Antitumor vaccination in patients with head and neck squamous cell carcinomas with autologous virus-modified tumor cells.

Prognosis of patients with advanced head and neck squamous cell carcinomas (HNSCC) is still poor. Therefore, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe in HNSCC patients. Furthermore, we determined the influence on disease-free survival and overall survival and the vaccination-induced antitumor reactivity. In a nonrandomized pilot study, 20 patients were vaccinated postoperatively. Vaccine was prepared from the tumor cell cultures of patients by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and vaccine was applied up to five times. Antitumor immune reactivity was determined in the skin by delayed type hypersensitivity skin reaction and in the blood by enzyme-linked immunospot assay. Establishment of tumor cell cultures was successful in about 80% of the cases. After vaccination, we observed no severe side effects. Percentages of survival of vaccinated patients with stage III and stage IV tumors (n = 18) were 61% at 5 years. Immune monitoring revealed significant increases of antitumor delayed type hypersensitivity reactivity especially in disease-free patients, and in a significant proportion of vaccinated patients the presence of tumor-reactive T-cells in the peripheral blood even 5 to 7 years after the last vaccination. Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and may improve the prognosis of HNSCC patients with advanced tumors. This could be supported by antitumor immune responses that we observed especially in long-term surviving patients.

Head and neck tumor sites differ in prevalence and spectrum of p53 alterations but these have limited prognostic value.

The tumor site is a strong clinical factor in head and neck squamous cell carcinoma (HNSCC). To clarify the biologic and clinical role of p53 alterations in HNSCC, we have examined the prevalence and the nature of p53 alterations in a large cohort of tumors from the different sites. For immunohistochemical analysis of p53 protein expression, we introduced tyramide signal amplification immunohistochemistry (TSA-IHC) on a tissue microarray. This allowed the discrimination between normal low-level expression and reduced or lost expression. Two hundred fifty-three tumors were subjected to mutational analysis by genomic DNA sequencing, employing also the p53 GeneChip from Affymetrix. The prevalence of all p53 alterations, i.e., mutations, overexpression and loss of expression, was significantly higher in hypopharyngeal tumors than in the other sites (p = 0.001). Laryngeal tumors showed the lowest rate of p53 alterations, but revealed a distinct mutation spectrum: most mutations affected exon 5 (p = 0.013) and the S2' domain (p = 0.002), and most hot-spot 248 mutations occurred in the larynx (p < 0.001). Sequencing by p53GeneChip technology was shown to be only insignificantly more sensitive than dideoxy sequencing. In agreement with p53 mutations occurring prior to invasiveness, their prevalence did not increase with tumor stage, and all mutation classes lacked prognostic significance. The large patient cohort of this study showed that p53 is differentially affected in the different tumor sites of the head and neck, but its mode of inactivation does not play a major role in tumor progression.

p53-positive tumor-distant squamous epithelia of the head and neck reveal selective loss of chromosome 17.

OBJECTIVES/HYPOTHESIS: The progression of clinically manifest premalignant lesions in the head and neck region to primary or second primary cancer is characterized by numerical and structural chromosomal aberrations. However, many tumors arise from histologically inconspicuous mucosal sites. The objective was to investigate whether chromosomal aberrations can be detected in tumor-distant mucosa and whether they can help predict the risk of second primary malignancy. STUDY DESIGN: A retrospective series of 72 clinically healthy, arbitrarily taken mucosal samples from 53 patients with squamous cell carcinoma of the head and neck was studied. A previous analysis of the p53 protein status had revealed both p53-positive and p53-negative samples. METHODS: The samples were analyzed by fluorescence in situ hybridization (FISH) using centromeric probes specific for the chromosomes 1, 10, 17, and 18. RESULTS: Tumor-distant mucosa generally showed increased numerical chromosomal aberrations, which consisted mainly of monosomies. In the group of patients with p53-positive epithelia, all aberrations including gains of chromosomes (trisomies, tetrasomies) were more frequent. Monosomy for chromosome 17 was most significantly and selectively enhanced in this group (Wilcoxon Scores [rank sum] test, P =.0002). CONCLUSION: Detectable chromosomal aberrations occur in clinically healthy epithelia in patients at risk for secondary head and neck cancer. Specifically, unbalanced chromosome 17 monosomy in conjunction with p53 protein overexpression may constitute a valuable biomarker for progressive "field cancerization."

Prognostic impact of reoxygenation in advanced cancer of the head and neck during the initial course of chemoradiation or radiotherapy alone.

BACKGROUND: Previous studies have shown that radiation of hypoxic tumors can result in reoxygenation phenomenon. The relevance of this phenomenon for prognosis is unclear. This study analyzes whether the presence of hypoxia, or the extent to which reoxygenation occurs during the initial phase of primary chemoradiation or radiotherapy, can predict the clinical outcome in advanced tumors of the head and neck. METHODS: The distribution of oxygen partial pressures was determined using pO(2) histography (Kimoc 6650, Sigma pO(2)-Histograph, Eppendorf, Hamburg, Germany). In cervical lymph node metastases of 37 patients with advanced carcinoma of the head and neck (stage IV, UICC), these values were determined before the start of primary chemoradiation or radiotherapy alone (pO(2)x). Thirty-two of 37 patients were reexamined after 1 week of therapy, and measurements were taken again in the same nodes (pO(2)y). The results obtained from these measurements were correlated with both, the initial response to therapy and follow-up results (43 months). RESULTS.: In all patients, pronounced hypoxia (median pO(2), 3.2 mmHg) was found before therapy. In 19 of 32 patients, chemoradiation/radiotherapy induced reoxygenation (deltaO(2) = pO(2)y - pO(2)x), with median deltapO(2) increasing to 6.5 mmHg after 1 week (p =.049). The group of patients with a complete or partial response showed only a slight increase of median deltapO(2) (1 mmHg) compared with a strong reoxygenation effect in the group of patients with no change (mean value of median deltapO(2) = 10.3 mmHg; p =.0062). The group of patients with deltapO(2) values lower than median showed significantly better survival rates compared with the other group (p =.036). CONCLUSION: These data suggest that reoxygenation under therapy may have prognostic relevance in patients with advanced carcinoma of the head and neck treated by primary chemoradiation or radiation therapy. Remarkably, however, a poor outcome was associated with a higher degree of reoxygenation.