Interleukin-2 and head and neck squamous cell carcinoma: clinical and pathological studies.
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Biomedical subjects
Publications and source records attributed to G Cortesina.
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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.
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Clinical, immunological, immunophenotypical, pathological and molecular biological studies were performed on tumor infiltrating lymphocytes (TIL) and lymph node lymphocytes (LN-ly) of 8 patients with squamous cell carcinoma of the oral cavity and oropharynx treated with 10 daily locoregional injections of low doses of IL-2 before surgery. No complications were seen during or after surgery. In 3 cases the LN-ly showed a moderate LAK activity, higher in the LN-ly omolateral to the tumor and near the IL-2 injection site; in 2 of these 3 patients a good LAK activity was induced after 6-day culture with IL-2. The LN-ly derived from nodes next to the tumor showed a decreased NK activity and proliferative ability both in basal conditions and after in vitro lymphokine challenging. LN-ly of 2 IL-2 treated patients showed high levels of mRNA encoding for IL-2-R, while it was absent in 2 untreated cases. Immunophenotypical studies on TIL showed statistically improved levels of CD25+ and LAK1+ cells in treated cases. Clusters of CD11c+ (macrophages) cells were seen close to the neoplastic sheets.
Nasal and paranasal sinus tumors extending through the cribriform plate to the overlying dura of the frontal lobe can be successfully treated by anterior craniofacial resection. During the period from 1986 to 1990, 14 patients (11 males, 3 females, age 18-67) with nasal/paranasal tumors extended to the nasal basis underwent craniofacial resection. From a histological point of view these patients were classified as follows: --8 adenocarcinomas --2 squamous cell carcinomas --2 esthesioneuroblastomas --1 cylindroma --1 haemangiopericytoma. In 6 of the 14 patients post-operative complications were encountered, 3 being resolved. Radical surgery was realised in 12 cases; post-operative radiotherapy was performed in 7. No contraindications were found because of previous chemo- and/or radiotherapy, even if it had been performed as treatment. Four of the patients died because of recurrences between the 6th and 20th month after surgery; 5 patients (all adenocarcinoma subjects) are disease-free respectively 8, 16, 17, 22 and 24 months after surgery.
Recurrence is a tumor renewal in a previously treated field or surgical wound after a disease-free period. The present work investigates loco-regional recurrences. In the first part of the work the most frequent recurrence sites, types and their characteristics (i.e. infiltrating, exophytic, ulcerating) are studied along with the problems in clinical and pathological diagnosis, new diagnostic imaging (CT and MR) and the UICC classification system. The second part of the work is dedicated to examining classical treatments (surgery, radiotherapy, chemotherapy and radiochemotherapy associations) as well new therapies (i.e. cryosurgery, hyperthermia, immunotherapy, photodynamic therapy). A review of the literature is made for indications, results and complications. An extensive study of the cases of the Head and Neck Group of the University of Turin during the 1983-1990 period is also reported. This experience is based on 312 cases: 68 (oropharynx and larynx) treated by surgery, 51 (neck nodes and stomal recurrences) treated by radiotherapy and hyperthermia, 35 (neck nodes) by hyperthermia alone, 168 (all sites) by chemotherapy and 20 by immunotherapy. In the third part of this work supportive therapies and practical problems are reported. In conclusion a therapeutic approach is proposed in relation to the site of the recurrence and previous treatments.
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The present study was undertaken to determinate whether immunosuppression, induced by perioperative allogenic whole-blood transfusions (AWBTs), adversely affects prognosis after total resection of laryngeal cancer by promoting the appearance of recurrences. We studied 62 patients, aged 37-82 years with TNM stage III and IV (UICC, 1987) laryngeal cancer treated between 1977 and 1983. AWBTs were administered to 30/62 patients perioperatively. All patients were followed up for 4 years. After 4 years we found the following disease-free survival indexes: transfused, 12/30 (40%); nontransfused, 22/32 (70%; p less than 0.05). On the base of these dates, we conclude that AWBTs exert a significant influence on early recurrence and on survival in patients with laryngeal cancer.
Various strategies for local immunotherapy performed by using lymphokines and lymphocytes are presented. In experimental mice models, the antitumor reaction elicited through the injection of little amounts of IL-2 and gamma-IFN at the tumor growth site is significantly enhanced by the concurrence of lymphocytes from tumor bearing mice artificially admixed to challenging tumor cells. These lymphocytes act as initiator or helper cells that elicit both a local and a systemic long lasting immune reaction by the release of additional lymphokines. The reaction activated mostly involves draining lymph nodes, where multiple reaction mechanisms are induced. The local injection of cocktails of molecularly defined lymphokines can also mimic the helper action of lymphocytes and trigger a similarly effective anti-tumor reaction. A set of pilot clinical trials with IL-2 or gamma-IFN injected perilymphatically were initiated in patients with advanced primary or recurrent localized tumors of the head and neck and the bladder. This treatment appears to elicit a local reaction by activating a few pathways of patients immunoreactivity, whose efficiency may well be high, as shown by the tumor inhibition often observed.
The possibility of applying immunological methods to head and neck tumors prevention is discussed. The biological significance of tests evaluating the natural killer activity is reviewed. The IgA serum level in patients at risk for head and neck malignancy is proposed as a screening test.
Nine patients with squamous cell carcinoma of the oral cavity and oropharynx underwent preoperative perilymphatic administration of recombinant interleukin 2 (rIL-2). A more marked eosinophil and lymphocyte infiltration and more extensive edema than in 13 untreated cases were observed in surgical specimens. Necrosis was present in five of nine cases, but involved no more than 10% of the neoplastic tissue; in three of nine cases, characteristic necrotic changes with intense eosinophil infiltration possibly induced by lymphokines involved the peritumoral soft tissues. Of the tumor-infiltrating lymphocytes, T-lymphocytes (mostly CD4+ cells) prevailed over B-lymphocytes. CD4+ and CD8+ cells were mainly located close to the neoplastic sheets. Moderate amounts of CD38+ and CD11c+ cells (macrophages) and few CD16+ and CD56+ lymphocytes were found in all cases. CD25+ and LAK1+ cells were significantly more numerous in treated than in untreated cases. This suggests that local administration of rIL-2 induces an increase in activated T-lymphocyte subsets infiltrating the neoplastic tissue, thus eliciting a tumor-specific T-lymphocyte reactivity.
Three hundred and thirty-four cases of salivary gland neoplasms are reported which were diagnosed by the Departments of Dentistry and Otolaryngology of the University of Turin. Data referring to patients under observation during the same period are compared. It is stressed that in order to obtain a statistically valid comparison of salivary gland neoplasms, the source of and chronological period relating to the sample group must be taken into consideration given the different statistical clinical methods adopted over the years by the two departments in question. The present study completes earlier research carried out by the same authors using this data.
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.
For 10 days, four patients with advanced squamous cell carcinoma of the head and neck received two daily injections of 100 units of natural IL-2, one around the tumor, the second near the tumor-draining lymph nodes. No side effects were observed. Histologic and ultrastructural examination of tumor and lymph nodes recovered at surgery showed that in many instances neoplastic cells were intermingled with numerous lymphocytes and eosinophils. Lymph nodes displayed hyperplasia of both cortical and paracortical areas and epithelioid venules infiltrated by lymphocytes and granulocytes. In a few cases, a decrease or disappearance of neoplastic lesions was also documented both clinically and histologically.
Three-hundred-ninety-two cases of salivary gland cancer observed at Turin University Dental and Ear, Nose and Throat Clinics have been examined. Statistical analysis of the age and sex of patients shows the importance of selecting the statistical population and of its origin for the purpose of reliable statistical study, examining the whole set and its structural breakdown in the two Clinics.
Ten patients with recurrent squamous cell carcinoma of the head and neck received daily injections of interleukin-2 (IL-2) from the Jurkat T-cell line purified by high pressure liquid chromatography for 10 days. Two hundred units of IL-2 in 0.5 ml were injected 1.5 cm from the insertion of the sternocleidomastoid muscle on the mastoid. When possible, courses were repeated at 45-day intervals. IL-2 was ineffective in two patients who had already undergone functional or radical neck dissection. By contrast, in six patients with contralateral or bilateral cervical lymph nodes, complete or partial disappearance of the tumor was observed. The injections were occasionally followed by moderate local swelling and lymph node pain, but no systemic disturbances.
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