Background: Although positron emission tomography computed tomography has proven diagnostic and staging value in head and neck carcinoma, it does not have optimal sensitivity or specificity. The positron emission tomography computed tomography fluorodeoxyglucose standardised uptake value has been shown to be associated with carcinoma stage. This study evaluated the impact of major clinicopathological factors on the standardised uptake value at the primary site and at neck lymph node metastases.Subjects and methods: Two hundred and forty-three oral cavity and laryngopharyngeal carcinoma patients who underwent positron emission tomography computed tomography were included. Correlation between the positron emission tomography computed tomography standardised uptake value and various clinicopathological factors was analysed.Results: A positive correlation was found between the standardised uptake value and the size and depth of tumour infiltration, and lymph node positivity. Higher standardised uptake values were seen for more advanced tumour stages. The presence of perineural invasion, lymphatic invasion and extracapsular spread were all associated with increased standardised uptake values.Conclusion: Most of the clinicopathological features of head and neck carcinoma which are well known to be poor prognostic factors have a significant impact on positron emission tomography computed tomography fluorodeoxyglucose standardised uptake value.

Gene amplification, a common mechanism for oncogene activation in cancer, has been used as a tag for the identification of novel oncogenes. DNA amplification is frequently observed in head and neck squamous cell carcinoma (HNSCC) and potential oncogenes have already been reported. We applied restriction landmark genome scanning (RLGS) to study gene amplifications and low-level copy number changes in HNSCC in order to locate previously uncharacterized regions with copy number gains in primary tumor samples. A total of 63 enhanced RLGS fragments, indicative of DNA copy number changes, including gains of single alleles, were scored. Enhanced sequences were identified from 33 different chromosomal regions including those previously reported (e.g. 3q26.3 and 11q13.3) as well as novel regions (e.g. 3q29, 8q13.1, 8q22.3, 9q32, 10q24.32, 14q32.32, 17q25.1 and 20q13.33). Furthermore, our data suggest that amplicons 11q13.3 and 3q26.3–q29 may be divided into possibly two and three independent amplicons, respectively, an observation supported by published microarray expression data.

CONTEXT:TGFBR1*6A is a common polymorphism of the type I transforming growth factor beta receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown.OBJECTIVES:To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells.DESIGN, SETTING, AND PATIENTS:Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A.MAIN OUTCOME MEASURES:TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-beta-dependent cell proliferation.RESULTS:TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-beta growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells.CONCLUSIONS:TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-beta. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-beta signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.

Head and neck squamous cell carcinomas (HNSCC) often metastasise to the cervical lymph nodes. It is known for HNSCC as well as other cancers that progression from normal tissue to primary tumour and finally to metastatic tumour is characterised by an accumulation of genetic mutations. DNA methylation, an epigenetic modification, can result in loss of gene function in cancer, similar to genetic mutations such as deletions and point mutations. We have investigated the DNA methylation phenotypes of both primary HNSCC and metastatic tumours from 13 patients using restriction landmark genomic scanning (RLGS). With this technique, we were able to assess the methylation status of an average of nearly 1300 CpG islands for each tumour. We observed that the number of CpG islands hypermethylated in metastatic tumours is significantly greater than what is found in the primary tumours overall, but not in every patient. Interestingly, the data also clearly show that many loci methylated in a patient's primary tumour are no longer methylated in the metastatic tumour of the same patient. Thus, even though metastatic HNSCC methylate a greater proportion of CpG islands than do the primary tumours, they do so at different subsets of loci. These data show an unanticipated variability in the methylation state of loci in primary and metastatic HNSCCs within the same patient. We discuss two possible explanations for how different epigenetic events might arise between the primary tumour and the metastatic tumour of a person.

Inactivation of the p16 tumor suppressor gene is a common phenomenon in squamous cell carcinoma of the head and neck (SCCHN). Less commonly described is the observation of p16 overexpression in SCCHN. Since overexpression of p16 is a potent predictor of outcome in other cancers, we were interested in determining the level of expression of p16 in our SCCHN specimens as a prerequisite to later prognostic studies. We were also interested in determining the mutational status of p16 in these tumors, in order to determine whether the combination of overexpression and gene alteration may predict a different clinical outcome from overexpression alone. A total of 84 specimens of SCCHN were selected for study. These specimens were obtained from all major sites within the oral cavity, oropharynx, pharynx and larynx. The level of expression of p16 in SCCHN specimens was measured by semi-quantitative RT-PCR. In 35 cases, RNA was also isolated from matched normal tissue obtained from a negative tumor margin. In the other 49 cases, the expression level was compared with the level of expression measured in pooled normal RNA obtained from 10 specimens of normal epithelial tissue. Overexpression of p16 was documented when the level of expression in the tumor specimen was 2-fold or greater above the level of expression found in normal tissue. A total of 46 specimens demonstrated overexpression of p16 (55%). All specimens demonstrating overexpression were then subject to sequence analysis. Thirty specimens (65%) showed p16-specific gene alterations, ranging from intragenic deletions to single point mutations, and 15 of these cases concomitantly affect p14ARF. A single specimen demonstrated a silent point mutation within the p16 reading frame. This mutation produces a stop codon at residue 85 in the context of the p14ARF reading frame, predicting premature termination of p14ARF within a previously determined nucleolar localization signal. This observation suggests that in some cases at least, p14ARF may be a selective target for alteration, independently of p16. Analysis of a normal tissue specimen obtained from a negative tumor margin, and a blood sample obtained approximately five years after surgery indicate that this p14ARF-specific alteration may represent a germline mutation.

Differential gene expression between squamous cell carcinoma of the head and neck and matched normal tissue was studied by utilizing Representational Difference Analysis. Using this methodology, a novel gene, DESC1 was isolated. DESC1 possesses strong identity to the serine protease super-family. Comparison of DESC1 expression between primary squamous cell carcinoma and matched normal tissue shows that the level of DESC1 expression is reduced or absent in 11/12 SCC tissue specimens when compared to specimens of matched normal tissue. Tissue-specific expression studies further show that DESC1 expression can only be detected in tissues derived from the head and neck, and in skin, prostate and testes. Cell line studies demonstrate that DESC1 expression is epithelial-specific. Chromosomal localization studies indicate that DESC1 is located on the long arm of chromosome 4 at position q12–13. © 2001 Cancer Research Campaign http://www.bjcancer.com

Objectives: Objectives of the study were 1) to analyze the complication incidence and resource utilization of two methods of bedside tracheostomy and 2) to define selection criteria for bedside tracheostomy. Study Design: Prospective randomized trial in the setting of a tertiary care center at a university hospital. Methods: One hundred sixty-four consecutive intubated patients selected for elective tracheostomy were enrolled, One hundred patients met selection criteria for bedside tracheostomy and were randomly assigned to either open surgical tracheostomy (50) or endoscopically guided percutaneous dilational tracheotomy(50), The remaining 64 patients received open surgical tracheostomies in the operating room. Main outcome measures were 1) perioperative and postoperative complication incidence and 2) resource utilization. Results: Patients meeting our selection criteria for bedside tracheostomy had a significantly reduced perioperative complication rate compared with those who failed to meet these criteria, and subsequently underwent tracheostomy placement in the operating room (5% vs, 20%, P less than or equal to .01). No statistically significant difference was found in the perioperative complication incidence between the two methods of bedside tracheostomy, However, percutaneous tracheostomy placement at the bedside resulted in a significant increase in postoperative complication incidence (16% vs. 2%, P <.05) and incurred an additional patient charge of $436 per bedside procedure. Conclusions: This investigation prospectively confirms the safety of bedside tracheostomy placement in properly selected patients. Complication incidence and resource utilization are defined for two methods of bedside tracheostomy, The results of this study confirm that open surgical tracheostomy represents the standard of care in bedside tracheostomy placement by providing a more secure airway at a markedly reduced patient charge. These findings will aid in the development of protocols and pathways for surgical airway management in critically ill patients to maximize cost-effective, high-quality care.

There are several surgical approaches for resection of parapharyngeal space (PPS) neoplasms. The purpose of this study was to evaluate local disease control, facial nerve injury, and need for mandibulotomy associated with resection of PPS neoplasms via the transcervical approach with submandibular gland excision. A retrospective chart review of 33 patients who underwent resection of a PPS neoplasm between October 1991 and July 2000 was performed. Of the 33 patients, 3 patients developed local recurrence after a median follow-up of 24 months, None of the patients experienced facial nerve paresis or paralysis. Three patients (9.1%) required a mandibulotomy for further exposure. This study demonstrated that the transcervical approach with submandibular gland excision for resection of PPS neoplasms provides excellent local disease control with minimal risk of facial nerve injury or need for mandibulotomy and/or tracheotomy.

Purpose: To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patientsare treated postoperatively with (60)C0, 4 MV, or 6 MV photon beam.Methods and Materials: This is a secondary analysis of the Intergroup Study 0034. Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0, 4 MV, or. 6 MV photon beam. All patients had advanced but operable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients were randomized following surgical resection to receive treatment with either postoperative irradiation alone, or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil. Patients were categorized as having either "low risk" or "high risk" treatment volumes based on whether the surgical margin was 5 mm or less, presence of extra capsular nodal extension, and/or carcinoma in situ at the surgical margins. Low-risk volumes received 50-54 Gy, and high-risk volumes were given 60 Gy. Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used.Results: One-hundred fifty-seven, 140, and 95 patients were treated by (60)C0, 4 MV, or 6 MV, respectively. No differences were seen in acute or late toxicity among treatment groups. Locoregional control was achieved in 75%, 79%, and 80% of patients treated with (60)C0, 4 MV, or 6 MV (p = 0.61). Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event (13%) than patients treated by (60)C0 and 4 MV (9%). This difference was not statistically significant.Conclusion: No differences in outcome, acute, or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0, 4 MV, or. 6 MV This result should be interpreted with caution as increased incidence, albeit nonsignificant, of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small. (C) 2000 Elsevier Science Inc.

BACKGROUND:Appropriate adjuvant chemotherapy for resected head and neck cancer patients has yet to be defined. Multiple trials have noted trends toward improved disease-free survival and local control. The Southwest Oncology Group undertook a feasibility trial of postoperative cisplatin and radiotherapy followed by three cycles of cisplatin and 5-fluorouracil.METHODS:Patients with resected stage III or IV head and neck cancer received cisplatin, 100 mg/m2, on days 1, 22, and 43 of radiotherapy. This therapy was followed by three cycles of cisplatin, 100 mg/m2 or last tolerated dose, and 5-fluorouracil, 1000 mg/m2, on days 1 to 4 every 21 days.RESULTS:Seventy-two patients from 22 institutions were registered; 68 were evaluable. Sixty-eight patients received radiotherapy. Only 25 of 68 patients (36.7%) were able to complete all six cycles of chemotherapy. Forty-three of 68 patients (63%) completed all three cycles with radiotherapy. Toxicities were tolerable. One toxic death occurred.CONCLUSIONS:It is not feasible to deliver six cycles of chemotherapy postoperatively in the sequence described. Compliance issues need further exploration to define effective adjuvant chemotherapy for head and neck patients.

PURPOSE:To develop a novel technique, intraoperative high-dose rate brachytherapy (IOHDR), in the treatment of previously irradiated head and neck cancers located at anatomical sites inaccessible to intraoperative electron beam radiotherapy (IOERT).METHODS:Between October 1992 and June 1997, seven patients (median age = 65 yrs; range = 52 to 71 years) with previously irradiated head and neck recurrences at anatomical sites inaccessible to IOERT in the base of skull were treated with IOHDR after maximal resection for microscopic residual disease. Treatment volume ranged from 6 cc to 24 cc. Six patients received 15 Gy of IOHDR at 0.5 cm; one received 10 Gy using custom-made surface foam applicators.RESULTS:The median follow-up was 59 months (range 33 to 67 months). It was technically feasible to deliver IOHDR in all seven patients at sites that were inaccessible to IOERT. The morbidity (observed in two patients) was acceptable and generally surgically related. Four of seven patients (57%) were locally controlled at IOHDR site. Two failed regionally, outside the IOHDR treated sites. The disease-free survival ranged from 3 to 30 months (median 9 months) with two patients still alive, disease-free at 28 and 30 months.CONCLUSIONS:IOHDR can be used, with limited toxicity, to treat previously irradiated head and neck cancers at sites inaccessible to IOERT. We are currently evaluating the addition of limited EBRT dose to improve the local control of these poor prognosis recurrent tumors.

PURPOSE:The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS:Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS:Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION:We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

Objective: To determine the feasibility, toxicity, and compliance of an intense treatment regimen for patients with advanced, previously untreated, resectable head and neck squamous cell carcinomas.Design: Prospective, nonrandomized, controlled (phase 1 or 2) clinical trial; median time at risk, 25 months (range, 7 days to 36 months).Setting: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus.Patients: Forty-three patients (median age, 59 years; range, 32-76 years) with resectable, previously untreated stage III or IV squamous cell carcinomas of the oral cavity, oropharynx, or hypopharynx or stage II squamous cell carcinomas of the hypopharynx (referred sample of patients).Interventions: Days 1 to 4, perioperative, slightly accelerated, hyperfractionated radiotherapy (9.1 Gy) to off cord fields; days 1 to 3, cisplatin, 30 mg/m(2) per day; day 4, surgical resection and intraoperative radiotherapy boost (7.5 Gy); days 45 to 52, postoperative radiotherapy (40 Gy to the primary site and upper neck and 45 Gy to the supraclavicular areas); days 24, 45, and 66, paclitaxel, 135 mg/m(2) per 24 hours, with routine granulocyte colony-stimulating factor support; and days 25 and 46, cisplatin, 100 mg/m(2).Main Outcome Measures: Toxicity, compliance, local control, and distant metastatic rates.Results: Patient compliance was 91% (39 of 43 patients),but protocol compliance was only 58% (25 of 43 patients), reflecting increased toxicity of the systemic regimen (2 [5%] of the 43 patients experienced grade 5 hematologic toxicity due to the regimen; 16 [37%], grade 4; and 10 [23%],grade 3). Local-regional control was 92% (23 of: 25 patients), and the distant metastatic rate was 8% (2 of:25) in patients completing treatment per protocol. One patient had surgical salvage of a second primary tumor.Conclusions: Local control and patient compliance were encouraging, but systemic toxicity was unacceptable. Thus, the paclitaxel was changed to a weekly regimen.

OBJECTIVES To evaluate and to compare rates and timing of exposure of alloplastic mandibular plates by plate type and tissue reconstruction technique. DESIGN A retrospective review series of 92 consecutive patients for 4 years (mean follow-up, 30 months). SETTING National Cancer Institute-designated comprehensive cancer center in a freestanding cancer hospital. PATIENTS Seventy-nine patients received alloplastic mandibular plates for segmental defects, and 13 patients received compression plates for mandibular osteotomies following ablative cancer surgery, including 21 titanium hollow osseointegrating reconstruction, 41 Storz, 16 Synthes, and 5 AO/ASIF (Arbeitsgemein schott fur Ostcosynthese fragen/Association for the Study of Internal Fixation) plates. Primary flap repair was provided by 71 pedicled soft tissue and 19 osseocutaneous free flaps, with primary closure in the remaining 2. INTERVENTION Most of the reconstructions of the mandibular defect was with an alloplastic plate with musculocutaneous flap or revascularized bone graft. OUTCOME MEASURES Clinically apparent intraoral or extraoral plate exposure. RESULTS Plate exposure occurred in 25 cases. Nine plates were exposed extraorally, at a mean postoperative interval of 40 weeks. The remaining 16 plates were exposed intraorally at a mean postoperative interval of 16 weeks. There was no significant difference in the exposure rates of different plate types or methods of reconstruction. The titanium hollow osseointegrating reconstruction plate had a similar exposure rate compared with the other plates. Size and site of the defect were the only significant predictors of plate exposure Radiotherapy and postoperative complications did not affect the rate of exposure. CONCLUSIONS Extraoral plate exposure occurs less commonly and later in the postoperative period than intraoral exposure, suggesting different causes. Plate type and type of flap reconstruction do not affect the rate of exposure. This may reflect long follow-up.

Each of the three embryologically distinct portions of the larynx has a characteristic lymphatic drainage pattern. One section of this article describes these drainage patterns, along with clinical examples. Traditional and contemporary imaging techniques for the neck are included in a second section, and the final section describes the authors' preferences for treatment of the neck with the rationale for this approach.

Cytokine production in squamous cell carcinoma (SCC) of the head and neck may directly influence the clinical behavior of this aggressive neoplasm since cytokines act as autocrine/paracrine growth factors, as well as immunomodulators. In the present study, the cytokine profiles of 16 SCCs of the head and neck and matched autologous, noncancerous mucosa were determined and compared to normal oral mucosa. Cytokine gene expression in noncancerous mucosa was similar to normal oral mucosa. Levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA expression were significantly increased in SCC relative to the mean +/- 2 SD of noncancerous mucosa or normal mucosa (p<0.05). Immunohistochemical analyses demonstrated that GM-CSF protein was produced by epithelial cells in the SCC. The overall mRNA expression relative to noncancerous-mucosa or normal mucosa of interleukin-1 beta, interleukin-1 alpha and tumor necrosis factor-alpha was not significantly increased in SCC, however, individual tumors did show selected increases in mRNA expression for these cytokines. These extensive differences in the levels of cytokine mRNA expression could modulate interactions between the tumor cells and the corresponding host cells affecting the behavior of head and neck SCC.

The potential for growth in a xenogeneic host and the pattern of histodifferentiation was examined in 56 human squamous cell carcinomas of the pharynx and larynx transplanted to nude mice. Among these 56 transplanted tumors, 13 of 36 primary and 12 of 20 metastatic tumors were found to be tumorigenic in nude mice. Eleven of 24 pharyngeal and 14 of 32 laryngeal tumors grew in nude mice. The dynamics of transplanted tumor growth in the surrogate host rook place independent of the tumor grade and site of tumor origin. Transplanted tumors exhibited a higher mitotic index compared with the original tumors. Each passage of a tumor line resulted in most of the xenograft tumors exhibiting an increased degree of differentiation without invasion of host tissues. No difference was observed between patients who engrafted tumors in the xenograft model and those who did not with respect to tumor biology or clinical findings, including survival.

Proliferative verrucous leukoplakia is a unique type of oral leukoplakia that has a high risk of malignant transformation. The aim of this study was to examine the expression of transforming growth factor-alpha in proliferative verrucous leukoplakia, oral squamous cell carcinoma, and normal mucosa. Transforming growth factor-alpha, a potent mitogen, is known to play an important role in various neoplasms including oral squamous cell carcinoma. Immunohistochemical localization of transforming growth factor-alpha in archival paraffin-embedded sections was performed with commercially available monoclonal antibodies. Ten cases each of normal mucosa, proliferative verrucous leukoplakia, and oral squamous cell carcinoma were stained. Quantification of the staining intensity, expressed as the cytoplasmic optical density, was done with the Roche Image Analysis System. The data were statistically analyzed with the one-way analysis of variance and Tukey tests. Notably, the mean cytoplasmic optical density of proliferative verrucous leukoplakia was significantly higher than the mean cytoplasmic optical density of normal mucosa (p < 0.01). The mean cytoplasmic optical density of proliferative verrucous leukoplakia was slightly higher than that of oral squamous cell carcinoma, however, this difference was not significant (p > 0.05). The mean cytoplasmic optical density values demonstrate that increased transforming growth factor-alpha immunoreactivity occurs in proliferative verrucous leukoplakia and oral squamous cell carcinoma relative to normal mucosa.