Practical applicability of the STAMCO and ChOLE classification in cholesteatoma care.

BACKGROUND: To compare cholesteatoma care internationally and to evaluate outcomes, ear surgeons must use the same terminology. However, a clear universal definition on how to describe the extension, destruction and accompanying morbidity caused by the cholesteatoma is lacking. The practical applicability by means of interrater agreement is assessed for the STAMCO and the ChOLE classification. METHODS: A total of 134 adult patients derived from the nationwide multicentre study in the Netherlands, entitled Dutch Cholesteatoma Data (DCD) were included. Retrospective analysis of 134 surgical reports according to the STAMCO and ChOLE classification for localisation/extension of the cholesteatoma, complication status and ossicular chain status. Both the percentage agreement and the interrater agreement were determined for each item of the classifications and interrater agreement was compared between the classifications as a whole. RESULTS: Differences in interrater agreement were found for both the localisation/extension of the cholesteatoma and ossicular chain status. STAMCO classification derived from the surgical report scored better on the localisation/extension of the cholesteatoma, whereas the ChOLE classification derived from the surgical report scored better on the status of the ossicular chain. In both classifications, complication status had a low agreement level but was also poorly registered in the surgical reports. CONCLUSION: Both STAMCO and ChOLE will be beneficial in uniform registration of cholesteatoma pathology in practice. Modifications proposed for both classifications may make them even more practical applicable in the future. A common denominator obtained from these two classifications may be incorporated in a standardised surgical report to facilitate evaluation which make outcomes transferable towards both classifications.

Evaluation of the SAMEO-ATO surgical classification in a Dutch cohort.

PURPOSE: Differences in the definition and classification of cholesteatoma hinders comparing of surgical outcomes of cholesteatoma. Uniform registration is necessary to allow investigators to share and compare their findings. For many years surgical cholesteatoma procedures were divided into two main groups: canal wall up mastoidectomy (CWU) and canal wall down mastoidectomy (CWD). Recently, mastoid obliteration can be added to both procedures. Because of great variation within these main groups, the International Otology Outcome Group (IOOG) proposed the new SAMEO-ATO classification system to categorize tympanomastoid operations. The aim of our study was to correlate the mastoid bone extirpation (M-stage) with the contemporary (CWU, CWD with or without obliteration) system. METHODS: Demographic characteristics and type of performed surgery were registered for 135 cholesteatoma patients from sixteen hospitals, both secondary and tertiary care institutions, across the Netherlands. In addition, the surgical reports were collected, retrospectively classified according to the contemporary system and the new system and compared. Correlations of the outcomes were calculated. RESULTS: In total, there were 112 CWU and 14 CWD (both with or without obliteration) suitable for correlation analysis. Z test for correlation between the M-stage and CWU procedure was significant for M1a and M1b procedure and significant for M2c with the CWD procedure. CONCLUSION: The newly proposed SAMEO-ATO classification seems to be more detailed in the registration of surgical procedures than surgeons currently are used to. All M-stages of the SAMEO-ATO system are correlating well to the standard CWU and CWD except one 'in between' M-stage.

Postoperative Patient Reported Outcomes After Cholesteatoma Surgery.

BACKGROUND: Results and success measures of cholesteatoma surgery are generally described using objective data whereas subjective data are mostly lacking. Patients experiences and complaints are becoming more important alongside clinical and audiometric outcome measures in cholesteatoma care. OBJECTIVE: To investigate the course of patient-reported complaints, the impact of complaints, audiometric measures and the stability of audiometric measures, and complaints over time after primary and recurrent/residual cholesteatoma surgery. METHODS: Postoperative patients were prospectively included and divided into primary acquired and recurrent/residual cholesteatoma. The EuroQol 5D (EQ-5D-3L), Otology Questionnaire Amsterdam (OQUA), and the Speech Spatial Questionnaire (SSQ) were completed by 144 patients up to 2 years postoperative. Patient-reported complaints divided in eight separate domains, postoperative hearing and impact on daily life were longitudinally assessed by means of linear mixed models. RESULTS: Hearing loss and tinnitus are the most reported postoperative complaints over time. Patient-reported loss of taste and the impact of all complaints decline over time. All other patient-reported complaints remain stable over time, only itch complaints fluctuate. Primary cholesteatoma patients score significantly higher on hearing loss complaints compared with recurrent/residual patients although they have comparable mean audiometric hearing loss. Furthermore, pure-tone hearing threshold, instead of asymmetric hearing loss, is correlated with the localization domain of the SSQ. CONCLUSION: This study provides important insights in the course of complaints and its impact on daily life after cholesteatoma surgery. Overall, the postoperative patient-reported complaints after cholesteatoma surgery are generally low in the studied population.

Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding.

In a Dutch pedigree suffering from autosomal dominant nonsyndromic hearing impairment (ADNSHI), linkage was found to the locus for DFNA15, with a two-point logarithm of the odds (LOD) score of 5.1. Sequence analysis of the POU4F3 gene that is involved in DFNA15 revealed the presence of a missense mutation (c.865C>T), segregating with the deafness in this family. The mutation is predicted to result in the substitution of a phenylalanine residue for a leucine residue (p.L289F) in the POU homeodomain of the transcription factor POU4F3. Mutation analysis of the POU4F3 gene in 30 patients suffering from dominantly inherited hearing impairment revealed a second novel missense mutation (c.668T>C), resulting in the substitution of a proline for a leucine residue (p.L223P) within the POU-specific DNA-binding domain of the protein. In a computer model describing the structure of the two DNA-binding domains, the alterations are predicted to affect the tertiary structure of these domains. Transient transfection studies showed that whereas the wild-type POU4F3 is located almost exclusively in the nucleus, part of the mutant proteins was also present in the cytoplasm. In addition, both mutant proteins showed greatly reduced capability for binding to DNA as well as transcriptionally activating reporter gene expression. Together, our results describe the identification of the first missense mutations in POU4F3 causing DFNA15. Furthermore, mutations in this gene do not seem to be a rare cause of hearing impairment in the Dutch population, and the POU4F3 gene may thus be suitable for implementation in diagnostic testing.

Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer.

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.

A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13-16.1.

Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3-0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13-16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13.

Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli. Delayed administration of tPA (10 mg/kg, 6 hours after ischemia) induced intracerebral hemorrhage at 24 hours. In control rats treated with tPA plus vehicle, hemorrhage volumes were 9.0 +/- 2.4 uL (n = 7). In rats treated with tPA plus antiactin immunoliposomes, hemorrhage volumes were significantly reduced to 4.8 +/- 2.7 uL (n = 8, P < 0.05). No significant effects were seen when rats were treated with tPA plus a nontargeted liposome (7.8 +/- 2.1 uL, n = 9). Fluorescent immunohistochemistry showed that rhodamine-labeled targeted liposomes colocalized with vascular structures in ischemic brain that stained positive for endothelial barrier antigen, a marker of cerebral endothelial cells. These data suggest that immunoliposomes may ameliorate vascular membrane damage and reduce hemorrhagic transformation after thrombolytic therapy in cerebral ischemia.

Phenotype description of a Dutch otosclerosis family with suggestive linkage to OTSC7.

This study reports on a clinical investigation of a Dutch family that shows suggestive linkage to OTSC7. Cross-sectional as well as longitudinal analyses of audiometric data were performed. Also, high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members were obtained to study the incidence and extent of otospongiotic foci. Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not show age-dependent progression of bone conduction (BC), air conduction (AC), and air-bone gap (ABG) levels. Longitudinal analysis of audiometric follow-up data of one family member showed age-dependent progression of AC, BC, and ABG levels. High-resolution CT images revealed an otospongiotic focus in six of six (100%) clinically affected individuals that carried the disease haplotype. In none of the clinically unaffected family members that showed linkage to OTSC7, an otospongiotic focus was detected by CT. In conclusion, hearing impairment in the present otosclerosis family seems to be variable in terms of onset age and level of progression. Long-term audiometric data of one patient proved to be valuable in understanding progression of hearing impairment in this individual. The detection rate of otospongiotic foci in our study group is similar compared to previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.

Comparison of FAIR perfusion kinetics with DSC-MRI and functional histology in a model of transient ischemia.

Flow-sensitive alternating inversion recovery (FAIR) is a noninvasive method for perfusion imaging. It has been shown that the FAIR signal may depend on hemodynamic parameters other than perfusion, the most important one being transit delays of labeled spins to the observed tissue. These parameters are expected to change with ischemia. The goal of this study was to assess the effect of these changes on the interpretation of FAIR results in the case of altered perfusion. This was investigated in a rat model of transient cerebral ischemia. It was shown that the ratio of FAIR signal in the infarct compared to the contralateral side was lower at short inflow times, which suggests that transit times affected the effective FAIR signal. The FAIR results were compared with those from functional histology and dynamic susceptibility contrast MRI, and the findings indicated that the altered kinetics of the FAIR signal were related to reduced and delayed inflow in the infarct region--not to a decrease in the number of functional vessels.