Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.

Hyperostosis cranialis interna (HCI) is a rare autosomal dominant disorder characterized by intracranial hyperostosis and osteosclerosis, which is confined to the skull, especially the calvarium and the skull base. The rest of the skeleton is not affected. Progressive bone overgrowth causes nerve entrapment that leads to recurrent facial nerve palsy, disturbance of the sense of smell, hearing and vision impairments, impairment of facial sensibility, and disturbance of balance due to vestibular areflexia. The treatment is symptomatic. Histomorphological investigations showed increased bone formation with a normal tissue structure. Biochemical parameters were normal. Until today the disease has been described in only three related Dutch families with common progenitors and which consist of 32 individuals over five generations. HCI was observed in 12 family members over four generations. Patients are mildly to severely affected. Besides HCI, several bone dysplasias with hyperostosis and sclerosis of the craniofacial bones are known. Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well. Linkage analysis in a family with HCI resulted in the localization of the disease-causing gene to a region on chromosome 8p21 delineated by markers D8S282 and D8S382. Interesting candidate genes in this region are BMP1, LOXL2, and ADAM28. Sequence analysis of these genes did not reveal any putative mutations. This suggests that a gene not previously involved in a sclerosing bone dysplasia is responsible for the abnormal growth in the skull of these patients.

Phenotypic manifestations and management of hyperostosis cranialis interna, a hereditary bone dysplasia affecting the calvaria and the skull base.

Hyperostosis cranialis interna is a hereditary bone disorder that is characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base (OMIM 144755). The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade. This study analyzes the clinical course of 13 affected individuals of three related families (32 individuals). The disorder appears to have an autosomal-dominant transmission pattern. Facial and vestibulocochlear nerve dysfunction are most frequently reported. Surgical decompression of the accessible impaired cranial nerves is advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals.

Synchronous bilateral epithelial-myoepithelial carcinoma of the parotid gland: case report and review of the literature.

Synchronous bilateral malignancy in the parotid glands is extremely rare. The English literature reveals nine case reports. The most common synchronous bilateral malignancies are acinic cell carcinoma. Epithelial-myoepithelial carcinoma is an uncommon neoplasm comprising 1% of all salivary gland tumours. In this case report, we describe, to our best of knowledge, the first case of a patient with a synchronous bilateral epithelial-myoepithelial carcinoma of the parotid gland. The clinical histopathological and immunohistochemical peculiarities are elucidated. Imaging studies like ultrasonography are mandatory for both parotid glands and upper necks in the clinical presence of a unilateral parotid gland tumour.

Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas.

Oncogenic human papillomavirus (HPV) is a causative agent in a subgroup of head and neck carcinomas, particularly tonsillar squamous cell carcinomas (TSCC). This study was undertaken because controversial data exist on the physical status of HPV-DNA and the use of p16(INK4A) overexpression as surrogate HPV marker, and to examine the impact of HPV and tobacco consumption on the clinical course of TSCC. Tissue sections of 81 TSCC were analyzed by HPV 16-specific fluorescence in situ hybridization (FISH) and p16(INK4A)-specific immunohistochemistry. Results were correlated with clinical and demographic data. HPV 16 integration was detected by FISH as punctate signals in 33 out of 81 (41%) TSCC, 32 of which showed p16(INK4A) accumulation. Only 5 out of 48 HPV-negative tumors showed p16(INK4A) immunostaining (p < 0.0001). The presence of HPV furthermore correlates significantly with low tobacco (p = 0.002) and alcohol intake (p = 0.011), poor differentiation grade (p = 0.019), small tumor size (p = 0.024), presence of a local metastasis (p = 0.001) and a decreased (loco)regional recurrence rate (p = 0.039). Statistical analysis revealed that smoking significantly increases the risk of cancer death from TSCC and that non-smoking patients with HPV-containing TSCC show a remarkably better disease-specific survival rate. HPV 16 is integrated in 41% of TSCC and strongly correlates with p16(INK4A) overexpression, implicating the latter to be a reliable HPV biomarker. Patients with HPV-positive tumors show a favorable prognosis as compared to those with HPV-negative tumors, but tobacco use is the strongest prognostic indicator. These findings indicate that oncogenic processes in the tonsils of non-smokers differ from those occurring in smokers, the former being related to HPV 16 infection.

Chromosome instability as an indicator of malignant progression in laryngeal mucosa.

PURPOSE: Routine histologic examination cannot predict whether premalignant laryngeal lesions will progress toward invasive growth. The acquisition of changes in chromosome constitution has been suggested to be essential for driving tumor progression by enhancing mutagenic mechanisms. The aim of the present study was to determine whether chromosomal changes occur in the subsequent stages of early laryngeal carcinogenesis and, if so, whether these changes can be of prognostic value. MATERIALS AND METHODS: Numerical aberrations for chromosomes 1 and 7 were detected in tissue sections from archival material using an improved in situ hybridization protocol. In total, eight benign laryngeal lesions, 37 premalignant laryngeal lesions, and 16 specimens containing histologically normal epithelia adjacent to laryngeal squamous cell carcinomas were studied. Both the histologic and the cytogenetic classifications were correlated with progression to laryngeal cancer. RESULTS: No evidence for chromosome alterations was obtained in the control group, nor in histologically normal epithelia adjacent to laryngeal squamous cell carcinomas, nor in all but one hyperplastic lesion (n = 11). In contrast, 14 of 15 dysplastic lesions and nine of 11 carcinomas-in-situ contained numerical chromosomal aberrations. Tetrasomy was present in the majority of the dysplastic lesions. An unstable chromosome content (indicated by the presence of chromosome imbalances and/or polyploidization) in the premalignant lesion strongly predicted its malignant progression. CONCLUSION: Our results show that laryngeal tumor development involves chromosome tetraploidization. The further change from a stable to an unstable chromosome constitution is of importance for malignant progression.

Thymic cyst in the neck.

A rare case of a thymic cyst in the neck containing both thymus and parathyroid tissue in a 7-year-old boy is presented. The clinical presentation, diagnostic evaluation, surgical management and histopathological features are described. The embryology of cervical thymic cysts and the differential diagnosis of cystic neck masses in children are briefly reviewed. The diagnosis is seldom made preoperatively. Surgical resection is the treatment of choice for definitive diagnosis, resolution of symptoms and cure.

Compliance, quality of life and quantitative voice quality aspects of hands-free speech.

CONCLUSIONS: With the use of a new automatic stoma valve (ASV) it appears possible to rehabilitate patients who have previously been unsuccessful in acquiring hands-free speech. As well as making daily ASV use possible for an additional group of patients, this new device was also appreciated by many patients as an additional rehabilitation tool for specific occasions. Despite statistically significant improvements in aspects of voice and breathing using this novel ASV, improvement of peristomal adhesion is probably the main factor needed to further increase success rates. Nevertheless, our results show that it makes sense to keep trying to achieve hands-free speech, even if previous attempts have failed. OBJECTIVE: To make a long-term (6 months) assessment of compliance and aspects of voice, breathing and quality of life using a new ASV: the Provox FreeHands heat and moisture exchanger (HME). MATERIAL AND METHODS: This was a prospective clinical multicentre trial in 79 laryngectomized patients (8 regular ASV users, 58 previously unsuccessful users and 13 new users). Data were collected at baseline and after 1 and 6 months by means of European Organization for Research and Treatment of Cancer Quality of Life questionnaires and specific structured questionnaires concerning compliance, skin adhesion, voicing and pulmonary aspects. An objective assessment of voice parameters (maximum phonation time, maximum phonation time while counting, dynamic loudness range and number of pauses in a standard read-aloud text) was made for comparison of different stoma occlusion methods (digital occlusion via an HME and two different ASVs). A subjective assessment of overall voice quality was made. RESULTS: After 6 months, 19% of patients used the new ASV on a daily basis (mean 5 h/day), while 57% used it on an irregular basis as an additional rehabilitation tool for special occasions. Two-thirds of the study group indicated that they would continue to use the new ASV after the study period. With respect to the objective parameters, statistically significantly better maximum phonation times and dynamic loudness ranges were observed with the new ASV compared to the Blom-Singer ASV. However, the best results for all the objective parameters were obtained with digital occlusion via the Provox HME.

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

The value of twice yearly bronchoscopy in the work-up and follow-up of patients with laryngeal cancer.

The aim of this retrospective study was to investigate the usefulness and feasibility of twice-yearly bronchoscopy and sputum cytology in patients with laryngeal cancer. In 170 selected patients, 500 (both initial and during follow-up) bronchoscopies were performed. There was a maximum follow-up of 34 months. 5 (2.8%) male patients developed lung cancer. In only 2 of them was the diagnosis based on bronchoscopy alone. After treatment with curative intent, both patients developed a recurrent lung carcinoma. According to most patients' experience, regular bronchoscopy is unpleasant. It is concluded that twice-yearly bronchoscopy and sputum cytology in patients with laryngeal cancer is not useful as a routine procedure. At present, chemoprevention of second primary tumours seems the most promising adjunctive treatment modality.

The value of ultrasound with ultrasound-guided fine-needle aspiration biopsy compared to computed tomography in the detection of regional metastases in the clinically negative neck.

PURPOSE: Head and neck oncologists have not reached consensus regarding the role of contemporary imaging techniques in the evaluation of the clinically negative neck in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of the present study was to compare the accuracy of ultrasound with guided fine-needle aspiration biopsy (UGFNAB) and computed tomography (CT) in detecting lymph node metastasis in the clinically negative neck. METHODS AND MATERIALS: Sixty-four neck sides of patients with HNSCC were examined preoperatively by ultrasound/UGFNAB and CT at one of five participating tertiary care medical centers. The findings were correlated with the results of histopathologic examination of the neck specimen. RESULTS: Ultrasound with guided fine-needle aspiration biopsy was characterized by a sensitivity of 48%, specificity of 100%, and overall accuracy of 79%. Three cases had nondiagnostic aspirations using UGFNAB and were excluded. CT demonstrated a sensitivity of 54%, specificity of 92%, and overall accuracy of 77%. UGFNAB detected two additional metastases not visualized on CT, whereas CT detected no metastases not seen on UGFNAB. The results of UGFNAB were similar between the participating centers. CONCLUSIONS: Approximately one half of the clinically occult nodal metastases in our patient group were identified by both CT and UGFNAB. Overall, UGFNAB and CT demonstrated comparable accuracy. The sensitivity of CT was slightly better than UGFNAB, but the latter remained characterized by a superior specificity. The results of CT and UGFNAB did not appear to be supplementary. The choice of imaging modality for staging of the clinically negative neck depends on tumor site, T-stage, and experience and preference of the head and neck oncologist. If CT is required for staging of the primary tumor, additional staging of the neck by UGFNAB does not provide significant additional value.

Vertical partial laryngectomy for recurrent glottic carcinoma after irradiation.

Vertical partial laryngectomy after a full course of irradiation was performed in 26 patients as salvage surgery for recurrent or residual glottic carcinoma. An excellent cure rate and conservation of function was obtained, while complications were few. A prerequisite for this type of surgery is a limited extent and infiltration of the recurrent local tumor growth. As the great majority of local recurrence appears within the first 2 years after radiotherapy, frequent follow-up during this period is stressed for early detection of a recurrence.

Supraomohyoid neck dissection with frozen section biopsy as a staging procedure in the clinically node-negative neck in carcinoma of the oral cavity.

A retrospective analysis was performed to evaluate the efficacy of elective supraomohyoid neck dissection in 57 newly diagnosed patients with squamous cell carcinoma of the oral cavity. The protocol included sampling of both the most suspicious and the largest node in the jugulodigastric region (if present) and the most distal jugulo-omohyoid lymph node (if present) for frozen section examination. In 10 cases, frozen section biopsy revealed metastatic disease, and surgery was continued using standard or modified radical neck dissection en bloc with the primary tumor. In another 10 cases, histologic examination of the supraomohyoid neck dissection specimens revealed occult nodal disease at other sites. In the histologically proven absence of metastatic disease in the supraomohyoid neck dissection specimens, disease recurrence in the neck occurred in only three cases (7%), all in the presence of local failure. The results of our analysis support the conclusion that elective supraomohyoid neck dissection with frozen section biopsy appears to be a valid staging procedure and a valuable approach to the management of the clinically node-negative neck in squamous cell carcinoma of the oral cavity.

Reanimation of the paralyzed face by indirect hypoglossal-facial nerve anastomosis.

BACKGROUND: The results of indirect hypoglossal facial nerve anastomosis with interposition of a free nerve graft, end-to-end to the periferal facial nerve stump, and end-to-side to the hypoglossal nerve are prospectively evaluated. This technique is supposed to overcome loss of hypoglossal function. METHODS: Tongue function in 39 consecutive patients and facial reanimation in 29 patients who completed 24 months follow-up were assessed. Facial nerve function was judged using the House-Brackmann (HB) grading system. RESULTS: Tongue movements were normal in all operated on patients. Initial facial movements occurred on average 7.5 months postoperatively. The results were graded HB II in 6 (20.9%), HB III in 13 (44.6%), HB IV in 7 (24.1%), HB V in 2 (6.8%) patients, and HB VI in 1 (3.4%) patient. The results were significantly better in young patients and when a short time interval between paralysis and surgery existed. CONCLUSIONS: Indirect hypoglossal-facial anastomosis is the preferred technique in most patients for whom the classical direct hypoglossofacial anastomosis is indicated.

A prospective longitudinal study on radiation-induced hearing loss.

Recent clinical reports indicate that patients receiving radiotherapy that includes the auditory system in the treatment volume are likely to develop an irradiation-induced hearing loss. Although the early, presumed reversible, conductive hearing impairment due to secretory otitis media following radiotherapy is a sequela well known by radiation oncologists, permanent hearing loss, both conductive and sensorineural, is believed to be rare. A prospective study was performed enrolling patients receiving postoperative radiotherapy for unilateral parotid tumors. Audiometric results prior to irradiation were compared with those obtained 2 years later. Up to 50% of the patients (9 of 18) developed a clinically relevant hearing loss in the irradiated ear, both conductive and/or sensorineural. The contralateral ear remained unaltered. The hearing loss was permanent in 6 patients (33%) and affected their quality of life. The data suggest that changes occur in the inner ear as well as in the auditory nerve and auditory brain stem with conventional irradiation schemes with daily fractions of 2 to 2.5 Gy with a total dose of 50 Gy.

Prognostic factors for survival in patients with T3 laryngeal carcinoma.

In a total of 511 patients with T3,N0-3,M0 laryngeal carcinoma, 24 possible prognostic factors were analyzed retrospectively. The factors were age, sex, mode of treatment, duration of several clinical symptoms, the presence of sore throat, otalgia, dyspnea, and dysphagia, previous tracheotomy, tumor extension, lymph node status (five items), histologic grading, smoking habits, and alcohol intake. For 300 patients in whom surgery was part of the primary treatment, pathologic staging of the primary tumor and of lymph nodes in neck dissection specimens, cartilage invasion, radicality of the operation, differentiation grade, and subglottic extension ware also evaluated. In a univariate analysis for the whole group, tumor extension (limited to the glottic region), lymph node status (clinically palpable lymph nodes, cytologically confirmed positive lymph nodes), level of lymph node metastasis (high and midjugular site), histologic grading (poor differentiation grade), and treatment modality (planned combined therapy) were considered to be prognostic factors of corrected actuarial survival. In the group that underwent surgery, all factors derived from specimens of the larynx and neck dissections had prognostic significance. Multivariate analysis revealed that the glottic site of the tumor, the presence of cyto- and histopathologically proven metastatic lymph nodes, pretreatment tracheotomy, positive resection margins, and planned combined treatment had a significant influence on corrected actuarial survival.

Longitudinal flow of macromolecules in the endolymphatic space of the rat. An autoradiographical study.

Secretion and resorption of sulphated glycoproteins by the epithelial lining of the endolymphatic space of the rat were studied autoradiographically with the use of 35SO4 as a selective marker. This isotope was found to be incorporated into the sensory area of cristae and maculae and a small area of epithelial cells adjacent to the sensory epithelium. Thereafter 35S-labelled glycoproteins were secreted into cupulae and otolithic membranes. No such process could be established in the tectorial membrane. From the gradual disappearance of 35S-labelled glycoproteins from cupulae and otolithic membrane coupled with an accumulation of this substance in the lumen of the endolymphatic sac, the existence of a longitudinal flow under physiological conditions could be concluded. Resorption of glycoproteins by the saccus epithelium was found to be very slow. Accumulation of 35S-labelled glycoproteins in the endolymphatic duct after saccus obstruction indicates that, in addition to the endolymphatic sac, also the duct contributes to the mechanism underlying the longitudinal flow of macromolecules.

Cochlear and vestibular functions of the rat after obliteration of the endolymphatic sac.

A combined morphological and physiological study on the effect of saccus obliteration on the cochlea and the vestibular labyrinth of the rat is presented. Endolymphatic hydrops was successfully induced in 49% of the animals. It was frequently associated with fistulae of the membranous wall and degenerative changes in the organ of Corti and spiral ganglion. In hydropic ears electrocochleography revealed a CAP threshold increase only in those cases where hydrops was associated with loss of hair cells and ganglion cells. In two of these animals also an increased negative SP was present. Static otolith reflexes were found to be normal in all hydropic ears despite severe lesions of the saccule in some of these. Abnormal canal reflexes measured by electronystagmography and cupulometry were established in animals with hydrops of the semicircular canals and in one animal with a fistula of the saccule.

Stapedius muscle fibre composition in the rat.

The stapedius muscle (SM) is supposed to prevent cochlear damage by noise. Consequently functional demands are the ability of fast contraction with long endurance. This implies the presence of a large fraction of myosin type II fibres with an appreciable oxidative capacity. We determined the myosin composition of SM fibres using consecutive complete SM cross-sections (6 week old rats) which were processed by enzyme histochemistry (EHC) to determine acid/alkali lability of myofibrillar adenosine triphosphatase (mATPase) or by immunohistochemistry (IHC) using myosin heavy chain (MyHC) antibodies. Method accuracy was determined in co-processed extensor digitorum longus (EDL). Four hundred SM and 200 EDL fibres were assigned to mATPase type I, IIA, IIB, IIX or 'miscellaneous' ('Misc') categories. Per mATPase category the fibres were attributed to groups with specific MyHC composition. In the EDL, mATPase type I and IIB fibres expressed only MyHC I and IIB respectively, whereas about 10% of the type IIA and 40% of the type IIX fibres expressed more than one MyHC. Thus IHC detects amounts of myosin isoforms which are not detected by EHC. The mATPase IIX category criterion leaves the possibility that this category contains fibres with myosin type IIA and/or IIB in larger amounts. The criteria of the mATPase categories type I, IIA or IIB preclude assignment to these categories of fibres which also contain other myosin isoforms in larger amounts. Such fibres were classified in one of the mATPase 'Misc' categories. Thus in the EDL the capability of the EHC criteria to select 'pure' fibres in terms of myosin differs per mATPase category. None of the SM fibres were assigned to the mATPase type I or IIB categories, about 25% to the type IIA, 60% to type IIX and 15% (including most fibres which expressed MyHC I) to a 'Misc' category. All SM fibres expressed two or more MyHC isoforms, MyHC IIB occurring in all fibres and substantial amounts of MyHC IIA and/or IIX in most. These findings confirm the hypothesis that such fibres have the capacity to contract fast and have the better fatigue resistance.

Reconstruction of the anterior oral cavity using the platysma myocutaneous island flap.

The platysma myocutaneous island flap has demonstrated high versatility and reliability when used to close defects in the oral cavity in a series of ten patients. The surgical technique for this one-stage reconstructive procedure is described. The advantages and disadvantages of this flap, the results, and complications are discussed.

Carcinoid of the larynx: a report of three cases and a review of the literature.

Carcinoid tumors are among the exceptional neoplasms of the larynx. The laryngeal carcinoid was first described in 1969 by Goldman, et al. Only 16 cases could be traced from the literature. This paper describes three additional cases. In one patient, the tumor infiltrated the laryngeal tissues and metastasized to the cervical lymph nodes breast. In the second case, the polypoid lesion could be excised completely. The third case was initially diagnosed as undifferentiated squamous cell carcinoma. The diagnosis of carcinoid was made a few years later when a metastasis was removed. The presence of intracellular membrane bound neurosecretory granules and positive argyrophilia in the Grimelius stain are characteristic. In half of the cases described in the literature, the tumor was initially misdiagnosed as undifferentiated carcinoma. The treatment of choice is surgical removal which may be curative. The literature is reviewed.