Epirubicin, cisplatin and protracted venous infusion 5-Fluorouracil chemotherapy for advanced salivary adenoid cystic carcinoma.

AIMS: Adenoid cystic carcinoma (ACC) is a rare tumour that usually arises in the salivary glands. Initial management is surgery often combined with adjuvant radiotherapy. Chemotherapy is reserved for treatment of symptomatic recurrence. We evaluated the combination of epirubicin, cisplatin and protracted venous infusion 5-fluorouracil (ECF) in the management of ACC. MATERIALS AND METHODS: Patients referred for treatment of advanced, symptomatic ACC were considered. The drugs given were epirubicin 50 mg/m(2) 3-weekly, cisplatin 60 mg/m(2) 3-weekly and protracted venous infusion 5-fluorouracil 200 mg/m(2)/day. RESULTS: Eight patients (median age 46 years) received a median of five cycles of chemotherapy. All patients had had previous surgery, seven had had previous radiotherapy and one had had previous chemotherapy. One patient showed a partial response (duration 34 months) and five showed stable disease (median duration 13.6 months [6.8-15.9+ months]). Median survival was 27 months (3.5-62.3 months). CONCLUSIONS: The activity of ECF in ACC of the head and neck seems to be similar to the combination of cisplatin and 5-fluorouracil and single-agent epirubicin.

Future perspectives for health related quality of life (HRQOL) studies in head and neck cancer.

The impact of a head and neck cancer (HNC) diagnosis on a person and the consequences of its treatment across multiple functional domains can profoundly alter quality of life (QOL). By pursuing patient-centered management and considering the entire gamut of physical, psychological and social problems, QOL studies contribute more than just routine mortality and morbidity data. Assessments can now be made using a variety of both specific and generic measures to optimise patient care and to aid the development of informed rehabilitation services. Unfortunately, there exists no 'gold-standard' questionnaire in the literature and the choice is largely based on clinician preference, research objectives and psychometric properties. Future efforts must be made to effectively use modern technological and computational advances to set up item banks and newer theoretical models. Longitudinal studies with pre-determined priori should be encouraged as should the utilisation of minimalist approaches and incisive item response theory. Most importantly, in order to link research to clinical practice, health related QOL (HRQOL) studies should be devised and utilised in a way as to provide clinically meaningful data to the treating physician useful for patient' care.

Questionnaire analysis of swallowing-related outcomes following glossectomy.

OBJECTIVE: To determine the effects of a partial/total glossectomy on the swallow-related quality of life (QOL). DESIGN: Cross-sectional, single-centre cohort study. PATIENTS AND METHODS: Thirty-one patients who underwent partial/total glossectomy at our centre participated in the study. Main outcome was measured using the MD Andersen Dysphagia Inventory (MDADI) questionnaire. RESULTS: Responses were received from 24 males and 7 females (response rate of 77.5%) with a median age of 50 years (range: 28-72). Median follow-up in patients was 33 months (range 4-210). The mean MDADI total score in our series of patients was 71.7 (SD 18.8). Mean MDADI global score was 64.5 (SD 29.1), mean Emotional score was 71.9 (SD 19.1), mean Functional score was 73.7 (SD 19.1) and mean Physical score was 69.3 (SD 21.7). Statistically significant differences were seen between the global, emotional and physical scores of patients who had received radiotherapy (Mann-Whitney, p < 0.05) and tracheostomy (functional score, Mann-Whitney, p = 0.038). CONCLUSION: The presence of tracheostomy tube and previous radiotherapy affects swallowing outcome in patients who have had surgery for squamous cell carcinoma of the tongue.

Does flexible videostroboscopy compare with rigid videostroboscopy in the assessment of the neoglottis? A preliminary report.

OBJECTIVE: To evaluate rigid and flexible stroboscopy of the neoglottis. STUDY DESIGN: Prospective pilot study set at a tertiary level Head & Neck Unit. PARTICIPANTS: Twenty-four patients recruited. All had undergone a total laryngectomy and were voicing using a Blom-singer valve. All had stroboscopic evaluation of their neoglottis using flexible and rigid endoscopes. MAIN OUTCOME MEASURES: A rating form was devised based on six parameters with clear definitions. Secondary measures included ability to tolerate the procedure and completeness of the rating form for each parameter using the two systems. RESULTS: There was good reliability between individual raters for the assessment of each system based on Spearman Rho correlation. Importantly, two-thirds of the patients were unable to tolerate the rigid videostroboscopy managed flexible videostroboscopy. Correlation between rigid and flexible videostroboscopy was poor for both raters. Flexible systems picked up more mucosal waves and allowed further analysis of the mucosal wave pattern. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that fibreoptic videstroboscopy is as good as rigid videostroboscopy in the assessment of the neoglottis. In fact, flexible videostroboscopy should be routinely used, as it is better tolerated and allows a more detailed analysis of the neoglottis.

The uncertainty of the surgical margin in the treatment of head and neck cancer.

We discuss our surgical philosophy concerning the subtle interplay between the size of the surgical margin taken and the resultant morbidity from ablative oncological procedures, which is ever more evident in the treatment of head and neck malignancy. The extent of tissue resection is determined by the "trade off" between cancer control and the perioperative, functional and aesthetic morbidity and mortality of the surgery. We also discuss our dilemmas concerning recent minimally invasive endoscopic microsurgical techniques for the trans-oral laser removal or co-ablation of aero-digestive tract tumours, which result in a minimal surgical margin of oncological clearance. By a process of inductive argument as to the nature of the surgical margin, we consider whether the risks of taking a lesser margin with adjuvant therapy is justified by the attendant gain in reduced surgical morbidity and the possible costs in tumour control.

Postlaryngectomy vocal rehabilitation: assessment using a validated questionnaire in 51 patients.

BACKGROUND: This study aimed to assess valved speech and related issues in total laryngectomy patients with the help of the validated Voice Prosthesis Questionnaire (VPQ). PATIENTS AND METHODS: We identified 61 patients who had undergone a surgical voice restoration with a valve following total laryngectomy and who were sent the VPQ by mail. RESULTS: Fifty-one patients (37 males) completed the questionnaire giving a response rate of 83.6%. Fifty-three percent of the patients (n = 27) were fully aware of the dimensions of their valve including the length and diameter, whilst 25% (n = 13) were aware of only one of the two. There was a strong correlation between the patient's perception of tone and their gender with the tone scores significantly lower in women as compared to men (Mann-Whitney test, p = 0.04). Ten patients (19.6%) had had leakage-related issues during the previous 7 days. CONCLUSIONS: This questionnaire provided a significant amount of valuable data. Based on our experience, we recommend the VPQ for prospective use in the serial monitoring and audit of total laryngectomy patients.

Voice-related Quality of Life in laryngectomees: assessment using the VHI and V-RQOL symptom scales.

The primary purpose of this study was to investigate the effect of the voice impairment across the physical, emotional, and functional domains in patients using valved speech following total laryngectomy with the help of two symptom specific scales. The study design used was a cross-sectional cohort. The setting was the Head and Neck Oncology Unit of a tertiary referral centre. Subjects were 54 patients who had undergone total laryngectomy. Two voice-specific questionnaires, the Voice-Related Quality of Life (V-RQOL-short form) Measure, and the Voice Handicap Index (VHI-long form) were used. The main outcome measure was patient perception of the voice following total laryngectomy in response to specific questions correlated with sociodemographic/treatment factors. Responses were received from 40 males and 14 females (response rate of 85.7%) with a median age of 63.4 years (range: 37-84). The V-RQOL overall analysis showed that 3 patients (5.6%) scored "excellent," 29 patients (53.7%) "fair to good," 14 patients (25.9%) "poor to fair," and 8 patients (14.8%) "poor." Analysis of the VHI revealed that 20 patients (37.0%) had a minimal handicap, 20 patients (37.0%) a moderate handicap, and 14 patients (25.9%) had a serious voice handicap. The individual domain or subscale scores for the VHI revealed a mean (SD) functional score of 15.8 (7.7), a physical score of 13.6 (7.2), and finally an emotional score of 11.6 (8.9). Functional aspects of the voice were significantly affected by age, radiotherapy, and chemotherapy (Spearman rho, P=0.01; Mann-Whitney, P=0.04 and P=0.01). The physical aspects of the voice were significantly affected by age and chemotherapy (Spearman rho, P=0.004; Mann-Whitney, P=0.04). Only age significantly affected the emotional aspects of the voice (Spearman rho, P=0.002). We found a strong correlation (Spearman rho, P<0.001) between the V-RQOL and VHI questionnaires. Our study revealed that the V-RQOL and VHI scores in our series of patients following voice restoration in laryngectomees were consistent with that reported in the literature. Only age, radiation, and chemotherapy were seen to influence the voice handicap scores. In addition, both symptom scales had good correlation between them and either one could be used with reliability in laryngectomees with a few modifications.

Aural exostoses (surfer's ear) provide vital fossil evidence of an aquatic phase in Man's early evolution.

For over a century, otolaryngologists have recognised the condition of aural exostoses, but their significance and aetiology remains obscure, although they tend to be associated with frequent swimming and cold water immersion of the auditory canal. The fact that this condition is usually bilateral is predictable since both ears are immersed in water. However, why do exostoses only grow in swimmers and why do they grow in the deep bony meatus at two or three constant sites? Furthermore, from an evolutionary point of view, what is or was the purpose and function of these rather incongruous protrusions? In recent decades, paleoanthropological evidence has challenged ideas about early hominid evolution. In 1992 the senior author suggested that aural exostoses were evolved in early hominid Man for protection of the delicate tympanic membrane during swimming and diving by narrowing the ear canal in a similar fashion to other semiaquatic species. We now provide evidence for this theory and propose an aetiological explanation for the formation of exostoses.

Metastasizing pleomorphic salivary adenoma.

OBJECTIVE: To address questions about the etiology, behavior, optimal treatment, and prognosis of metastasizing pleomorphic adenoma (MPA), we undertook a review of the literature (1953-2005) and constructed a virtual series of all identified cases of MPA, metastatic lesions that are very occasionally identified in patients with a history of pleomorphic salivary adenoma and, on detailed pathological evaluation, found to exhibit all the histological hallmarks of the preceding benign lesions. DATA SOURCES: A review of the English-language literature between 1953 and 2005 using MEDLINE, secondary references identified from bibliographies of pertinent articles, and a further case from one of our institutions. DATA SYNTHESIS: A virtual case series was constructed and quantitatively analyzed. Forty-two patients with an average age of 33 years were identified. There were 20 male and 22 female patients. There was an overwhelming history of incomplete surgery for pleomorphic salivary adenoma. Most patients had locoregional recurrences before metastasis, and the mean presentation-to-metastasis latency was 16 years. Bone was the most common site for metastases (45%), followed by the head and neck (43%) and lung (36%). There was significant morbidity and mortality from distant disease, with 5-year disease-specific and disease-free survival of 58% and 50%, respectively. Developing distant lesions within 10 years of the primary tumor and presence of metastases in multiple sites were independent predictors of survival on Cox regression analysis. Metastasectomy conferred significant survival advantage over nonoperative treatment (log-rank analysis, P<.02). Chemotherapy and radiotherapy were of limited value. CONCLUSIONS: Meticulous surgery is crucial in preventing MPA. Metastatic disease carries significant morbidity and mortality and should be treated surgically when feasible.

Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes, with distant metastases developing in 30-40% of cases. Overexpression of the epidermal growth factor receptor (EGFR/c-erbB-1) and/or its ligands and high levels of certain matrix metalloproteinases (MMPs) have been associated with poor prognosis. The aim of this study was to examine the effects of EGFR ligands on gelatinase expression and invasion in HNSCC cell lines. We tested epidermal growth factor (EGF), transforming growth factor alpha, betacellulin, heparin-binding EGF, and amphiregulin and measured expression of gelatinases MMP-9 and MMP-2 in an established squamous carcinoma cell line (Detroit-562) and in two cell lines newly derived from patients with head and neck cancers (SIHN-005A and SIHN-006). Incubation of the cell lines with EGF-like ligands up-regulated MMP-9 (but not MMP-2) expression as measured by semiquantitative reverse transcription-PCR in a dose-dependent manner, with the effects being most marked in cells with high EGFR levels and undetectable in cells with low levels. Maximum stimulation was obtained in a concentration range of 10-100 nM. In addition, we confirmed by zymography that gelatinolytic activity consistent with MMP-9 (Mr 92,000) was up-regulated in parallel with increases in gene expression. Betacellulin (which binds both to EGFR and c-erbB-4 receptors) consistently increased MMP-9 expression and activation to a significantly greater degree than the other four ligands when tested at equimolar concentrations. In parallel with MMP-9 up-regulation, all EGF-like ligands increased tumor cell invasion through Matrigel in in vitro Transwell assays. These activities were independent of ligand effects on cell proliferation. Antagonist (ICR62) or agonist (ICR9) anti-EGFR monoclonal antibodies, respectively, inhibited or potentiated MMP-9 activity and tumor cell invasion induced by all ligands. Furthermore, a monoclonal antibody that neutralizes MMP-9 activity (Abl) also inhibited ligand-induced invasion of HNSCC. We confirmed that tumor cell lines used in these studies (and a larger series not reported here) generally expressed multiple c-erbB receptors and ligands. These results indicate that autocrine or paracrine signaling through EGFR potentiates the invasive potential of HNSCC via the selective up-regulation and activation of MMP-9. Furthermore, ligands such as betacellulin (which is commonly expressed in HNSCC), which can bind to and activate other c-erbB receptors, may be especially potent in this regard.

Association between polymorphisms of the GPX1 gene and second primary tumours after index squamous cell cancer of the head and neck.

We investigated the association between genetic polymorphisms in GPX1 gene amongst patients who had index squamous cell carcinoma (SCCHN) and a second primary tumour (SPT) after a primary SCCHN in a case-control study. GPX1 genotypes were determined for 61 patients with SPT and for 259 control subjects by a PCR technique using a fluorescent-labelled primer. Analysis was by an ABI automated fluorescent sequencer. The associations between specific genotypes and the development of SPT were examined by logistic regression. A significant difference was found between the control group and the SPT cases in allele frequencies of GPX1 ALA( *)6 and ALA( *)7 (p(trend)=0.04). These results suggest that polymorphisms in the GPX1 gene may be a marker for SPT development and further studies are indicated.

Asymptomatic oropharyngeal lipoma complicating intubation.

Oropharyngeal lipomas are rare tumours. We present the case of a young man with an asymptomatic lipoma almost completely occluding his supraglottic airway, found on magnetic resonance imaging (MRI) for a separate oral cavity lesion. Pre-operative anaesthetic assessment was undertaken because of the risk of airway obstruction at induction of general anaesthesia. We discuss the awake fibre-optic technique used for induction, as well as the treatment and follow-up of these tumours. This case highlights the need for formal anaesthetic assessment, in such cases, to avoid total airway obstruction at induction of general anaesthesia. It also emphasizes the extent of supraglottic obstruction that can be present without giving rise to any symptoms.

Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells.

Aberrant expression of tyrosine kinases such as c-erbB and EGFR contributes to the progression of head and neck squamous cell carcinomas (HNSCCs). One mechanism may be potentiation of angiogenesis, since upregulation of vascular endothelial growth factor (VEGF) expression by activation of epidermal growth factor receptor (EGFR) and/or c-erbB-2 has been described. Firstly, we demonstrated expression of all 4 members of the VEGF family in a panel of 15 HNSCC cell lines which over-express one or more c-erbB receptors. We then explored the regulatory roles of three major ligands with different selectivity of binding to c-erbB receptors (namely transforming growth factor-alpha (TGF-alpha), betacellulin (BTC) and heregulin-beta1 (HRG-beta1)) on VEGF-A, B, C and D expression in selected HNSCC lines. Using semi-quantitative reverse transcription-PCR, we showed that all three c-erbB ligands up-regulated VEGF-A mRNA (all isoforms) and VEGF-C (BTC max at 1-10 nM; TGF-alpha and HRG-beta1 max at 10-100 nM) but had no effect on VEGF-B. Interestingly, all ligands simultaneously down-regulated the expression of VEGF-D mRNA. A monoclonal antibody (mAb) which blocks EGFR ligand binding (ICR62) down-regulated the basal levels of VEGF-A (all isoforms) and VEGF-C, had no detectable effects on VEGF-B and increased VEGF-D. ICR62 also reversed the effects of all three erbB ligands (TGF-alpha, BTC and HRG-beta1) on VEGF-A, VEGF-C and VEGF-D expression. An anti-c-erbB-2 mAb (ICR12) showed similar effects on basal or ligand-modulated expression of VEGF in these cell lines, although to a lesser extent. Our results reveal that the four VEGF genes are regulated by c-erbB signaling pathways in a strikingly different manner, suggesting that they serve distinct, although perhaps complimentary (VEGF-A and VEGF-C) or antagonistic (VEGF-D) functions. The EGFR and c-erbB-2 signaling pathway(s) plays a role in VEGF regulation in HNSCC, although EGFR would appear to be dominant in this cell type.

Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands.

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.

Anterior cervical-transsternal approach for resection of benign tumors at the thoracic inlet.

BACKGROUND: Neural tumors at the thoracic apex, even when benign, present technical problems for the surgeon because of their inaccessibility. The standard approach from below, using a posterolateral thoracotomy, offers suboptimal access to the vascular and neural structures of the thoracic inlet. METHODS: We present a new technique for the resection of benign tumors of the thoracic inlet, combining an anterior cervical approach with a limited median sternotomy. We do not find it necessary to resect any part of the clavicle or to add a thoracotomy. We used this technique in 4 patients with apical tumors. In 3 patients the tumor arose from the sympathetic chain and in 1 patient from the T1 component of the brachial plexus. RESULTS: The tumors ranged from 30 to 70 mm in diameter, and histologic findings were neurilemoma in 3 cases and ganglioneuroma in 1. There were no complications or deaths. All 4 patients were discharged 3 to 6 days postoperatively. CONCLUSIONS: In our experience this new technique provides improved exposure, good control of the neurovascular bundle, and less morbidity than that associated with thoracotomy. For malignant Pancoast's tumors we would still advocate the approach of Dartevelle or Grunenwald, supplemented by lateral thoracotomy to facilitate systematic intrathoracic evaluation.

C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors.

We studied the profile of four c-erbB receptors in head and neck squamous cell carcinomas (HNSCC) and to determine whether their expression was associated with clinicopathological features and key molecules involved in angiogenesis and metastasis. We also assessed the impact of expression on survival. This study included 54 cases of primary HNSCC, of which 27 cases showed lymph node metastasis. The expression of c-erbB receptors, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) family members was analysed in the same tissue homogenates by semi-quantitative RT-PCR. HNSCC frequently co-expressed multiple c-erbB receptors and showed significant correlations amongst their levels. High expression of epidermal growth factor receptor (EGFR), c-erbB-2 or c-erbB-3 was associated with an infiltrating mode of invasion, nodal metastases and advanced pathological stages. EGFR and c-erbB-2 levels were strongly correlated (P=0.0004-0.029) with the expression of MMP-2, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, VEGF-A and VEGF-C whereas the levels of c-erbB-3 and B-4 showed a weaker correlation (P=0.049-0.01) with some MMPs and VEGF-C. Only nodal metastasis and EGFR levels were significantly associated with poor outcome in uni- and multi-variate analysis. We conclude that co-operative signalling of all four c-erbB receptors may play a significant role in the pathogenesis of HNSCC. Amongst these, EGFR appears to be the dominant component controlling the invasive and angio-/lymphangiogenic phenotype in HNSCC via upregulation of multiple MMPs and VEGFs.

Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.

Squamous cell carcinoma (SCC) of the oral tongue is characterized by a high propensity for cervical nodal metastasis, which affects the probability of regional control and survival. Until now, elective treatment of the clinically negative neck in early lesions (T(1-2)) of the oral tongue cancer remains controversial. This study attempted to identify predictive factor(s) for cervical nodal metastasis and treatment outcomes in patients with early stage SCC of the oral tongue treated primarily by surgery. Fifty patients with previously untreated Stage I/II primary tongue carcinomas with available archival specimens treated at the Royal Marsden Hospital between 1981 and 1998 were reviewed. Clinico-pathological features including age, gender, alcohol and tobacco consumption, tumour location, histological grade, tumour-stromal border, growth pattern, tumour thickness, and clinical stage were evaluated and the correlations with cervical metastases and outcome analysis were determined. The overall occult nodal metastatic rate was 40% (20/50). Tumour thickness exceeding 5 mm was statistically significantly correlated with cervical metastases (P = 0.003; relative risk = 2.429). No statistical correlation was observed between other clinico-pathological parameters and nodal metastasis. With a median follow-up of 98 months, 5-year actuarial overall, disease-specific (DSS), and relapse-free survival were 65.71, 67.77, and 68.18%, respectively. Univariate analysis for DSS showed poorer outcomes for patients with age > 60 years (P = 0.0423) and tumour thickness > 5 mm (P = 0.0067). The effect of tumour thickness was maintained (P = 0.005) on multivariate analysis. The present study indicates that the thickness of primary tumour has a strong predictive value for occult cervical metastasis and poor outcomes in patients with Stage I/II oral tongue SCC. Thus, elective neck treatment (surgery or irradiation) is indicated for tumours exceeding 5 mm thickness.

Cisplatin and 5-fluorouracil for symptom control in advanced salivary adenoid cystic carcinoma.

Adenoid cystic carcinoma is a relatively rare tumour which arises in the parotid and submandibular salivary glands. Initial management is surgical, often with post-operative radiotherapy, but local relapse is common and distant metastasis not infrequent. Chemotherapy is generally reserved for cases where symptoms are not controlled by other means, since the tumour is slow growing and the response rate frequently disappointing. Cisplatin and 5-fluorouracil (5-FU) both show single agent activity in this disease but had not been previously investigated in combination. All patients referred for palliative chemotherapy of metastatic, symptomatic, histologically confirmed adenoid cystic carcinoma between November 1990 and February 1994 were considered for this study. The drugs were administered as follows: cisplatin 100 mg/m2 with appropriate pre- and post-hydration and 5-FU on a 4-day schedule of 1 g/m2/day. A total of 11 patients (7 male, 4 female) with median age 53 years (range 34-69) received 46 courses of chemotherapy (median four, range one to six). All patients had prior surgery and 8 had previously received radiotherapy. There were no objective responses of > 50% reduction in tumour size. 3 patients had a minor response and two progressed on treatment. The symptomatic response rate, however, was 64%, which compares favourably with other previously reported regimens. Toxicity was manageable. The median time to tumour progression was 9 months (range 0-38) and median survival was 12 months (range 1-65). This cisplatin/5-FU regimen would appear to produce a low rate of objective response but useful palliative benefits in advanced symptomatic adenoid cystic carcinoma. Prior series suggest that a higher objective response rate may be possible with a platinum/anthracycline/fluorouracil combination, and investigation of such a regimen is warranted.

Characterization of ten newly-derived human head and neck squamous carcinoma cell lines with special reference to c-erbB proto-oncogene expression.

Ten human head and neck squamous carcinoma (HNSCC) cell lines were established in order to study the role of c-erbB signaling pathways in HNSCC progression. Five cell lines were derived from primary tumors at four different sites, and five were from lymph node metastases in the neck. Two pairs of lines were derived from the primary tumor and metastatic lymph node in the same patient. Basic characteristics including morphology, doubling time, phenotypes, cytogenetic profiles and tumorigenicity in nude mice were described. We examined the expression of c-erbB receptors and ligands in early passage new HNSCC lines and compared with five long-term established lines, normal keratinocytes and fibroblasts. Amplification of c-erbB-1 (EGFR) gene was observed in only one cell line whereas no amplification of other c-erbB genes was found. Overexpression of EGFR, c-erbB-2, c-erbB-3 and c-erbB-4 mRNAs was observed in 10, 14, 10 and 8 out of 15 head and neck cell lines respectively. Overexpression of c-erbB-3 and c-erbB-4 was more frequently observed in newly derived HNSCC lines than in long-established cell lines. The majority of tumor cells also expressed multiple c-erbB ligands. One selected cell line, SIHN-006, was shown to exhibit tyrosine phosphorylation via all four receptors. These new cell lines could provide a useful experimental model to study the co-operative signaling of type I tyrosine kinase receptors in HNSCC progression.

Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). However, a detailed analysis of MMPs and tissue inhibitors of MMPs (TIMPs) in relation to the biological behavior of HNSCC has yet to be performed in clinical material. OBJECTIVES: To study a comprehensive profile of MMPs and their 2 main inhibitors in HNSCC tissue samples and to correlate the patterns of expression with clinicopathological characteristics, invasion, and metastasis. DESIGN: This study included 54 consecutive patients with primary HNSCC, 27 of which showed lymph node metastasis. Expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14, TIMP-1, and TIMP-2 was simultaneously analyzed in tissue homogenates using semiquantitative reverse transcription-polymerase chain reaction assay. Where feasible, levels of protein and enzyme activity were confirmed by Western blot, enzyme-linked immunosorbent assay, and substrate zymography. Conventional clinicopathological features, including mode of tumor invasion, were also examined. RESULTS: Significantly higher MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, and TIMP-1 levels were found in tumors vs specimens of matched normal mucosa. No difference in the distribution of MMPs and TIMPs in relation to age, sex, tumor site, or histological grade was observed. A significant correlation was demonstrated between levels of MMP-1, MMP-9, and TIMP-1 and advanced T stage and between MMP-9 expression and an infiltrative pattern of growth. Enhanced expression of MMP-9 was strongly correlated (P<.001) and levels of MMP-2, MMP-7, and MMP-11 were weakly correlated (P =.03-.05) with lymph node involvement. CONCLUSIONS: Overexpression of multiple MMPs and TIMPs is characteristic of HNSCC, and analysis of specific MMPs, MMP-9 in particular, might be useful for evaluating the malignant potential in individual HNSCC.