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Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

The Tumor Node Metastasis (TNM) classification system describes head and neck tumors using anatomic or unidimensional criteria and may therefore fail to define the actual three-dimensional tumor bulk. To investigate this we measured variability of tumor volumes (Vvol) in T3-staged head and neck tumors. Patient material consisted of pretreatment computerized tomography (CT) scans of 71 patients, seen between 1990 and 1995, with T3 head and neck carcinoma involving different subsites. Computerized tomographic scans of 42 patients displayed distinct tumor boundaries and were free of motion and/or dental artifacts. Using these scans, tumor volumes were measured using the summation-of-areas technique, and Vvol was determined. Following are the tumor-volume measurements: T3 larynx carcinoma (n = 12) Vvol, 1.7-17.0 mL (median 3.7 mL); T3 oropharynx carcinoma (n = 13) Vvol, 10.0-41.2 mL (median 18.3 mL); T3 hypopharynx carcinoma (n = 10) Vvol, 8.9-67.8 mL (median 17.4 mL); T3 nasopharynx carcinoma (n = 3) Vvol, 3.7-30.1 mL; T3 maxillary sinus carcinoma (n = 4) Vvol, 56.0-103.1 mL. T3-Staged tumors of the head and neck show considerable variability of tumor volumes. Incorporation of tumor volume data may further refine the TNM staging system

The accuracy of SPECT with 201Tl-chloride for the diagnosis of primary tumors, lymph node metastases and recurrences in head and neck cancer was evaluated for clinical applicability. SPECT images, obtained 60 min after administration of 150 MBq 201Tl-chloride, were compared with clinical, CT and/or MRI and histology results. In addition, whole-body images were obtained to detect distant metastases. In 79 patients studied for primary tumors (principally larynix, hypopharynx, oropharynx, nasopharynx and oral cavity), 201Tl SPECT correctly identified 69 of 73 (95% versus 88% for CT/MRI) histologically confirmed malignancies including 63 squamous-cell carcinomas. The method localized four occult naso- and oropharynx carcinomas not seen on CT/MRI and was correctly negative in two patients without tumor and in three of four patients with no confirmed primary tumor in the head and neck. With respect to regional spread, only patients who had cervical lymph node dissection were evaluated, and the findings were recorded per side of the neck. Thallium-201 SPECT correctly identified metastases in 31 of 36 neck dissections with proven lymph node involvement (86%), was correctly negative in nine and false-positive in one. Although the sensitivity of CT/MRI was clearly higher (97%), considerably more false-positive cases affected its accuracy (81% versus 87% for SPECT). In 30 patients investigated for recurrences, 201Tl SPECT correctly identified 27 of 29 microscopically confirmed tumor sites (93%) and was correctly negative in seven. Sensitivity of CT/MRI was lower (76%), and a greater number of false-positives (seven versus three for SPECT) further decreased its accuracy (64% versus 87% for SPECT). Distant metastases were detected in five patients. Thallium-201 SPECT appears to be an accurate method for the diagnosis of head and neck cancer. The method is particularly useful for detection of occult head and neck tumors and for assessing recurrences. It also may be of complementary value in the staging of primary tumors, in the differentiation of metastatic from reactive lymph nodes in the neck and, on the basis of whole-body scanning, for screening of distant metastases

Previous clinical research has provided sound knowledge about the effects of heat and moisture exchangers on clinical pulmonary functioning, clinical symptoms, and intra-tracheal climate changes in laryngectomized patients. The aim of this thesis was to further enhance our understanding of how an HME device functions, to develop new techniques and approaches to assess HME performance. A newly developed, universally applicable ex vivo method that measures the HME water exchange performance, was introduced and validated. This method assesses the HME weight end-inspiratory and end-expiratory. A wide range of water exchange and humidity performances was found in 23 tested HME types. Next, we have found that the total water uptake of a hygroscopic HME during breathing is related to its humidity and water exchange performance. Loss of HME water uptake capacity was found after 24-hour tracheostoma application, however, the remaining water uptake was still clinically acceptable. Tracheal mucus transport velocity and tracheal epithelial brush biopsies assessment were used to evaluate the effects of HME on mucociliary clearance. Significantly more ciliated cells were found in HME users than in non-HME users. The tracheal mucus transport velocity was not significantly higher in HME users than in non-HME users. The incidence of pulmonary infections in laryngectomized patients shows a tendency that the number of tracheobronchitis and pneumonia episodes is lower in HME users than in non-HME users based on a retrospective clinical study and a European wide survey among head and neck surgeons.