Efficacy of S53P4 Bioactive Glass for the Secondary Obliteration of Chronically Discharging Radical Cavities.

Objective: Present the results of the secondary obliteration of chronically discharging radical cavities using S53P4 bioactive glass (BAG). Study Design: Retrospective cohort study. Setting: Single-center study. Methods: A single-center retrospective cohort study was conducted of all patients that underwent secondary obliteration of persistently draining radical cavities using S53P4 BAG between 2011 and 2022. Patients with middle ear cholesteatoma were excluded. The main outcome was postoperative otorrhea, as indicated by Merchant grading. Results: In total, 97 patients were included. The median postoperative follow-up time was 3.9 years (range 0.5-10.4). Average time between the original canal wall down surgery and the secondary obliteration was 25.3 years (SD 11.7, range 2-66). At the most recent follow-up visit, a Merchant grade of 0 to 1 was observed in 95% of the cases. There were no cases of sensorineural hearing loss or facial palsy, one case developed a retro auricular skin defect and 1 patient developed CSF leakage. Minor complications were seen in 10 patients (10%). Ossicular chain reconstruction with a titanium prosthesis was performed in 42 cases, resulting in a median improvement of 11.2 dB in air conduction thresholds. In 9/42 cases (21%), closure of the postoperative air-bone gap to ≤20 dB was achieved. Twenty-five percent of cases could be discharged from out-patient visits. Conclusion: Revision of persistently draining radical cavities with BAG obliteration is feasible and results in a dry and safe ear in 95% of the patients, thereby enabling wearing of a conventional hearing aid. Out-patient visits could be ceased in 25% of the cases.

Cholesteatoma surgery in the pediatric population: remaining challenges in the era of mastoid obliteration.

PURPOSE: To present the first pediatric study on the safety and efficacy of mastoid obliteration using S53P4 bioactive glass (BAG) for cholesteatoma surgery. METHODS: A single-center retrospective cohort study was conducted. Inclusion criteria were pediatric cases (≤ 18 years) and at least at least one year of follow-up including non-echo planar diffusion-weighted MRI to assess cholesteatoma recidivism. Both canal wall up (CWU) and canal wall down (CWD) procedures were evaluated. RESULTS: A total of 61 cases (56 patients) were included. Most cases had an otologic history before the development of the cholesteatoma. CWU procedure was performed in 18 cases (30%) and CWD procedure in 43 cases (70%). The cholesteatoma recidivism rate was 33% after a mean follow-up period of 58 months. Kaplan-Meier curve estimated a 5-year recidivism rate of 40%. Few complications were seen that were all minor and resolved spontaneously or after local or systemic treatment. Control of the infection (merchant grade 0-1) was achieved in 98% of the cases. Closure of the air-bone gap within 20 dB was achieved in 22% of the cases with complete audiometric evaluation. CONCLUSION: In this MRI-controlled study, we show the safety and efficacy of S53P4 BAG for mastoid obliteration in a pediatric cholesteatoma cohort. Postoperative complications were both rare and minor, and a dry ear was achieved in almost all patients. Nevertheless, persistent hearing loss and the apparent high recidivism rate reflect the challenging nature of pediatric cholesteatoma.

Mastoid Obliteration Using S53P4 Bioactive Glass in Cholesteatoma Surgery: A 10-Year Single-Center Experience in 173 Adult Patients with Long-Term Magnetic Resonance Imaging Controlled Follow-up.

OBJECTIVE: To present the long-term outcomes of mastoid obliteration in cholesteatoma surgery using S53P4 bioactive glass (BAG) in an adult population. STUDY DESIGN: Retrospective cohort study. SETTING: Single-center study. PATIENTS: All 173 adult patients who underwent primary or revision surgery for cholesteatoma with mastoid obliteration using S53P4 BAG with at least 1 year of follow-up including nonecho planar diffusion-weighted magnetic resonance imaging (MRI) (non-EP DWI MRI) and/or second-look surgery to evaluate recidivism. Both canal wall up (CWU) and canal wall down (CWD) procedures were included. INTERVENTIONS: Patients underwent CWU or CWD mastoidectomy using S53P4 BAG. MAIN OUTCOME AND MEASURES: Cholesteatoma recidivism, postoperative complications, Merchant grade, hearing outcome. RESULTS: Cholesteatoma recidivism was assessed by MRI in 97% of all cases and second-look surgery look surgery in 3% of cases. After a mean follow-up period of 53 months, cholesteatoma recidivism was seen in 10% of the cases (n = 18). Using the Kaplan-Meier curve to extrapolate, a 5-year recidivism rate of 12% was estimated. Only minor complications occurred, all resolving spontaneously or after minor treatment. Merchant grade of 0 to 1 was achieved 95% of the patients, no persistently wet ears were observed. Closure of the air-bone gap within 20 dB was possible in 32%. CONCLUSION: In this long-term (up to 10 yr) follow-up study, we demonstrated the safety of S53P4 BAG. Minimal and only minor postoperative complications were observed. The effectiveness of BAG was indicated by the low rate of recidivism, even when using non-EP DWI MRI, a sensitive and specific noninvasive technique to detect cholesteatoma recidivism.

18F-NaF PET/CT imaging of bone formation induced by bioactive glass S53P4 after mastoid obliteration.

PURPOSE: Bioactive glass has been successfully used for surgical treatment of chronic infections in bone and bone cavities. Besides infection control, new bone formation is induced by the bioactive glass which is considered to have osteoconductive properties. Evaluation of postsurgical changes after bone graft surgery is generally performed with conventional radiographs or CT/MR imaging, but 18F-NaF PET/CT might be more suitable since it has a high and rapid bone uptake, accompanied by a fast blood clearance leading to a high bone to background ratio. CASE: Obliteration with S53P4 bioactive glass of the mastoid and middle ear was performed in a patient suffering from chronic otitis media. Control of the chronic otitis media was achieved, and follow-up imaging after 3 years with 18F-NaF PET/CT showed increased uptake in the obliterated cavity indicating new bone formation. CONCLUSION: 18F-NaF PET/CT is able to detect new bone formation after obliteration of the mastoid with S53P4 bioactive glass.

Mastoid obliteration with S53P4 bioactive glass in cholesteatoma surgery.

CONCLUSION: Evaluation of the follow-up of 67 patients shows that S53P4 bioactive glass (BAG) granules are safe and effective as obliteration material in cholesteatoma surgery. OBJECTIVES: To investigate the safety and efficacy of mastoid obliteration using S53P4 BAG in cholesteatoma surgery. Clinical outcomes were infection control (Merchant's grading), cholesteatoma recidivism, and audiometric performance. METHODS: Retrospective follow-up study at the Diakonessenhuis, Utrecht, the Netherlands. Eighteen young (age <17 years) and 49 adult (age ≥17 years) patients treated for cholesteatoma underwent tympanomastoidectomy with mastoid obliteration using S53P4 BAG in the period 2012-2015. Outcome was monitored with clinical otoscopy, otorrhea incidence measurement (Merchant's grading), DW-MRI, and audiographic performance analyses (pure tone average and air bone gap). RESULTS: During the follow-up period (mean = 22 months; range = 12-54 months) cholesteatoma recidivism was observed in 6% of the patients (four ears), mostly in young patients (three ears). An acceptably dry ear (Merchant grade 0-1) was achieved in 96% of all cases. The remaining 4% of cases scored a Merchant grade 2. Overall, both air conduction thresholds and air bone gap were slightly lowered when comparing post-operative values to pre-operative values and significantly in the case of ossicular reconstruction. In none of the patients (0%) did post-operative wound infections occur.

Lyme disease associated with sudden sensorineural hearing loss: case report and literature review.

OBJECTIVE: Is sudden sensorineural hearing loss associated with Lyme disease in adults? STUDY DESIGN: A retrospective case report and a systematic literature search in PubMed and Embase were performed. RESULTS: We describe a patient presenting with sudden sensorineural hearing loss, followed by a facial paralysis, which could be attributed to Lyme disease confirmed by positive serology and a positive immunoblot. She was successfully treated with ceftriaxone, with recovery of the facial paralysis, although no recovery of the hearing loss was observed. A systematic literature search resulted in 4 relevant and valid articles revealing that confirmed positive serology for Borrelia burgdorferi varies from 0% to 21.3%, suggesting active Lyme disease as a cause in patients with sudden sensorineural hearing loss. Two studies demonstrated a significantly higher incidence of confirmed positive serology for Borrelia burgdorferi as compared with the incidence in the general local population. CONCLUSION: Literature suggests that sudden sensorineural hearing loss may coincide with Borrelia burgdorferi infection. A higher incidence of confirmed positive serology for Borrelia burgdorferi in patients with sudden deafness seems to be depending on the country and on the tests used to confirm Lyme disease. This should be taken into account if serologic testing for Lyme disease in patients with sudden deafness is considered.

[Hypoxaemia and bradycardia in children during guillotine adenotonsillectomy without intubation]. / Hypoxemie en bradycardie bij kinderen tijdens adenotonsillectomie volgens Sluder zonder intubatie.

OBJECTIVE: To study the incidence of hypoxaemia and bradycardia in children who undergo guillotine adenotonsillectomy in a sitting position, without intubation and under inhalation anaesthesia. DESIGN: Retrospective study. METHOD: Analysis of age, weight, sex, oxygen saturation, heart rate and subsequent bleeding in all children up to the age of 11 years who underwent guillotine adenotonsillectomy in the period December 1999 to December 2007. Hypoxaemia was defined as oxygen saturation of less than 85% for longer than 60 s. Bradycardia was defined as a heart rate of less than 60/min for longer than 30 s. RESULTS: We analysed data from 2963 patients. The mean age was 4.7 years and mean weight 18.8 kg. There was no significant relationship between age, weight and the onset of incidental desaturation or bradycardia. A total of 132 patients (4.5%) had hypoxaemia and 280 patients (9.4%) had bradycardia. Twenty-five patients had both hypoxaemia and bradycardia, of whom 3 (0.1%) had bradycardia immediately following hypoxaemia. In none of the recorded episodes of hypoxaemia and bradycardia did this lead to peri- or postoperative complications. CONCLUSION: Hypoxaemia and bradycardia occurred during guillotine adenotonsillectomy in non-intubated children in a sitting position under inhalation anaesthesia. The simultaneous onset of hypoxaemia and bradycardia is rare, however, and does not lead to perioperative complications. A further study is required using adenotonsillectomy with a large number of intubated and non-intubated children in order to compare the incidence of hypoxaemia and bradycardia and the occurrence of complications.

Clinical significance of micrometastatic cells detected by E48 (Ly-6D) reverse transcription-polymerase chain reaction in bone marrow of head and neck cancer patients.

PURPOSE: Despite improvements in locoregional treatment of head and neck squamous cell carcinoma (HNSCC), local and distant failure rates remain high. The strongest prognostic indicator of HNSCC is the presence of lymph node metastases in the neck, but the value of this indicator has limitations when using for the individual patient. The presence of micrometastatic cells in bone marrow has been shown to be a putative prognostic indicator in HNSCC and other epithelial malignancies, which might allow more accurate staging and selection of patients for whom adjuvant or experimental therapy is recommended. The gene encoding the E48 antigen is selectively expressed by HNSCC, and the detection of E48 transcripts in bone marrow by reverse transcription-polymerase chain reaction (RT-PCR) presumably represents the presence of micrometastatic cells. The purpose of this study was to determine the association between the presence of micrometastatic cells in bone marrow of HNSCC patients and clinical outcome. EXPERIMENTAL DESIGN: A total of 162 patients treated surgically for primary HNSCC underwent a single bone marrow aspiration from the upper iliac crest for detection of micrometastatic cells using E48 RT-PCR. In total, 139 patients were evaluable. The primary statistical endpoints were disease-free survival and distant metastasis-free survival. In addition, bone marrow samples of 30 noncancer controls were evaluated. RESULTS: E48 RT-PCR indicated the presence of micrometastatic cells in the bone marrow in 56 of 139 (40%) of the HNSCC patients and 0 of 30 of the noncancer controls (P < 0.0001). The presence of micrometastatic cells had no significant influence on disease-free survival or distant metastasis-free survival for the whole group of HNSCC patients (P = 0.1460 and P = 0.2912, respectively). For patients with >or=2 lymph node metastases, however, the presence of micrometastatic cells was associated with a poor distant metastasis-free survival (P = 0.0210). CONCLUSIONS: The presence of micrometastatic cells in bone marrow of HNSCC patients with >or=2 lymph node metastases is correlated with a poor distant metastasis-free survival. In this subgroup of HNSCC patients, E48 RT-PCR seems to be a valuable tool to identify patients who are at increased risk for development of distant metastases and therefore might benefit from experimental adjuvant systemic therapy.

Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25 mg (n=3), 50 mg (n=4), and 100 mg (n=3). Patients received 2 mg of 750 MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1 h and after 21 h, and patients underwent surgery at 48 h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48 h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti-human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8 +/- 11.5 h, 76.1 +/- 21.8 h, and 68.5 +/- 21.2 h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9 +/- 5.9, 26.2 +/- 3.1, and 15.4 +/- 1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group, respectively, while the tumor to bone marrow ratios for these groups were 1.7 +/- 0.5, 3.2 +/- 1.1, and 2.0 +/- 0.6, respectively. CONCLUSION: 99mTc-BIWA 4 can safely be administered to patients with HNSCC, with absence of detectable HAHA responses. The 50-mg dose level showed the highest tumor uptake and tumor to nontumor ratios. These findings support the use of BIWA 4 for RIT studies in patients with HNSCC.

Phase I therapy study with (186)Re-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with head and neck squamous cell carcinoma.

PURPOSE: In previous studies, we have shown the potential of radioimmunotherapy (RIT) with (186)Re-labeled chimeric monoclonal antibody (MAb) U36 for treatment of head and neck cancer. A limitation of this anti-CD44v6 MAb, however, appeared to be its immunogenicity, resulting in human antichimeric antibodies in 40% of the patients. Aiming for a less immunogenic anti-CD44v6 MAb, the humanized MAb BIWA 4 (bivatuzumab) was introduced. In the present Phase I RIT study, we determined the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity, and therapeutic potential of (186)Re-labeled BIWA 4 in patients with squamous cell carcinoma of the head and neck. EXPERIMENTAL DESIGN: Twenty patients with inoperable recurrent and/or metastatic head and neck squamous cell carcinoma received a single dose of (186)Re-labeled BIWA 4 in radiation dose-escalation steps of 20, 30, 40, 50, and 60 mCi/m(2). Three patients received a second dose at least 3 months after the initial dose. After each administration, whole-body images as well as planar and tomographic images of the head and neck region were obtained, and the pharmacokinetics and the development of human antihuman antibody responses were determined. Radiation absorbed doses were calculated for whole body, red marrow, organs, and tumor. RESULTS: First and second administrations were all well tolerated, and targeting of tumor lesions proved to be excellent. The only significant manifestations of toxicity were dose-limiting myelotoxicity consisting of thrombo- and leukocytopenia and, to a lesser extent, oral mucositis (grade 2). Grade 4 myelotoxicity was seen in two patients treated with 60 mCi/m(2). The MTD was established at 50 mCi/m(2), at which level dose-limiting myelotoxicity was seen in one of six patients. Stable disease, varying between 6 and 21 weeks, was observed in three of six patients treated at the MTD level. The median tumor dose, recalculated to MTD level, was 12.4 Gy. The absorbed dose in red marrow was 1.82 +/- 0.11 cGy/mCi for males and 2.35 +/- 0.10 for females. Two patients experienced a human antihuman antibody response. Pharmacokinetics showed consistency across patients and within the three patients receiving (186)Re-BIWA 4 on two occasions. CONCLUSIONS: This study shows that (186)Re-labeled BIWA 4 can safely be administered, also in a repeated way. The MTD was established at 50 mCi/m(2). In comparison with the previously described anti-CD44v6 MAb U36, the humanized MAb BIWA 4 seems to be less immunogenic. The fact that antitumor effects were seen in incurable patients with bulky disease justifies the evaluation of RIT with (186)Re-labeled BIWA 4 in an adjuvant setting.

Reinfusion of unprocessed, granulocyte colony-stimulating factor-stimulated whole blood allows dose escalation of 186Relabeled chimeric monoclonal antibody U36 radioimmunotherapy in a phase I dose escalation study.

PURPOSE: In an earlier Phase I radioimmunotherapy (RIT) study with rhenium-186-labeled chimeric monoclonal antibody (cMAb) U36 in patients with refractory head and neck squamous cell carcinoma, the maximum tolerated activity was established at 1.0 GBq/m2, at which bone marrow doses ranged from 0.7 to 1.1 Gy. In the present study, further dose escalation in RIT was evaluated using a facile method of reinfusion of granulocyte colony-stimulating factor (G-CSF)-stimulated unprocessed whole blood. EXPERIMENTAL DESIGN: Nine patients with recurrent or metastatic head and neck squamous cell carcinoma were treated at radiation dose levels of 1.0, 1.5, and 2.0 GBq/m2. Before RIT, G-CSF (10 microg/kg/day) was administered s.c. at home during 5 days. On day 6, just before administration of 186Relabeled cMAb U36, 1 liter of whole blood was harvested and kept unprocessed at 4 degrees C until reinfusion after 72 h. Blood samples were taken for analysis of pharmacokinetics and bone marrow dosimetry. Patients were evaluated for myelotoxicity and tumor response. RESULTS: Blood harvesting, RIT, and reinfusion of whole blood were well tolerated by all patients. G-CSF stimulation resulted in a mean of 0.41 x 10(6) CD34+ cells/kg (range, 0.15-0.83 x 10(6) CD34+cells/kg) and a mean committed colony-forming units granulocyte macrophage count of 5.62 x 10(4)/kg (range, 0.62-13.37 x 10(4)/kg). The mean biological half-life of 186Relabeled cMAb U36 in blood was 72.6 +/- 16.0 h, and bone marrow doses ranged from 2.1 to 2.8 Gy at the highest dose level. Myelotoxicity exceeding grade 3 was not observed. Stable disease was observed in five of nine patients, ranging from 3 to 5 months, and was still ongoing in one of these patients. CONCLUSIONS: This study indicates that a doubling of the maximum tolerated activity and bone marrow dose of 186Relabeled cMAb U36 can be achieved using reinfusion of G-CSF-stimulated unprocessed whole blood.