Nasopharyngeal radium irradiation: The lessons of history.

In the Netherlands, nasopharyngeal radium irradiation was started in 1945. The indications included refractory symptoms of otitis media with effusion and other adenoid-related disorders after adenoidectomy. It was considered a safe and effective therapy. Its use decreased sharply in 1958, following a worldwide media avalanche around the dramatic events in the treatment of a 5-year-old child in Utrecht, enhancing the widespread fear of radioactivity. This case history illustrates the powerful role of the media in medical decision-making.

Microbial profiling does not differentiate between childhood recurrent acute otitis media and chronic otitis media with effusion.

OBJECTIVES: Otitis media (OM) is one of the most frequent diseases of childhood, with a minority of children suffering from recurrent acute otitis media (rAOM) or chronic otitis media with effusion (COME), both of which are associated with significant morbidity. We investigated whether the microbiological profiling could be used to differentiate between these two conditions. METHODS: Children up to five years of age, with rAOM (n = 45) or COME (n = 129) and scheduled for tympanostomy tube insertion were enrolled in a prospective study between 2008 and 2009. Middle ear fluids (n = 119) and nasopharyngeal samples (n = 173) were collected during surgery for bacterial culture and PCR analysis to identify Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and to detect 15 distinct respiratory viruses. RESULTS: The occurrence of bacterial and viral pathogens in middle ear fluids did not significantly differ between patients suffering from rAOM and COME. In both patient cohorts, H. influenzae and rhinovirus were the predominant pathogens in the middle ear and nasopharynx. Nasopharyngeal carriage with two or three bacterial pathogens was associated with the presence of bacteria in middle ear fluid (P = 0.04). The great majority of the bacteria isolated from middle ear fluid were genetically identical to nasopharyngeal isolates from the same patient. CONCLUSIONS: Based on these results, we propose that the common perception that rAOM is associated with recurrent episodes of microbiologically mediated AOM, whereas COME is generally a sterile inflammation, should be reconsidered.

Inflammation in the middle ear of children with recurrent or chronic otitis media is associated with bacterial load.

BACKGROUND: Viral upper respiratory tract infections have been described as an important factor in the development of otitis media (OM), although it is unclear whether they facilitate bacterial OM or can directly cause OM. To clarify the role of viral infections in OM, we compared the relative contribution of viruses and bacteria with the induction of inflammatory cytokine responses in the middle ear of children suffering from OM. METHODS: Children up to 5 years of age, with recurrent or chronic episodes of OM and scheduled for ventilation tube insertion were enrolled in a prospective study. Middle ear fluids (n = 116) were collected during surgery, and quantitative polymerase chain reaction was performed to detect bacterial and viral otopathogens, that is, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and 15 respiratory viruses. Finally, concentrations of the inflammatory mediators interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17a and tumor necrosis factor-α were determined. RESULTS: Middle ear fluids were clustered into 4 groups, based on the detection of viruses (28%), bacteria (27%), both bacteria and viruses (27%) or no otopathogens (19%). Bacterial detection was associated with significantly elevated concentrations of cytokines compared with middle ear fluids without bacteria (P < 0.001 for all cytokines tested) in a bacterial load-dependent and species-dependent manner. In contrast, the presence of viruses was not associated with changes in cytokine values, and no synergistic effect between viral-bacterial coinfections was observed. CONCLUSIONS: The presence of bacteria, but not viruses, is associated with an increased inflammatory response in the middle ear of children with recurrent or chronic OM.

Gamma knife radiosurgery for vestibular schwannomas: identification of predictors for continued tumor growth and the influence of documented tumor growth preceding radiation treatment.

OBJECTIVES/HYPOTHESIS: Gamma knife radiosurgery (GKRS) has become an important treatment modality for vestibular schwannomas. The primary aim of this study was to investigate whether tumor growth at the moment of GKRS has any correlation with the outcome. The secondary aim was to identify clinical predictors of radioresistance in vestibular schwannoma patients treated with GKRS. STUDY DESIGN: One hundred vestibular schwannoma patients, treated with GKRS, were divided into two groups: 1) proven tumor growth preceding GKRS; and 2) previous history of growth unknown. GKRS outcome was defined in two ways. According to the first definition, GKRS was said to have failed when additional treatment had taken place. According to the second one, a volume decrease >20% after 2 years marked successful treatment. METHODS: Correlations between outcome and growth status were determined with SPSS software. Furthermore, the study assessed how different variables (patient data, history, tumor characteristics, imaging, and audiovestibular examinations) correlated with the outcome of GKRS. RESULTS: No significant difference regarding success and failure of GKRS was found between the two patient groups. The mean reduction in tumor volume after GKRS was less pronounced in patients in whom tumor growth was demonstrated before treatment, but this finding was not significant. No significant predictors (P < .05) could be identified in this data set. CONCLUSIONS: This study found no indication that growth at the moment of GKRS influences therapeutic outcome, nor did it identify any predictors of the outcome after GKRS in vestibular schwannoma patients.

Follow-up after gamma knife radiosurgery for vestibular schwannomas: volumetric and axial control rates.

OBJECTIVES/HYPOTHESIS: A prospective long-term follow-up study was conducted to evaluate the results of gamma knife radiosurgery (GKRS) for vestibular schwannoma (VS) patients. Both axial and volumetric measurements are used to determine tumor size during follow-up. STUDY DESIGN: Individual prospective cohort study. METHODS: A total of 110 VS patients were referred for radiosurgery between 2002 and 2007. All patients were treated with a Leksell 4C gamma knife. There were 12.5 to 13 Gy prescribed to the isodose covering 90% of the tumor volume. The resulting marginal dose was on average 11.0 Gy (range, 9.3-12.5 Gy). Tumor size and tumor volume were determined before and after gamma knife treatment at regular intervals. The minimal follow-up period was 2 years. RESULTS: There were 100 patients included in the study. Eight patients needed additional treatment after a mean follow-up period of 38 months. One patient experienced a temporary facial nerve deficit. No growth pattern could be recognized for tumor growth after GKRS. Based on the measurements of the largest extrameatal diameter, the tumor size would have decreased or remained stable in 94%. Based on volumetric measurement, the tumor size was decreased or remained stable in 79%. CONCLUSIONS: High tumor control and low complication rates make GKRS a good therapy for VS. If tumor growth occurs after GKRS, a conservative management can be considered because continued tumor growth is uncertain. The extrameatal diameter on axial magnetic resonance imaging seems to be a reliable parameter of the size of a VS. Volumetry is the preferred method to assess the dimensions of a VS, although the consequences of strong volumetric increase, especially in small tumors, can be different depending on individual differences in tumor size.

Prediction of vestibular schwannoma growth: a novel rule based on clinical symptomatology.

OBJECTIVES: The aim of this study was to formulate a predictive rule for vestibular schwannoma growth during the initial observation period after diagnosis. METHODS: Logistic regression models were fitted, with tumor growth in the first year as the dependent variable and patient characteristics as the independent variables. Backward selection was used to eliminate superfluous predictors. The area under the receiver operating characteristic curve was taken as a measure of the model's discriminative power. RESULTS: Eventually, the model or rule consisted of 4 significant growth predictors: localization (if extrameatal, +1; if intrameatal, 0), sudden sensorineural hearing loss (if present, -1; if absent, 0), balance symptoms (if present, +1; if absent, 0), and complaints of hearing loss for less than 2 years (if present, +1; if absent, or present for more than 2 years, 0). A higher score indicates a higher likelihood of tumor growth during the period of observation after diagnosis. If the total score is 0 or less, the likelihood of tumor growth during the first year after diagnosis is less than 10%. If the score is 3, the likelihood of growth during the first year after diagnosis is more than 70%. CONCLUSIONS: We were able to create a useful rule to predict vestibular schwannoma growth during the first year after diagnosis.

Quality of life after gamma knife radiosurgery treatment in patients with a vestibular schwannoma: the patient's perspective.

This study evaluates the impact of gamma knife radiosurgery (GKRS) on the quality of life (QOL) of patients with a sporadic vestibular schwannoma (VS). This study pertains to 108 VS patients who had GKRS in the years 2003 through 2007. Two different QOL questionnaires were used: medical outcome study short form 36 (SF36) and Glasgow benefit inventory (GBI). Radiosurgery was performed using a Leksell 4C gamma knife. The results of the QOL questionnaires in relation to prospectively and retrospectively gathered data of the VS patients treated by GKRS. Eventually, 97 patients could be included in the study. Their mean tumor size was 17 mm (range 6-39 mm); the mean maximum dose on the tumor was 19.9 Gy (range 16-25.5 Gy) and the mean marginal dose on the tumor was 11.1 (range 9.3-12.5 Gy). SF36 scores showed results comparable to those for a normal Dutch population. GBI showed a marginal decline in QOL. No correlation was found between QOL and gender, age, tumor size, or radiation dose. Increased audiovestibular symptoms after GKRS were correlated with a decreased GBI score, and decreased symptoms were correlated with a higher QOL post-GKRS. In this study shows that GKRS for VS has little impact on the general QOL of the VS patient. However, there is a wide range in individual QOL results. Individual QOL was influenced by the audiovestibular symptoms. No predictive patient, tumor, or treatment factors for QOL outcome after GKRS could be determined. Comparison with microsurgery is difficult because of intra group variability.

Gamma knife radiosurgery for vestibular schwannomas: results of hearing preservation in relation to the cochlear radiation dose.

OBJECTIVES/HYPOTHESIS: This study was designed to evaluate hearing preservation after gamma knife radiosurgery (GKRS) and to determine the relation between hearing preservation and cochlear radiation dose in patients with a sporadic vestibular schwannoma (VS). METHODS: Prospective study involving patients suffering from VS who received GKRS from June 2003 until November 2007. Pure tone and speech audiometry were conducted before and after GKRS. The thresholds at pure tone audiometry were taken as a measure of hearing. Pure tone average (PTA) was defined as the mean threshold at 0.5 kHz, 1.0 kHz, 2.0 kHz, and 4.0 kHz. Hearing was classified according to the 2003 consensus meeting in Tokyo. Stereotactic surgery was performed using a Leksell 4C Gamma Knife (Elekta, Stockholm, Sweden). RESULTS: A total of 69 patients were included in the study. Mean tumor size was 17 mm. Mean marginal dose at the tumor was 11.0 Gy (range, 9.3 Gy-12.3 Gy), mean maximal dose was 19.7 Gy (range, 16 Gy-25.5 Gy). Mean maximal dose at the cochlea was 10.27 Gy (range, 3.1 Gy-16.1 Gy), and mean minimal dose at the cochlea was 2.6 Gy (range, 0.9 Gy-7.4 Gy). Mean PTA before GKRS was 43 dB (standard deviation [SD] 20 dB), mean PTA after GKRS was 63 dB (SD 30 dB). Mean interval between pre-GKRS audiometry and GKRS was 8.0 months. Between GKRS and post-GKRS audiometry, mean interval was 14.2 months. Hearing was considered to be preserved (max +1 class, Tokyo classification) in 52 (75%) of 69 patients. However, only 32 patients had class A, B, or C (serviceable hearing) before GKRS. Within this group, only 13 patients (41%) had a hearing class A, B, or C after GKRS. A significant relation was found between the maximal cochlear dose and the difference in PTA before and after GKRS. CONCLUSIONS: Hearing preservation is correlated to the maximal radiation dose at the cochlea. The purpose of developing GKRS techniques was to avoid collateral damage in healthy tissues. This study emphasizes the need for exact radiation planning to reduce the cochlear radiation dose if the hearing is to be preserved. Laryngoscope, 2009.

Imaging of electrode position in relation to electrode functioning after cochlear implantation.

This study assessed the electrode position in cochlear implant patients and evaluated the extent to which the electrode position is determinative in the electrophysiological functioning of the cochlear implant system. Five consecutively implanted adult patients received a multichannel cochlear implant. In all patients, the electrical impedance and the electrically evoked compound action potentials were recorded immediately after implantation. Multislice computer tomography was performed 6 weeks postoperatively before switch-on of the cochlear implant. The electrode position relative to the modiolus was assessed and correlated to the electrophysiological measurements. All electrodes were fully inserted; this was confirmed by computer tomography. The individual electrode distance toward the modiolus could be most precisely analyzed for the basal part of the electrode array. It was thus decided to study the data of electrodes one, four, and seven. No correlation was found between electrical impedance and electrode distance. A significant correlation was found between electrode distance and the electrically evoked compound action potentials, with a 96% probability using Kendall's rank correlation. We conclude that the electrode-modiolus distance is of importance to the stimulation of auditory nerve fibers. Future developments in imaging will further improve and refine our insight in the relation between electrode positioning.

Predictors of future growth of sporadic vestibular schwannomas obtained by history and radiologic assessment of the tumor.

Management of a sporadic vestibular schwannoma (VS) is still a subject of controversy, mainly due to distinct and unpredictable growth patterns. To embark on an appropriate therapy it is necessary to dispose of a reliable prediction about tumor progression. This study aims to design a risk profile with predictors for VS growth. A total of 234 VS patients who were managed conservatively were included. Data concerning (duration of) symptoms and localization of VS were analyzed with Cox proportional hazards regression models. Predictors for growth are unsteadiness/vertigo, no sudden onset of hearing loss and short duration of hearing loss. High-risk patients have (1) VS with an extrameatal localization, short duration of hearing loss and at least one of the two other predictors (unsteadiness/vertigo or no sudden sensorineural hearing loss) or (2) VS with an intrameatal localization and all three other predictors. Low-risk patients have (1) VS with an extrameatal component and no other predictor or (2) VS with an intrameatal localization and at most one other predictor. High-risk patients have a risk of growth of 36.9% in the first year and 64.6% in the second year. For patients with a low risk this is 2.5 and 12.7%, respectively. Simple data gathered at the moment of diagnosis may provide useful information since they may lead to a risk profile for growth.

Giant Cholesteatoma: Recommendations for Follow-up.

This report presents the management of five patients who presented with giant recurrent or residual cholesteatoma after periods of 2 to 50 years. Their case histories are highly diverse, but all provide evidence of the need for long-term follow-up.

Advances in understanding the pathogenesis of pneumococcal otitis media.

In this review, a state of the art on otitis media research is provided with emphasis on the role of Streptococcus pneumoniae in the pathogenesis of this disease. Articles have been selected by MEDLINE search supplemented with a manual crosscheck of bibliographies. Pathogenic mechanisms in middle ear and eustachian tube are described. Furthermore, pneumococcal characteristics and pneumococcus-host interactions are highlighted as well as the possible role of biofilms in persistence or recurrence of otitis media. Because of the availability of new techniques, an increasing number of pneumococcal features contributing in the pathogenesis of otitis media are identified and in-depth knowledge of pneumococcus-host interactions has been gained. The present advances in research on otitis media open up new perspectives for therapeutic or preventive strategies.

The relationship between pre-treatment clinical profile and treatment outcome in an integrated stuttering program.

UNLABELLED: A procedure for subtyping individuals who stutter and its relationship to treatment outcome is explored. Twenty-five adult participants of the Comprehensive Stuttering Program (CSP) were classified according to: (1) stuttering severity and (2) severity of negative emotions and cognitions associated with their speech problem. Speech characteristics (percentage of stuttered syllables, distorted speech score, and the number of correctly produced syllables on a diadochokinesis task) and emotional/cognitive states (emotional reaction, speech satisfaction, and attitudes toward speaking) were assessed before and after treatment, and at a 1- and 2-year follow-up. The results showed that: (a) there was no relationship between stuttering severity and the severity of negative emotions and cognitions, (b) the severe stuttering group had the largest treatment gains but also the highest level of regression, and (c) at post-treatment and both follow-up assessments the differences on measures of emotions between the mild and severe emotional group had disappeared, chiefly due to a large decrease in the latter group's negative emotions and cognitions. Our findings show that, based on treatment gains, specific subgroups can be identified, each requiring different treatment approaches. This underlines the necessity of developing a better understanding of how various dimensions of stuttering relate to treatment outcome. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe why stuttering severity and negative emotions and cognitions that are related to stuttering should be investigated separately and (2) describe how treatment outcome relates to subtypes of persons who stutter.

Immune status and eustachian tube function in recurrence of otitis media with effusion.

OBJECTIVE: To study the combined role of immune status and eustachian tube function in the development of recurrent bilateral otitis media with effusion (OME). DESIGN: Prospective cohort study. SETTING: Three academic and general hospitals. PATIENTS: Children aged 2 to 7 years with a first clinical episode of bilateral OME that persisted for at least 3 months; 136 (81%) of 168 eligible children participated. All children received bilateral tympanostomy tubes at study entry. MAIN OUTCOME MEASURE: Recurrence of bilateral OME within 6 months after tube extrusion. RESULTS: Univariate analyses of various immunologic factors (IgA, IgG1, IgG2, IgG3, IgG4, mannose-binding lectin, and the FcgammaRIIa-H/R131 genotype) and eustachian tube function (forced response test) did not show any significant associations with bilateral OME recurrence. Multivariate analyses showed that children with closing pressures higher than the 75th percentile and IgA or IgG2 levels below the 50th percentile of the cohort were more likely to develop recurrent OME than children with closing pressures higher than the 75th percentile and IgA or IgG2 levels above the 50th percentile. The corresponding risk ratios were 6.3 (95% confidence interval [CI], 1.0-40.1) for IgA level and 3.0 (95% CI, 1.1-8.2) for IgG2 level. The multivariate analyses also revealed that increasing serum levels of functional mannose-binding lectin were associated with decreasing probabilities of developing recurrent OME (odds ratio, 0.7; 95% CI, 0.6-1.0). CONCLUSION: Recurrence of bilateral OME after tympanostomy tube placement is more likely in children with a combination of low IgA or low IgG2 levels with poor eustachian tube function and decreased levels of mannose-binding lectin.

The effect of otitis media in childhood on the development of middle ear admittance on reaching adulthood.

OBJECTIVES: To determine the long-term change in static admittance values of subjects with a positive or negative history of otitis media (OM) and ventilation tube (VT) insertion; and to investigate the association between static admittance values and tympanic membrane abnormalities. DESIGN: Prospective follow-up study. SUBJECTS: A total of 358 subjects with or without a history of OM (OM+ or OM-) and VT insertion (VT+ or VT-) derived from a birth cohort that had been observed from preschool to adulthood. MAIN OUTCOME MEASURES: Otomicroscopic and tympanometric data obtained at subject ages 8 and 18 years. RESULTS: Static admittance values generally increased with age. At age 8 years, static admittance values were highest in OM+VT+ ears and lowest in OM- ears. At age 18 years, the difference between OM+VT+ and OM+VT- ears was larger, while the difference in static admittance values between OM+VT- and OM- ears had disappeared. In the group of VT+ subjects, the proportion of extreme static admittance values increased from 16% to 35% between ages 8 and 18 years. Correlation coefficients of individual static admittance values at 8 and 18 years were high in all groups and ranged from 0.61 to 0.85. We could not demonstrate an intermediate role of tympanic membrane abnormalities in the relation between VTs and static admittance at young adult age, except for atrophy. CONCLUSIONS: The static admittance value at age 8 years was a strong predictor for the value at age 18 years. A VT+ status was associated with a larger increase in static admittance than can be explained on the basis of age alone.

Immunological status in the aetiology of recurrent otitis media with effusion: serum immunoglobulin levels, functional mannose-binding lectin and Fc receptor polymorphisms for IgG.

The objective was to study the role of serum immunoglobulin levels, mannose-binding lectin (MBL), and Fc gamma receptor (FcgammaR) polymorphisms on the development of recurrent otitis media with effusion (OME). Children aged between two and seven years with persisting OME received bilateral tympanostomy tubes and immunological parameters were investigated in relation with OME recurrence within six months after tube extrusion. No statistically significant differences in serum immunoglobulin levels were present between children with and without OME recurrence. In children with bilateral recurrence (n = 56), median levels of MBL were 1.39 mg/L compared to 2.48 mg/L in children with OME recurrence (n = 17) (p = 0.29). In addition, 34% of the children with bilateral recurrence were homozygous for the genotype FcgammaRIIa-R/R131, whereas less than 20% of the children with unilateral recurrence or those without recurrence were homozygous for this Fcgamma receptor (p = 0.26). Serum mannose-binding lectin and FcgammaRIIa-R/R131 polymorphism may play a role in the aetio-pathogenesis of recurrent OME.

Hearing loss in young adults who had ventilation tube insertion in childhood.

It is known that insertion of ventilation tubes can cause damage to the tympanic membrane and hearing deterioration in the long-term. To investigate long-term effects of recurrent otitis media and of ventilation tube insertion, we used a study group (n = 358 subjects), with or without a history of otitis media and/or ventilation tube insertion, derived from a birth cohort that had been followed for 16 years. At 18 years of age, a standardized audiometric and otoscopic examination was performed. We found that ventilation tube insertion in childhood was associated with a mean persistent hearing loss in young adults of about 5 to 10 dB at the group level with a sensorineural component of 3 to 4 dB. This hearing loss could not be explained by the disease load of otitis media in childhood. Repeated insertions of ventilation tubes caused a greater deterioration of hearing than did a single insertion. Structural changes of the tympanic membrane were a mediating factor in the causal relationship between ventilation tube insertion and hearing loss. We conclude that ventilation tube insertion in childhood may induce hearing deterioration in the long-term.

Semilongitudinal and axial CT planes in assessing cochlear patency in cochlear implant candidates.

OBJECTIVE: To investigate how cochlear patency as seen on computed tomography (CT), using axial plus semilongitudinal planes, is correlated with findings at surgery in cochlear implant patients. METHODS: Pre-operative CT scans of 45 patients were reviewed by three, independent observers. They classified the cochlear patency and recorded the location of any suspected decreased patency. The results were compared with the findings noted during surgery. RESULTS: In nine patients a decreased cochlear patency was found at surgery. The sensitivity and specificity of CT assessment were, respectively, 56-33-11% and 100-86-94%. The interobserver reproducibility is reflected in a mean kappa of 0.46. The sensitivity increased when only patients suffering from post-meningitic deafness were considered. CONCLUSION: Our study suggests that CT scans can be useful in assessing cochlear patency, especially in patients with post-meningitic deafness. This good performance might be explained by the combined use of scans in semilongitudinal and axial planes.

Hearing deficits in young adults who had a history of otitis media in childhood: use of personal stereos had no effect on hearing.

OBJECTIVE: To test the hypothesis proposed in a recent French study that a history of recurrent otitis media (OM) in childhood increases susceptibility to hearing loss from frequent exposure to a personal stereo (PS) during development to early adulthood. METHODS: A subcohort of 358 young adults selected from a historic cohort study, all 18 years old and with a well-documented OM history (secretory and acute), provided data on the sound level and length of exposure to PSs. Four contrasting groups were formed: those with the highest or lowest PS exposure combined with a positive or negative history of OM (n = 238). The main outcome measure was hearing thresholds from pure-tone audiometry (0.5-8 kHz). RESULTS: Young adults with a history of recurrent OM in childhood did not show greater susceptibility to hearing loss from PS use than their peers without a history of OM. However, a history of recurrent OM was associated with significant mean air-conduction hearing loss of 4 dB and a mean bone-conduction hearing loss of 2 dB compared with the participants without a history of OM (Fig 1). CONCLUSIONS: Recurrent OM in childhood may have an irreversible effect on the middle ear and the cochlea and may lead to hearing deficits in later life. No interaction with PS exposure is seen.

Hearing deterioration in patients with a non-growing vestibular schwannoma.

OBJECTIVE: The aim of this study was to document and analyse the course of several audiometric parameters in 49 patients with a non-growing unilateral vestibular schwannoma (VS). MATERIAL AND METHODS: Patients received conservative management and absence of tumour growth was ascertained by means of serial magnetic imaging studies. Pure-tone audiometry and speech audiometry were performed at yearly intervals. RESULTS: Pure-tone audiometry revealed a significant increase in thresholds at all frequencies, except for 8.0 kHz. The maximum yearly threshold increase was 2.4 dB hearing level at 1.0 and 2.0 kHz. Speech audiometry revealed a significant decrease in maximum discrimination over the course of time. No significant changes were observed in the following parameters: the intensity level at which maximum discrimination was achieved; the roll-over index; the speech reception threshold; and the slope of the curve in the speech audiogram. No change was observed in the relation between pure-tone audiometry thresholds and speech audiometry scores. Apparently, the deterioration of pure-tone perception and speech discrimination ran parallel courses. CONCLUSIONS: The results of this study indicate that hearing loss is a predominant symptom in patients with a non-growing VS, as is also known in patients with a growing lesion. Moreover, it seems unlikely that the hearing loss in VS patients is merely the result of mechanical influences on retrocochlear neural or vascular structures.