Abnormalities of molecular regulators of proliferation and apoptosis in carcinoma of the oral cavity and oropharynx.

OBJECTIVE: Abnormalities in genes regulating cell proliferation and death may affect disease outcome in squamous cell carcinoma (SCC) of the head and neck. METHODS: Proliferative activity (Histone H3 in-situ-hybridization (HISH) labeling index (LI)) and the genes and/or gene products of Cyclin D-1, c-erbB-2, Bcl-2, p21, and p53, were investigated in 35 patients with SCC of the oral cavity and oropharynx, previously studied for p27 expression. RESULTS: Overexpression or very low expression of Cyclin D-1 was associated with unfavorable disease outcome and shorter time-to-recurrence. High c-erbB-2 expression was significantly associated with shorter overall survival and was synergistic with low p27 expression. Bcl-2, HISH LI, p21 expression, and p53 mutation and protein analysis were not significantly predictive, but there were trends suggesting shorter disease-free/overall survival for patients with undetectable Bcl-2, high HISH, and mutant p53. CONCLUSIONS: Several cell proliferation and death regulators appeared to predict disease outcome. Limited evidence of cooperativeness among regulators was also seen.

The 'parachute' bolster technique for securing intraoral skin grafts.

Successful skin grafting of intraoral defects can be challenging. The tie-over bolster method is the most popular technique in use today. We describe an alternate method of securing intraoral skin grafts--the "parachute" bolster technique--and we present a case report.

Electroporation therapy for head and neck cancer including carotid artery involvement.

OBJECTIVES: Electroporation therapy with intralesional bleomycin (EPT) is a novel, technically simple outpatient technique in which high-voltage electric impulses delivered into a neoplasm transiently increase cell membrane permeability to large molecules, including cytotoxic agents, causing localized progressive necrosis. Unlike many laser ablation methods, EPT can treat bulky tumors (>2 cm) with complete penetration. Our recent publication confirms an excellent response rate in the use of EPT in a clinical trial. STUDY DESIGN, PATIENTS, AND METHODS: Following our initial prospective study report in 1998, we have followed our entire initial cohort (10 patients) of patients with head and neck cancer beyond 24-months follow-up. Additionally, we have used this approach to treat four additional patients (total: 9 males/5 females) with upper aerodigestive tract squamous cell carcinoma, including three with internal carotid artery (ICA) involvement up to or within the skull base. Two patients underwent preoperative balloon test occlusion with cerebral perfusion studies followed by carotid embolization. EPT was then done safely at least 2 weeks later to avoid the temporary hypercoagulable state. RESULTS: Within the overall cohort (14 patients) 6 patients had a complete response, 6 had a partial response, and 2 did not respond (overall 85.7% response rate). Both patients with ICA involvement had a partial or complete response to treatment; neither patient had a hemorrhagic or neurologic complication. Overall, 13 of the 14 patients were treated for persistent or recurrent head and neck cancer. Two of the four patients with early recurrent stage tumors had no evidence of recurrence after EPT with an average follow-up of 31.5 months. The overall early stage tumor group had four complete responders out of five (80%). On the contrary, only 2 of 9 patients with advanced recurrent stage tumors were disease-free at 18 months. Morbidity was low for early stage tumors, but higher for advanced tumors with complications, including poor wound healing, dysphagia, and osteomyelitis. There were no treatment-related deaths. CONCLUSION: We found EPT to be safe and efficacious in patients with head and neck cancer, even with internal carotid artery involvement. Patients with early stage recurrences have the potential for prolonged survival beyond 2 years without the morbidity of surgery and radiation or toxicity of systemic chemotherapy. Because of its superb access qualities even for bulky tumors, EPT is a potential method of delivery for other tumoricidal agents such as in genetic-altering schemes.

Endoscopic and electroporation therapy of paranasal sinus tumors.

The purpose of this article is to introduce the concept of endoscopic and electroporation therapy for the treatment of sinonasal carcinomas. Electroporation therapy is a technique that combines intralesional injection of bleomycin combined with application of high-voltage square wave electrical impulse into the tumor. A transient increase in cell membrane permeability allows intracellular entry of bleomycin, with subsequent cytotoxicity. Two cases of sinonasal cancer were treated with this technique. One patient had complete response and is free of disease at 20 months. The other had partial response with control of the disease up to a year. Endoscopic electroporation therapy is potentially a minimally invasive method for the treatment of sinonasal malignancies in an experimental setting where other treatment options do not exist. Phase II/III national clinical trials have been initiated to study the efficacy of electroporation therapy.

Prognostic significance of p27 expression in carcinoma of the oral cavity and oropharynx.

OBJECTIVE: To study the role of p27, a cyclin-dependent kinase inhibitor, as a prognostic indicator in squamous cell carcinoma of the oral cavity and oropharynx. STUDY DESIGN: Retrospective review of 35 patients with squamous cell carcinoma of the oral cavity and oropharynx who presented to Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, between 1986 and 1995. METHODS: Inclusion criteria were the availability of clinical information, archival pretreatment biopsy material, and a minimum follow-up of 24 months. p27 staining was scored for frequency and intensity of tumor cell expression following immunoperoxidase staining using standard techniques. Samples of squamous epithelium from the uvula of 15 nonsmoking patients without past or present squamous cell carcinoma were used as normal controls. RESULTS: The association of p27 staining and other factors with response to treatment was evaluated by Fisher's Exact Test and with overall and disease-free survival by the Kaplan-Meier method with multivariate Cox regression. Low levels of p27 expression correlated significantly with unfavorable treatment response (P<.0001), shorter overall survival (P = .0001), and shorter disease-free survival (P = .003). Tumor site (alveolus) was also associated with shorter disease-free (though not overall) survival, but the association with p27 was independent of stage and site in multivariate analysis.

Electroporation therapy of head and neck cancer.

The purpose of this paper is to introduce the concept of electroporation therapy and present our results from using this new technique combined with intralesional bleomycin in head and neck cancer patients. Electroporation therapy is a technique wherein high-voltage electric impulses delivered into a neoplasm transiently increase cell membrane permeability to large molecules, including cytotoxic agents. In this phase I/II study, extremely low-dose bleomycin sulfate was electroporated into head and neck malignant neoplasms in 10 patients. Tumor responses included 2 nonresponders, 3 partial responders, and 5 complete responders, with a mean follow-up of 40 weeks. We conclude that this technique offers promising possibilities in the local treatment of head and neck cancer.

Regulators of proliferation and apoptosis in carcinoma of the larynx.

Expression of interrelated gene products regulating cell proliferation and apoptosis may be disordered in squamous cell carcinoma (SCC) of the larynx compared with normal squamous mucosa. Certain of these abnormalities, alone or in combination, may be of prognostic significance in low-stage carcinomas of the larynx. A retrospective study of archival material was made. Expression of the Bcl-2 family of apoptosis-related genes (bcl-2, bcl-X, mcl-1, and bax) and the proliferation- and apoptosis-related genes p53 and cyclin D-1 were determined in 40 low-T-stage laryngeal carcinomas and in uvular epithelium from patients without SCC. Among the antiapoptotic members of the Bcl-2 family, Bcl-X and Mcl-1 showed more intense and widespread staining than Bcl-2 itself in both normal squamous mucosa and SCC. The well-ordered expression patterns of Bcl-2-related proteins found in normal epithelium were lost in SCC, and patterns of expression varied widely among individual tumors. Also, mean expression levels for Bax and cyclin D-1 were significantly lower than in normal epithelium (P = .036 and P = .009, respectively), whereas expression of p53 was higher in tumors (P = .034). Expression of Bcl-X and Mcl-1 was greater in poorly differentiated than in well-differentiated tumors (P = .014 and P = .031, respectively). No associations were seen between marker expression patterns and clinical outcome in this group of patients. Bcl-x and Mcl-1 appear to be the most abundantly expressed antiapoptotic proteins of the Bcl-2 family in both normal squamous mucosa and SCC of the larynx. Multiple genes regulating proliferation and apoptosis are expressed abnormally in laryngeal SCC compared with normal epithelium. In particular, loss or measurable decrease in expression of the proapoptotic protein Bax in tumors may contribute to the deranged growth control of SCC. Further study is needed to evaluate the prognostic significance of particular patterns of disordered expression of proteins regulating proliferation and apoptosis in SCC of different head and neck sites.

Endoscopic ligation of the internal maxillary artery for treatment of intractable posterior epistaxis.

Lack of universal success with both transantral ligation of the internal maxillary artery and percutaneous embolization of the distal branches of the internal maxillary distribution has led to consideration of alternative techniques to control intractable posterior epistaxis. One such technique takes advantage of advances in endoscopic technology and instrumentation, as well as a nearly constant anatomic configuration. The internal maxillary artery divides into terminal branches within the pterygomaxillary fossa, sending branches through the bony maxilla to exit the posterolateral nasal wall in the posterior aspect of the middle meatus. Endoscopic identification and ligation of these terminal branches of the internal maxillary artery (the sphenopalatine and nasopalatine arteries) as they exit the maxilla has been performed on 10 patients with a 100% success rate and no morbidity or mortality associated with the procedure. These results compare favorably to the average reported success rates of 89% for transantral ligation and 94% for percutaneous embolization, and average complication rates of 28% and 27%, respectively. This endonasal procedure has been performed for spontaneous epistaxis as well as postsurgical nasal bleeding with equal success. The ascending scale of treatment previously outlined in the literature may be amended, as a potentially definitive procedure is available, and we believe that this technique is easier to perform, has less associated morbidity, and has equal efficacy in comparison to transantral ligation or percutaneous embolization in the treatment of intractable posterior epistaxis.

The use of percutaneous implants for the prosthetic rehabilitation of orbital defects in irradiated cancer patients: a report of clinical outcomes and complications.

This retrospective study evaluated the use of percutaneous craniofacial implants for the prosthetic rehabilitation of patients with a history of orbital exenteration and irradiation for oncologic tumors of the head and neck. A total of 24 implants were placed in six patients. All implants were determined to be osseointegrated at the time of uncovering. Three implants were subsequently resubmerged beneath the soft tissue because of positional interferences with prosthesis fabrication. The remaining 21 implants were ultimately used to retain six orbital prostheses. Two implants failed to maintain osseointegration during the follow-up period and were subsequently removed without complications. This represents an overall integration success rate of 90.5% over a mean follow-up period of 32.8 months (range = 11 to 68 months). The significance of these findings and their relationship to comparable reports in the literature are discussed.

Tumor angiogenesis and p53 mutations: prognosis in head and neck cancer.

OBJECTIVES: To assess how p53 gene mutations and microvessel density (MVD) may be used as prognostic markers for the study and management of head and neck squamous cell carcinomas and to investigate putative associations between p53 gene mutations and MVD and the relationship of these factors to tumor response to radiotherapy and/or chemotherapy at 6 weeks. PATIENTS AND DESIGN: Thirty-nine patients with squamous cell carcinoma of the head and neck, stages I to IV, who were examined at Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill, and its affiliated hospitals between 1993 and 1995 were monitored. Mutations in the p53 gene were identified by microdissection of tumor cells on frozen sections, followed by single-strand conformation polymorphism analysis of the products of polymerase chain reaction amplification of exons 5 to 9. The microvessels were immunostained with monoclonal antibodies to factor VIII and/or CD31. Microvessel counts were done by 2 investigators blinded to each other's counts and to the p53 gene status. Intratumoral or peritumoral microvascular "hot spots" were assessed and counts were done with an ocular grid in 3 x 200 fields of hot spots by each investigator. The mean of the highest values was considered. Statistical analysis was done with the Wilcoxon rank sum test, the log-rank test, and proportional hazard models. RESULTS: Of the 39 patients, 13 had mutations in exons 5 to 9. Mutations in the p53 gene were associated with unfavorable overall (P=.003) and disease-free (P=.02) survival. A strong inverse relationship was seen between MVD and p53 mutations (P=.01). No statistically significant relationship was seen between mean MVD and overall and disease-free survival. The response to therapy differed significantly (P=.03) by p53 mutations, whereas there was no statistical significance with MVD counts. CONCLUSION: In this study a strong inverse relationship was seen between MVD and p53 mutations. p53 Mutations in exons 5 through 9 were associated with unfavorable survival, whereas MVD showed no association with survival.

Surgical closure of persisting failed tracheoesophageal voice fistula.

Tracheoesophageal puncture (TEP) is a highly successful procedure for voice restoration. Occasionally, however, patients fail to achieve satisfactory voice or develop salivary leakage through the fistula into the trachea. Closure of the TEP is then necessary. In most cases, spontaneous closure occurs once the prosthesis has been removed. When the fistula does not close spontaneously, surgical closure is indicated to prevent aspiration and pulmonary complications. We describe a three-layer technique that employs interposition of dermal graft. The technique was used on 14 patients over a 7-year period. Most patients received irradiation to the neck. Complete closure was achieved in 13 of 14 cases; 1 patient developed partial breakdown of the closure. Our technique is relatively easy to perform and has a high success rate (92%). Irradiation did not adversely affect the closure rate.

Mutation of p53 in squamous cell cancer of the head and neck: relationship to tumor cell proliferation.

Rapid proliferation of squamous cell carcinomas of the head and neck (SCCHN) during therapy may contribute to treatment failure. We have investigated the presence of p53 abnormalities in patients with SCCHN as a correlate of proliferation rate and other pathologic and clinical variables. p53 Mutation, as determined by polymerase chain reaction and single-strand conformation polymorphism analysis of microdissected frozen sections of tumor biopsies, was significantly associated with a high labeling index, as determined by in vivo infusion of IUdR and BrdU (P = 0.017). p53 Protein expression was detected by immunohistochemistry with two different antibodies, followed by quantitative image analysis. Many cases exhibited strong p53 protein expression in the absence of mutations within the conserved region of the gene, and expression was not related to proliferation. The presence of p53 mutations was related to tumor differentiation in this group of patients.