Markers of neck failure in oral cavity and oropharyngeal carcinomas treated with radiotherapy.

BACKGROUND: Neck management after radiotherapy remains controversial. It is not clear which patients may benefit from postradiotherapy neck dissection. Biologic markers may be useful in this setting. METHOD: This study includes 81 patients with oral cavity and oropharyngeal carcinomas. The primary tumor had been treated with radical radiotherapy. Immunohistochemical staining to p53, ki-67, NEU, HSP-27, and GST has been performed. RESULTS: There were 50 T1-2 and 31 T3-4 patients, as well as 36 NO and 45 N1-3. A total of 25 nodal failures was observed. With expressed HSP2, 23% of patients had neck failure compared with 51% when HSP-27 was absent (p = .02). With NEU overexpression, nodal control decreased from 72% to 34% (p = .008). In a Cox model, NEU (p = .01) and HSP-27 (p = .05) were associated with neck failure. CONCLUSIONS: HSP-27 and NEU expression may play a role in predicting nodal failure. This should be confirmed in a larger, prospective study.

Overexpression of the 27 KDa heat shock protein is associated with thermoresistance and chemoresistance but not with radioresistance.

PURPOSE: The heat shock protein (hsp27) correlates with thermotolerance and chemoresistance. Our main objective was to assess the response to radiotherapy both in vitro and in vivo in correlation with various concentrations of hsp27. The second objective was to evaluate the relation between hsp27 and glutathione-s-transferase pi (GST pi). METHODS AND MATERIALS: For the in vitro study, thermoresistant cell lines, expressing various amounts of hsp27, were used to assess the role of this protein in radioresistance. To verify the efficiency of hsp27 in these cells lines to confer resistance to cytotoxic agents, these cells were also treated with heat shock and cisplatin. Furthermore, the role of hsp27 expression was studied in vivo by immunochemistry in 98 patients with head and neck squamous cell carcinoma treated by radiotherapy. hsp27 was correlated with local control of the tumor and with clinical and biologic factors potentially able to affect the local control, including p53, ki-67, ploidy, and GST. RESULTS: In vitro, high constitutive levels of expression of hsp27 did not significantly influence the survival curves of transfected cells exposed to radiation as compared to control cells although hsp27 overexpression was confirmed to increased the cellular resistance to heat and to cisplatinum. In vivo, we showed that overexpression of various amounts of hsp27 did not correlate with local control of the tumor. In vivo, hsp27 was only significantly associated with GST pi. Expression of GST pi was associated with poor local (p = 0.01) control and survival (p = 0.08) in a Cox model. CONCLUSIONS: It is concluded that the mechanisms responsible for hsp27-mediated heat and drug resistance are not involved in radioprotection.

Markers of radioresistance in squamous cell carcinomas of the head and neck: a clinicopathologic and immunohistochemical study.

PURPOSE: The lack of accurate criteria to predict the response to radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HN-SCC) remains a major problem. The purpose of this study was to investigate the role of several biologic tumor markers to complement clinical prognostic factors in the assessment of response to radiotherapy in SCCs. PATIENTS AND METHODS: p53, ki-67, c-erb B-2, heat-shock protein-27 (HSP-27), and glutathione S transferase (GSTpi) were evaluated by immunohistochemistry on biopsies from 101 patients treated for head and neck cancer by radical radiotherapy. Expression of each marker was correlated with local control and survival using Kaplan-Meier curves. A Cox regression multivariate analysis was also performed that included all clinical and immunohistochemical variables. RESULTS: Expression of p53 and low cell proliferation allowed identification of patients whose tumors did not respond to radiation. Patients with p53-expressing tumors displayed a relative risk (RR) of 3.78 for not being controlled by radiotherapy compared with patients with p53-negative tumors. For tumors with a high growth fraction (ki-67 > 20%) the RR was 0.25 compared with tumors with a low growth fraction (ki-67 < 20%). When p53 expression and cell proliferation were considered simultaneously in a Cox model, the association with resistance to radiation was significant (P = .000004). The RR for resistance with one (p53 staining or ki-67 < 20%) or two (p53 staining and ki-67 < 20%) unfavorable markers was, respectively, 3.8 and 14.87. CONCLUSION: Patients whose tumor expressed p53 with low growth fraction (ki-67 < 20%) had a strong probability not to respond to radiation therapy. Similarly, absence of p53 expression with a high cell proliferation predicted an excellent outcome after radiotherapy even for patients with advanced disease. Prediction of the outcome of radiotherapy would eventually facilitate the early choice of an adequate treatment.

[Buccal dryness, xerostomia and measurement of salivary secretory activity]. / Sécheresse buccale, xérostomie et mesure de l'activité sécrétoire salivaire.

Xerostomia is a marked reduction in saliva production and may occur as an early symptom of various systemic diseases. It is also secondary to the administration of numerous drugs. Severity of salivary gland dysfunction cannot be predicted from subjective reports of oral dryness by patient, and accurate assessments of salivary gland function should be managed. Several procedures for saliva samplings and secretory activity measurements have been reported. In normal individuals, the mean values of unstimulated whole saliva was slightly higher in males (0.42 ml/min) than in females (0.37 ml/min). Corresponding mean values for stimulated whole saliva are 1.77 ml/min and 1.38 ml/min. Unstimulated whole saliva collection during 15 min is recommended as the most reliable test for clinical diagnosis. It is found that an unstimulated salivary flow of 0.1 ml/min represents the cut-off limit for the diagnosis of xerostomia.

p53 overexpression in head and neck squamous cell carcinoma: review of the literature.

As a tumour suppressor gene, the inactivation of p53 induces the development of numerous human cancers. Mutations of p53 have been implicated in the pathogenesis of head and neck squamous cell carcinoma (HN-SCC) at a high incidence. In premalignant lesions and in situ carcinomas, p53 overexpression is not exclusively restricted to neoplastic cells, but frequently affects the normal appearing keratinocytes adjacent to p53 positive neoplasms or present in dysplastic areas. These results suggest that as contributors to the early phases of HN-SCC development, p53 alterations may be excellent biomarkers that indicate the predisposition of a particular oral cavity premalignant lesion toward malignancy. In most cases, the p53 overexpression status of a tumour metastasis is identical to that of a primary tumour, indicating that a p53 mutation precedes metastatic spread. In patients with multiple primary tumours, multiple foci of p53 overexpression are observed in epithelia distant from the tumour. So the expression of p53 in normal epithelium would indicate an increased risk for transformation to second or third primary cancers. Distinct p53 mutations in different primary tumours of the same patient indicate that these cancers arise as independent events; these results support the existence of multifocal polyclonal processes. Regardless of the aforementioned results that support p53 as a valid tumour biomarker, most studies have shown no relationship between the expression of p53 and clinical and histopathological parameters. The role played by p53 mutations in the progression and vital prognosis of HN-SCC has not yet been demonstrated.