hyperplasia and a significant reduction in Foxp3(+) regulatory T cells were observed only in Mutyh(-/-) mice., Conclusions: The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response.

Background: The aim of this study was to illustrate the anatomy of the medial compartment of the orbit by comparing the endoscopic transnasal perspective with the external ones., Methods: 8 orbits from 5 double-injected heads were carefully dissected. An endoscopic anterior transconjunctival dissection was performed in one orbit while an endoscopic transnasal intraconal dissection was conducted in 3 orbits. External dissections (from medial, superior and anterior perspective) were also performed., Results: The role of the medial rectus muscle is emphasised. It represents the first important landmark encountered, covering all the other structures during transnasal approaches. By displacing it, the medial intraconal space with its contents becomes visible: the ophthalmic artery and related branches, the superior ophthalmic vein, the nasociliary nerve and, in the deepest part of the medial compartment, the optic nerve., Conclusion: The medial compartment of the orbit can be addressed transnasally. By displacing the medial rectus muscle, it is possible to gain adequate space for the instruments and to control all of the medial compartment, including the medial aspect of the optic nerve., (© Georg Thieme Verlag KG Stuttgart · New York.)

The MUTYH DNA glycosylase specifically removes adenine misincorporated by replicative polymerases opposite the oxidized purine 8-oxo-7,8-dihydroguanine (8-oxoG). A defective protein activity results in the accumulation of G>T transversions because of unrepaired 8-oxoG:A mismatches. In humans, MUTYH germline mutations are associated with a recessive form of familial adenomatous polyposis and colorectal cancer predisposition (MUTYH-associated polyposis, MAP). Here we studied the repair capacity of the MUTYH variants R171W, E466del, 137insIW, Y165C and G382D, identified in MAP patients. Following expression and purification of human proteins from a bacterial system, we investigated MUTYH incision capacity on an 8-oxoG:A substrate by standard glycosylase assays. For the first time, we employed the surface plasmon resonance (SPR) technology for real-time recording of the association/dissociation of wild-type and MUTYH variants from an 8-oxoG:A DNA substrate. When compared to the wild-type protein, R171W, E466del and Y165C variants showed a severe reduction in the binding affinity towards the substrate, while 137insIW and G382D mutants manifested only a slight decrease mainly due to a slower rate of association. This reduced binding was always associated with impairment of glycosylase activity, with adenine removal being totally abrogated in R171W, E466del and Y165C and only partially reduced in 137insIW and G382D. Our findings demonstrate that SPR analysis is suitable to identify defective enzymatic behaviour even when mutant proteins display minor alterations in substrate recognition., (Copyright 2010 Elsevier B.V. All rights reserved.)

Endoscopic techniques have undergone tremendous advancement in the past years. From the management of phlogistic pathologies, we have learned to manage skull base lesions and even selected intracranial diseases. Current anatomical knowledge plus computer-aided surgery has enabled surgeons to remove large lesions in the paranasal sinuses extending beyond the boundaries of the sinuses themselves. In this sense, management of benign diseases via endoscopic routes is nowadays well accepted whilst the role of endoscopic techniques in sinonasal malignancies is still under investigation. Nowadays, it is possible to tackle different pathologies placed not only in the ventral skull base, but also extended laterally (infratemporal fossa and petrous apex) and even, in really selected cases, within the orbit. The ability to resect and reconstruct has improved significantly. At the moment, the improvement in surgical techniques, like the four-handed technique, has rendered endoscopic procedures capable of managing complex pathologies, according the same surgical principles of the open approaches. From now onwards, frameless neuronavigation, modular approaches, intraoperative imaging systems and robotic surgery are and will be an increasingly important part of endonasal surgery, and they will be overtaken by further evolution.

Objective: To evaluate the feasibility of endoscopic surgery in the management of selected nasopharyngeal cancers. Three different types of nasopharyngeal endoscopic resections (NER) are described., Method of Study: From January 1997 to October 2008, 17 consecutive patients (mean age: 50 years) with previously untreated (5) or recurrent nasopharyngeal tumours (12) were treated with curative intent by pure endoscopic resection. The extent of surgical resection was classified as follows: type I NER: resection limited to the postero-superior nasopharyngeal wall; type 2 NER: resection superiorly extended to the sphenoid sinus; type 3 NER: resection with lateral extension including the cartilaginous portion of the Eustachian tube and parapharyngeal space., Results: Type 1 NER was performed in 4 cases, type 2 in 6, and type 3 in 7. No intra- or post-operative complications were observed. Mean hospitalization time was 4 days (range: 1-7). Follow-up ranged from 10 to 138 months (mean: 41.2±38). At the time of writing, 12 (71/%) patients were free of disease, 3 (17%) alive with disease, and 2 (12%) dead of disease., Conclusions: NER is a feasible surgical technique that can be tailored in relation to tumour extension. Larger series and longer follow-up are needed to further validate the long-term results.

MUTYH-associated polyposis (MAP) is a colorectal cancer syndrome, due to biallelic mutations of MUTYH. This Base Excision Repair gene encodes for a DNA glycosylase that specifically mitigates the high mutagenic potential of the 8-hydroxyguanine (8-oxodG) along the DNA. Aim of this study was to characterize the biological effects, in a mammalian cell background, of human MUTYH mutations identified in MAP patients (137insIW [c.411_416dupATGGAT; p.137insIleTrp]; R171W [c.511C>T; p.Arg171Trp]; E466del [c.1395_1397delGGA; p.Glu466del]; Y165C [c.494A>G; p.Tyr165Cys]; and G382D [c.1145G>A; p.Gly382Asp]). We set up a novel assay in which the human proteins were expressed in Mutyh(-/-) mouse defective cells. Several parameters, including accumulation of 8-oxodG in the genome and hypersensitivity to oxidative stress, were then used to evaluate the consequences of MUTYH expression. Human proteins were also obtained from Escherichia coli and their glycosylase activity was tested in vitro. The cell-based analysis demonstrated that all MUTYH variants we investigated were dysfunctional in Base Excision Repair. In vitro data complemented the in vivo observations, with the exception of the G382D mutant, which showed a glycosylase activity very similar to the wild-type protein. Our cell-based assay can provide useful information on the significance of MUTYH variants, improving molecular diagnosis and genetic counseling in families with mutations of uncertain pathogenicity., ((c) 2009 Wiley-Liss, Inc.)

Background: Because of a better understanding of the anatomy from an endoscopic perspective, the acquisition of surgical experience, and concomitant technological advances, endoscopic resection of the anterior skull base (ASB) and overlying dura has now become a reality, opening new possibilities in the management of sinonasal malignancies. Here, the authors review a series of 62 patients, the largest reported to date, who underwent endoscopic transnasal craniectomy (ETC) and endoscopic dural repair for the management of selected sinonasal malignancies. Special emphasis is placed on the surgical technique, technical tricks, choice of materials for endoscopic dural repair, postoperative management, and complications., Methods: From 2004, 62 patients underwent ETC at two referral hospitals, which extended anteroposteriorly from the frontal sinus to planum sphenoidale and laterolaterally from the nasal septum to the lamina papyracea (unilateral resection, n = 28; 45%) or from papyracea to papyracea (bilateral resection, n = 34; 55%). Duraplasty with a three-layer technique was performed using the iliotibial tract and fat tissue., Results: The most frequent histotypes were adenocarcinoma (58%) and olfactory neuroblastoma (22%). Forty-five (73%) patients were previously untreated. The incidence of early (T1-2, Kadish A-B) and advanced (T3-4, Kadish C) tumors was similar. The complication rate was 15%, mostly cerebrospinal fluid leaks (13%). Its prevalence did not correlate with patient age, medical comorbidities, previous treatment, presence of ASB involvement, or whether ETC was mono- or bilateral, but tended to correlate with advanced tumor stage, dural involvement, and the period of treatment. After a mean follow-up of 17.5 months (range, 1-54 months), 58 (94%) patients had no evidence of disease., Conclusion: In correctly selected patients with sinonasal tumors involving the ASB, ETC offers a less invasive alternative than resection by an open approach with an acceptable morbidity.

Epithelial cells of cylindrical cell papilloma are oncocytes, which arise from the sinonasal respiratory epithelium, hence the term Oncocytic Schneiderian papilloma.This is a rare and benign neoplasm of the nose and paranasal sinuses and it should be considered in the work-up of all unilateral nasal polypoid lesions. Clinically behaviour is comparable to inverted papillomas for local recurrence and malignancy coexistence. We report a case arisen from the nasoethmoidal space that extended to the anterior skull base through a bone dehiscence with intradural invasion and orbital space involvement. Surgical therapy is the treatment of choice, the endonasal endoscopic approach can be used in most of the cases and this surgical technique is safe and suitable also in presence of an extra nasal extension. We describe our experience for management of this kind of lesions and some notes on our operative technique.

Objective: Skull base encephaloceles are difficult to diagnose and to treat. Traditionally, they are approached externally via craniotomic routes. Endoscopic management of skull base defects is the standard treatment in adults. Our aim is to evaluate the efficacy and safety of endoscopic endonasal repair of basal encephaloceles in the paediatric population., Methods: Retrospective evaluation of paediatric encephaloceles managed endoscopically at a tertiary referral centre., Results: Eleven subjects fitted the criteria of the study. Mean age at surgery was 6.1+/-4.6 SD years, while mean follow-up was 46.5+/-28 SD months. Most of the defects were located in the anterior cranial fossa. All patients were managed successfully with no complications., Conclusions: Endonasal endoscopic management of congenital encephaloceles is feasible in paediatric patients. Meticulous pre-op neuroimaging is of paramount importance when dealing with such cases.

Mismatch repair is the major pathway controlling genetic stability by removing mispairs caused by faulty replication and/or mismatches containing oxidized bases. Thus, inactivation of the Msh2 mismatch repair gene is associated with a mutator phenotype and increased cancer susceptibility. The base excision repair gene Mutyh is also involved in the maintenance of genomic integrity by repairing premutagenic lesions induced by oxidative DNA damage. Because evidence in bacteria suggested that Msh2 and Mutyh repair factors might have some overlapping functions, we investigated the biological consequences of their single and double inactivation in vitro and in vivo. Msh2(-/-) mouse embryo fibroblasts (MEF) showed a strong mutator phenotype at the hprt gene, whereas Mutyh inactivation was associated with a milder phenotype (2.9 x 10(-6) and 3.3 x 10(-7) mutation/cell/generation, respectively). The value of 2.7 x 10(-6) mutation/cell/generation in Msh2(-/-)Mutyh(-/-) MEFs did not differ significantly from Msh2(-/-) cells. When steady-state levels of DNA 8-oxo-7,8-dihydroguanine (8-oxoG) were measured in MEFs of different genotypes, single gene inactivation resulted in increases similar to those observed in doubly defective cells. In contrast, a synergistic accumulation of 8-oxoG was observed in several organs of Msh2(-/-)Mutyh(-/-) animals, suggesting that in vivo Msh2 and Mutyh provide separate repair functions and contribute independently to the control of oxidative DNA damage. Finally, a strong delay in lymphomagenesis was observed in Msh2(-/-)Mutyh(-/-) when compared with Msh2(-/-) animals. The immunophenotype of these tumors indicate that both genotypes develop B-cell lymphoblastic lymphomas displaying microsatellite instability. This suggests that a large fraction of the cancer-prone phenotype of Msh2(-/-) mice depends on Mutyh activity.

Objectives: Ethmoidal arteries (EAs) can be responsible for severe bleeding. Clinical features of EA bleeding are rather extensive because it can occur within the nasal cavity or in orbital spaces. Furthermore, surgical management of EA bleeding is challenging., Study Design: Retrospective evaluation., Method of Study: Five clinical patients with severe bleeding from EAs and/or epistaxis refractory to sphenopalatine artery closure were included in this work. Careful anatomic dissection of the orbitoethmoidal region was performed in 3 fresh injected heads., Results: Ethmoidal artery management is not uniform because it depends on the rapidity and severity of the bleeding and the chambers within which it happens. Trauma-related bleeding usually requires a lateral canthotomy, whereas in intraoperative bleeding, efforts should be made to directly coagulate the bleeding vessel, even within the orbital fat. Spontaneous epistaxis refractory to sphenopalatine artery closure is to be addressed externally, preferably under endoscopic vision., Conclusions: Ethmoidal artery management differs according to the clinical situation. Elective surgery is advisable for spontaneous epistaxis, whereas emergency treatment, ranging from intraorbital coagulation of the bleeding vessel to lateral canthotomy (when the patient is in a sight-threatening condition), is necessary when the bleeding occurs within orbital spaces. A treatment management algorithm is useful in cases of severe and refractory EA bleeding.

The frontal sinus, because of its proper anatomic features, has a particular relation with nasal cavities. Indeed, its anatomic opening (ostium) is strictly related to a complex ethmoidal structure prechamber mainly composed of the frontal recess.This constitutional feature makes the endoscopic approach more complex in comparison with other major sinuses treatment.In the following work, we present a systematization of surgical approach in relation to different pathologies, analyzing differences and results throughout the comparison of 2 groups: one treated with the endoscopic approach, and the other with open surgery.From these observations, we can assess that surgical approach choice must consider several parameters such as neoplasm localization, extension, dimension, and frontal recess anatomic features.

Background: Endonasal management of most anterior cranial fossa cerebrospinal fluid leaks is a well established procedure, and even some middle cranial fossa cerebrospinal fluid leaks can be managed safely endonasally. Endonasal endoscopic management of leakages of the posterior cranial fossa represents an unique challenge., Objective: The aim of this study was to assess the feasibility of an endoscopic endonasal approach for treating well-selected cerebrospinal fluid leaks of the petroclival region., Methods: Clinical charts of patients with leakages of the petroclival region treated at our institution were retrospectively reviewed. Careful dissection of the petroclival region was performed, both endonasally and externally, in three fresh injected heads., Results: Two patients presented a leakage of the petroclival region. Both the patients presented multiple skull base defects. The two patients underwent a supratubaric trans-spheno-petroclival approach; in one of these, it was performed in combination with a middle cranial fossa approach. Multilayer reconstruction was performed in both patients. No cerebrospinal fluid leak recurrences were observed during follow-up (17 and 19 months, respectively)., Conclusions: Endonasal endoscopic management of well-selected petroclival cerebrospinal fluid leaks is feasible.

Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease-like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In a complementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder., Competing Interests: The authors have declared that no competing interests exist.

Maxillofacial district osteomas are benign lesions with very slow growth. The most frequent localization is the frontal sinus, about 57% of all paranasal cavity osteomas; less frequently, they can be located in the ethmoidal sinus or sphenoidal and maxillary. Etiology has not completely clarified yet; nevertheless, there are 3 main pathogenetic theories: osteogenic, traumatic, and infective. Open procedures represent the gold standard, but there is still an unsolved debate for the best treatment option. Endoscopic techniques offer an alternative approach, enabling closer and more direct visualization of the anatomy as well as avoiding damage to surrounding structures. In our study, we analyzed all patients treated with endoscopic approach for paranasal sinus osteomas in the ENT unit of the University of Varese and compared them with patients treated for the same pathology with open surgery in the Maxillo-facial Department of the University of Rome "La Sapienza." The purpose of the work was to compare the advantages and disadvantages of the 2 procedures. In conclusion, this study underlines the importance of flexibility in surgical approach decision, which must fit the different issues of the pathology and of the patient.

Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.

Tumor resistance to cytotoxic chemotherapy drugs and their toxicity to normal cells are major clinical obstacles to anticancer therapy effectiveness. Alterations in various DNA repair pathways play a key role in the development of both mechanisms of drug resistance and toxicity. Since deregulation of the DNA damage response and alterations in DNA repair pathways are relatively common in human cancer, the knowledge of these alterations in cancer cells would be an important predictive factor for the clinical response to chemotherapy and a useful guide in designing an appropriate therapeutic strategy. This review is focused on the mismatch repair (MMR) pathway and the O(6)-methylguanine-DNA-methyltransferase (MGMT) repair protein. In particular, we examine how inactivation of these DNA repair mechanisms might affect the response of tumor cells to chemotherapy, with a special emphasis on agents inducing methylation and oxidative DNA damage and interstrand DNA cross-links (ICLs). In addition, we provide novel experimental evidence indicating that MMR is required for efficient repair of ICLs via stabilization of RAD51 containing repair intermediates. Finally, we discuss possible emerging therapeutical strategies for treating MMR-defective tumors.

Background: The increasing expertise in the field of transnasal endoscopic surgery recently has expanded its indications to include the management of sinonasal malignancies. We report our experience with the endoscopic management of nasoethmoidal malignancies possibly involving the adjacent skull base., Methods: A retrospective analysis was performed of patients treated by an exclusive endoscopic approach (EEA) or a cranioendoscopic approach (CEA) from 1996 to 2006 managed by two surgical teams at the Departments of Otorhinolaryngology of the University of Brescia, and the University of Pavia/Insubria-Varese, Italy., Results: One-hundred eighty-four patients were considered eligible for the present analysis. An EEA was performed in 134 patients and the remaining 50 patients underwent the CEA. The most frequent histotypes encountered were adenocarcinoma (37%), squamous cell carcinoma (13.6%), olfactory neuroblastoma (12%), mucosal melanoma (9.2%), and adenoid cystic carcinoma (7.1%). Overall, 86 (46.7%) patients received some form of adjuvant treatment. The patients were followed up for a mean of 34.1 months (range, 2-123 months). The 5-year disease-specific survival was 91.4 +/- 3.9% and 58.8 +/- 8.6% (p = 0.0004) for the EEA and CEA group, respectively., Conclusion: To the best of our knowledge, this is the largest series reported to date of malignant tumors of the sinonasal tract and adjacent skull base treated with pure endoscopic or cranioendoscopic techniques. A 5-year disease-specific survival of 91.4% and 58.8% for the EEA and the CEA groups, respectively, seem to indicate that endoscopic surgery, when properly planned and in expert hands, may be a valid alternative to standard surgical approaches for the management of malignancies of the sinonasal tract.

The production of reactive oxygen species (ROS) in mammalian cells is tightly regulated because of their potential to damage macromolecules, including DNA. To investigate possible links between high ROS levels, oxidative DNA damage, and genomic instability in mammalian cells, we established a novel model of chronic oxidative stress by coexpressing the NADPH oxidase human (h) NOX1 gene together with its cofactors NOXO1 and NOXA1. Transfectants of mismatch repair (MMR)-proficient HeLa cells or MMR-defective Msh2(-/-) mouse embryo fibroblasts overexpressing the hNOX1 complex displayed increased intracellular ROS levels. In one HeLa clone in which ROS were particularly elevated, reactive nitrogen species were also increased and nitrated proteins were identified with an anti-3-nitrotyrosine antibody. Overexpression of the hNOX1 complex increased the steady-state levels of DNA 8-oxo-7,8-dihydroguanine and caused a threefold increase in the HPRT mutation rate in HeLa cells. In contrast, additional oxidatively generated damage did not affect the constitutive mutator phenotype of the Msh2(-/-) fibroblasts. Because no significant changes in the expression of several DNA repair enzymes for oxidative DNA damage were identified, we suggest that chronic oxidative stress can saturate the cell's DNA repair capacity and cause significant genomic instability.

WRN is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks. Fragile sites have been proposed to be DNA regions particularly sensitive to replicative stress. Here, we establish that WRN is a key regulator of fragile site stability. We demonstrate that in response to mild doses of aphidicolin, WRN is efficiently relocalized in nuclear foci in replicating cells and that WRN deficiency is associated with accumulation of gaps and breaks at common fragile sites even under unperturbed conditions. By expressing WRN isoforms impaired in either helicase or exonuclease activity in defective cells, we identified WRN helicase activity as the function required for maintaining the stability of fragile sites. Finally, we find that WRN stabilizes fragile sites acting in a common pathway with the ataxia telangiectasia and Rad3 related replication checkpoint. These findings provide the first evidence of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork stalling sites.

Background: This study reviews the outcome of patients with adenocarcinoma (AC) and squamous cell carcinoma (SCC) of the naso-ethmoidal complex treated by endoscopic surgery., Methods: Sixteen patients underwent a purely endoscopic excision of AC (n = 12) or SCC (n = 4) at 2 university hospitals. All patients were prospectively followed by endoscopic and MRI evaluations., Results: The tumor originated from the ethmoid in 13 cases and the nasal fossa in 3. Lesions were staged as follows: 5 T1, 10 T2, and 1 T3. Adjuvant radiotherapy was delivered in 7 cases. Follow-up (range, 28-70 months; mean, 47.25) was available for all patients. One patient died for brain metastases 28 months after surgery. Another patient required salvage craniofacial resection and radiotherapy for recurrent AC. Five-year disease-specific and disease-free survival rates were 93.3% and 87.0%, respectively., Conclusions: In selected T1-T2 lesions of the naso-ethmoidal complex, endoscopic surgery seems to offer a satisfactory alternative to external procedures.

Objective: Management of symptomatic osteomas involving the frontal sinus is challenging. Traditional external approaches have been used in the surgical management of these lesions. Recently, endonasal endoscopic surgery has become a valid alternative to the traditional external approach in selected cases., Method of Study: Retrospective evaluation of the patients with symptomatic fronto-ethmoidal osteomas surgically managed in the last 10 years at a tertiary care facility., Results: Twenty-six osteomas involving the frontal sinus were treated surgically. In 11 cases a purely endoscopic approach was performed while in 13 patients a combined procedure was used. In two patients, an exclusively external procedure was performed. No osteoma recurrence has been observed yet (mean follow up: 40 +/- 31.75 SD months)., Conclusions: Endonasal endoscopic resection of a frontal sinus osteoma is feasible when the lesion is medial to a virtual plane through the lamina papyracea and is attached in the lower portion of the posterior wall of the frontal sinus.

Background: Our aim was to evaluate the efficacy of a bimodal method of treatment consisting in endoscopic resection followed by radiotherapy in patients with olfactory neuroblastoma (ON)., Methods: This is a retrospective review on 10 patients with ON treated at a tertiary referral center. All the patients were treated with endonasal endoscopic resection, and 1 refused postoperative radiotherapy., Results: No mortality was observed. Local tumor control was obtained in all the patients. Follow-up ranged from 15 to 79 months (median, 37 months). One patient developed a regional recurrence and for this was treated with bilateral, modified type III radical neck dissection plus radiotherapy on the neck. All patients regained a good quality of life after the treatment., Conclusions: This method of treatment causes minimal injury to the patients, reduces side effects, and improves the quality of life of those with olfactory neuroblastoma., ((c) 2007 Wiley Periodicals, Inc. Head Neck, 2007.)

The cellular response to methylation DNA damage was compared in multipotent CD34(+) hematopoietic stem cells and mature CD34(-) cells isolated from cord blood of the same donor. Cytofluorimetric analysis of freshly isolated cord blood cells indicated that both cell types were in the G0/G1 phase of the cell cycle. Quantitative RT-PCR identified a general trend towards high expression of several DNA repair genes in CD34(+) cells compared to their terminally differentiated CD34(-) counterparts. The overexpressed genes included members of the mismatch repair (MMR) (MSH2, MSH6, MLH1, PMS2), base excision repair (AAG, APEX), DNA damage reversal (O(6)-methylguanine DNA methyltransferase) (MGMT), and DNA double strand breaks repair pathways. These differences in gene expression were not apparent in CD34(+) and CD34(-) cells obtained following expansion of CD34(+) cells in a medium containing early acting cytokines. Early progenitor CD34(+) and early precursor CD34(-) cells form the two populations isolated under these experimental conditions, and both contain a significant proportion of cycling cells. The methylating agent N-methyl-N-nitrosourea (MNU) induced similar levels of apoptosis in these cycling CD34(+) and CD34(-) cells. Cytotoxicity required the presence of the MGMT inhibitor O(6)-benzylguanine and the timing of MNU cell death (48 and 72h) was similar in CD34(+) and CD34(-) cells. These data indicate that cycling CD34(+) and CD34(-) cells are equally sensitive to methylation damage. MGMT provides significant protection against MNU toxicity and MGMT and MMR play the expected roles in the MNU sensitivity of these cells.

2-Hydroxyadenine (2-OH-A), a product of DNA oxidation, is a potential source of mutations. We investigated how representative DNA polymerases from the A, B and Y families dealt with 2-OH-A in primer extension experiments. A template 2-OH-A reduced the rate of incorporation by DNA polymerase alpha (Pol alpha) and Klenow fragment (Kf(exo-)). Two Y family DNA polymerases, human polymerase eta (Pol eta) and the archeal Dpo4 polymerase were affected differently. Bypass by Pol eta was very inefficient whereas Dpo4 efficiently replicated 2-OH-A. Replication of a template 2-OH-A by both enzymes was mutagenic and caused base substitutions. Dpo4 additionally introduced single base deletions. Thermodynamic analysis showed that 2-OH-A forms stable base pairs with T, C and G, and to a lesser extent with A. Oligonucleotides containing 2-OH-A base pairs, including the preferred 2-OH-A:T, were recognized by the human MutSalpha mismatch repair (MMR). MutSalpha also recognized 2-OH-A located in a repeat sequence that mimics a frameshift intermediate.

Objectives: Management of cerebrospinal fluid leaks or encephaloceles of Sternberg's canal is challenging. Transnasal visualization of this area is difficult, especially when large pneumatization is present. External approaches to this region involve aggressive surgery and are often associated with significant morbidity. The aim of the study was to assess the real effectiveness of an endoscopic endonasal approach for treating cerebrospinal fluid leaks of the lateral recess of the sphenoid sinus., Study Design: The authors conducted a retrospective evaluation., Methods: Clinical charts of patients with cerebrospinal fluid leaks and/or encephaloceles of Sternberg's canal treated at our institution were retrospectively reviewed. All these patients were managed with an endonasal endoscopic procedure., Results: Fifteen patients (9 female and 6 male) were included in this study. Nine patients underwent a transethmoidal-pterygoidal-sphenoidal approach with a multilayer reconstructive technique. No cerebrospinal fluid leak recurrences were observed during follow up (mean follow up 37.6 +/- 21.7 standard deviation months), Conclusions: The transethmoidal-pterygoidal-sphenoidal approach provides a wide, safe, and direct route to the lateral recess of the sphenoid sinus. Multilayered reconstruction of the skull base defects must be considered the first option for this kind of lesion.

Oxidative DNA damage is one of the most common threats to genome stability and DNA repair enzymes provide protection from the effects of oxidized DNA bases. In mammalian cells, base excision repair (BER) mediated by the OGG1 and MYH DNA glycosylases prevents the accumulation of 8-oxoguanine (8-oxoG) in DNA. When steady-state levels of DNA 8-oxoG were measured in myh(-/-) and myh(-/-)/ogg1(-/-) mice, an age-dependent accumulation of the oxidized purine was found in lung and small intestine of doubly defective myh(-/-)/ogg1(-/-) mice. Since there is an increased incidence of lung and small intestinal cancer in myh(-/-)/ogg1(-/-) mice, these findings are consistent with a causal role for unrepaired oxidized DNA bases in cancer development. We previously presented in vitro evidence that mismatch repair (MMR) participates in the repair of oxidative DNA damage and msh2(-/-) mouse embryo fibroblasts also have increased steady state levels of DNA 8-oxoG. To investigate whether DNA 8-oxoG also accumulates in vivo, basal levels were measured in several organs of 4-month-old msh2(-/-) mice and their wild-type counterparts. Msh2(-/-) mice had significantly increased levels of DNA 8-oxoG in spleen, heart, liver, lung, kidney and possibly small intestine but not in bone marrow, thymus or brain. The tissue-specificity of DNA 8-oxoG accumulation in msh2(-/-) and other DNA repair defective mice suggests that DNA protection of different organs is mediated by different combinations of repair pathways.

Acute promyelocytic leukemia (APL) is a clonal expansion of hematopoietic precursors blocked at the promyelocytic stage. Gene expression profiles of APL cells obtained from 16 patients were compared to eight samples of CD34+-derived normal promyelocytes. Malignant promyelocytes showed widespread changes in transcription in comparison to their normal counterpart and 1020 differentially expressed genes were identified. Discriminating genes include transcriptional regulators (FOS, JUN and HOX genes) and genes involved in cell cycle and DNA repair. The strong upregulation in APL of some transcripts (FLT3, CD33, CD44 and HGF) was also confirmed at protein level. Interestingly, a trend toward a transcriptional repression of genes involved in different DNA repair pathways was found in APL and confirmed by real-time polymerase chain reactor (PCR) in a new set of nine APLs. Our results suggest that both inefficient base excision repair and recombinational repair might play a role in APLs development. To investigate the expression pathways underlying the development of APL occurring as a second malignancy (sAPL), we included in our study eight cases of sAPL. Although both secondary and de novo APL were characterized by a strong homogeneity in expression profiling, we identified a small set of differentially expressed genes that discriminate sAPL from de novo cases.

Introduction: We studied 12 pediatric patients with congenital or acquired anterior skull base defects. All subjects underwent surgery owing to progressive symptoms. The endoscopic endonasal approach is a new method in the treatment of this pathology in children., Materials and Methods: Twelve children had surgery to correct anterior skull base defects: seven patients with a spontaneous anterior basal meningoencephalocele and five with posttraumatic cerebrospinal fluid (CSF) leakage. The defects were repaired using the endoscopic endonasal approach, which combined with the fluorescein diagnostic test, detects the exact location of the skull base defect. Different closure techniques were used to obtain a permanent graft, depending on the type, location, and size of the defect. An intraoperative fluorescein test confirmed the absence of CSF leakage after surgery., Results: The follow-up period ranged from 3 to 72 months. Symptoms resolved in all patients after surgery and none of them experienced complications or recurrence of CSF leakage. Postoperative magnetic resonance scans showed that the defect had successfully been repaired in all patients., Discussion: The surgical treatment of skull base defects in children reduces life-threatening risks, which include infections, CSF leaks, and enlargement or trauma of the sac. The endoscopic technique minimizes surgical scars and has little impact on brain tissue. The endoscopic endonasal approach to the anterior skull base helps to preserve the physiology of the nose and sinuses and reduces the impact on the still developing splanchnocranium in pediatric patients. It ensures a definitive repair of the defect and requires a very short inpatient period.

We describe a new approach to investigate alterations in the human MLH1 mismatch repair (MMR) gene. This is based on complementation of the phenotype of a MLH1-defective subclone of the ovarian carcinoma A2780 cells by transfection of vectors encoding altered MLH1 proteins. Measurements of resistance (tolerance) to methylating agents, mutation rate at HPRT, microsatellite instability (MSI), and steady-state levels of DNA 8-oxoguanine were used to define the MMR status of transfected clones. The approach was validated by transfecting cDNA of wild-type (WT) MLH1, cDNAs bearing two previously identified polymorphisms (I219V and I219L) and two with confirmed hereditary nonpolyposis colorectal cancer (HNPCC) syndrome mutations (G224D and G67R). A low-level expression of two MLH1 polymorphisms partially reversed methylation tolerance and the mutator phenotype, including MSI. Higher levels of I219V resulted in full restoration of these properties to WT. Increased expression of I129L did not fully complement the MLH1 defect, because there was a simultaneous escalation in the level of oxidative DNA damage. The findings confirmed the important relationship between deficient MMR and increased levels of oxidative DNA damage. Mutations from Italian HNPCC families (G224D, G67R, N635S, and K618A) were all ineffective at reversing the phenotype of the MLH1-defective A2780 cells. One (K618A) was identified as a low penetrance mutation based on clinical and genetic observations.

Objective: To describe surgical endoscopic experience in the repair of cerebrospinal fluid leaks treated by transnasal approaches., Methods: Different surgical approaches and techniques in the repair of cranial base defects are reviewed in a series of 135 patients., Results: Success rate at first attempt was 93.3%. Only 9 patients (6.7%) needed a second surgical repair, and in one patient, a coronal approach with frontal craniotomy was necessary. In the other eight cases, an endoscopic procedure was chosen. Two patients needed a third endonasal endoscopic surgical repair, with successful outcome., Conclusion: The target of endoscopic endonasal technique in the repair of cerebrospinal fluid leaks is to ensure a stable duraplasty with the least invasive approach avoiding craniotomy. A correct diagnosis surely allows the choice of the best treatment, surgical approach, graft, and technique. Our multidisciplinary approach to this pathology during these years has been essential to gain our challenging results.

Objective: Endoscopic repair of cerebrospinal fluid (CSF) leaks is a recognized technique. We consider our experience and evaluate the outcomes in patients who underwent endoscopic repair of CSF leaks., Methods: A retrospective case note review of 135 patients who underwent anterior cranial repairs of CSF leaks between August 1995 and December 2004 at a tertiary referral center. We describe the technical details and outcomes of care by purely endoscopic procedures., Results: Thirteen patients had combined transcranial and endonasal repairs and 122 patients had their repairs using an endoscopic approach only. There were 64 males and 71 females with ages that ranged from 1 to 75 years (mean age 42 years, median age 44 years). The success rate for first attempt only was 93.4%. Eight of the 122 patients (6.6%) needed a second surgical repair. In one patient a bicoronal approach was necessary while in the other cases a revision endoscopic procedure was appropriate. The period of follow-up ranged from 2 months to 9 years (mean 5 years, median 39 months)., Conclusions: Our experience confirmed that endoscopic surgery is an effective and safe method of treatment for most CSF leaks. A variety of different endoscopic techniques allowed CSF leaks to be repaired in almost every site of the anterior skull base with very few exceptions.

Objectives: The traditional approach to sinonasal tumors involving the skull base has been the anterior craniofacial resection. The first report by Ketcham et al (American Journal of Surgery, 1963;106:698-703) documented their experience with 17 anterior craniofacial resections for malignant tumors of the sinonasal tract. Later experience with this technique at several centers has resulted in the publication of many refinements of technique and further reduction in the morbidity and mortality associated with this procedure. In our hands, endoscopic techniques have allowed us to approach the intranasal aspect of skull base lesions without external incisions and yet still achieve an en bloc resection. The type of lesions suitable for this approach and the associated technical issues are discussed in this article., Methods: Between 1999 and 2004, 18 patients with malignant nasoethmoid tumors underwent endoscopic nasal and anterior craniotomy resections. The average age of the patients 60.2 years, with a male-to-female distribution of 15 to 3. Mean follow-up period was 25.1 months., Results: Two patients died from postoperative complications, three died from recurrent disease and two from unrelated causes. Eleven patients are free of disease with a mean survival of 19.8 months., Conclusions: Although we do not consider this approach a replacement for the traditional anterior craniofacial resection, it is an important adjunct in the skull base surgeon's armamentarium.