Molecular markers in laryngeal squamous cell carcinoma: towards an integrated clinicobiological approach.

Of the most frequent malignancies in the United States, cancers of the larynx and of the uterine corpus are the only ones not to show an increase in 5-year survival rates over the last 30 years. The increasing use of chemo- and radiotherapy and conservative surgery to preserve organs and their functions has probably led to a better quality of life in patients with laryngeal cancer, but has definitely failed to improve survival, which remains the primary aim. In our opinion, to reduce laryngeal cancer-related mortality, a change in clinical approach is required. We have reviewed the literature on the potential role of molecular markers in the clinical management of laryngeal cancer. We believe that some of the most significant biological markers might be integrated with the evaluation of behavioural risk factors, clinical TNM staging and histopathological grading for a novel clinicomolecular approach to laryngeal cancer. We foresee the use of the most promising biological markers in the phases of prevention, diagnosis, prognostic assessment and drug design.

Laser carbon dioxide cordectomy versus open surgery in the treatment of glottic carcinoma: our results.

OBJECTIVE: To analyze oncologic results in patients with glottic cancers treated respectively, by laser CO 2 or open surgery, taking into account specific-disease survival, rate of locoregional recurrences, and their salvageability. STUDY DESIGN: Retrospective study of 198 patients treated from January 1993 to June 2002 in the department of otorhinolaryngology at a Catholic university in Rome. METHODS: Glottic carcinoma were treated by laser CO 2 cordectomy in 132 patients (group 1) and by open surgery in 66 patients (group 2). The statistical analysis was performed by Kaplan Meyer method, log rank test, and chi 2 test. RESULTS: The log-rank test points out significant differences between the 2 groups regarding specific-disease survival; no differences were found for disease-free survival. Within group 1, 16 patients developed local failure, which was retreated in 6 cases with laser surgery; in 9 (6.8%) with total laryngectomy, only 1 case was inoperable. In this group, 10 patients (62.5%) were salvaged. Within group 2, 18 patients developed local recurrences, which was retreated in 14 (21.21%) cases with total laryngectomy; the other 4 cases were not suitable for surgery. Of these 18, 8 patients (44.5%) were salvaged. CONCLUSIONS AND SIGNIFICANCE: Our results show significant differences between the 2 groups concerning the specific-disease survival and the salvageability of local recurrences. In fact, in group 1 we found a higher salvage rate and a lower incidence of total laryngectomy. As already suggested, laser therapy leaves the laryngeal cartilaginous framework intact, avoiding the spread of the tumor out of laryngeal organ and resulting in a more favorable oncologic outcome.

VEMPs and dynamic posturography after intratympanic gentamycin in Menière's disease.

In this study, we investigated whether vestibular evoked myogenic potentials (VEMPs) and dynamic posturography (DP) are useful in the evaluation of the vestibular function in patients affected by active monoaural Menière's disease (MD) treated with intratympanic gentamycin. Twelve subjects affected by monoaural MD were treated with weekly intratympanic injections of 0.5 ml of gentamycin at a concentration of 20 mg/ml. VEMPs were used to test saccular function, while postural control was analyzed by DP. The results obtained with these two techniques were compared with those obtained by using bithermal caloric test. The mean follow-up was 15.3 months (6--28 months). Therapy resulted in complete absence of the caloric response in six subjects (50) and in caloric test-induced asymmetry in the remaining individuals, ranging from 83 to 27. At follow-up, eleven patients (91.6%) were free of vertigo, while one patient had two vertigo spells 9 months after treatment. Before treatment, VEMPs were present in the affected ear of eleven patients. After treatment VEMPs were absent in all the patients. At the end of follow-up, reappearance of VEMPs was observed in two patients, with no changes in latency values and amplitude ratio. DP demonstrated a reduction of the Composite Score (CS) one week after therapy, with a prevalent reduction of the vestibular component. After 6 months, there was an improvement of the CS and, in particular, of the vestibular component. The present study demonstrates that bithermal caloric test and VEMPs allow for the functional evaluation of both the horizontal semicircular canal and the sacculus, suggesting that these techniques might be used together to monitor the efficacy of intratympanic gentamycin therapy. In addition, our data indicate that DP might provide important information on compensation phenomena and show that intratympanic gentamycin can improve postural control in MD patients.

Multistep laryngeal carcinogenesis helps our understanding of the field cancerisation phenomenon: a review.

In this paper, we try to briefly review the most recent knowledge on head and neck cancer, and especially multistep laryngeal carcinogenesis, and to simply explain how this has modified our understanding of field cancerisation phenomenon. Experimental studies, made possible by the recent evolution of microdissection systems, have demonstrated that the "spatial progression"of the histopathological phenotype in the surroundings of malignant or premalignant head and neck lesions correlates with molecular progression. Such a "spatial progression" can be hypothesised to reflect temporal progression. The field cancerisation process has been divided into three phases, each with its own histological and molecular characteristics. Each of these phases may have clinical implications: detection and monitoring of fields may help cancer prevention (molecular epidemiology), early detection of recurrence (or, more exactly, of second field tumours (SFTs)) (molecular diagnostics) and prognostic prediction after treatment. This model appears plausible, especially in explaining the development of multiple primary tumours (MPTs) in adjacent head and neck mucosal regions, with peculiar clinical and prognostic implications: These tumours can be defined as multiple field tumours (SFTs). However, the model, in our opinion, does not convincingly explain the development of second primary tumours (SPTs) at more distant sites, such as the lung, colon and prostate.

Results of the MXM Digisonic auditory brainstem implant clinical trials in Europe.

OBJECTIVE: To assess the potential benefit of the MXM auditory brainstem implant for patients with neurofibromatosis type 2. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral centers. PATIENTS: Fourteen patients with neurofibromatosis type 2 and bilateral acoustic neuromas underwent implantation with the MXM auditory brainstem implant during surgery to remove the second-side tumor. RESULTS: There were no complications related to the auditory brainstem implantation. Auditory sensations were present for 12 of 14 patients (86%). Global results indicated an improved quality of life for the patients receiving auditory sensations, in part because of their auditory orientation within the environment. Eighty-nine percent of patients tested with an open-set sentence test demonstrated enhancement of speech understanding as a result of lip-reading improvement when auditory brainstem implant sound was combined with lip-reading. A few patients (36%) had some speech understanding in sound-only mode. One patient was able to have limited phone conversations. CONCLUSION: These results indicate that significant auditory benefit can be derived from the MXM auditory brainstem implant.

Pilot phase IIA study for evaluation of the efficacy of folic acid in the treatment of laryngeal leucoplakia.

BACKGROUND: It has been previously observed that patients with head and neck squamous cell carcinoma or with laryngeal leucoplakia present a significant reduction in plasma folate levels. The current Phase IIA pilot study assessed the effectiveness of folic acid as a chemopreventive agent in patients affected by glottic laryngeal leucoplakia. METHODS: Forty-three untreated patients affected by glottic laryngeal leucoplakia were enrolled in the Ear, Nose, and Throat Department (Universita Cattolica del Saco Cuore, Rome, Italy). Glottic leucoplakia was initially diagnosed by indirect laryngoscopy and successively confirmed by diagnostic direct microlaryngoscopy with a biopsy for histologic assessment. Folic acid (Folina, Schwarz Pharma, Germany) was administered orally (5 mg every 8 hours) for 6 months. Patients were monitored every 30 days by videolaryngoscopy. RESULTS: Twelve (28%) patients had no response, 19 (44%) had a partial response, and 12 (28%) had a complete response. The mean increase in serum folate levels (10.06 +/- 0.53) and the mean decrease in homocysteine serum (3.65349 +/- 0.85526) at the end of the study were highly significant (P = .0001). CONCLUSIONS: The larynx is 1 of the sites of major interest and a good model for the development of chemopreventive agents, but so far the proposed agents have shown no clear efficacy on precancerous lesions or on the development of second malignancies.

Hypofolatemia as a risk factor for head and neck cancer.

Head and neck cancer (HNSCC) includes squamous cell carcinomas of the oral cavity, pharynx and larynx. Approximately 38,500 cases of HNSCC are estimated to occur in the USA in 2004, with 11,000 deaths. HNSCCs represent about 3% of all malignant tumors in the USA. However, in other parts of the world, as India, Southeast Asia or Brazil, the disease is much more prevalent. The standard therapeutic approach, focused on surgery, irradiation and chemotherapy, alone or in combination, has been in part modified in the last 30 years, but the overall survival of HNSCC patients has not substantially improved. To characterize and thus identify high-risk mucosal areas and preclinical tumors, molecular abnormalities in head and neck carcinogenesis have been extensively studied. Metabolic aspects in head and neck carcinogenesis have been less extensively studied. Nevertheless, we know that metabolic alterations, often aspecific, are frequently associated with cancer. These may be secondary or may precede tumor development and favorite progression. In particular, based upon our results, a role for folate deficiency as a risk factor in head and neck carcinogenesis seems plausible. A chemoprevention protocol with folate is at present feasible and ethically correct and is already in progress at our institution. Homocysteine levels in cancer patients are probably largely affected by the HNSCC phenotype. An accumulation of homocysteine might reveal a genetic defect which is theoretically a target for pharmacological therapy, for example by antifolic drugs.

Serum levels of folate, homocysteine, and vitamin B12 in head and neck squamous cell carcinoma and in laryngeal leukoplakia.

BACKGROUND: The authors evaluated serum levels of folate, homocysteine, and vitamin B(12) in patients with head and neck squamous cell carcinoma (HNSCC) and in patients with laryngeal leukoplakia, a well known preneoplastic lesion. METHODS: One hundred forty-four consecutive, untreated patients with HNSCC and 40 consecutive, untreated patients with laryngeal leukoplakia were enrolled in the Department of Otolaryngology at the authors' institution. Data from those patients were compared with data from one control group, which included 90 smokers, and from another control group, which included 120 nonsmokers. Serum levels of homocysteine, folate, and vitamin B(12) were measured by an automated immunoassay method based on fluorescence polarization immunoassay technology. RESULTS: Comparing groups by Student-Newman-Keuls test, serum folate levels were significantly lower in patients with HNSCC and in patients with laryngeal leukoplakia compared with serum folate levels in both the smoker control group and the nonsmoker control group. Serum homocysteine levels in patients with HNSCC were significantly higher compared with homocysteine levels both in the smoker and nonsmoker control groups and in patients with laryngeal leukoplakia. There were no statistically significant differences between groups in serum vitamin B(12) levels. CONCLUSIONS: A role for folate deficiency as a risk factor in head and neck carcinogenesis is plausible. A chemoprevention protocol with folate is both feasible and ethically correct and is in progress at the authors' institution. Homocysteine levels in patients with HNSCC probably are affected largely by the HNSCC phenotype. An accumulation of homocysteine may reveal a genetic defect, which, theoretically, may be a target for pharmacologic therapy, for example, with antifolic drugs.

Human papillomavirus infection and cyclin D1 gene amplification in laryngeal squamous cell carcinoma: biologic function and clinical significance.

BACKGROUND: Human papillomavirus (HPV) infection is suspected to be a risk factor for head and neck, and in particular for laryngeal, carcinogenesis. Cyclin D1 gene (CCND1) overexpression and amplification have been shown to play a role as prognostic factors in many human cancers, among which are head and neck cancers. METHODS: A literature review of the role in head and neck cancers of HPV infection and CCND1 overexpression and amplification was undertaken. We have evaluated the extent of the current knowledge in this field under the light of recent acquisitions, in particular, about a correlation between HPV infection, a suspected risk factor, and CCND1 amplification, a frequent mutation (about 20% of laryngeal cancers) and a prognostic factor in laryngeal SCC. RESULTS AND DISCUSSION: The significant correlation between HPV infection and CCND1 amplification supports the hypothesis of the involvement of HPV infection in laryngeal carcinogenesis and suggests that HPV positive laryngeal cancers may constitute a different subset of tumors with a peculiar molecular pattern and thus with a different clinical behavior. HPV infection may be considered a synergistic risk factor with smoking and/or alcohol consumption to be investigated in heavy smokers and drinkers, thus contributing to the identification of patient at high-risk for the development of laryngeal cancer who should undergo strict follow-up and primary and secondary prevention.

Association of laryngeal cancer with previous gastric resection.

OBJECTIVE: To investigate the association between gastric surgery and cancer of the larynx. SUMMARY BACKGROUND DATA: Biliary reflux is frequent after gastric surgery and may reach the proximal segment of the esophagus and the larynx. It is possible that duodenal content (consisting in bile acids, trypsin), together with pepsin and acid residues when gastric resection is partial, may cause harmful action on the multistratified epithelium of the larynx. METHODS: A retrospective case-control study on subjects admitted between January 1987 and May 2002 in the same hospital in Rome was carried out. The study included 828 consecutive patients with laryngeal cancer (cases) and 825 controls with acute myocardial infarction. Controls were randomly sampled out of a total of 10,000 and matched with cases for age, sex, and year of admission. Logistic regression models were used to assess the role of gastric resection in determining laryngeal cancer risk while controlling for potential confounding factors. RESULTS: Previous gastrectomy was reported by 8.1% of cases and 1.8% of the controls (P < 0.0001). A 4-fold association emerged between gastric surgery and laryngeal cancer risk (adjusted OR = 4.3, 95% CI: 2.4-7.9). The risk appeared strongly increased 20 years after surgery (OR = 14.8, 95% CI: 3.4-64.6). Heavy alcohol drinking (OR = 2.5, 95% CI: 1.8-3.5), smoking (OR = 4.7, 95% CI: 3.3-6.7), and blue-collar occupation (OR = 4.6, 95% CI: 3.2-6.7) were all independently associated with the risk of laryngeal cancer. CONCLUSIONS: Previous gastric surgery is associated with an increased risk of laryngeal cancer. A periodic laryngeal examination should be considered in long-term follow-up of patients with gastric resection.