Efficacy and Safety of Tacrolimus as Treatment for Bleeding Caused by Hereditary Hemorrhagic Telangiectasia: An Open-Label, Pilot Study.

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I (ACVRL1/ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.

Evaluation Criteria for Chromosome Instability Detection by FISH to Predict Malignant Progression in Premalignant Glottic Laryngeal Lesions.

Background: The definition of objective, clinically applicable evaluation criteria for FISH 1c/7c in laryngeal precursor lesions for the detection of chromosome instability (CI). Copy Number Variations (CNV) for chromosomes 1 and 7 reflect the general ploidy status of premalignant head and neck lesions and can therefore be used as a marker for CI. Methods: We performed dual-target FISH for chromosomes 1 and 7 centromeres on 4 µm formalin-fixed, paraffin-embedded tissue sections of 87 laryngeal premalignancies to detect CNVs. Thirty-five normal head and neck squamous cell samples were used as a control. First, the chromosome 7:1 ratio (CR) was evaluated per lesion. The normal range of CRs (≥0.84 ≤ 1.16) was based on the mean CR +/− 3 x SD found in the normal population. Second, the percentage of aberrant nuclei, harboring > 2 chromosomes of chromosome 1 and/or 7 (PAN), was established (cut-off value for abnormal PAN ≥ 10%). Results: PAN showed a stronger correlation with malignant progression than CR (resp. OR 5.6, p = 0.001 and OR 3.8, p = 0.009). PAN combined with histopathology resulted in a prognostic model with an area under the ROC curve (AUC) of 0.75 (s.e. 0.061, sensitivity 71%, specificity 70%). Conclusions: evaluation criteria for FISH 1c/7c based on PAN ≥ 10% provide the best prognostic information on the risk of malignant progression of premalignant laryngeal lesions as compared with criteria based on the CR. FISH 1c/7c detection can be applied in combination with histopathological assessment.

[Consider the diagnosis 'Bell's palsy' carefully]. / Overweeg de diagnose 'Bellse parese' zorgvuldig.

Patients with facial palsy present with both cosmetic and functional symptoms. When a facial palsy develops quickly (within 72 hours) with no other symptoms, and no cause can be identified, it is probably an idiopathic facial palsy or 'Bell's palsy'. The diagnosis Bell's palsy is, thus, to a certain extent a diagnosis 'per exclusionem'. We present three cases with an incorrectly diagnosed Bell's palsy or inadequate diagnostics or treatment: a 5-year-old male with recurrent facial palsy caused by acute otitis media; a 46-year-old male with facial palsy caused by a malignant parotid tumour; and a 75-year-old female with facial palsy caused by a facial nerve schwannoma in the mastoid segment of the facial nerve. We, therefore, emphasize the importance of thorough history-taking and adequate diagnostics and imaging when patients present with facial palsy.

Three-year Outcomes of a Randomized Controlled Trial Comparing a 4.5-mm-Wide to a 3.75-mm-Wide Titanium Implant for Bone Conduction Hearing.

OBJECTIVE: To compare 3-year implant stability, survival, and tolerability of a 4.5-mm-wide (test) and a 3.75-mm-wide (control) percutaneous titanium implant for bone-conduction hearing, loaded with the sound processor after 3 weeks. METHODS: Sixty implants were allocated in a 2:1 ratio (test-control) in 57 adult patients included in this prospective randomized controlled clinical trial. Follow-up visits were performed at 7, 14, 21, and 28 days; 6 and 12 weeks; 6 months; and at 1, 2, and 3 years after implantation. During these visits, the implant stability quotient (ISQ) was measured by means of resonance frequency analysis (RFA). The peri-abutment soft tissue status was assessed according to the Holgers classification. Skin height around the abutment was evaluated. RESULTS: The mean area-under-the-curve (AUC) of ISQ-low was statistically significantly higher for the test implant (65.7 versus 61.4, p = 0.0002). Both implants showed high survival rates (97.4% versus 95.0%, p = 0.6374). Adverse soft tissue reactions were observed sporadically, with no significant inter-group differences. Skin thickening was seen in the majority of the patients, but no correlation with adverse soft tissue reactions or implant type was observed. CONCLUSION: The 4.5-mm-wide implant provides significantly higher ISQ values during the first 3 years after surgery compared with the previous generation 3.75-mm-wide implant. Both implants showed high survival rates and good tolerability. These long-term results indicate that the wider implant, loaded with a sound processor at 3 weeks, is a safe and well-performing option for hearing rehabilitation in specific types of hearing loss.

Stability, Survival, and Tolerability of an Auditory Osseointegrated Implant for Bone Conduction Hearing: Long-Term Follow-Up of a Randomized Controlled Trial.

OBJECTIVE: To compare implant stability, survival, and soft tissue reactions for a novel (test) and previous generation (control) percutaneous auditory osseointegrated implant for bone conduction hearing at long-term follow-up of 5 years. STUDY DESIGN: Single follow-up visit of a previously completed multicenter, randomized, controlled trial. PATIENTS: Fifty-seven of the 77 participants of a completed randomized controlled trial on a new auditory osseointegrated implant underwent a single follow-up visit 5 years after implantation, which comprised implant stability measurements and collection of Holgers scores. Additionally, implant survival was recorded for all 77 patients from the original trial. RESULTS: The test implant showed significantly higher implant stability quotient (ISQ) values compared with the control implant throughout the 5-year follow-up. Mean area under the curve of ISQ high from baseline to 5 years was 71.6 (standard deviation [SD] ±2.0) and 66.7 (SD ±3.4) for the test and control implant, respectively (p < 0.0001). For both implants, the mean ISQ value recorded at 5 years was higher compared with implantation (test group +2.03 [SD ±2.55, within group p < 0.0001] and control group +2.25 [SD ±4.95, within group p = 0.12]). No difference was noticed in increase from baseline between groups (p = 0.64). Furthermore, evaluation of soft tissue reactions continued to show superiority of the test implant. At the 5-year follow-up visit, one patient (2.5%) presented with a Holgers grade 2 in the test group, compared with four patients (23.5%) in the control group (p = 0.048); no patient presented with more severe soft tissue reactions. Excluding explantations, the survival rate was 95.8% for the test group and 95.0% for the control group. The corresponding rates including explantations were 93.9 and 90.0%. CONCLUSION: The test implant showed superiority in terms of higher mean ISQ values and less adverse soft tissue reactions, both at the single 5-year follow-up visit and during the complete follow-up. In addition, both implants showed an equally high implant survival.

Three-year experience with the Sophono in children with congenital conductive unilateral hearing loss: tolerability, audiometry, and sound localization compared to a bone-anchored hearing aid.

Bone conduction devices (BCDs) are advocated as an amplification option for patients with congenital conductive unilateral hearing loss (UHL), while other treatment options could also be considered. The current study compared a transcutaneous BCD (Sophono) with a percutaneous BCD (bone-anchored hearing aid, BAHA) in 12 children with congenital conductive UHL. Tolerability, audiometry, and sound localization abilities with both types of BCD were studied retrospectively. The mean follow-up was 3.6 years for the Sophono users (n = 6) and 4.7 years for the BAHA users (n = 6). In each group, two patients had stopped using their BCD. Tolerability was favorable for the Sophono. Aided thresholds with the Sophono were unsatisfactory, as they did not reach under a mean pure tone average of 30 dB HL. Sound localization generally improved with both the Sophono and the BAHA, although localization abilities did not reach the level of normal hearing children. These findings, together with previously reported outcomes, are important to take into account when counseling patients and their caretakers. The selection of a suitable amplification option should always be made deliberately and on individual basis for each patient in this diverse group of children with congenital conductive UHL.

Controlled Clinical Trial on Bone-anchored Hearing Implants and a Surgical Technique With Soft-tissue Preservation.

OBJECTIVE: To compare the clinical and audiological outcomes after linear incision with soft-tissue preservation and standard linear incision with soft-tissue reduction for placement of percutaneous bone-anchored hearing implants. STUDY DESIGN: Clinical trial with historical control-group from a previous randomized controlled trial. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: Twenty-five patients were enrolled in a prospective cohort of bone-anchored hearing implant placement with linear incision and tissue preservation with a follow-up of 6 months. The control-group consisted of 25 patients from a previous randomized controlled trial in the same tertiary referral center. All sound processors were fitted 3 weeks after surgery. MAIN OUTCOME MEASURES: Numbness around the abutment, length of surgery, soft-tissue reactions according to Holgers' classification, Patient and Observer Scar Assessment Scale, implant loss, Implant Stability Quotient, and audiological outcome. RESULTS: Tissue preservation resulted in better results on sensibility (mean percentage correct responses 98% [SD 4.4] versus 89% [SD 15.0], p = 0.003), on the Patient and Observer Scar Assessment Scale (mean observer score 15.3 [SD 4.3] versus 19.4 [SD 6.3], p = 0.006), and shorter total surgery time (mean 24.6 min [SD 6.2] versus 31.9 min [SD 6.5], p < 0.001). More adverse soft-tissue reactions as measured by the Holgers classification were observed in the test-group (n = 7 [28%] versus n = 1 [4%], p = 0.049). For Implant Stability Quotient and audiology the study did not provide evidence that tissue preservation is better or worse compared with tissue reduction. CONCLUSION: Tissue preservation compared with tissue reduction leads to a generally favorable clinical outcome, comparable audiology results, and significantly shorter surgery time. Longer follow-up is warranted to conclude on the increased adverse soft-tissue reactions after 6 months.

Loading of osseointegrated implants for bone conduction hearing at 3 weeks: 3-year stability, survival, and tolerability.

The objective of this study was to ascertain the long-term safety of loading osseointegrated implants for bone conduction hearing 3 weeks post-surgery. Thirty consecutive adult patients were implanted with the Baha BI300 (Cochlear Bone Anchored Solutions) in our tertiary referral center. Implants were loaded with the sound processor 3 weeks post-surgery. Follow-up examinations were performed at 10 days; 3, 4, 6, 8, and 12 weeks; 6 months; and 1, 2, and 3 years after implant surgery. At each follow-up visit, implant stability quotient (ISQ) values were recorded by means of resonance frequency analysis, and soft tissue status was evaluated according to Holgers' classification. ISQ trends, implant survival, and soft tissue reactions were compared to a population of 52 patients with the same type of implants loaded from 6 weeks post-surgery as part of another study. Subjective benefit was measured by means of the Glasgow Benefit Inventory (GBI). After an initial dip in ISQ at 10 days after implantation, a gradually increasing trend in ISQ was found until 6 months in both populations, after which ISQ values remained above baseline values. Implant survival was 97 % in the study population and 96 % in the comparison population. Clinically relevant soft tissue reactions were found in 0.9 % (study population) and 1.7 % (comparison population) of all visits. Patients reported subjective benefit; the mean GBI score was 22.8. In conclusion, loading these implants at 3 weeks post-surgery is safe based on the current study, as long-term results show high ISQ values and good implant survival and tolerability.

Stability, survival, and tolerability of a 4.5-mm-wide bone-anchored hearing implant: 6-month data from a randomized controlled clinical trial.

The objective of this study was to compare the stability, survival, and tolerability of 2 percutaneous osseointegrated titanium implants for bone conduction hearing: a 4.5-mm diameter implant (test) and a 3.75-mm diameter implant (control). Fifty-seven adult patients were included in this randomized controlled clinical trial. Sixty implants were allocated in a 2:1 (test-control) ratio. Follow-up visits were scheduled at 7, 14, 21, and 28 days; 6 and 12 weeks; and 6 months. At every visit, implant stability quotient (ISQ) values were recorded by means of resonance frequency analysis (RFA) and skin reactions were evaluated according to the Holgers classification. Implants were loaded with the bone conduction device at 3 weeks. Hearing-related quality of life was evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB), the Glasgow Benefit Inventory (GBI), and the Glasgow Health Status Inventory (GHSI). ISQ values were statistically significantly higher for the test implant compared to the control implant. No implants were lost and soft tissue reactions were comparable for both implants. Positive results were reported in the hearing-related quality of life questionnaires. These 6-month results indicate that both implants and their corresponding hearing devices are safe options for hearing rehabilitation in patients with the appropriate indications. Loading at 3 weeks did not affect the stability of either implant.

Application and Interpretation of Resonance Frequency Analysis in Auditory Osseointegrated Implants: A Review of Literature and Establishment of Practical Recommendations.

OBJECTIVE: To establish standardization of implant stability measurements in auditory osseointegrated implants by means of resonance frequency analysis (RFA) through reviewing the currently published literature. METHODS: Studies reporting on RFA in auditory osseointegrated implants were identified, and the outcomes and the way these were reported were evaluated. RESULTS: Thirteen clinical studies reporting RFA outcomes of auditory osseointegrated implants were identified and analyzed, which demonstrated variations in methodology and reporting of data. The different reporting standards made a meta-analysis impossible. Heterogeneity and limitations were found in reporting of the types of implants, abutments, and SmartPegs used; study population sizes; follow-up duration; and, reporting of the implant stability quotient (ISQ). CONCLUSION: RFA is an interesting outcome of clinical studies on auditory osseointegrated implant research and might have potential as a clinically relevant tool for assessing implant stability. Because of the heterogeneous data that have been reported to date, the following guidelines for standardization of application and reporting were established. The implant and abutment type and length, and the type of SmartPeg should always be stated. Absolute stand-alone ISQ values should not be interpreted individually. ISQ values are at this moment most meaningful as a trend in the individual patient or in a population over time. No conclusions should be based on individual ISQ values. Standardized time points for RFA in research should be determined prospectively, with surgery as a baseline. After abutment replacement, individual ISQ trends from baseline cannot be interpreted anymore if the abutments differ in length.

Bone-anchored hearing implants in single-sided deafness patients: Long-term use and satisfaction by gender.

OBJECTIVES/HYPOTHESIS: To examine the long-term satisfaction and possible effects of gender in patients with single-sided deafness (SSD) who underwent bone-anchored hearing implant (BAHI) surgery. STUDY DESIGN: Retrospective case-control study. METHODS: All (n = 145) consecutive SSD patients fitted with a BAHI between January 2001 and October 2011 were asked to complete a questionnaire consisting of the Abbreviated Profile of Hearing Aid Benefit (APHAB), the Communication Profile for the Hearing Impaired (CPHI), and the SSD questionnaire. RESULTS: Twenty-three of the 135 responding patients (17%) reported discontinuation of the device over an average follow-up time of 61.7 months. No significant differences were found in the degree of disability or coping between men and women, according to the APHAB and CPHI scores. Improvement in quality of life and appreciation of the BAHI were not affected by gender, age, directional hearing ability, and handling of the device. The appearance of the device positively affected their appreciation. At the mean follow-up time of 117 months, 69.2% was using their BAHI. In the domains background noise, reverberant surroundings, and aversion to sounds, the mean APHAB scores were significantly changed at 3 months, 1 year, and 10 years after implantation. CONCLUSION: Our study examined the results of BAHI use in SSD patients over a relatively long follow-up period, with an average of 5 years. The majority of users (83%) were satisfied with the device. No significant gender differences were in terms of reported appreciation, hearing disability, or coping with a BAHI. LEVEL OF EVIDENCE: 3b.

Long-term Compliance and Satisfaction With Percutaneous Bone Conduction Devices in Patients With Congenital Unilateral Conductive Hearing Loss.

OBJECTIVE: Patients with congenital unilateral conductive hearing loss (UCHL) can either be watchful monitored or treated surgically through the fitting of a percutaneous bone conduction device (BCD) or, in some cases, atresia repair. The current study evaluated the long-term compliance and satisfaction with a percutaneous BCD in this specific population. STUDY DESIGN: Fifty-three consecutive patients with congenital UCHL treated with a percutaneous BCD in our tertiary referral center between 1998 and 2011 were identified. Clinical and audiological data were retrospectively gathered from the patients' files. The patients were interviewed by telephone about their current device usage status and were asked to complete the Speech, Spatial and Qualities of Hearing Scale (SSQ). RESULTS: Compliance with the BCD was 56.6% after a mean follow-up of 7 years. The mean age at implantation of the users (22 years) was significantly higher than that of the nonusers (10 years). The mean time of device usage before the patients stopped using the BCD was 5 years. The primary reasons mentioned for quitting the BCD were experiencing excess background noise and/or subjectively not receiving enough benefit. Objectively measured features of binaural processing affected by the BCD were found to correlate with long-term BCD usage. The SSQ revealed significant improvement in the aided condition compared with the nonaided condition in the users, in contrast to the nonusers. CONCLUSION: The current disappointing long-term compliance figures indicate the need for an even more careful and individualized approach with life-long follow-up when fitting BCDs in this specific population, especially in children.

A Retrospective Cohort Study on the Influence of Comorbidity on Soft Tissue Reactions, Revision Surgery, and Implant Loss in Bone-anchored Hearing Implants.

OBJECTIVE: To identify risk factors for complications after bone-anchored hearing implant (BAHI) surgery. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: All adult patients who received titanium bone-anchored hearing implants at our clinic between September 1, 1988 and December 31, 2007 were approached to fill out a questionnaire on comorbidity factors. A total of 581 patients with 669 implants were included in the analysis. MAIN OUTCOME MEASURES: Implant loss, soft tissue reactions, and revision surgery after BAHI implantation. RESULTS: Skin disease and profound learning difficulties were risk factors for time to first soft tissue reaction, hazard rate ratio of 3.41 (95% CI 1.45-8.01) and 3.42 (1.03-11.39), respectively. Female gender showed a trend toward a negative risk for time to first soft tissue reaction, hazard rate ratio 0.60 (0.35-1.03). In multivariable analysis, skin disease and female gender were observed as independent associative factors, adjusted hazard ratio 3.08 (1.32-7.16) and 0.56 (0.33-0.94). For revision surgery, female gender and cardiovascular disease were identified as negative risk factors in univariable analysis, and smoking showed a trend toward a negative risk, with hazard ratios of 0.15 (0.07-0.32), 0.07 (0.03-0.20), and 0.51 (0.24-1.07), respectively. In multivariable analysis, smoking and female gender were observed as independent associative factors, adjusted hazard ratio 0.45 (0.22-0.95) and 0.14 (0.06-0.30). Smoking could be identified as a risk factor for implant loss with a hazard ratio of 3.32 (1.36-8.09). CONCLUSION: Retrospective analysis of comorbidity factors and clinical outcomes revealed risk factors for postoperative complications after BAHI surgery.

Long-term stability, survival, and tolerability of a novel osseointegrated implant for bone conduction hearing: 3-year data from a multicenter, randomized, controlled, clinical investigation.

OBJECTIVE: To compare the 3-year stability, survival, and tolerability of 2 osseointegrated implants for bone conduction hearing: a wide 4.5-mm-diameter moderately roughened implant with a rounded 6-mm abutment (test) and a 3.75-mm diameter as-machined implant with a conically shaped 5.5-mm abutment (control). STUDY DESIGN: In this randomized, prospective, controlled, multicenter clinical study, 77 adult patients were included. Test and control implants were randomly assigned in proportions of 2:1. The implants were loaded with the sound processor from 6 weeks postimplantation. Follow-up after surgery was conducted at 10 days; at 4, 6, 8, and 12 weeks; and at 6, 12, 24, and 36 months after surgery. At every visit, implant stability quotient (ISQ) values were recorded by means of resonance frequency analysis (RFA), and skin reactions were evaluated according to Holgers' classification. RESULTS: Statistically significantly higher mean ISQ values were recorded for the test implant compared with the control implant at each evaluation time point. Between 2 and 3 years after surgery, ISQ values decreased but remained above baseline values. Implant survival was high for both implants: 96.2% of the test implants and 100% of the control implants survived these 3 years. Statistically significantly improved soft tissue outcomes were observed in the test implant group. CONCLUSION: This extensive long-term clinical investigation demonstrated that the test implant is more stable in terms of ISQ-values and provides high tolerability for the soft tissue. The results show that implant loading at 6 weeks is safe.

Comparison between a new implantable transcutaneous bone conductor and percutaneous bone-conduction hearing implant.

OBJECTIVES: Despite good results on osseointegration and limited skin reactions with percutaneous bone conductors, there remains room for improvement. Especially in children, adverse events with percutaneous bone conductors might occur more frequently. Transcutaneous bone conductors, if powerful enough, can provide a solution that minimizes adverse events and implant loss. This study compares a new transcutaneous bone conduction hearing aid, the Sophono Alpha 1 (Sophono), with the percutaneous BAHA system (BAHA). METHODS: In our tertiary referral center, 12 patients (age 5-12 yr) with congenital unilateral conductive hearing loss were enrolled in the study as follows: 6 patients with the Sophono and 6 with the BAHA. Both clinical results and audiologic data were gathered. For an objective audiologic comparison between both systems, we used a skull simulator. RESULTS: The skin reactions were comparable between both groups, in 1 implant was lost 1 month after second phase surgery (BAHA). The users received audiologic benefits from both systems. The BAHA-based outcome was slightly better compared with Sophono-based results in sound field thresholds, speech recognition threshold, and speech comprehension at 65 dB. The skull simulator demonstrated that the BAHA device has an output that is 10 to 15 dB higher compared with the Sophono device. CONCLUSION: The Sophono offers appealing clinical benefits of transcutaneous bone conduction hearing; however, the audiologic challenges of transcutaneous application remain, as the Sophono does not exceed percutaneous application regarding audiologic output.

A new bone-anchored hearing implant: short-term retrospective data on implant survival and subjective benefit.

This report provides the first short-term follow-up data on the Ponto bone-anchored hearing implant from our tertiary referral centre. Thirty-one consecutive patients with a mean age of 51 years who received the implant between October 2010 and December 2011 were included retrospectively in this study. Implant loss, skin reactions around the implant (according to Holgers' grading system), revision surgery, and abutment replacements were retrospectively gathered from the patients' files as objective outcome measures. To obtain information on subjective patient satisfaction, the Glasgow Benefit Inventory (GBI) was used. The mean follow-up period was 16.9 months (range 12.1-25.2 months). One implant was lost. Over a total of 94 follow-up visits, 21 skin reactions were observed in 16 patients: Holgers grade 1 (slight redness, no need for treatment) in 18.1 % of the visits,and grade 2 (redness and moist, needing conservative treatment) in 4.3 % of the visits. Four 6-mm abutments (12.9 %) were replaced for a 9-mm abutment during the follow-up period, of which one (3.2 %) was in combination with revision surgery. In one patient keloid formation around the implant was observed. The GBI revealed a moderate subjective benefit. The short-term results with these percutaneous implants demonstrate a clinically stable implant with a low percentage of skin reactions that require treatment. Long-term, prospective follow-up data are needed to draw firmer conclusions.