Bioactive glass (S53P4) as obliteration material in subtotal petrosectomy: initial experience.

BACKGROUND: Subtotal petrosectomy for chronic suppurative otitis media requires obliteration of the mastoid cavity and middle ear. Usually, abdominal fat is used for this purpose. However, infection is a risk of using fat, which might require revision surgery. The use of S53P4 bioactive glass with antibacterial properties seems an attractive alternative. METHODS: Two patients with a history of chronic suppurative otitis media, complicated by profound perceptive hearing loss, had already been surgically treated, and were thereafter extensively treated conservatively. Because of recurrent chronic otorrhoea and pain, subtotal petrosectomy with obliteration of the cavity with S53P4 bioactive glass was performed. RESULTS: Follow-up duration was 84 months and 18 months, respectively. No complications occurred peri-operatively. A dry ear was obtained and no late adverse events were observed. CONCLUSION: S53P4 bioactive glass is feasible to use for obliteration after subtotal petrosectomy. Elimination of chronic suppurative otitis media can be achieved with this technique. The bioactive glass granules might be an attractive alternative to abdominal fat, which has a risk of infection.

[Cholesteatoma: rare, but can have serious consequences]. / Cholesteatoom.

Cholesteatoma is a mass formed by the keratinizing squamous epithelium in the tympanic cavity and/or mastoid that can lead to the destruction of surrounding structures in the ear. It can arise at any age. Symptoms are non-specific and diagnosis may be difficult on otoscopic examination. The management of cholesteatoma is surgical; mastoid obliteration has reduced the incidence of recurrent cholesteatoma in recent years. The use of diffusion-weighted MRI has proven to be a reliable technique for the detection and follow-up of cholesteatoma.

The value of non echo planar, diffusion-weighted magnetic resonance imaging for the detection of residual or recurrent middle-ear cholesteatoma.

OBJECTIVE: To determine the value of non echo planar, diffusion-weighted magnetic resonance imaging for detection of residual and recurrent middle-ear cholesteatoma after combined-approach tympanoplasty. METHOD: The magnetic resonance imaging findings after primary surgery for cholesteatoma were compared with intra-operative findings at 'second-look' surgery or with clinical follow-up findings. RESULTS: Forty-eight magnetic resonance imaging studies were performed in 38 patients. Second-look surgery was performed 21 times in 18 patients. The remaining patients were followed up at the out-patient clinic. There were no false-positive findings with non echo planar, diffusion-weighted magnetic resonance imaging; however, there were four false-negative findings. The mean maximum diameter of recurrent cholesteatoma, as assessed using magnetic resonance imaging, was 11.7 mm (range, 4.4-25.3 mm). The sensitivity of non echo planar, diffusion-weighted magnetic resonance imaging for detecting cholesteatoma prior to second-look surgery was 0.76, with a specificity of 1.00. When clinical follow up of the non-operated ears was included in the analysis, sensitivity was 0.81 and specificity was 1.00. CONCLUSION: Recurrent cholesteatoma can be accurately detected using non echo planar, diffusion-weighted magnetic resonance imaging. Our study, however, also showed some false-negative results. Therefore, strict out-patient follow up is mandatory for those considering using this technique instead of standard second-look surgery.

Evaluation of limited blood sampling in a preceding 99mTc-labeled diagnostic study to predict the pharmacokinetics and myelotoxicity of 186Re-cMAb U36 radioimmunotherapy.

UNLABELLED: 186Re-labeled chimeric monoclonal antibody U36 (cMAb U36) was recently evaluated in a phase I dose escalation study in head and neck cancer patients. All 13 patients received 99mTc-labeled cMAb U36 before 186Re-cMAb U36 radioimmunotherapy. The aim of this study was to evaluate the suitability of multiple or limited blood sampling to predict clearance, red marrow absorbed dose, and myelotoxicity of 186Re-cMAb U36. METHODS: Population pharmacokinetics of 186Re-cMAb U36 were analyzed with a nonparametric expectation algorithm (NPEM 2) and used for Bayesian analysis of individual patient data to predict cMAb U36 clearance. RESULTS: 186Re-cMAb U36 clearance was most accurately predicted (r = 0.91, P < 0.001) with limited sampling for sample points 4 and 72 h after administration of 186Re-cMAb U36. These predictions were less accurate with 99mTc-cMAb U36 (r = 0.51, P = 0.078 for multiple sampling; r = 0.47, P = 0.104 for sampling at 4 and 21 h after administration). Thrombocytopenia was found to be correlated with the red marrow absorbed dose and was equally well predicted by limited blood sampling after administration of 99mTc-cMAb U36 (r = 0.81, P < 0.01) or 186Re-cMAb U36 (r = 0.79, P < 0.01). CONCLUSION: Limited sampling seems useful to predict pharmacokinetics and myelotoxicity of 186Re-cMAb U36.

Radioimmunotherapy in patients with head and neck squamous cell carcinoma: initial experience.

BACKGROUND: Despite improvements in locoregional treatment of stages III/IV squamous cell carcinoma of the head and neck (HNSCC), local and distant failure rates remain high. An effective adjuvant therapy is required for these patients. Among novel approaches is radioimmunotherapy, in which monoclonal antibodies (MAbs) are used for selective delivery of radiation to tumor cells. METHODS: The suitability of 186Re-labeled chimeric MAb U36 (186Re-cMAb U36) for radioimmunotherapy was evaluated in a phase I study, with radiation dose escalating steps of 11, 27, and 41 mCi/m2. Tumor targeting was monitored with a gamma camera, and the maximum tolerated dose was established in 13 patients with recurrent or metastatic disease. RESULTS: Administrations were well tolerated, and excellent targeting of tumor lesions was seen. Myelotoxicity was the only toxicity observed, resulting in dose-limiting toxicity in two patients treated with 41 mCi/m2. The MTD was established at 27 mCi/m2. A marked reduction in tumor size was observed in two patients, another showed stable disease for 6 months. CONCLUSIONS: Radioimmunotherapy with 186Re-cMAb U36 seems to be well tolerated, with bone marrow being the dose-limiting organ. The observation of antitumor effects is encouraging for further development of radioimmunotherapy for HNSCC.

Head and neck squamous cell carcinoma: US-guided fine-needle aspiration of sentinel lymph nodes for improved staging--initial experience.

Ultrasonography (US)-guided fine-needle aspiration with cytologic examination was combined with lymphoscintigraphy for the identification of sentinel lymph nodes (SLNs) in 12 patients with a squamous cell carcinoma of the oral cavity or oropharynx. Dynamic lymphoscintigraphy and a hand-held gamma probe were used to depict the SLNs to be aspirated. Cytologic examination of the aspirated SLNs revealed neck lymph node status in patients who underwent neck dissection (n = 6). In patients who underwent only transoral excision, one false-negative cytologic result was observed. This combined approach is expected to improve the detection of occult neck lymph node metastases.

Molecular diagnosis of head and neck cancer.

Patients with advanced stages of head and neck cancer frequently develop locoregional recurrence as well as distant metastases. These data indicate that traditional diagnostic methods such as histopathology and radiology are not sensitive enough to detect the small numbers of tumor cells which are left behind, defined as minimal residual disease (MRD). Sensitive diagnostic assays based on molecular markers appear to be powerful tools to improve the staging of these patients. At the DNA level, tumor-specific p53 mutations seem to have great potential for the detection of "occult" tumor cells at surgical margins and lymph nodes. At the RNA level HNSCC associated antigens like the E48 antigen, allow the detection of rare HNSCC cells in blood and bone marrow and, it is hoped, also in lymph nodes and lymph node aspirates. However, the molecular assays which are used to detect MRD are subject to certain (technical) problems which affect their sensitivity and specificity. In this paper we will present examples of molecular assays such as the plaque assay using p53 mutations and the E48 RT-PCR, and show their use for MRD detection in cervical lymph nodes. In addition, we will discuss the problems and pitfalls associated with these sensitive techniques.

Lymphoscintigraphy and ultrasound-guided fine needle aspiration cytology of sentinel lymph nodes in head and neck cancer patients.

Accurate staging of the regional lymph nodes is crucial for the appropriate management of patients with squamous cell carcinoma of the head and neck (HNSCC). However, the current diagnostic modalities have low accuracy for N0 neck, and even the most optimal procedure, ultrasound-guided fine needle aspiration cytology (USgFNAC), still has a sensitivity of only 42%-73%. In this study we evaluated whether the identification of the sentinel node might improve the selection of lymph nodes for USgFNAC. Twelve HNSCC patients received 3-4 peritumoral injections of 10-30 MBq 99mTc-labeled colloidal albumin, and the sentinel node was identified by dynamic scintigraphy and marked on the skin using a handheld probe, and/or by scintillation counting of the aspirates. After sentinel node identification USgFNAC was performed. Correct aspiration of the identified sentinel node(s) was confirmed by scintillation counting. In 11 out of 12 cases the sentinel node(s) could be visualized by dynamic planar imaging. In one case the sentinel node(s) were identified by scintillation counting only. In a number of patients different or supplementary lymph nodes were aspirated on the basis of sentinel node identification. These initial data strongly suggest that sentinel node identification might improve the staging of the neck by USgFNAC.

Phase I therapy study of 186Re-labeled chimeric monoclonal antibody U36 in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: A phase I therapy study was conducted to determine the safety, maximum tolerated dose (MTD), pharmacokinetics, dosimetry, immunogenicity, and therapeutic potential of 186Re-labeled anti-CD44v6 chimeric monoclonal antibody (cMAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC). The potential of a diagnostic study with 99mTc-cMAb U36 to predict the biodistribution of 186Re-cMAb U36 was evaluated. METHODS: Thirteen patients with recurrent or metastatic HNSCC were given 750 MBq 99mTc-cMAb U36 (2 mg) followed 1 wk later by a single dose of 186Re-cMAb U36 (12 or 52 mg) in radiation dose-escalating steps of 0.4, 1.0, and 1.5 GBq/m2. After each administration, planar and SPECT images were obtained, and the pharmacokinetics and development of human antimurine as well as anti-cMAb responses were determined. Radiation absorbed doses to tumor, red marrow, and organs were calculated. RESULTS: Administration was well tolerated, and excellent targeting of tumor lesions was seen in all patients. Dose-limiting myelotoxicity (thrombocytopenia being most prominent) was the only toxicity observed, resulting in grade 4 myelotoxicity in 2 patients treated with 1.5 GBq/m2. The MTD was established at 1.0 GBq/m2, at which a transient grade 3 thrombocytopenia was seen in 1 patient. One patient showed stable disease for 6 mo after treatment at the MTD. The 2 patients with dose-limiting myelotoxicity showed a marked reduction in tumor size. The reduction was of short duration and, therefore, not considered an objective response. Tumor absorbed doses at MTD ranged from 3.0 to 18.1 Gy. Red marrow doses ranged from 20 to 112 cGy (mean, 51 +/- 16 cGy/GBq) and correlated with platelet nadir (r = 0.8; P < 0.01). Pharmacokinetics varied between patients treated at the same dose level and were accurately predicted by the diagnostic procedure. Five patients experienced a human anti-cMAb response, 1 of which was a human antimouse antibody response. CONCLUSION: This study shows that 186Re-cMAb U36 can be safely administered, with dose-limiting myelotoxicity at 41 mCi/m2. The use of cMAb U36 instead of its murine counterpart did not decrease the induction of human antibody responses. The availability of a 99mTc-labeled diagnostic study that can predict the pharmacokinetics of 186Re-cMAb U36 offers the possibility of using such a study for selection of a safe radioimmunotherapy dose.

Imaging and analysis of perivascular nerves in human mesenteric and coronary arteries: a comparison between epi-fluorescence and confocal microscopy.

Perivascular nerves supplying human arteries can be visualised after immunohistochemical staining for a variety of markers. The pattern and density of perivascular nerves vary with region, age and disease. Quantification of the nerve plexus, which may be performed by image analysis, is a prerequisite to assess differences in nerve density. The use of epi-fluorescence microscopy (EFM) presents difficulties in visualising the nerve plexus in certain tissues, which can affect the reliability with which specific staining can be localised and distinguished from non-specific staining. In this study, confocal scanning laser microscopy (CSLM) was used in parallel with EFM, in order to compare images from both techniques. In a comparison of identical areas of nerve plexuses of human mesenteric and coronary arteries stained for protein gene product (PGP) 9.5 and imaged using CSLM and EFM, higher values for area percent (area occupied by nerves), and intercept density (ID/mm, which reflects the number of nerve bundles detected) were found in CSLM images. Similar comparisons of unmatched epi-fluorescence and confocal images from a group of 45 mesenteric arteries revealed no significant difference for area percent, but significantly higher values for ID/mm in CSLM images. These findings illustrate that the better image quality in CSLM influences image analysis and can be very useful in studies of dynamic changes in nerve plexuses. We recommend CSLM for tissues that suffer from high background staining, such as human mesenteric and coronary arteries.