Interleukin 2 Receptors on Squamous Cell Carcinomas of the Head and Neck

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 17×10^?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.     

Elevated Arginine Vasopressin Levels in Squamous Cell Cancer of the Head and Neck

The reported effectiveness of single tumor markers (TMs) associated with squamous cell cancer of the head and neck ranges from 15% to 71%, with most studies reporting sensitivity no higher than 50%. An increased incidence of the syndrome of inappropriate secretion of antidiuretic hormone or arginine vasopressin (SIADH) in patients with head and neck cancer has been reported. Serum arginine vasopressin (AVP) was studied as a possible TM in these patients. Sixty-three patients with squamous cell carcinoma of the head and neck determined as potentially curable were prospectively evaluated before treatment and compared to 17 patients with apparent cure of head and neck squamous cell cancer who served as controls. Serum AVP levels were obtained and determined by radioimmunoassay in the preoperative period and 1 week postoperatively in 15 patients. Thirty-four patients were staged as T4, 26 as T3, and 3 as T2. Twenty-one (33%) of the 63 patients had no neck involvement. Twenty-four (38%) of 63 patients had elevated serum AVP levels corrected for serum osmolarity. Of the 15 patients evaluated before and after surgery, 8(53%) had elevated serum AVP levels preoperatively. Of these 8 patients, 3 had reduction in AVP levels and 5 had complete normalization after 1 week. The results obtained for serum AVP do not exceed results of other TMs reported. AVP may also not be as specific as other TMs for cancer of the head and neck. Our group with AVP sampled postoperatively is too small for us to draw conclusions, but reduction of its levels after treatment in all patients may be significant. These preliminary results indicate that further evaluation of AVP during the posttreatment course in a larger number of cases, and perhaps with other TMs as well, is warranted.     

Increased Levels of Urokinase Receptor in Plasma of Head and Neck Squamous Cell Carcinoma Patients

Urokinase-type plasminogen activator (uPA) is important for matrix degradation and motility of cancer cells. The binding of uPA to its cell surface receptor on cancer cells is essential for effective invasion. A soluble form of urokinase receptor (suPAR) has been described in serum and ascites of ovarian cancer patients and in plasma samples of non-small cell lung cancer patients. Plasma samples from 36 head and neck squamous cell carcinoma patients and 24 healthy control persons were analysed for the presence of suPAR using enzyme-linked immunosorbent assay (ELISA) and the expression levels were correlated with clinical and histopathological data. Significantly elevated levels of suPAR in blood plasma from head and neck cancer patients were observed (p=0.000), and the suPAR plasma levels decreased after resection of the carcinoma in 8 of 11 patients. suPAR plasma levels of cancer patients showed no significant correlations with T staging, metastasis, recurrence or differentiation stage of the tumours. The significance of suPAR plasma levels in head and neck squamous cell carcinoma patients for prognosis of the disease is discussed.     

Wound Complications in Head and Neck Squamous Cell Carcinomas After Anti–PD‐1 Therapy

Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long‐term sequelae. We describe four patients who, after complete responses to anti–PD‐1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57‐year‐old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39‐year‐old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66‐year‐old male with craniofacial osteoradionecrosis. Patient 4 is a 71‐year‐old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 129:E428–E433, 2019     

Sentinel Lymph Node Radiolocalization in Head and Neck Squamous Cell Carcinoma

Objectives: To determine the feasibility of sentinel node radiolocalization in stage N0 in head and neck squamous cell carcinoma and to gain insight as to whether the sentinel node could be prognostic of regional micrometastatic disease. Study Design: A prospective report on the application sentinel node radiolocalization in eight patients with N0 squamous cell carcinoma of the head and neck region. Methods: For each patient a peritumoral submucosal injection of filtered technetium (^99mTc) prepared with sulfur colloid was performed immediately following intubation. After at least 30 minutes, focal areas of accumulation corresponding to a sentinel node were marked on the skin surface. Complete neck dissections were performed, and the sentinel nodes were identified for later histological evaluation and comparison to the remaining lymphadenectomy specimen. Results: Sentinel node radiolocalization accurately identified two or more sentinel lymph nodes in all eight cases. In one patient, two of the three lymph nodes containing micrometastatic disease were sentinel lymph nodes. There was no instance in which sentinel node was negative for micrometastatic disease while being positive in a nonsentinel lymph node. Conclusions: Accurate localization of the sentinel lymph node using radiolabeled sulfur‐colloid is feasible in patients with squamous cell carcinoma of the head and neck region. Although sentinel node radiolocalization in head and neck squamous cell cancer may potentially reduce the time, cost, and morbidity of regional lymph node management, more experience with technique is required before its role can be determined.     

Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck Region

Cutaneous squamous cell carcinoma has a relatively low metastatic rate (0.5% to 16%), but patients with the disease should always be evaluated for possible regional nodal involvement. We reviewed the records of 37 patients with metastatic disease among the 388 patients with head and neck cutaneous squamous cell carcinoma who were treated at New York University Medical Center between 1961 and 1992. In this group of patients the most common primary site was the cheek or preauricular region and the most common metastatic site was the level I neck lymph nodes. Seven patients (18%) had metastases at initial presentation. Among the remaining patients the average time to the development of metastases was 19 months. Nineteen patients (51%) had recurrence at the primary site before metastasis; 11 (30%) developed metastases with control of the primary tumor. Analysis of the records of 31 patients treated for cure revealed that 13 were treated by surgery, 2 by radiation therapy, and 16 by a combination of surgery and radiation therapy. During the mean follow-up period of 49 months, 11 (35%) of these 31 patients died of their disease. Recurrence of the primary tumor appeared to increase the risk for nodal and distant metastases.     

头颈部中晚期鳞癌大剂量滴注化疗的应用

对３６例初治头颈部中晚期鳞癌患者进行前瞻性随机对照研究。第一组（２０例）为大剂量顺铂（ｐＤＤ）加５－氟脲嘧啶（５－Ｆｕ）１２０小时连续滴注组（连续组）。另一组（１６例）为ＰＤＤ加５－Ｆｕ常规点滴组（常规组）。连续组和常规组有效率分别为９０．０％（完全缓解２０％，部分缓解７０％）和４３．８％（完全缓解６，３％，部分缓解３７．５％），差异有非常显著性意义（Ｐ＝０．００３９）。二组副作用相似且临床可接受（各项Ｐ值均大于０．０５）。认为２～３段大剂量ＰＤＤ＋５－Ｆｕ１２０小时连续滴注化疗是高度有效和安全的。     

Nitric Oxide Improves Cisplatin Cytotoxicity in Head and Neck Squamous Cell Carcinoma

Objective To test whether nitric oxide (NO) enhances the cytotoxicity of cisplatin in a head and neck squamous cell carcinoma (HNSCC) cell line. Background Cisplatin is one of the most frequently used chemotherapeutic agents in the treatment of HNSCC. NO has been shown to play an important role in regulating tumor growth. Previous studies demonstrate that NO can enhance the cytotoxicity of cisplatin in Chinese hamster lung fibroblasts. In this report, we examined the in vitro interaction of NO and cisplatin in a HNSCC cell line. Materials and Methods CCL23 cells were pretreated with three different NO donors: PAPA/NO (t 1/2 = 15 min), DPTA/NO (t 1/2 = 3 h), and DETA/NO (t 1/2 = 20 h). The cells were rinsed and exposed for 6 hours to a culture medium containing cisplatin. Cell survival and LD₅₀ of cisplatin were calculated with and without NO pretreatment. Results PAPA/NO and DPTA/NO did not show any cytotoxic activity and did not change the LD₅₀ of cisplatin. DETA/NO when used alone resulted in 25.6% cell death at its peak dose (100 μM). Pretreatment with DETA/NO resulted in almost a threefold reduction of the LD₅₀ of cisplatin (6.8 vs. 2.4 μg/mL). Pretreatment with DETA/NO sensitized the HNSCC cells to subsequent cisplatin activity (two‐sided P = .00016). Conclusion Pretreatment of HNSCC cells with long‐acting NO donors enhances cisplatin activity. Short‐ and medium‐acting NO donors do not exert a toxic effect and do not augment the activity of cisplatin. NO agonists should be considered in the future as a possible adjunct to cisplatin in the treatment of HNSCC. Further studies with animal models are necessary to further clarify this relationship.     

Ethanol Decreases Negative Cell-cycle-regulating Proteins in a Head and Neck Squamous Cell Carcinoma Cell Line

Epidemiologic studies have provided evidence of an alcohol-associated increased risk of upper aerodigestive tract cancers. Recently we reported ethanol-induced proliferation in a squamous cell carcinoma of the head and neck (SCCHN) cell line, but the underlying mechanisms are unknown. In order to further clarify these findings, major G0/G1-regulating proteins were investigated in the present study. Synchronized cells of a SCCHN line (JP-PA) and a human immortalized keratinocyte line (HaCaT)--used as a control--were cultured with or without 10 -3 M ethanol for up to 96 h. At distinct time intervals the expression of cyclin D1 and the inhibitors p16, p18, p19 and p21 were determined by Western blot analyses. In both lines ethanol had no influence on the protein expression of cyclin D1. In contrast, distinct downregulations of p21, p18 and p19 were detectable at the protein level. The p16 protein was not expressed in the SCCHN line and was unchanged in the control line after the addition of ethanol. In these in vitro experiments the marked downregulation of important cell-cycle inhibitors may accelerate progression from the G1 to the S phase of the cell cycle. The relevance of our findings to in vivo conditions remains speculative, but the observed mechanisms of significantly reduced expression of cell-cycle inhibitor proteins may be involved in the carcinogenesis of head and neck malignancies.     

Expression of VEGF, HGF, IL-6, IL-8, MMP-9, Telomerase in Peripheral Blood of Patients with Head and Neck Squamous Cell Carcinoma

Objectives

This study investigated the telomerase expression in peripheral blood mononuclear cells (PBMCs) and the relationship between the serum level of several soluble factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor, interleukin (IL)-6, IL-8, and matrix metallopeptidase-9 and the clinicopathological features of patients with head and neck squamous cell carcinoma (HNSCC).

Methods

Peripheral blood samples were collected from 50 HNSCC patients and 15 normal controls. The telomerase activity in the PBMCs was measured by Telomere Repeat Amplification Protocols. The serum levels of the soluble factors were analyzed by enzyme-linked immunosorbent assay.

Results

The expression of telomerase in the PBMCs of HNSCC patients was significantly correlated with the N and American Joint Committee on Cancer (AJCC) stages. The serum VEGF level was significantly higher in the patients with an advanced T stage, N stage and AJCC stage. Serum VEGF was significantly related with the expression of telomerase in the PBMCs. The telomerase expression and the VEGF expression were shown to be independent factors associated with poor survival.

Conclusion

The telomerase expression in the PBMCs and the serum VEGF level of HNSCC patients were significantly correlated with the N stage, the AJCC stage and the prognosis.     

Head and Neck Squamous Cell Carcinoma Detection and Surveillance: Advances of Liquid Biomarkers

Head and neck squamous cell carcinomas are aggressive tumors that often present at advanced stage in difficult‐to‐biopsy regions of the head and neck. With the rapid move to analyze circulating tumor DNA (ctDNA) to either detect cancer or monitor disease progression and response to therapy, we have designed this article as a primer to understand the recent studies that support a transition to use these circulating biomarkers as a part of routine clinical care. Whereas some technical challenges still need to be overcome, the utility of ctDNA in cancer care is already evident from these early studies. Therefore, it is critical to understand recent advances in this area as well as emerging questions that need to be addressed as these biomarkers move closer to enhancing routine clinical care paradigms. Laryngoscope, 129:1836–1843, 2019     

Vascular Endothelial Growth Factor Expression Correlates with p53 Mutation and Angiogenesis in Squamous Cell Carcinoma of the Head and Neck

We present a case of squamous spindle cell carcinoma of the external auditory meatus in a 38-year-old man. The tumour was extended to the inner ear, the temporal bone, the middle cranial fossa and the meningo-cerebral tissue. The surgical intervention of temporo-occipital craniotomy removed most of the neoplasia. At pathologic examination, the tumour showed an undifferentiated spindle cell pattern. Immunohistochemistry with a large antibody panel found a weak positivity only to EMA. The diagnosis was made when the electron microscopy showed rare junctional structures and tonofilaments.     

Heterogeneity of Squamous Cell Carcinomas of the Head and Neck-Analysis of Tumor Biologic Factors and Proliferation Rates

Specimens obtained from five different tumor regions in 12 patients who underwent surgery for squamous cell carcinoma (SCC) of the oropharynx were examined. The evaluation of each biopsy included quantitative DNA measurements based on image analysis, immunohistochemical assessment of proliferations markers (i.e., Ki67-MIB1, proliferating cell nuclear antigen [PCNA]), and morphological tumorfront grading. From single cell measurements, several DNA indices were derived which are known to reflect tumor aneuploidy. The results revealed a marked variation of proliferation and cellular differentiation in different regions of tumors and a wide intraindividual variation between particular tumors for all markers examined. There was good correlation between DNA data and proliferative cell fractions (Ki67 score, PCNA score). With the use of diagrams, three-dimensional distribution of proliferation rates and markers reflecting tumor aggressiveness within each tumor was obtained. The results confirmed previous clinical and histological observations that SCCs of the oropharynx are heterogeneous tumors. One might expect that the regions with increased proliferation and aggressiveness may predict the location of possible tumor recurrence.     

The Role of Copper Suppression as an Antiangiogenic Strategy in Head and Neck Squamous Cell Carcinoma

Objective To determine whether tetrathiomolybdate (TM), a powerful chelator of copper, is capable of lowering the body stores of copper and suppressing the growth of head and neck squamous cell carcinoma in an orthotopic murine model. Study Design In vivo, murine model. Methods Twelve 8‐week‐old male C3H/HeJ mice were assigned to either a TM treatment group (n = 7) or a control group (n = 5). Serum samples were obtained from a single mouse in each group to measure the level of ceruloplasmin as a surrogate marker of total body copper on days 0, 4, and 7. Mice in both groups received a floor‐of‐mouth injection of 1.5 × 10⁵ SCC VII/SF cells. After 7 to 10 days of tumor growth the treatment group received fresh water daily, to which TM was added to achieve an oral intake of 50 mg per mouse. The control group received only fresh drinking water daily. Tumor volume measurements were obtained every other day. Microvessel density counts were assessed in the tumors by Factor VIII analysis. Results Measurable tumor growth was achieved in 100% of the mice by the tenth day. Total body copper was reduced by 28% from baseline levels in mice in the treatment group. The difference in mean tumor volume in the control group was 4.7 times greater than the TM‐treated group at the completion of treatment (3004 mm³ and 633mm³, respectively). This accounted for an overall suppression rate of 79% (P = .008; two‐tailed Student t test). In addition, microvessel density was reduced by 50% in the TM‐treated group. Conclusion In this initial study, the first of its kind in head and neck squamous cell carcinoma, we have demonstrated the ability of TM to significantly suppress both the growth of squamous cell carcinoma and tumor vascularity in this orthotopic murine model, suggesting its potential for efficacy in the treatment of this disease in humans.     

Mutation of p53 in Squamous Cell Cancer of the Head and Neck: Relationship to Tumor Cell Proliferation

Rapid proliferation of squamous cell carcinomas of the head and neck (SCCHN) during therapy may contribute to treatment failure. We have investigated the presence of p53 abnormalities in patients with SCCHN as a correlate of proliferation rate and other pathologic and clinical variables. p53 Mutation, as determined by polymerase chain reaction and single-strand conformation polymorphism analysis of microdissected frozen sections of tumor biopsies, was significantly associated with a high labeling index, as determined by in vivo infusion of IUdR and BrdU (P = 0.017). p53 Protein expression was detected by immunohistochemistry with two different antibodies, followed by quantitative image analysis. Many cases exhibited strong p53 protein expression in the absence of mutations within the conserved region of the gene, and expression was not related to proliferation. The presence of p53 mutations was related to tumor differentiation in this group of patients.     

XPD Polymorphisms and Risk of Squamous Cell Carcinoma of the Head and Neck in a Korean Sample

Objectives

XPD is a major player in nucleotide excision repair, which is one of the basic pathways of DNA repair. The objective of this study was to investigate the association of XPD single nucleotide polymorphisms (SNPs) and the risk of squamous cell carcinoma of the head and neck (SCCHN) in Koreans.

Methods

We performed XPD +23591G>A and +35931A>C genotyping in 290 SCCHN patients and 358 controls.

Results

The frequencies of the XPD +23591G>A (GG/GA/AA) genotypes were 89.0%/11.0%/0% in the patients and 90.3%/8.8%/0.9% in the controls, respectively. The odds ratio (OR) of the XPD +23591 GA genotype was 1.94 (0.92 to 4.08) in reference to the GG genotype. The frequencies of the XPD +35931A>C (AA/AC/CC) genotypes were 86.9%/12.0%/1.1% in the patients and 85.6%/13.8%/0.6% in the controls, respectively. The OR of the XPD +35931 AC and CC genotypes were 0.98 (0.51 to 1.88) and 2.68 (0.71 to 10.1), respectively, in reference to the AA genotype. On the subgroup analyses according to the smoking and drinking statuses, the SNPs and haplotypes of XPD showed no statistically significant association with the risk of SCCHN.

Conclusion

The results of this study suggest that the XPD +23591G>A and +35931A>C SNPs are not associated with the risk of SCCHN in Koreans; however, a further study with a larger number of subjects is necessary to verify this conclusion.