Induction chemotherapy followed by concurrent chemoradiotherapy in advanced head and neck squamous cell carcinoma.

BACKGROUND: A phase II study was carried out to investigate an induction regimen with cisplatin, paclitaxel followed by radiotherapy concurrent with weekly cisplatin for locally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Stage III-IV disease patients were eligible. Two cisplatin (100 mg/m2) and paclitaxel (175 mg/m2) courses were administered every 21 days followed by standard fractionated external beam radiotherapy (approximately 70 Gy), concomitant to weekly cisplatin (30 mg/m2). RESULTS: Thirty-five patients were enrolled: over 70% had unresectable disease with bulky lesions. Grade 3-4 neutropenia developed in 14% and G3 mucositis in 23%. Locoregional control was achieved in 51%. Median time to progression and overall survival were 10,7 and 17 months respectively; 2- and 3-year survival rates were 30% and 25% respectively. CONCLUSION: Our induction two-drug regimen followed by chemoradiotherapy with concurrent weekly cisplatin was well tolerated with low acute toxicity and good locoregional control and survival rate.

Molecular metastases markers in head and neck squamous cell carcinoma: review of the literature.

It is now widely accepted that the presence of lymph node metastases is a negative prognostic factor in head and neck squamous cell carcinoma. It follows that the ability to determine the presence of micro-metastases or the metastatic potential of a tumour at an early stage would condition the therapeutic strategy and evolution of this type of tumour. Prediction of the metastatic potential of head and neck squamous cell carcinoma is still, today, entrusted to clinical and histological evaluation of the tumour. However, the high percentage of relapse in this tumour shows the inadequacy of these parameters in predicting metastatic potential. Furthermore, progress made over the last ten years in understanding the molecular mechanisms involved in the process of neoplastic tumour progression has led to the identification of molecules that can be used as potential prognostic markers of head and neck squamous cell carcinoma. There are many molecules involved in the process of forming metastases. This process represents the final stage of a multistep model, in which alterations occur to genes that are important for growth, proliferation and migration, to which are added variations in the expression of molecules involved in the process of homeostasis of the extra-cellular matrix, of angiogenesis and lymphangiogenesis, favouring tumour invasion and the formation of metastases. This review of the literature shows that the tumour invasion process is associated with numerous molecular alterations that might be used as potential prognostic molecular markers. However, none of these alterations is univocally associated with the metastasization used in clinical practice. Further studies on larger series and on a larger scale, such as genome studies, and preclinical studies on markers used as targets in specific therapies, will provide a valuable contribution to their use in clinical practice in the short term.

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.

A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identified two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.

Current role of chemotherapy in exclusive and integrated treatment of malignant tumours of salivary glands.

In the management of salivary glands carcinomas, surgery is the treatment of choice. Post-operative radiotherapy is indicated in cases with high risk of loco-regional relapse. Radiotherapy is also standard treatment in cases that are inoperable at onset. Chemotherapy plays a palliative role. Today, the integration between radiotherapy and chemotherapy, which provides increased local control, represents a significant step forward. This integration is important since 5-year survival in tumours with high grade histology is approximately 50%. Overall incidence of metastases is approximately 25%. Primary locations of metastases are lungs, liver, bone, central nervous system and other organs. In cases of metastatic disease, chemotherapy plays only a palliative role.

Differential integrin expression in thyroid and laryngeal carcinomas.

Several laryngeal and thyroid carcinomas were studied immunohistochemically to evaluate whether the expression and distribution of integrins and basal lamina components can represent reproducible markers for correct early diagnosis and prognosis. In laryngeal cancers, the depolarization and pericellular redistribution of alpha 3 beta 1 and alpha 6 beta 4, and focal or massive fragmentation of the basal lamina, according to tumor prognosis, occurred. In thyroid carcinomas, loss of polar topography of alpha 3 beta 1 and neo-expression of alpha 6 beta 4 in histopathologically or clinically aggressive cancers were observed. Therefore, the addition of a panel of adhesion molecules to the toolbox of surgical pathologists may improve diagnostic and prognostic procedures.

Relationships between cervical node histological patterns and rosette test scores: possible prognostic value in laryngeal cancer.

In previous research the authors have remarked that some hystological patterns--macrophagic hyperplasia and thymus-dependent areas hyperplasia--when prevailing in cervical nodes of laryngeal cancer patients, possess a positive prognostic value. In this study the possible relationship between the results of E and EAC-rosettes and prevailing hystologic patterns in cervical nodes is investigated. A positive correlation was not found. Conclusively, the inconsistency of aspecific tests for prognostic purposes and the need for a specific immunological monitoring system are outlined.

Specific lymphokine responses in cervical nodes of patients with laryngeal cancer.

The role of lymphokines in modulating the immune response in patients suffering from neoplastic disease is still controversial. Recent studies indicate that in patients with head and neck cancer, a decrease in LIF (leukocyte migration inhibiting factor) production is usually present in advanced disease. In this study, the authors investigate: the LIF production in lymphocytes derived from the peripheral blood and cervical nodes of patients with laryngeal carcinoma by using an autologous pattern (i.e., for each patient, the specific LIF production was challenged by means of an autologous cell extract derived from his own tumor); the influence of histologically confirmed cervical node metastases on LIF production. Our results indicate that: There is a significant decrease in LIF production in patients with histologically proven cervical node metastases as compared to patients with no metastatic foci. The decrease of LIF production is related to the presence of mononuclear adherent cells. When the latter are removed, there is a significant reversal of specific LIF suppression. The possible meaning of the data is discussed.

Evaluation of blocking mechanisms against immunological responses in patients with laryngeal carcinoma.

The specific tumor-induced leukocyte inhibition factor (LIF) production in laryngeal cancer patients has been investigated before and after the removal of adherent cells in order to evaluate the existence of a suppressor activity; 20 patients served as subject. The LIF production, after challenging the lymphocytes with 3MKC1 autologous tumor extracts, was significant in 12 patients and showed a further significant increase after the removal of adherent cells. In 3 patients with no previous significant LIF production, there was a conversion to significance when the adherent cells were removed. The other patients did not show any significant variation. These data seem to suggest the existence of a suppressor activity exerted by adherent cells in laryngeal cancer patients on LIF production.

Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records.

Pharyngocutaneous fistula is the most common complication of total laryngectomy. The management of this problem increases hospitalization time and delays initiation of postoperative radiotherapy, where indicated. To identify factors predisposing to the development of pharyngocutaneous fistula, we reviewed the postoperative courses of 293 patients who underwent total laryngectomy at our clinic. General factors taken into account were concurrent diseases such as diabetes, liver diseases, or chronic anemia; local factors included radiotherapy before and after surgery, preoperative tracheostomy, type of cervical lymph node removal, and method of pharyngeal closure. We then compared our data with those reported in the literature by other authors. Last, we applied the Fisher exact test to a correlation we found between the higher incidence of fistula in patients with diabetes, liver diseases, or anemia. The local factor that turned out to be statistically most significant for the development of fistula was preoperative radiotherapy.

Adjuvant radiotherapy influences the survival of patients with squamous carcinoma of the head and neck who have poor prognoses.

The treatment of carcinoma of the head and neck in recent years has improved significantly, chiefly thanks to progress in surgery and radiotherapy. Despite these advances, the survival statistics reported in the literature show no appreciable evidence of radical improvement. The aims of this study were to evaluate the impact on survival achieved with the combination of surgical and postoperative radiotherapy in patients with advanced head and neck carcinomas and to identify the prognostic value of several host- and tumor-related factors that can influence the results of combined treatment. We retrospectively reviewed the medical records of 394 patients with stage III and IV carcinoma of the head and neck, of whom 170 (43%) underwent surgery alone and 224 (57%) received combined surgery and postoperative radiotherapy. The 394 patients were stratified for a set of variables including the patient's condition, the characteristics of the tumor, and the modality of treatment. Univariate analysis revealed that coexistent medical diseases, the size and site of the primary lesion, the stage of the tumor, and certain pathologic features had a negative impact on survival. Multivariate analysis showed that the removal of lymph nodes and postoperative radiotherapy can have a positive influence and can improve the prognosis. We compared the survival rates of the patients treated with surgery alone with those of the patients who underwent combined treatment, and we observed that the two survival curves were comparable, even if there was a bias because the combined treatment group consisted of patients with negative prognostic factors. The meaning of these results, compared with data from the literature, has been discussed.

Nasal secretory IgA circadian rhythm: a single-dose suppression test.

The existence of a clear circadian rhythm in the local secretion of nasal IgA is well-known phenomenon which is confirmed in the present research. Since the temporal pattern of secretory IgA (SIgA) strictly parallels the ACTH-cortisol cycle, a dependence was hypothesized in previous research, but the suppression of adrenal rhythm by means of massive doses of exogenous corticosteroids showed no influence on the SIgA cycle. In the present research a more sophisticated method of corticoid-incretion suppression was used; the single-dose suppression test with dexamethasone, which influences only the impulsive phase of the rhythm. In this case too, however, no influence was demonstrated on nasal SIgA secretion.

Natural killer-mediated cytotoxicity in patients with laryngeal carcinoma.

Natural killer (NK)-mediated cytotoxicity against the K562 cell line was evaluated in normal subjects and in patients with laryngeal cancer. Results showed reduced lymphocyte cytotoxicity in patients with neoplastic disease and further reduction in NK activity following postoperative radiation therapy. The authors discuss the possibility of using this test in the immunological monitoring of patients with laryngeal carcinoma.

Prognostic factors of cervical lymph node metastasis in head and neck squamous cell carcinoma.

AIMS AND BACKGROUND: The metastatic spread of squamous cell carcinoma of the head and neck (SCCHN) to the cervical lymph nodes is a negative prognostic factor in terms of survival. We have used multivariate analysis to identify the possible prognostic significance of a number of clinical and pathological characteristics in relation to possible involvement of the cervical lymph nodes in a series of 396 patients. METHOD: 396 patients with SCCHN were studied. Variables regarding the patient, the carcinoma and histology were analysed by multivariate analysis using BMDP's PLR programme. RESULTS: Some variables appear to represent predisposing factors for tumor spread to the lymph nodes: tumor site (supraglottic larynx: P = 0.005; base of the tongue: P = 0.02; hypopharynx: P = 0.02), grading (P = 0.001), and a number of histological parameters (lower degree of histological differentiation: P = 0.001; vascular permeation: P = 0.04; perineural invasion: P < 0.05; prevalently plasmocytic infiltrate: P < 0.05). CONCLUSION: The identification of cases at risk for metastasis can be improved by the assessment of prognostic factors, with a consequent improvement in treatment strategies.

Prognostic significance of the expression of immunohistochemically detectable differentiation markers in laryngeal carcinomas.

Expression of immunocytochemically detectable markers in 100 cases of laryngeal carcinomas, homogeneous for staging and treatment, was correlated with clinical evolution of the disease. Follow-up for a minimum of 5 years was obtained in all cases. Paraffin sections were re-cut and stained in immunoperoxidase with monoclonal KL1, detecting medium-to-low molecular weight keratins, and with monoclonal HMFG2, revealing a surface glycoprotein. Expression of KL1-related antigen did not correlate with prognosis, whereas cases extensively positive for monoclonal HMFG2 (more than 50% cells stained) had a significantly better recurrence-free rate. In a group of tumors classified as Grade 3 (histologically poorly differentiated) and expressing a low degree of HMFG2-detectable surface glycoprotein (less than 50% cells stained), a high rate of recurrences (93%) was observed. This study indicates that the combined use of morphologic and biologic (immunohistochemical) criteria may constitute an independent parameter of primary importance in predicting the evolution of laryngeal carcinomas.

Specific LIF production in laryngeal cancer patients: evidence of suppressor activity exerted by adherent cells.

The specific tumor-induced LIF production in 30 laryngeal cancer patients has been investigated before and after the removal of adherent cells to evaluate the existence of a suppressor activity. LIF production, after challenging lymphocytes with 3 M KCI autologous tumor extracts, was significant in 16 patients and showed a further significant increase after removal of adherent cells. A conversion to significance when the adherent cells were removed was shown in 6 patients, with no previous significant LIF production. These data suggest the existence of a suppressor activity exerted by adherent cells on LIF production in laryngeal cancer patients.

Surgery or radiotherapy for early stages carcinomas of the glottic larynx.

AIMS AND BACKGROUND: The choice of treatment in limited squamous cell carcinoma of the glottic larynx often depends on individual and tumor factors. Data of the literature clearly show that surgery and radiotherapy tend to give identical results in terms of survival. We examined 196 cases of T1-T2/N0 cancers of the glottic larynx. We review the literature and discuss the indications and the efficacy of the various available treatments. METHODS AND STUDY DESIGN: 196 consecutive cases of T1-T2/N0 cancers of the glottic larynx were examined. In 54.5% the tumor was confined to the vocal cord; in 38.2% it extended to the anterior commissure, in 4.6% to the arytenoid cartilage and in 2.5% to the floor of the ventricle. We performed partial laryngeal surgery in 41.3% (81 cases). Radiotherapy alone was employed in 58.6% (115 cases). RESULTS: In T1a and T1b cases there was no statistically significant difference in 5-year disease-free survival. In T2 cases the NED survival of patients who underwent partial laryngectomies (90% of cases) was significantly better (P <0.05) than among patients given radiotherapy (73%). NED survival at 5 years in patients with the primary tumor on a vocal cord, ventricle or anterior commissure was 78%, 80% and 81%, respectively, with no statistically significant difference among the various sites. It is possible that involvement of the anterior commissure exposes patients to greater risk of recurrence when radiotherapy alone is used (5 out of 23 cases, 21.7%, compared to 3 out of 52 cases, 5.7%, among our surgically treated patients). CONCLUSIONS: When the tumor is confined to the vocal cord and mobility is not impaired (T1a), surgery and radiotherapy give comparable results, and the latter yields a better functional outcome. When the anterior commissure is involved, recurrences appear to be less likely after surgery. In T2 glottic carcinoma, surgery gives better results than radiotherapy alone. In any event, the choice of treatment should be patient-specific and based on a careful analysis of the factors involved in each case.

Production of leukocyte migration inhibition factor by lymphocytes of larynx cancer patients stimulated by laryngeal carcinoma solubilized membrane antigens.

The production of leukocyte migration inhibition factor (LIF) from lymphocytes after stimulation with 3 M KCl soluble tumor and normal mucosa extracts was investigated in 30 patients with laryngeal carcinoma at different development stages and in 30 normal donors. The experiments were performed in heterologous and autologous systems. In heterologous systems 3 M KCl tumor extracts induced LIF production by heterologous lymphocytes from patients in 91% of the cases, and normal mucosa extracts induced LIF production by heterologous lymphocytes from patients in 73% of the cases and from normal donors in 90% of the cases. In autologous systems 3 M KCl tumor extracts induced LIF production by autologous lymphocytes from the same patients in 65% of the cases, whereas the normal laryngeal mucosa extracts induced LIF production by the same autologous lymphocytes in the 6% of the cases. The high positivity percentage of the test in heterologous systems could be related to differences in the major histocompatibility complex. The 65% test positivity in autologous systems using tumor extracts could be related to the presence of tumor associated antigens.

Prospects and limitations of systematic monitoring in patients with laryngeal cancer.

The authors report the first results concerning the systematic use of "immunological monitoring" in patients suffering from well-developed laryngeal cancer. The authors have also studied, in 50 cases in different stages of development, the activity of T-cells using the cutaneous tests (BCG, PPD, PHA and SK-SD), the E-rosette test and the PHA-induced lymphocytic blastization test (it is well known that the T-cells are responsible for a cytotoxic effect against neoplastic cells). The authors have also studied the activity of B-lymphocytes by means of the EA and EAC rosette test and of IgG, IgA, IgM and complement serum titles. They have observed a progressive depression of the T-cell activity after surgical intervention, whereas the B-cell activity in several cases tends to increase. The authors discuss these immunological results and the possibility that these findings may represent the basis for a complementary immunotherapy following the surgical treatment and/or radiotherapy or chemotherapy. Finally, the authors discuss the possibilities and the limitations of these immunological methods from the point of view of clinical application.

Interleukin 2 receptors on squamous cell carcinomas of the head and neck. Characterization and functional role.

IL2Rs, in the presence of IL2, mediate activation and proliferation of human normal lymphocytes and modulate functional changes of some human leukocytic malignancies. IL2Rs have been demonstrated also on human neoplastic and fetal non-hematologic cells in vitro, although their functional role has not been described. We describe the presence of high affinity IL2Rs on squamous cell carcinoma of the head and neck (SCCHN) lines in vitro. Expression of 200 binding sites for IL2 with an affinity of 17 x 10(-12) was demonstrated by radiobinding experiments. When cytocentrifuged SCCHN cells were studied by immunoperoxidase staining, strong positive staining was repeatedly obtained using a monoclonal antibody to the p70 subunit of the IL2Rs. Experiments in vitro and in vivo, in a nude mouse model, showed a functional role for these receptors. In fact, low doses (8-500 U/ml) of IL2 were able to inhibit growth of 11 of the 16 SCCHN lines tested. Our observations may have broad implications for the immunotherapy of cancer in general, showing the complementary immunomodulatory and direct effects of IL2.

Study of ethmoidal mucosa in a population at occupational high risk of sinonasal adenocarcinoma.

The occurrence of nasal adenocarcinomas was first described in 1965. Since 1988 these tumors have been accepted as an occupational disease for woodworkers in Italy. There are several underlying reasons why there is interest in studying the ways in which sinonasal adenocarcinomas occur. Often diagnosed at advanced stages of development because their symptoms are non-specific, these tumors are associated with a high mortality rate. A multidisciplinary study protocol was developed in this investigation. The aim was to identify the factors and conditions that promote sinonasal tumor growth in a population at risk due to occupational exposure to wood dust. Sixty-eight carpenters with a minimum of 10 years exposure to wood dust were studied. The control group comprised 81 volunteers. The patients underwent the following protocol: completion of a case report form, physical examination, evaluation of nasal cavity patency, clinical laboratory tests and histological study of the nasal mucosa. Our study provides significant evidence of the elevated incidence of pavimentous metaplasia in workers occupationally exposed to wood dust. In addition, it underscores a significant deficit of immunoglobulin A in such workers compared to the controls. However, we did not find, as reported elsewhere in the literature, a statistically significant difference between cases and controls as regards nasal symptoms and hyperemia of the nasal mucosa. Our study showed that, even in the absence of evident sinonasal lesions, it is still possible to determine an increased incidence of morphofunctional changes in subjects occupationally exposed to wood dust. Our findings may lead to the identification of occupational groups prone to elevated risk of the disease.