Frontal sinus ablation (Riedel-Mosher’s procedure): indications and role in the endonasal endoscopic era.

BACKGROUND: The aim of this article is to describe the Riedel-Mosher’s surgical technique and identify its current role in the endoscopic endonasal era based on the experience of a tertiary care medical centre. It also provides a brief excursus on materials available for frontal reconstruction. METHODS: A retrospective review of patients submitted to Riedel-Mosher’s procedure from 2005 to 2018 at a single tertiary care centre was carried out. Details of the surgical technique along with data on frontal reconstruction timing and materials used were collected. RESULTS: A total of 21 patients (16 males and 5 females) underwent the Riedel-Mosher’s procedure. The age of the patients ranged from 15 to 84 years. The underlying pathology was represented mainly by chronic osteitis of the frontal bone (17 cases), followed by benign tumours (3 cases) and malignancy (1 case). Perioperative complications occurred in 3 patients. Cranioplasty was carried out only on 16 cases and delayed by an average time of 10 months. Materials for reconstruction included titanium, ceramic, plastic and free flap . CONCLUSIONS: Nowadays, Riedel-Mosher’s procedure is still indicated in selected cases of benign and malignant pathologies of the frontal sinus and/or frontal bone. Surgical expertise is key to approach the frontal sinus safely. Its reconstruction requires proper planning and a wide variety of materials to perform it is now available.

Post-traumatic optic neuropathy: our surgical and medical protocol.

Post-traumatic optic neuropathy (TON) is a rare, but very much feared event. It is a traumatic injury of the optic nerve at any level along its course (often inside the optic canal), with partial or total loss of visual acuity, temporarily or permanently. Until now, an univocal treatment strategy does not exist. The clinical records of 26 patients, treated from 2002 to 2013, were reviewed. The most frequent cause of injury was road traffic accident (63%), followed by iatrogenic damage, work injuries, sport or home accidents. All patients underwent pre-operative ophthalmological evaluation, neuro-imaging (angio-CT or angio-MRI scans) and systemic corticosteroid therapy. All patients required a surgical treatment, due to poor response to medical therapy; it consisted of an endonasal endoscopic decompression of the intracanalicular segment of the optic nerve, performed by removing the bony wall of the optical canal and releasing the perineural sheath. Improvement of visual acuity was reached in 65% of cases. No minor or major complication occurred intra- or post-operative, with a maximum follow-up time of 41 months. An improvement in visual acuity was achieved, although very limited in some cases, when surgery was performed as close as possible to the traumatic event. In the literature, there is no evidence-based data evaluating both of the two main treatment options (medical therapy versus surgical decompression), to state which is the gold standard in the treatment for TON. We discuss the pro and cons of our protocol: medical endovenous steroid treatment, within 8 h of injury, and endoscopic surgical decompression within 12-24 since the beginning of medical therapy, represent the best solution in terms of risk-benefit ratio for the patients.

Endoscopic endonasal management of non-functioning pituitary adenomas with cavernous sinus invasion: a 10- year experience.

BACKGROUND: The management of Non-Functioning Pituitary Adenoma (NFPA) invading the cavernous sinus (CS) is currently a balancing act between the surgical decompression of neural structures, radiotherapy and a wait-and-see policy. METHODS: We undertook a retrospective review of 56 cases of NFPA with CS invasion treated through an endoscopic endonasal approach (EEA) between 2000 and 2010. The Knosp classification was adopted to describe CS involvement using information from preoperative MRI and intraoperative findings. Extent of resection and surgical outcomes were evaluated on the basis of postoperative contrast-enhanced MRI. Endocrinological improvement and visual outcomes were assessed according to the most recent consensus criteria. RESULTS: EEA was performed using direct para-septal, trans-ethmoidal-sphenoidal or trans-ethmoidal-pterygoidal-sphenoidal approach. Visual outcomes improved in 30 (81%) patients. Normalization or at least improvement of previous hypopituitarism was obtained in 55% of cases. A gross total resection was achieved in 30.3% of cases. The recurrence-free survival was 87.5%, with a mean follow-up of 61 months (range, 36-166 months). No major intraoperative or postoperative complications occurred. DISCUSSION: EEA is a minimally-invasive, safe and effective procedure for the management of NFPA invading the CS. The extent of CS involvement was the main factor limiting the degree of tumor resection. The EEA was able to resolve the mass effect, preserving or restoring visual function, and obtaining adequate long-term tumor control.

Cross-over septal flap technique for choanal atresia surgery in two centres: how I do it.

BACKGROUND: Choanal atresia is a congenital obstruction of the posterior nasal aperture. Endoscopic endonasal surgery has led to successful choanal atresia repair. This paper describes our surgical technique using septal mucosal flaps without the need for stenting. METHODS: This study comprised a multicentre retrospective review of patient notes. A cross-over septal technique is described, whereby bilateral vertical mucosal incisions are made at the posterior third of the septum, and the atretic plate and posterior vomer are removed. One flap is pedicled superiorly and rotated over the bare skull base and sphenoid bone; the contralateral flap is pedicled inferiorly to cover the exposed vomer remnant and hard palate. RESULTS: There were 12 patients from 2013 to 2020, aged 0.07-50 years, with a male to female ratio of 1:5. Ten patients had unilateral and two had bilateral choanal atresia. Nine patients had bony choanal atresia, with the remainder mixed. CONCLUSION: The cross-over technique for choanal atresia has low morbidity and 100 per cent success in our series. The use of mucoperiosteal flaps to cover exposed bone and minimal instrumentation to the lateral nasal wall reduce post-operative stenosis.

Transnasal approach to the medial intraconal space: anatomic study and clinical considerations.

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.

Endoscopic transnasal anatomy of the infratemporal fossa and upper parapharyngeal regions: correlations with traditional perspectives and surgical implications.

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.

Nasopharyngeal endoscopic resection in the management of selected malignancies: ten-year experience.

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.

A rare case of oncocytic Schneiderian papilloma with intradural and intraorbital extension with notes of operative techniques.

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.

Processing of O6-methylguanine by mismatch correction in human cell extracts.

Human cell extracts perform an aberrant form of DNA synthesis on methylated plasmids [1], which represents processing of O6-methylguanine (O6-meG). Here, we show that extracts of colorectal carcinoma cells with defects in the mismatch repair proteins that normally correct replication errors do not carry out this synthesis. hMSH2-defective LoVo cell extracts (hMSH for human MutS homologue) performed O6-meG-dependent DNA synthesis only after the addition of the purified hMutS alpha mismatch recognition complex. Processing of O6-meG by mismatch correction requires PCNA and therefore probably DNA polymerase delta and/or epsilon. Mismatch repair-defective cells withstand O6-meG in their DNA [2], making them tolerant to methylating agents. Methylation-tolerant HeLaMR clones, with a mutator phenotype and a defect in either mismatch recognition or correction in vitro, also performed little O6-meG-dependent DNA synthesis. Assays of pairwise combinations of tolerant and colorectal carcinoma cell extracts identified hMLH1 as the missing mismatch repair function in a group of tolerant clones. The absence of processing by extracts of methylation-tolerant cells provides the first biochemical evidence that lethality of DNA O6-meG derives from its interaction with mismatch repair.

Identification of a molecular signature for leukemic promyelocytes and their normal counterparts: Focus on DNA repair genes.

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.

Multiple mutations and frameshifts are the hallmark of defective hPMS2 in pZ189-transfected human tumor cells.

Two HeLa variants defective in the mismatch repair protein hPMS2 were isolated by selection for methylation tolerance. Neither variant expressed detectable hPMS2 protein as determined by western blotting. Cell extracts were defective in correcting a single base mispair and were unable to perform mismatch repair-dependent processing of a methylated DNA substrate. Correction of the repair defect and restoration of sensitivity to a methylating agent was achieved by introducing a wild-type copy of chromosome 7 on which the hPMS2 gene is located. Loss of hPMS2 function in the HeLa variants was associated with a 5-fold increase in mutation frequency in the supF gene of the pZ189 shuttle vector. Wild-type levels of mutagenesis were restored by the transferred chromosome 7. Comparisons of mutational spectra identified multiple base substitutions, frameshifts and, to a lesser extent, single base pair changes as the types of mutation which are selectively increased in a hPMS2-defective background. The location of multiple mutations and frameshifts indicates that misalignment-mediated mutagenesis could underlie most of these events. Thus the mutator phenotype associated with loss of hPMS2 most likely arises because of the failure to correct replication slippage errors. Our data also suggest that a considerable fraction of mutagenic intermediates are recognized by the hMutSbeta complex and processed via the hMLH1/hPMS2 heterodimer.

1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.

BACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent. METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided. RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2. CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.

A mutator phenotype characterizes one of two complementation groups in human cells tolerant to methylation damage.

Sixty % of clones isolated from HeLa cells treated with toxic concentrations of a methylating carcinogen showed increased resistance to the cytotoxicity of N-methyl-N-nitrosourea. D37 values were 6- to 100-fold higher than in the parental cell population. The absence of detectable levels of the repair enzyme O6-methylguanine-DNA methyltransferase indicated that the resistant clones were able to tolerate the presence of O6-methylguanine in their DNA. Analysis of N-methyl-N-nitrosourea survival in the hybrids between tolerant clones and HeLa cells showed that tolerance can be either recessive or codominant. Fusion between tolerant clones indicated two complementation groups. We measured spontaneous mutation rates at microsatellites and at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus in several tolerant clones. All the clones of Complementation Group I showed unstable microsatellites and 4-8-fold increases in mutation rates at hprt. No significant alterations in spontaneous mutation rates were found in clones of Complementation Group II. The data indicate that tolerance to methylation damage can be conferred by alterations in at least two different gene products and that one of the two groups has the mutator phenotype typical of mismatch correction defective cells.

Expression of the endogenous O6-methylguanine-DNA-methyltransferase protects Chinese hamster ovary cells from spontaneous G:C to A:T transitions.

We have investigated whether the presence of a DNA repair enzyme, O6-methylguanine-DNA-methyltransferase (MGMT), affects the nature of spontaneous mutations in a mammalian cell line. We compared spontaneous mutations in the adenine phosphoribosyl transferase gene of a Chinese hamster ovary (CHO) cell line that expressed 14,000 MGMT molecules/cell with those in the parental CHO cells lacking this DNA repair activity. The mutation rate/cell/generation of the two CHO cell lines did not differ significantly. However, DNA sequence analysis of spontaneous mutations in the MGMT-proficient CHO cell line revealed a complex picture. No significant difference from the parental CHO cells was found in the number or type of deletions, frameshifts, multiple substitutions, or insertions. The frequency of G:C to T:A transversions was elevated in MGMT-proficient CHO cells. Expression of the enzyme considerably reduced G:C to A:T transitions (25% versus 8.3%). This latter result is the first evidence that this protein is active on an endogenous source of O6-methylguanine that is normally responsible for spontaneous G:C to A:T transition mutations.

N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea sensitivity in mismatch repair-defective human cells.

To determine whether loss of mismatch repair (MMR) confers sensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU), the sensitivity of MMR-defective (MMR-) variants was compared to that of their parental cells. Loss of MMR confers between 2- and 5-fold hypersensitivity to CCNU on HeLa, Raji, or Chinese hamster ovary cells. We also examined whether the sensitivity to CCNU is a general feature of MMR-human tumor cells. The majority expressed O6-methylguanine-DNA-methyltransferase (MGMT; Mex+ phenotype) that confers resistance to CCNU independent of their MMR status. The single Mex- MMR- SW48 cells were 4-fold more sensitive to CCNU than the Mex- MMR+ SW620 cells. CCNU sensitivity of the Mex+ cells was analyzed after treatment with the MGMT inhibitor O6-benzylguanine. The MMR- AN3CA, LS174T, LoVo, and DU145 cells were 1.4-4.3-fold more sensitive to CCNU than the MMR+ HeLaS3, HT29, and A2780 cells. Hypersensitivity to CCNU was not seen in the MMR- cell lines DLD1, HEC1A, and HCT116, suggesting that other parameters, besides the MGMT and MMR defects, affect the cell's response to this drug. In contrast, loss of MMR was always associated with tolerance to the methylating agent N-methyl-N-nitrosourea. The sensitivity to CCNU in MMR- cells suggests a possible involvement of this repair pathway in repairing interstrand cross-links and may have implications for clinical treatment of MMR- tumors.

Mutagenic processing of ethylation damage in mammalian cells: the use of methoxyamine to study apurinic/apyrimidinic site-induced mutagenesis.

The aldehyde reagent methoxyamine is able to interact with apurinic/apyrimidinic sites formed in vivo within cells and displays both an anti-cytotoxic and an antimutagenic activity on N-ethyl-N'-nitro-N-nitrosoguanidine-induced DNA damage in Chinese hamster ovary cells. To clarify the underlying mechanism we have examined the mutational spectra induced by N-ethyl-N'-nitro-N-nitrosoguanidine alone and in the presence of methoxyamine in the hypoxanthine-guanine phosphoribosyltransferase gene of Chinese hamster ovary cells. In both cases all mutations were base pair substitutions, and their distribution among various classes did not differ significantly. Almost 60% were transitions, predominantly GC to AT, and the remaining 40% were transversions, mainly at AT base pairs. The analysis of the proportion of the different types of mutations showed that in the presence of methoxyamine, GC to AT transitions decreased by a factor of 1.8, and AT to CG transversions were reduced by a factor of 13. These data indicate that in mammalian cells the fixation of ethylation damage into mutations occurs by both (a) direct mutagenesis likely driven by O6-ethylguanine adducts and to a minor extent by O4-ethylthymine and (b) apurinic/apyrimidinic site-mediated mutagenesis. These apurinic/apyrimidinic sites are formed during the processing of ethylation at critical sites and are likely to involve O6-ethylguanine and O2-ethylthymine adducts.

Temporal dissociation in the exposure times required for maximal induction of cytotoxicity, mutation, and transformation by N-methyl-N'-nitro-N-nitrosoguanidine in the BALB/3T3 ClA31-1-1 cell line.

Cytotoxicity, alkali-labile DNA lesions, ouabain resistance mutations, and neoplastic transformation were analyzed concurrently in the BALB/3T3 ClA31 -1-1 cell line treated with the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for different exposure times (15, 30, 60, 90, 120, and 240 min; 24, 48, and 72 hr). The half-life of MNNG in complete medium was approximately 70 min, both without cells and with cell numbers as used in the assays for cytotoxicity (2 X 10(2) cells/60-mm dish), transformation (1 X 10(4) cells/dish), and mutation (1 X 10(5) cells/dish). The cytotoxic effect of MNNG (0.5 or 2 micrograms/ml) appeared to be completed after an exposure time between 100 and 200 min. Maximal frequency of ouabain resistance mutations, however, was reached after a much shorter treatment time (30 to 60 min). Detection of DNA damage by alkaline elution analysis showed maximal increase in single-strand breaks already after treatment for 30 min. Exposures for 30 min followed by posttreatment incubation for 30 or 90 min showed active repair of single-strand breaks during these periods, indicative of an even balance between the additional MNNG-induced damage and its repair. Morphological transformation assays, at the same treatment times and concentrations used in the mutation assays, yielded frequency curves that reached their maxima 1 to 3 hr later than did the mutation frequencies. The ratio of transformation to ouabain resistance mutation frequencies was 3.7 for short treatment times (30 to 60 min), while it increased to more than 20 for exposure times of 240 min or longer. The temporal dissociation in the exposure times for maximal induction of mutation and transformation, observed with MNNG in this cell line, supports the hypothesis that a single gene mutational event is not sufficient to account for the full expression of neoplastic transformation.

Tolerance to O6-methylguanine and 6-thioguanine cytotoxic effects: a cross-resistant phenotype in N-methylnitrosourea-resistant Chinese hamster ovary cells.

The biochemical and genetic characteristics of a clone of Chinese hamster ovary cells displaying resistance to N-methyl-N-nitrosourea (MNU) and 6-thioguanine (6-TG) were analyzed. The initial level of 7-methylguanine, 3-methyladenine, and O6-methylguanine formation and the repair rates for these alkylated bases were the same in the resistant and in the parental cell line, indicating that the resistance to alkylation damage is not due to differences in DNA alkylation. After exposure for 24 or 48 h to 6-TG (0.6 micrograms/ml) in culture medium, the resistant clone in contrast to them, was able to replicate the DNA containing the base analogue during the following 24 h. These data are in agreement with the hypothesis that resistant cells tolerate both O6-methylguanine and 6-TG present in DNA. The tolerance to MNU and 6-TG also included chromosomal damage induced by these two agents, and MNU-resistant cells incurred less sister chromatid exchanges after treatment with either MNU or 6-TG. 6-TG-resistant cells, selected by growth in 6-TG, exhibited cross-resistance to MNU but not to methyl methanesulfonate, confirming that a common pathway of tolerance is responsible for resistance to 6-TG and O6-methylguanine.

From modeling to remodeling of upper airways: Centrality of hyaluronan (hyaluronic acid).

After traumatic events (accidental or surgical), the respiratory tract activates specific and prolix repairing mechanisms which tend to claw back the primitive differentiated state. The attempt of reactivation of the normal tissue functions is called 'remodeling' and its aim is to reinstate the modeling mechanisms that existed before the damaging event or the pathology's establishment. Endoscopic sinus surgery represents the gold standard treatment for inflammatory, malformative, benign, and, in selected cases, malignant diseases. The surgical technique is commonly described as minimally invasive as the nostrils are used as an access route and therefore does not leave any external scars. Currently, the surgical procedures, even though minimally invasive regarding the way in, are in fact widely destructive towards the surgical target. The healing process and re-epithelialization will depend on the amount of bony tissue that has been exposed and it will be important to stratify the different surgical typologies in order to foresee the increasing difficulty of mucosal healing process. As far as upper inflammatory diseases are concerned, recent studies demonstrated how intranasal hyaluronic acid can positively regulate mucosal glands secretion and modulate inflammatory response, being a useful tool for the improvement of remodeling after endoscopic sinus surgery. Acid has shown to be able to regulate mucosal glands secretion and modulate the inflammatory response.

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells.

The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects were not associated with a predictable degree of resistance among several tumor cell lines. Repair defective variants of the A2780 ovarian carcinoma cell line which were isolated by selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resistant to cisplatin. Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulation of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two complementary approaches indicated that each defect contributes to cisplatin resistance independently and to a different extent. Firstly, separate introduction of a p53 defect into A2780 cells significantly increased their cisplatin resistance; defective hMLH1 provided less extensive protection. Secondly, azadeoxycytidine reactivation of the silent hMLH1 gene or expression of a transfected hMLH1 cDNA sensitized the doubly hMLH1/p53 deficient cells only slightly to cisplatin. Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repair is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.