[Occupational hazardous substance exposure and nutrition. Risk factors for mouth, pharyngeal and laryngeal carcinomas?]. / Berufliche Schadstoffexposition und Ernährung. Risikofaktoren für Mundhöhlen-, Rachen- und Kehlkopfkarzinome?

BACKGROUND AND OBJECTIVE: A case-control study was conducted to investigate occupational and other risk factors for squamous cell carcinoma of the oral cavity, the pharynx and the larynx. The study included 209 male cancer patients and 110 male control persons without known malignant disease, matched for age, alcohol consumption and tobacco consumption. PATIENTS/METHODS: Cases and controls were interviewed using a standardized questionnaire which has been used before in the Heidelberg case-control studies. RESULTS AND CONCLUSIONS: The educational level in the cancer group was significantly lower (p < 0.001). 17.2% of the cancer patients and 7.3% of the control persons had not completed their professional training. The percentage of so-called "blue-collar workers" was significantly higher in the cancer group (20.9% vs. 7.3%; p < 0.002). An increased cancer risk was observed for workers exposed to asbestos (OR = 8.7; p = 0.004) and cement dust (OR = 12.9; p < 0.001). A frequent consumption of various vegetable food like carrots (OR = 0.17; p < 0.001), fruits (OR = 0.38; p < 0.001) or green salad (OR = 0.25; p < 0.001) was associated with a significant reduction of cancer risk.

Human leukocyte antigens and prognosis in patients with head and neck cancer: results of a prospective follow-up study.

BACKGROUND: Prognostic information is essential for optimal treatment of patients with head and neck cancer. We studied the relationship of class I and class II human leukocyte antigens (HLA) on prognosis in patients with head and neck cancer. METHODS: HLA-A, -B, -C and -DR antigens were determined in 209 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. The patients were subjected to follow-up investigations for a period of 5 years. RESULTS: Five-year survival rates in relation to tumor stage varied between 86% for stage I tumors and 28% for stage IV tumors (P <.0001, log-rank trend test). The EBA-A11 antigen showed a significant negative correlation with survival. While the 5-year survival of 124 HELA-A11-negative patients was 58%, none of the 17 HLA-A11-positive patients survived 5 years (P = .0002). A significant negative correlation with survival was also observed for HLA-DR6. While the 5-year survival rate of 106 HLA-DR6-negative patients was 60%, it was only 40% in 35 HLA-DR6-positive patients (P = .0313). CONCLUSIONS: If the findings of our study can be confirmed, HLA-A11 and HLA-DR6 might become clinically important supplemental prognostic markers in head and neck cancer.

[Organ preservation in advanced laryngeal and hypopharyngeal carcinoma by primary radiochemotherapy. Results of a multicenter phase II study]. / Organerhalt beim fortgeschrittenen Larynx- bzw. Hypopharynxkarzinom durch primäre Radiochemotherapie. Ergebnisse einer multizentrischen Phase-II-Studie.

INTRODUCTION: Regarding the promising results of international trials we conducted the first German prospective multicentre phase II trial for organ preservation with primary simultaneous chemoradiation in advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: 28 of 30 recruited patients suffering from stage II and III (UICC) laryngeal and hypopharyngeal cancer were treated with primary simultaneous chemoradiation within an organ preservation program and monitored in follow-up of one year. Exclusion criteria included tumor infiltration of the laryngeal cartilage, bilateral neck nodes (N2c) and need for flap reconstruction in case of laryngectomy. The protocol included an accelerated concomitant boost chemoradiation (66 Gy) with Carboplatinum (70 mg/m2 1st and 5th week) and a restaging procedure one month after therapy. In case of residual disease, salvage laryngectomy and/or neck dissection were performed. RESULTS: After follow-up of one year 20 of 28 patients (71%) were presented with stable complete remission and functionally preserved larynx. Of these 20 patients 3 developed pulmonary metastases, 1 secondary primary carcinoma of the lung and 3 neck metastases which needed neck dissections. The other patients showed in 4 cases relapsing tumor which was indicated for laryngectomy. One patient needed tracheotomy because of persisting edema and 2 patients died due to tumor progress. One patient died after complications due to salvage surgery. CONCLUSION: The organ preservation protocol was feasible with well tolerated early toxicity. Problems of screening for recurrent disease, salvage surgery and late toxicity should be noted and pronounced in patient information. Further studies should focus on the improvement of patient selection which could be realized by induction Chemotherapy (using new components like taxan) and/or use of prediction factors such as tumor volume and hemoglobin levels.

Ginkgo biloba extract EGb 761 or pentoxifylline for the treatment of sudden deafness: a randomized, reference-controlled, double-blind study.

In a randomized, prospective, double-blind study involving 72 patients, the therapeutic efficacy of ginkgo extract EGb 761 (n = 37) was compared to that of pentoxifylline (n = 35) for the treatment of sudden deafness. The two therapeutic schedules were equally well tolerated and showed a statistically significant equivalence in improvement or in return to normal of the auditory thresholds in the two patient groups. Furthermore, no differences were found between the treatment groups with regard to the criteria for a return to normal of speech discrimination and reduction of the tinnitus which arose at the same time as the sudden hearing loss. The patient's subjective assessment of the treatment with regard to improvement in hearing and reduction in tinnitus suggested that Ginkgo biloba extract was more beneficial than pentoxifylline. In summary, it was shown that treatment of sudden deafness with ginkgo special extract EGb 761 was as effective as treatment with pentoxifylline.

Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma.

Second primary carcinoma is a peculiar feature of head and neck cancer and represents a form of treatment failure distinct from the recurrence of the primary tumor. Whether altered p53 expression in tumor-distant epithelia at the time of diagnosis is of clinical value as a biomarker for second primary carcinoma development has not been rigorously answered because of the lack of long-term follow-up studies involving a sufficiently large patient cohort. In this prospective study, we have investigated p53 expression in tumor-distant epithelia and in the corresponding primary tumors of 105 head and neck cancer patients by immunohistochemistry on frozen sections. After a median follow-up of 55 months, the clinical course of disease parameters, i.e., local recurrences, lymph node and distant metastasis, incidence of second primary carcinoma, and survival, was evaluated. Overexpression of p53 in tumor-distant epithelia was found in 49 patients (46.7%), and it was independent of the p53 protein status of the primary tumor and of the tumor site, size, stage, and grading. Mucosal p53 overexpression was not associated with local primary recurrences, lymph node or distant metastases, or overall survival. Importantly, mucosal p53 overexpression, but not overexpression in the primary tumors, was significantly associated with an increased incidence of second primary carcinomas (P = 0.0001; Fisher's exact test). When the times to second primary tumor occurrence were analyzed by the Kaplan-Meier method, the difference remained significant (P = 0.005; log rank test). We conclude that IHC staining for p53 overexpression in tumor-distant epithelia provides a simple and rapid tool to identify head and neck cancer patients at increased risk of developing second primary tumors. Because p53 overexpression in these epithelia in our patient cohort was specifically associated with second primary cancer but not with recurrences, at least a fraction of the second primary cancers appears to have resulted from genetic events in the mucosa ("field cancerization").

[Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas]. / Prognostischer Stellenwert des Hämoglobinwertes vor primärer Radiochemotherapie von Kopf-Hals-Karzinomen.

The pretherapeutic hemoglobin level (Hb) has been postulated to constitute a prognostic marker for outcome after primary chemoradiation of patients with advanced cancer of the head and neck. However, this hypothesis has not been tested systematically in large study samples. In the years 1992-1997, 125 patients with advanced head and neck cancer (stages III/IV UICC) were treated with primary chemoradiation in two different prospective multicentric trials, 62 patients in trial A (phase II, 1992-1995), and 63 in trial B (phase III, 1995-1997). Beside initial Hb, other pretherapeutic parameters with potential prognostic relevance were assessed and correlated with clinical outcome after 43-months follow-up: total tumor volume (TTV; calculated in initial CT scans), tumor oxygenation (polarographic measurements with Eppendorf histography), TNM, tumor localization, age, and performance status. The evaluation of the clinical end points (progression-free and overall survival and local tumor control) revealed that Hb and TTV were independent parameters with strong predictive character of outcome after primary chemoradiation in both trials (n = 125). Bivariate analysis showed < median (13.5 g/dl) a hazard ratio of 2.1 (P = 0.002) for Hb; and > median (98 ml) a Hazard ratio of 2.0 (P = 0.006) for TTV. Severe anemia (Hb < 10 g/dl) was an adverse factor in three patients. Hypoxia was associated with poorer initial therapeutical response but was not predictive of clinical outcome. Furthermore, tumor oxygenation showed no correlation with Hb. The other parameters examined failed to show prognostic significance. Our results indicate a high prognostic value of initial Hb for outcome after primary chemoradiation in advanced head and neck cancer and imply a therapeutic benefit of Hb substitution or erythropoietin administration. We propose to test this in randomized clinical trials.

Prognostic relevance of serum levels of the angiogenic peptide bFGF in advanced carcinoma of the head and neck treated by primary radiochemotherapy.

BACKGROUND: The objective of this trial was to analyze the prognostic relevance of the angiogenic peptides basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in the serum of patients with advanced carcinoma of the head and neck treated by primary radiochemotherapy. METHODS: From 1992 to 1995, 26 patients with advanced head and neck cancer (25 stage IV, 1 stage III UICC) were treated according to the protocol of radiochemotherapy with carboplatin. The pretreatment serum levels VEGF, bFGF, and MMP-2 were measured by ELISA, and data were correlated with tumor characteristics and followed up (median time of follow up, 60 months). RESULTS: An increase in bFGF serum level above the upper limit of normal controls showed a significant correlation with shorter time the of locoregional control (p =.036). In covariant analysis bFGF serum concentration proved to be independent of other prognostic factors like tumor site, age, total tumor volume, and response to therapy. No prognostic relevance of VEGF and MMP-2 serum levels could be determined. CONCLUSIONS: The results of this pilot study indicate that the serum concentration of bFGF has prognostic relevance for advanced head and neck cancer.

Immunomodulating effects of surgical intervention in tumors of the head and neck.

The immunomodulating effect of primary surgical intervention in 33 patients with squamous cell carcinoma of the oral cavity, pharynx, and larynx was analyzed prospectively. An operation time of longer than 7 hours was significantly associated with a decrease of total lymphocyte counts, CD4(+) T lymphocytes, and CD8(+) T lymphocytes. The CD4/CD8 ratio as a marker for the downregulation of the cellular immune response was slightly decreased but still in the normal range. CD4(+) lymphocyte counts increased within 7 days, and CD8(+) lymphocytes increased 4 weeks after the operation. The in vitro stimulation of the lymphocytes was impaired for 1 to 4 weeks. Release of interleukins, interferon-gamma, and tumor necrosis factor-alpha remained low despite the surgical trauma. The decreased lymphocyte counts, especially CD4(+) and CD8(+) lymphocytes, were significantly associated with duration of operation and volume of blood loss. Extension of trauma, age, type of anesthesia, and type of intensive care intervention were not associated with specific immunomodulating effects. However, these factors might be responsible for suppression of the immune system, which is expressed by lymphocyte depletion, lymphocyte dysfunction, and impaired upregulation of cytokine secretion.

[Detection of numerical chromosome aberrations in leukoplakia and squamous epithelial carcinomas of the head-neck area using fluorescence in situ hybridization]. / Nachweis von numerischen Chromosomenaberrationen in Leukoplakien und Plattenepithelkarzinomen des Kopf-Hals-Bereichs mittels der Fluoreszenz-in-situ-Hybridisierung.

The tumorigenesis of head and neck squamous cell carcinoma (HNSCC) has been proposed to represent a multistep process characterized by an accumulation of genetic alterations. To study numerical chromosomal aberrations and chromosomal imbalances, biopsies of 11 malignant tumours and biopsies of 16 oral premalignant lesions (leukoplakias) were analyzed by fluorescence in situ hybridization (FISH) using centromeric probes for chromosomes, 1, 7, 9, 10 and 17. The comparison of the alterations observed in simple leukoplakias (group 1, n = 8), dysplastic leukoplakias (group 2, n = 8) and malignant tumours (group 3, n = 11) by the Cochran-Armitage Trend Test revealed an increasing number of numerical chromosomal abberations. This difference was statistically highly significant (p < 0.001). The data open up the possibility that FISH analysis might help to better characterize the progression of premalignant oral leukoplakias.

[Carcinoid of the middle ear. Further therapy after primary tumor excision?]. / Karzinoid des Mittelohrs. Weitere Therapie nach primärer Tumorexstirpation?

The carcinoid tumor of the middle ear is a very rare neoplasm which in general is regarded as benign but may be mistaken for an adenocarcinoma because of its histological heterogeneity. Typical, however, is its neuroendocrine and mucinous differentiation so that an unequivocal diagnosis is possible by means of immunohistochemistry and electron microscopy. As the tumor is very rare, there is no statistical evidence as to whether further treatment is necessary after primary exstirpation of the tumor. Therefore, a review of the literature was performed. We report about a 28-year-old male patient with a carcinoid tumor of the left tympanic cavity. Without any further treatment there has been no evidence for either recurrence or metastases 32 months after surgical resection. As treatment of choice we recommend conservative surgery with complete removal of the tumor and a clinical follow-up on a regular basis.

Prognostic assessment of sonography and tumor volumetry in advanced cancer of the head and neck by use of doppler ultrasonography.

OBJECTIVE: The objective of this trial was to examine the degree of tumor vascularity in lymph node metastases as depicted by computer-assisted color Doppler sonography and the tumor volumes associated with prognosis in carcinomas of the oropharynx and hypopharynx after primary radiochemotherapy. PATIENTS AND METHODS: In a prospective trial, 25 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx (stage IV UICC 1997) were treated with radiochemotherapy. The color Doppler findings were quantified with a computer-assisted protocol that quantitatively describes color Doppler images by the relative color pixel density (CPD). As important prognostic cofactor, total tumor volume (TTV) was calculated from CT sections and related to the degree of vascularity. RESULTS: Low CPD in neck metastases showed a correlation with better overall survival. A high-CPD group and a high-TTV group (median survival 10.1 months) were determined and were compared with all other CPD/TTV combinations (median survival 28.4 months); the difference in survival was significant (P = 0.002). CONCLUSION: The results indicate that high tumor vascularity in combination with high TTV indicates a particularly bad prognosis in patients treated with primary radiochemotherapy for head and neck cancer.

The septal mucosa decongests with naphazoline: a study of mucosal dynamics with sonography.

A new method using B-mode and power-Doppler-mode (pD) sonography for the investigation of changes in nasal mucosa swelling and perfusion was developed. The effect of naphazoline (0.25 mg/mL) on the nasal mucosa was visualized and recorded in 1-minute intervals in 40 patients. The effect of normal saline solution was studied in 27 healthy volunteers. The decongestant and normal saline were applied by flooding the anterior nasal cavity. A computer program automatically quantified pD color information. Normal saline solution induced a 4.8 +/- 2.4% increase in perfusion (+/- SEM, n.s.) after 5 minutes. In the naphazoline group, changes in stereometry were measured on B-mode-sequences in 24 (60%) and perfusion changes in 24 participants (60%). In 16 of 40 patients (40%), both stereometry and perfusion were analyzed. After 10 minutes, the septum and inferior turbinate mucosa thickness were reduced by 17 +/- 2.8% (p < 0.001) and 25 +/- 2.6% (p < 0.001). Perfusion of the septum and inferior turbinate mucosa as visualized with pD-sonography decreased by 33 +/- 3.3% (p < 0.001). The reduction of bloodflow induced by naphazoline as visualized with pD-sonography is within the range of perfusion changes found in LDF and Xenon clearance studies. Decongestion of the septum mucosa demonstrates erectile properties of the septum, which may contribute to the increase of nasal patency after nasal decongestion.

Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy.

The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.

[Chronic laryngeal edema as a late reaction to radiochemotherapy]. / Das chronische Larynxödem als Spätreaktion nach Radiochemotherapie.

In addition to mucositis and myelotoxicity as well known early reactions after radiotherapy or radiochemotherapy in advanced head and neck tumors, late toxicity following treatment is an often underestimated problem. Between 1992 and 1995, 68 patients with advanced oro- and hypopharyngeal tumors were treated primarily with accelerated concomitant boost radiochemotherapy (total dose irradiations of 66 Gy and carboplatin as chemotherapy). Ninety-three per cent of the patients had stage IV disease according to the UICC-TNM classification. Monitoring of follow-up included late toxicity with special attention given to laryngeal edema. In 37 patients (54%) edema of the larynx as a late complication of radiochemotherapy was observed by clinical investigation and CT scan. The median onset of laryngeal edema was found 121 days after completion of therapy, with a median time of observation of 250 days. Observations in these patients demonstrated the chronic character of this edema. An increase in the laryngeal edema in 5 cases resulted in tracheostomy. Laryngeal edema in 10 patients was associated with recurrence of tumor. These results show that after xerostomia laryngeal edema is the main late toxicity in the head and neck after radiochemotherapy and should lead to further investigations to exclude possible recurrent tumor.

Oral leukoplakias show numerical chromosomal aberrations detected by fluorescence in situ hybridization.

To examine at which stage in the multistep process of head and neck tumorigenesis numerical chromosomal alterations can be detected by fluorescence in situ hybridization (FISH), biopsies and cell smear preparations of clinically healthy oral tissue, premalignant lesions (leukoplakias), and tumors were analyzed by FISH using chromosome-specific centromeric probes. Aberrations found in tumor biopsies and in tumor cell smears consisted of trisomy of chromosomes 1, 7, 10, and 17 and monosomy of chromosomes 1, 7, 9, 10, and 17. In five of eight dysplastic oral leukoplakia biopsies, aberrations were seen consisting of trisomy of chromosome 1, 7, and 17, and monosomy of chromosome 9. No aberrations were found in biopsies of hyperplastic lesions (n = 8), or in oral cell smears of persons at risk. Because numerical chromosomal aberrations seem to be highly specific for malignant cells, FISH may help to identify leukoplakias that have a high risk of malignant conversion.

TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer.

Recent studies have suggested that different mutation types within the core domain of the tumour suppressor protein p53, i.e. DNA contact mutations and structural mutations, confer different biological properties. We have analysed in 86 head and neck squamous cell carcinomas (HNSCC), whether these p53 mutation types have a differential clinical impact. Thirty-seven missense mutations were identified. Thirteen of these (36%) were DNA contact mutations, occurring in the L3 loop, in the H2 loop sheet helix motif, in the S10 beta strand and in Zinc binding residues. Microsatellite marker analysis revealed a selective association between these mutations and the loss of wild-type alleles (100% LOH vs 50% LOH in tumours with structural mutations; P=0.0034, Fisher's exact, 2-tailed). In comparison to structural mutations or to the absence of mutations in the core domain, DNA contact mutations were associated with higher tumour stages (84.6% vs 62%), a higher incidence of lymph node metastasis (91.7% vs 56%; P=0.014, Fisher's exact, 2-tailed), a shortened recurrence-free survival (8.1 months vs 23.7 months, P=0.047, log rank test) and overall survival (11 months vs 29.2 months; P=0.003, log rank test). The latter was also the case when only stage IV tumours were analysed (P=0.0055, log rank test). These data indicate that in HNSCC, TP53 DNA contact mutations confer a strong selection pressure to eliminate wild-type alleles, and that they result in an accelerated tumour progression and reduced therapeutic responsiveness.

Bazex syndrome (acrokeratosis paraneoplastica).

Acrokeratosis paraneoplastica (Bazex syndrome) is a rare but distinctive dermatosis associated with carcinomas of the upper aerodigestive tract with possible cervical lymph node metastases. The cutaneous lesions occurring in the syndrome are non-metastatic skin involvement that parallels (as cutaneous marker) the evolution of the malignancy. Since only a few case reports have been published in the otolaryngologic literature, we present our experience and review some of the findings previously reported.

Carcinoid tumor of the middle ear in a 28-year-old patient.

Carcinoid tumor of the middle ear is an extremely rare condition. The origin of the tumor cells is still speculative and the closeness of relationship to adenomas of the middle ear has been a matter of discussion since the first description of this tumor entity in 1980. In this study we report a case of a 28-year-old male patient with a carcinoid tumor of the middle ear. We present the results of histomorphological, immunohistochemical and electron microscopic examinations and compare our findings to those of previously published cases.

Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control.

Two hundred eight primary squamous cell carcinomas of the head and neck have been analyzed with respect to the presence of the retinoblastoma tumor suppressor protein, pRb. Of these, 23 tumors (11%) that preferentially localized to the tonsils revealed complete absence or dramatic reduction in the amount of pRb. Other cell cycle components, cyclin D1 and p16INK4A, which are intimately related to pRb through an autoregulatory loop, were also dramatically decreased or overexpressed, respectively, in these pRb-defective tumors. On the other hand, the majority of the pRb-defective tumors contained the wild-type p53 gene. No evidence was found for genetic defects at the Rb locus in these tumors. Very significantly, in 11 of 12 pRb-defective tonsillar tumors, but in none of 9 pRb-positive tonsillar tumors (P < 10[-7]), DNA of oncogenic human papillomavirus types was identified, providing a strong indication for a human papillomavirus-associated etiology of these tumors and suggesting the functional inactivation of the pRb protein by the viral E7 gene product. In comparison to all head and neck squamous cell carcinomas studied, the pRb-defective tonsillar tumors were in general more poorly differentiated (P = 0.0059), and they were all metastatic at the time of resection. Of particular clinical interest, despite these adverse histopathological factors, the clinical outcome for these patients was relatively favorable, strongly implying that the pRb-defective tumors responded uniformly well toward postoperative radiation therapy.