Effects of docetaxel plus three-dimensional conformal radiation therapy on microvessel density and apoptosis expression in local advanced squamous non-small-cell lung cancer.

We examined the effects of weekly single-agent docetaxel plus three-dimensional conformal radiation therapy (3D-CRT) on apoptotic index (AI) and microvessel density (MVD) in local advanced non-small-cell lung squamous cancer patients and analyzed the correlation of MVD, AI, and 50% tumor shrinkage time (T0.5) The molecular mechanism of docetaxel radiosensitization was investigated. Sixty untreated patients with stage IIIA or IIIB lung squamous cancer were enrolled and randomly divided into two groups: observation (N = 30; 3D-CRT + docetaxel + adjuvant chemotherapy) and control (N = 30; 3D-CRT + adjuvant chemotherapy). From day 1 radiotherapy, the observation group received intravenous docetaxel (36 mg/m(2)) once weekly for 6 weeks. Post-radiotherapy, chemotherapy of docetaxel combined with cisplatin lasted 4-6 cycles in both groups. Before radiotherapy and within 24 h after radiotherapy (20 Gy), bronchoscopic biopsy was performed twice at the same site. To analyze the MVD of tumor specimens with immunohistochemical staining . The AI of lung cancer cells was assessed with TUNEL assay, T0.5 values were calculated. The observation group had significantly lower MVD than the control group (P < 0.05). AI significantly increased before and after treatment in the observation group compared with the control group (P < 0.05). The decreased MVD values negatively correlated with T0.5 values (r = -0.624, P < 0.05), whereas the increased AI values did not correlate with the T0.5 values. Docetaxel radiosensitization may occur by decrease in MVD and increase in AI values. Weekly single-agent docetaxel plus 3D-CRT can improve prognosis and quality of life in local advanced non-small-cell lung squamous cancer patients.

Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy.

Cutaneous squamous cell carcinoma (SCC) ranks second in the frequency of all skin tumors. Its incidence has risen significantly due to an increased sun exposure and the number of immunocompromised patients. It has a well-defined progression with known precursor lesions called actinic keratosis. The degree of cellular differentiation, tumor thickness, location, and other features has prognostic value. It has a better prognosis than mucosal SCC of the head and neck, also called head and neck squamous cell carcinoma (HNSCC). Ultraviolet light plays a fundamental role as an initiator and promoter of carcinogenesis of SCC, allowing the accumulation of genetic alterations that allows a selective growth advantage. The TP53 (p53) gene often mutates and Ras is frequently activated, but with low frequency of mutations. Normally, the extracellular signals determine whether the cells move from a quiescent state into an active proliferative state. In tumor cells an increase in the production of growth factors and its receptors can be often seen that gives rise to such an autocrine circuit facilitating cellular division. Recently, frequent mutations in the epidermal growth factor receptor (EGFR) have been detected in lung cancer, mainly deletions in exon 19 and L858R mutation in exon 21. These are located at the EGFR tyrosine kinase domain (TK). EGFR TK mutations produce activation of the signaling pathways downstream and preferentially activated antiapoptotic pathways (PI3K/AKT, JAK-STAT and ERK/MAPK). These mutations are correlated with the clinical response of patients to tyrosine kinase inhibitors (gefinitib and erlotinib), because the tumor cells are addicted to the constant activation of specific signaling pathways. Glioblastoma shows another EGFR mutation (EGFRvIII), corresponding to a deletion of the extracellular domain, and it is present in 24-67% of these tumors. This variant has been found in 42% of HNSCC, related to the poor response to monoclonal antibody cetuximab. Many observations show that there are abnormalities in the expression of epidermal growth factor receptor (EGFR) and/or its ligands in HNSCC with frequent activation of multiple pathways downstream EGFR, and unrelated to RAS mutation. This suggests the possibility of activation by mutation or overexpression of a component of the pathway located upstream-Ras. While in other tumors, especially lung cancer and glioblastoma, the EGFR mutations are frequent genetic events, it is unknown whether EGFR is mutated or amplified in SCC of the skin and what would be its pathogenic role in this malignancy and its precursors.

Bcl-2 targeted-therapy for the treatment of head and neck squamous cell carcinoma.

Despite recent advances in treatment of head and neck cancer, survival has not improved as expected. Bcl-2 family proteins play important role in regulating apoptosis. Recently, newer molecules have been developed for inhibition of Bcl-2 related proteins. We, herein aim to discuss the importance of Bcl-2 family proteins to the development of head and neck cancer and how the targeted-therapy for inhibition of Bcl-2 and related proteins, based on new drugs and recent patents, could improve the efficacy of the systemic therapy.

Lymph node histology in head and neck cancer: impact of immunotherapy with IRX-2.

OBJECTIVE: To determine if lymph nodes (LN) of patients receiving IRX-2 immunotherapy reflect changes in histology. SETTING: National Cancer Institute, Mexico City, Mexico. PATIENTS: Thirty patients with advanced squamous cell carcinoma of the head and neck (H and N SCC) and 10 non-cancer controls. INTERVENTION: A 21-day cycle of preoperative immunotherapy, including a single intravenous infusion of low-dose cyclophosphamide (300 mg/M(2)), 10 or 20 daily perilymphatic injections of a natural cytokine mixture (IRX-2) (approximately 200 U interleukin-2 equivalence by enzyme-linked immunosorbent assay), daily oral indomethacin, and daily oral zinc with multivitamins, followed by surgery (20 patients); surgery only (10 patients); LN biopsy controls (10). OUTCOME MEASURES: Pretreatment biopsies were performed to confirm the diagnosis. Clinical responses were assessed at surgery, and the specimen and a sample of lymph node were analyzed with respect to changes in morphology and lymphoid and inflammatory infiltration (T and B lymphocytes, plasma cells, macrophages, granulocytes, and giant cells). The postsurgical characteristics were ascribed percentages based on a representative section and compared. RESULTS: All 20 H and N SCC patients treated with IRX-2 showed the changes of immune regression of their tumors, previously characterized [Arch. Pathol. Lab. Med. 122 (1998) 447]. The 10 H and N SCC controls showed no such changes. Lymph node histology of the 10 H and N SCC controls showed, compared to non-cancer controls, reduced size, decreased T cell area and density and increased sinus histiocytosis. The lymph nodes of IRX-2-treated H and N SCC patients showed increased size (over both control groups), increased T cell area and density and decreased follicles and sinus histiocytosis. The T cell and/or B cell areas of LN of IRX-2-treated patients showed a high correlation with T and/or B cell infiltration into these tumors (p<0.001). CONCLUSION: The lymph nodes of patients with H and N SCC are distinguished by T cell depletion and sinus histiocytosis (SH). Immunotherapy reverses these changes and induces nodal expansion and lymphoid infiltration into the tumor that correlates with LN changes. The correlation of nodal expansion with tumor lymphoid infiltration and regression implies an effective immunization to host tumor antigens occurring at the level of the regional lymph node. The reversal of sinus histiocytosis, by IRX-2 treatment, in association with nodal expansion suggests that tumor antigen processing via dendritic cells is defective in cancer-bearing patients and that it is corrected by the treatment.