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Hypopharyngeal cancer is squamous cell carcinoma (SCC) with the worst prognosis among the head and neck cancers. Overall, the 5-year survival rate remains poor although diagnostic imaging, radiation, chemotherapy, and surgical techniques have been improved. The mortality of patients with hypopharyngeal cancer is partly due to an increased likelihood of developing a second primary malignancy and metastasis. In this study, we found that MLCK expression, compared to healthy tissue, was up-regulated in hypopharyngeal tumor tissue. Of particular interest, a low 5-year survival rate was positively correlated with MLCK expression. We hypothesized that MLCK might be a target for hypopharyngeal cancer prognosis and treatment. In order to explore the function of MLCK in the development of cancer, we knockdown MLCK in hypopharyngeal cancer FaDu cells. The results showed that MLCK knockdown reduced the migration and invasion of FaDu cells. 4-amino-2-trifluoromethyl-phenyl retinate (ATPR) is the derivative of all-trans retinoic acid (ATRA), which was able to reduce both MLCK expression and activity in FaDu cells. ATPR induced FaDu cells apoptosis in a dose-dependent manner and also inhibited cell growth both in vivo and in vitro. Further experiments showed that overexpression of MLCK reduced ATPR induced-migration inhibition while increase of ATPR induced apoptosis, which suggested that MLCK was involved in ATPR's anti-cancer function. In conclusion, MLCK is a novel prognostic marker and therapeutic target for hypopharyngeal cancer. By targeting MLCK, ATPR exhibits its potential application in the treatment of this type of cancer., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

BACKGROUND Ras-related C3 botulinum toxin substrate 1 (Rac1) is implicated in a variety of cellular functions and is related to tumor growth and metastasis. This study aimed to explore the role of Rac1 in hypopharyngeal squamous cell carcinoma (HSCC). MATERIAL AND METHODS The Rac1 expression in HSCC tissues was determined by quantitative real-time polymerase chain reaction and Western blot analysis. The level of Rac1 in HSCC cells was downregulated by a Rac1-specific shRNA. Then, the growth and metastasis of HSCC cells were assessed in vitro by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry, Hoechst staining, and Transwell assay. Moreover, cells transfected with Rac1 shRNA or negative control were injected subcutaneously into the right axilla of mice, and then the effects of Rac1 silencing on the growth of HSCC were also explored in vivo. Additionally, activation of the P38 mitogen-activated protein kinase (MAPK) signaling pathway was assessed by Western blot. RESULTS Rac1 was highly expressed in HSCC tissues. Silencing Rac1 inhibited the proliferation and cell cycle progress of HSCC cells, and induced their apoptosis. Rac1 silencing also suppressed the migration and invasion of HSCC cells. In vivo study showed that silencing Rac1 suppressed the growth of tumor bodies. Moreover, the P38 MAPK signaling pathway was implicated in the tumor-suppressing effect of Rac1 silencing in vitro and in vivo. CONCLUSIONS Silencing Rac1 suppressed the growth and migration of HSCC through the P38 MAPK signaling pathway. Due to its contribution in HSCC, Rac1 has the potential to become a promising antitumor therapeutic target for HSCC.

Background: Focal adhesion kinase (FAK) plays an important role in tumor metastasis. The purpose of this study was to evaluate the significance of FAK expression in surgically treated patients with hypopharyngeal cancer., Methods: We retrospectively reviewed the clinical charts of patients treated at our institution between 2004 and 2012 and identified 87 patients with hypopharyngeal cancer. FAK expression status was retrospectively evaluated using immunohistochemistry., Results: FAK-positive patients displayed significantly worse disease-specific survival than FAK-negative patients (p = .001). Multivariate analyses revealed that FAK positivity and extracapsular spread (ECS) were independent, significant adverse prognostic factors. Furthermore, FAK positivity significantly correlated with the number of metastatic lymph nodes (p = .048), and FAK-positive patients displayed a higher incidence of distant metastases (p = .009)., Conclusion: The current study demonstrated that upregulated FAK expression correlates with poor prognosis and tumor dissemination in surgically treated patients with hypopharyngeal cancer. © 2016 Wiley Periodicals, Inc. Head Neck 38:1164-1169, 2016., (© 2016 Wiley Periodicals, Inc.)

Aim: Overexpression of histone demethylase PHF8 has been reported to function as an oncoprotein in many cancers; however, the implications of PHF8 involvement in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remain unclear. This study aims to explore the expression of PHF8 and its clinical significance in LHSCC., Materials & Methods: Western blotting and immunohistochemistry were performed to evaluate PHF8 protein expression in fresh and archived LHSCC samples. Global expressions of H3K27 and H3K9 methylation were analyzed in a cell line with PHF8 siRNA treatment., Results & Conclusion: In our study, PHF8 was upregulated in fresh LHSCC tissues. Immunohistochemical staining revealed that the expression of PHF8 was positively associated with T classification, clinical stage, primary tumor position and tumor relapse. Survival analysis demonstrated that high PHF8 expression was significantly associated with shorter overall survival and disease-free survival. Moreover, PHF8 regulates the levels of H3K9me2 and H3K27me2 in LHSCC. Taken together, PHF8 might be a novel prognostic marker for this disease.

Background: The present study was designed to evaluate the efficacy and safety of a combination of helical tomotherapy (HT) or intensity-modulated radiotherapy (IMRT) and EGFR (epidermal growth factor receptor) inhibitor (Cetuximab or Nimotuzumab) with or without chemotherapy in patients with locally advanced hypopharyngeal carcinoma., Patients and Methods: The retrospective study included forty-six patients (12 stage III and 34 stage IV) with locally advanced hypopharyngeal cancer. Among them, 20 were treated with induction chemotherapy with docetaxel and cisplatin (TP) followed by concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, 13 received concurrent chemoradiotherapy with cisplatin and EGFR inhibitor, and 13 were treated with concurrent radiotherapy plus EGFR inhibitor. HT and IMRT were performed in 33 and 13 patients, respectively. Side effects were evaluated with the established CTCAE (Common Terminology Criteria for Adverse Events) 3.0 criteria., Results: The median follow-up time was 39.4 months (range 3-69 months). All patients completed the planned RT without any treatment breaks. The 3-year local control survival, disease-free survival, overall survival, and laryngeal preservation survival rates were 66.8%, 59.0%, 68.9%, and 86.7%, respectively. The most common grade 3 or higher side effect was oropharyngeal mucositis. One patient required dilatation of a pharyngeal stricture 18 months after treatment. No patient required percutaneous gastrostomy and tracheostomy tube., Conclusion: The treatment with EGFR inhibitor in combination with non-surgical combined modality in patients with hypopharyngeal carcinoma was well tolerated and resulted in encouraging laryngeal preservation survival rate. HT or IMRT, EGFR inhibitor, and effective management of severe oropharyngeal mucositis contributed to the positive outcomes.

To assess the expression of COX-2,CD44v6 and CD147 in hypopharyngeal squamous cell carcinomas and the three biomarkers correlation with tumor invasion and lymph node metastasis of Chinese people. 101 cases of surgically excised primary tumor were included in this study, and 40 tissues of epithelium adjacent to carcinoma were used as controls. We characterized the immunohistochemical expression of COX-2, CD44v6, and CD147 in 141 formalin-fixed, paraffin-embedded tissues, and measured the mean optical density (OD) of the positive area to identify the expression of the three bio-markers and relationship with tumor invasion and lymph node metastasis. Our study demonstrates that the expression of the COX-2 and CD147 were significantly increased in carcinoma tissues compared to the epithelium adjacent to carcinoma. We also observed that the expression of COX-2, CD44v6, and CD147 were significantly associated with T classification, lymph node metastasis and clinical stage. There was strong significant correlation among the three biomarkers as well. Additionally, we indicated that recurrence and ≥ P50 level of COX-2 expression had an independent prognostic effect on prognosis. In conclusion, the three biomarkers play important roles in tumor invasion and lymph node metastases and might be valuable indicators of tumor metastasis in hypopharyngeal squamous cell carcinoma.

RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers., (©2011 AACR.)

High levels of mitotic progression-associated PLK1 and stress-associated HSF1 have been observed in various human cancers. In the present study, we investigated the effects of PLK1 and HSF1 knockdown on the proliferation of oral cancer cells using small interfering RNA. In human oral squamous cell carcinoma (SCC) tissues, the levels of PLK1 and HSF1 were higher compared to normal tissues. The expression levels of PLK1 and HSF1 were also elevated in the human oral SCC cell lines FaDu and HEp-2. Disruption of PLK1 induced cell cycle arrest at G2/M phase as well as apoptosis in oral cancer cells. Interestingly, knockdown of both PLK1 and HSF1 expression decreased cell proliferation while increasing apoptotic cell death in synergistic fashion. These results establish the potential value of PLK1 and HSF1 as targets for oral cancer therapy.

Objective: To explore the potential clinical application of the oncolytic activity of cyclooxygenase 2 (COX-2) promoter-based, conditional, replication-selective adenovirus vector for hypopharyngeal squamous cell carcinoma., Design: In vivo study and retrospective study., Setting: Kobe University Hospital, Kobe, Japan., Subjects: Expression of COX-2 in hypopharyngeal cancers treated at Kobe University Hospital was immunohistochemically investigated. In addition, nude mice bearing human hypopharyngeal cancer cells (H891) were used to analyze oncolytic activity of a conditional replication-selective adenovirus vector in which the expression of E1a, required for viral replication, is controlled by the COX-2 promoter Ad-COX2-E1a., Results: In vivo assays showed significant growth suppression in the murine hypopharyngeal model. Cyclooxygenase 2 expression was observed in 75.3% of hypopharyngeal cancers, especially in differentiated tumor cells (P = .001; r = 0.433)., Conclusion: In this study, we demonstrated the potential of oncolytic therapy using the COX-2-promoter based, conditional, replication-selective adenovirus for COX-2-expressing hypopharyngeal squamous cell carcinomas.

The enzymatic activity of matrix metalloproteinase-9 (MMP-9) suggests that its presence in hypopharyngeal and laryngeal squamous cell carcinomas (HSCCs, LSCCs) could have prognostic value. We tested this hypothesis by quantitative morphometric analysis of immunohistochemical staining in histological sections of 73 stage IV HSCCs and 45 LSCCs (30 cases of stage I/II, 15 cases of stage IV). As compared to tumour-free epithelium an increase for the labelling index in LSCCs reached statistical significance (p=0.04). Specimens of Reinke's edema were strongly higher in this parameter compared to tumour-free tissue area (p=0.000001), underscoring an association between the level of MMP-9 expression and inflammation. Focusing on patients' recurrence status we identified thresholds for the labelling index of 10% for HSCCs and 18% for LSCCs, both indicating rapid recurrence and dismal prognosis unless surpassed. When relating data for MMP-9 to those for three adhesion/growth-regulatory galectins, a positive correlation with galectin-7 expression was detected in LSCCs. This finding suggests a possible potential role of this endogenous lectin as inducer of MMP-9 gene expression in situ. Of note, galectin-1 expression was negatively correlated with MMP-9 and that of galectin-3, a substrate of MMP-9, not related. In conclusion our study delineated a prognostic role of MMP-9 immunodetection in high-stage HSCCs and in LSCCs when separating patients by a distinct threshold for the labelling index. Moreover, it indicated associations between MMP-9 and multifunctional galectins-1 and -7 in situ.

Hepatocyte growth factor (HGF) has recently attracted a considerable amount of attention as a stromal-derived mediator in tumor-stromal interactions, particularly because of its close involvement in cancer invasion and metastasis, and (-)-epigallocatechin-3-gallate (EGCG) can modulate the cell signaling associated with angiogenesis, metastasis, and migration of cancer cells. In the present study, we have investigated the effects of HGF on invasion and metastasis of hypopharyngeal carcinoma cells and the effect of EGCG on blocking HGF-induced invasion and metastasis in these cells. We found that HGF promoted the autophosphorylation of c-Met, HGF receptor, and that HGF-induced proliferation, colony dispersion, migration and invasion of tumors. We also observed that HGF enhanced the activity of matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA) in hypopharyngeal carcinoma cells. In addition, HGF-induced the activation of Akt and Erk pathway as a downstreaming pathway of invasion. On the other hand, EGCG at physiologically relevant concentration (1 microM) suppressed HGF-induced tumor motility and MMP-9 and uPA activities, and the suppression of Akt and Erk pathway by EGCG was one of the downstream mechanisms to facilitate EGCG-induced anti-invasion effects. These results suggest that EGCG may serve as a therapeutic agent to inhibit HGF-induced invasion in hypopharyngeal carcinoma patients.

The purpose of this study was to determine the expression of cyclooxygenase-2 (COX-2) in normal epithelium, dysplasia and squamous cell carcinoma of the hypopharynx and to investigate associations with clinicopathological factors and survival. Seventy-five patients with hypopharyngeal squamous cell carcinomas (HPSCC) who underwent surgical treatment at the Department of Otolaryngology, Osaka Medical Center for Cancer and Cardiovascular Diseases, were investigated. COX-2 expression was determined by immunohistochemistry and 97.3% (73/75) of samples displayed immunostaining in tumor cells. COX-2 staining was localized mainly in the cytoplasm (73/75) and was rare in stromal cells (2/75). Over half of the areas of dysplastic cells adjacent to carcinomas also showed COX-2 staining (41/70, 58.6%). There were no significant correlations between the COX-2 expression and tumor size, location and tumor growth type, T- and N-stage, tumor recurrence, lymph node metastasis and survival in this study. COX-2 expression thus does not appear to have a prognostic significance for hypopharyngeal SCC although there was a tendency for higher values in T3/T4 than T1/T2 cases. Furthermore, COX-2 was found to be more strongly expressed in poorly-differentiated than in moderately/well-differentiated carcinomas. In this study group, COX-2 was up-regulated not only in SCCs but also in the dysplastic lesions of the hypopharynx, suggesting that COX-2 inhibition may be a useful chemopreventive strategy.

Background: The tumor microenvironment is believed to contribute to the malignant properties of tumor cells in heterogeneous tumor tissues. We investigated the impact of hypoxia (1% oxygen) on the expression of cathepsin B and its natural inhibitors cystatin B and C., Materials and Methods: Patient-matched oral carcinoma cell lines from primary tumor and lymph node metastasis were used to study the effects of hypoxia on proliferation, protein expression, and proteolytic and inhibitor activities., Results: Hypoxic growth led to elevated cathepsin B expression and activity, and this effect was greater in metastatic than in primary tumor cells. Also, hypoxia led to down-regulation of the inhibitors cystatin C and B, resulting in increased residual activity of cathepsin B., Conclusion: These data suggest that the invasive and/or metastatic potential of cells may be enhanced under hypoxia by increasing cathepsin-mediated proteolysis. The results provide strong evidence for the involvement of cathepsin B and its cystatin inhibitors in hypoxia-enhanced tumor progression.

Background: The reactivation of the telomerase seems to be an important step in the carcinogenesis of most human cancer types. Cell clones, which express this enzyme, get the ability of indefinite proliferation, means become immortal., Methods: In this study, 80 patients with squamous cell carcinomas (SSC) in oral cavity, oropharynx, hypopharynx and larynx were recorded prospectively concerning a possible correlation of telomerase activity and clinical and prognostic factors. Telomerase activity was analysed by a modified telomeric repeat amplification protocol (TRAP) assay., Results: In 75% of the tumour tissues the telomerase was demonstrated independently of the localization of the tumour. The known clinical prognostic factors did not show any correlation to the expression rate of the telomerase activity in the tumour tissues. Also, reactivated telomerase did not affect the tumour-dependent survival. Only the number of lymph node metastases was in tendency higher in patients with telomerase-positive tumours. The number and timeframe of local and regional recurrences was not influenced by the telomerase status., Conclusions: Although telomerase seems to be an important part of the carcinogenesis of SCC our data show that the reactivation of telomerase in tumour tissue did not have any prognostic significance for these tumours. The tendency that tumours with active telomerase developed lymph node metastases in a higher number should be evaluated by further enlarged studies for its clinical relevance.

Objective: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Possible underlying mechanisms and genotype-phenotype correlations are not adequately investigated. The aim of this study was to investigate the influence of the GSTM1-null-genotype on the level of GSTM enzyme concentration and on the enzyme activity of GST in patients with head and neck cancer (HNC)., Methods: We investigated in 83 patients and 91 healthy controls the GSTM1 polymorphisms, GSTM1 protein concentration, GSTM1 protein in tumor tissues, and total GST enzyme activity., Results: Total GST enzyme activity was significantly lower in patients with HNC (208 +/- 9 micromol/min*l) than in controls (264 +/- 11 micromol/min*l, P< 0.0001) but did not depend on GSTM1-genotype (P = 0.1). GSTM protein concentration in null-genotype patients (3.6 +/- 2.5 microg/mL, mean +/- SE) was significantly lower than in GSTM1 allele carriers (26.7 +/- 9.6 microg/ml, P< 0.0001); GSTM protein expression did not depend on GSTM1-genotype (P> 0.5)., Conclusion: GST enzyme activity in patients with HNC is suppressed, indicating impaired detoxification capacity of tobacco-smoke-related carcinogens. This suppression is not correlated with the GSTM1-genotype.

Objective: To study the relationship between matrix metalloproteinase-2,9 (MMP-2,9) and the biology behavior, lymphatic metastasis of hypopharyngeal carcinoma by investigating the expression of MMP-2,9., Method: Two-step immunohistochemical method was used to examine the expression of monoclona antibody in hypopharyngeal carcinoma tissues., Result: It was found that the positive rate of MMP-2 in 32 hypopharyngeal carcinoma tissues was 53.12% (17/32),and the positive rate of MMP-9 was 59.38% (19/32). The difference of the expression in tumor tissue and normal mucosa beside the tumor was significant. The positive rate in those carcinoma with cervical lymph node metastasis was much higher than that in cases without cervical lymph node metastasis. And there was no significant difference found in the expression of MMP-2 and MMP-9., Conclusion: MMP-2 and MMP-9 may relate with the lymph node metastasis in hypopharyngeal carcinoma.

Background: It has previously been shown that the proliferative activity, determined by means of the monoclonal antibody Ki-S11 against the Ki-67 protein, is a significant prognostic factor for squamous cell carcinoma of the hypopharynx (SCCH). We now investigated the prognostic and the predictive impact of Ki-S1, a monoclonal antibody which detects an epitope of topoisomerase II alpha, another proliferation-associated antigen., Materials and Methods: The proliferation index (PI) in terms of Ki-S1 immunolabeling was evaluated on tumor specimens from 131 patients with SCCH. Survival probabilities over an observation time of 72 months were calculated by Kaplan-Meier analysis., Results: Patients with low PI (< or = 45%) had a significantly improved 5-year survival (33.2%) compared with patients with high PI (> 45%), of whom only 11% survived after 5 years (p = 0.001). Since there was no significant difference between the results obtained with Ki-S1 and Ki-S11, the present data confirm the prognostic significance of the proliferative activity in SCCH., Conclusion: Topoisomerase II alpha is also the target of many antineoplastic drugs and it has been proposed that its expression in tumor cells correlates with chemosensitivity. The high average topoisomerase II alpha content in SCCH therefore promises a good responsiveness to topoisomerase inhibitors. Because Ki-S1 directly measures cellular topoisomerase II alpha expression, it might be exploited not only as a prognostic indicator but also as a predictive marker for patients with SCCH.

Objective: To study the relationship between matrix metalloproteinase-2(MMP-2) and the biological behavior, metastasis and prognosis of hypopharyngeal carcinoma., Methods: Two-step immunohistochemical method was used to examine the expression of MMP-2 mAb in 32 specimens of hypopharyngeal carcinoma tissues and adjacent normal mucosa. Statistical comparison was performed after grouping., Results: It was found that the positivity rate for MMP-2 in the hypopharyngeal carcinoma tissues was 53.1%(17/32). Significant differences were noted when the expression levels of the mAb were compared between the normal mucosa adjacent to the carcinomas and the carcinomatous tissue, and between non-metastatic carcinomas and those with cervical lymph node metastasis. Patients with a positive result had obviously lower 3-year survival rate than those with negative results., Conclusion: MMP-2 may play a role in the lymph node metastasis of hypopharyngeal carcinoma, and is likely to be indicative of the patients' prognosis.

Objective: To investigate the expression of inducible nitric oxide synthase (iNOS) in oropharyngeal and hypopharyngeal squamous cell carcinoma (SCC) and its relation to p53 expression, histologic differentiation, clinical data, and prognosis., Study Design: A retrospective survey., Methods: Primary tumors for analyses were obtained from 118 patients diagnosed with SCC of the oropharynx or hypopharynx between 1975 and 1998 in eastern Finland. Immunohistochemical analysis was used to evaluate the expression of iNOS and p53. The expression pattern of iNOS was related to p53 expression, clinical data, and survival., Results: High iNOS score was associated significantly with high nuclear p53 expression index (P = .006) and positive cytoplasmic p53 expression (P = .025). The score for iNOS expression was significantly lower in the largest (T4) tumors (P = .043). No association was seen between iNOS score and N or M class, tumor stage, or histologic differentiation. The score for iNOS expression was not related to overall survival., Conclusions: The expressions of iNOS and p53 seem to be inter-related in pharyngeal SCC, although the causality remains to be clarified. The expression of iNOS shows no prognostic value in pharyngeal SCC.

We analyzed the relationship between clinical response to neo-adjuvant chemotherapy including 5-fluorouracil (5-FU) in patients with hypopharyngeal carcinoma (HPC) and thymidylate synthase (TS) expression in their tumors. TS expression was evaluated with immunohistochemical staining techniques on biopsy specimens from HPC patients. TS immunostaining was divided into four levels (TS0-TS3) according to its level and pattern. The relationship between prognosis, tumor size, nodal status, differentiation of tumor cells and TS expression were also investigated. There was a statistically significant association between the level of TS expression and tumor size (p < 0.01). In terms of the effectiveness of chemotherapy, tumor differentiation, nodal status and prognosis, a statistical difference was not found in TS expression. These results suggest that the level of TS expression may show the degree of tumor proliferation, but may not necessarily be useful to obtain a response to chemotherapy including other drugs, e.g., cisplatin and other derivatives of platinum.

Head and neck cancer arises and progresses through specific genetic alterations which lead to an invasive immortal phenotype. The process of immortalization is associated with the activation of the enzyme telomerase, a ribonucleoprotein with reverse transcriptase activity which is capable of synthesizing telomeric repeats at the end of chromosomes. This enzyme is expressed in nearly all neoplasms and germline cells and is absent in most normal human somatic cells. Because of this expression pattern testing for telomerase activity may deliver useful diagnostic and/or prognostic information about clinical tumour behaviour. Telomerase activity was therefore analysed in 16 primary lesions of head and neck squamous cell carcinomas (HNSCC) using the polymerase chain reaction-based telomeric repeat amplification protocol (TRAP). For a sensitive semiquantitative analysis of telomerase activity TRAP products were mixed with Pico Green I and the fluorescence emission intensities were measured. All 16 samples tested positive. When the Pico Green I data were compared with clinical parameters, it was obvious that N0 necks revealed significantly (p < 0.05) lower emission intensities (i.e. telomerase activity) than N + necks. Our results indicate that a high telomerase activity in HNSCC may facilitate lymph node metastasis and that the estimation of telomerase activity is a useful diagnostic tool which could influence treatment modalities.

Background: Serum liver function tests (LFTs) are used in the initial evaluation of patients with head and neck squamous cell carcinoma (SCC) to evaluate hepatic function and to screen for liver metastases., Methods: One hundred forty patients initially seen with SCC between 1988 and 1991 were followed for a minimum of 2 years to determine the significance of abnormal LFTs at presentation., Results: Abnormal values were found in 69 patients (49%), including elevated alkaline phosphatase in 37 (26%) and lactic dehydrogenase in 25 (18%). Abnormal values were most commonly attributed to alcohol-related liver disease. No liver metastases were identified at initial screening. LFTs were normal at presentation in all three patients subsequently identified with liver metastases during follow-up., Conclusions: Abnormal LFTs are commonly encountered but are of little value in identifying patients with liver metastases during initial assessment. Modest elevation of LFTs should not necessitate costly and time-consuming investigation to exclude hepatic metastasis.

The gene expression of two type IV collagenases (matrix metalloproteinase [MMP]-2, a 72 kd type IV collagenase, and MMP-9, a 92 kd type IV collagenase) was investigated in carcinomas of the hypopharynx. We examined 27 cases operated on in our hospital by an in situ hybridization technique to detect their messenger RNA signals in cancer cells and surrounding stroma. Both signals were detected in all cancer nests and in stromal cells in the same specimens. Clinicopathologic studies showed a significant relationship between MMP-2 expression in the primary cancer and the outcome of treatment. Our present study suggests that hypopharyngeal squamous cell carcinoma producing MMP-2 has a high potential for invasion and metastasis and a poor outcome. The analysis of MMPs will be useful for treatment planning in hypopharyngeal carcinoma and for prognosis.

Protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTPase) activity in tumor tissue, obtained from 107 patients with squamous cell carcinoma of the upper aerodigestive tract, was determined. In 79 patients samples were also taken from a histologically proven non-tumourous part of the mucosa. In this extensive study we confirmed our previous findings of increased enzyme activities (cytosol PTK, membranes PTK, cytosol PTPase) in non-tumour tissues compared with control tissues. These biochemical changes suggesting a premalignant mucosa could not be correlated to a higher probability of secondary tumours.

Identification of prognostic factors in squamous cell head and neck cancers involves analysis of highly diverse clinical and biological parameters. This study analyzed the prognostic value of clinical variables (age, sex, tumor site, stage) and biologic parameters (squamous cell carcinoma antigen [SCC], serum thymidine kinase activity [TK], fibrin, sedimentation rate [SR]) at the time of diagnosis of squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx) in 189 patients. Among the clinical variables investigated, UICC stage III-IV disease (p < .0002), a hypopharyngeal site (p < .02), and age over 60 years (p < .01) were all associated with a poor prognosis. Similarly, analysis of biological blood variables allowed definition of cut-off values above which the prognosis was poor: SCC 2.5 ng/mL (p < .01), fibrin 3.5 g/L (p < .01), TK 7 IU/L (p < .0005), and SR 15 mm per first hour (p < .0000). Cox regression analysis of overall survival identified the UICC stage (p < .000), the SR (p < .001), and serum TK (p < .02) as the main independent prognostic factors. A separate study on a small number of head and neck cancer patients revealed higher TK levels in malignant squamous cell carcinoma tissue than in adjacent healthy tissue.