Giovana R. Thomas

Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) involves the upper aerodigestive tract and can destroy the structure and function of organs involved in voice, speech, taste, smell and hearing, as well as vital structures necessary for survival. HNSCC has long been a treatment challenge because of the high rate of recurrences and of advanced disease at the time of diagnosis. Molecular identification of tissue biomarkers in diagnostic biopsy specimens may not only identify patients at risk for developing HNSCC but may also select patients that may benefit from more aggressive treatment modalities. Several biomarkers studied to date such as the proteins p53, cyclin D1, p16, Cox‐2 enzyme, epidermal growth factor and vascular endothelial growth factor receptors, matrix metalloproteinases and the Fhit marker for genomic instability could be manipulated for the therapeutic benefit of these patients. This review presents the most updated information on molecular biomarkers with the greatest prognostic potential in HNSCC and discusses some factors that contribute to the controversy concerning their prognostic importance.

Unequal burden of head and neck cancer in the United States

Black Americans are adversely affected by many types of malignancies.

Cytokines IL-1α, IL-6, and GM-CSF constitutively secreted by oral squamous carcinoma induce down-regulation of CD80 costimulatory molecule expression: Restoration by interferon γ

We previously characterized the expression of CD80 in different murine head and neck squamous cell carcinoma (HNSCC) clones derived following tumor progression in the absence of T cell–mediated immunity in severe combined immunodeficient (SCID) mice. We found that HNSCCs that did not express CD80 grew as progressors, while those that expressed CD80 were regressors when grown in immune-competent animals. In the present study, we characterized expression of a repertoire of immunoregulatory cytokines in these HNSCC lines, and found that HNSCCs that express cytokines IL-1α, IL-6, and GM-CSF do not express CD80, suggesting the hypothesis that these cytokines may down-modulate expression of CD80. Cytokine-conditioned medium from progressor HNSCC and recombinant IL-1α, IL-6, and GM-CSF caused a reduction of CD80 expression in regressor HNSCCs without affecting proliferation. Conversely, the decrease in CD80 expression in progressor HNSCCs could be restored by IFN-γ, a known inducer of CD80 expression. These data strongly suggest that high levels of cytokines IL-1α, IL-6, and GM-CSF expressed by tumor cells can down-regulate CD80 expression in HNSCC, and that IFN-γ can independently stimulate expression. These data provide evidence for a novel mechanism of cytokine-mediated down-modulation of CD80 during malignant progression of HNSCC that can be restored by IFN-γ.

Perceived social support as a predictor of disease-specific quality of life in head-and-neck cancer patients.

BACKGROUND Treatment for head-and-neck cancer (HNC) can lead to severe decrements in disease-specific quality of life (DSQOL) due to disfigurement and disability in speech, eating, and/or breathing. Psychosocial factors such as social support may explain individual variance in DSQOL outcomes. OBJECTIVE The researchers sought to evaluate changes in perceived availability of social support from pretreatment to posttreatment and to determine whether decreases in perceived social support predicted poorer posttreatment DSQOL among HNC patients, controlling for disease- and treatment-related factors. METHODS Participants (n = 32) were newly diagnosed with HNC and were awaiting surgery and/or radiation treatment. Measures included the ENRICHD Social Support instrument (ESSI) to assess perceived social support and the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) to assess DSQOL. Paired-samples t-tests and hierarchical regression analyses were conducted to determine relationships between pretreatment and posttreatment perceived social support and DSQOL. RESULTS Perceived social support decreased significantly from pre- to posttreatment (F[31] = -2.71, P < .01). After adjusting for relevant covariates and pretreatment DSQOL, change in perceived social support remained a significant predictor of posttreatment DSQOL (β = .47, P < .01). LIMITATIONS This study included a relatively small sample of HNC patients, which limited power to evaluate mechanisms of observed relationships. CONCLUSIONS Increased social isolation may be a risk factor for poorer physical recovery from, or adjustment to, treatment-related side effects. Social support may be an important target for psychosocial interventions for patients who face challenging treatment side effects.

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: A historical perspective with review of their utility and limitations Part B. Transgenic mouse models

Experimental multistage carcinogenesis involves three broad sequential steps: tumor initiation, tumor promotion and tumor progression, and appear to be similar to human carcinogenesis. However, we expect that these processes in humans will be more complex and may not occur in a predictable order. The net result of a number of events such as activation of oncogenes, inactivation of tumor suppressor genes and expression of apoptosis-regulating genes may likely contribute to the accumulation of multiple genetic alterations, leading to tumor formation. In addition, humans are exposed to multiple mutagenic agents that may act at the same time on tumor initiation, promotion or progression. The classical animal models fall short of providing important information concerning carcinogen–host and tumor–host interactions. The development of animals with overexpression or inactivation of carcinogenesis-related genes has expedited studies on carcinogenesis and its prevention and treatment. These transgenic animals provide a powerful model to explore mechanisms of gene expression as well as the regulation of cellular and physiologic processes involved in initiation, promotion and progression of cancer. With this technology, targeted expression of a protein can be achieved in a controlled fashion by expressing the corresponding gene in vivo ectopically, ubiquitously or in a tissue-specific manner, using its own promoter. These newer models may provide more precise control over gene expression at various stages of development through activation of mutant alleles at precise points in the developmental process using conditional Cre-Lox and tetracycline-inducible technology. The Cre-LoxP and the tetracycline (Tet)-inducible systems are useful methods of conditional gene expression that allow spatial (celltype-specific) and temporal (inducer-dependent) control. The Cre-LoxP system, which has been widely used for gene manipulation in animal models, uses P1 phage Cre-recombinase to catalyze the excision of DNA located between flanking loxP sites for conditional gene inactivation. Tetracycline-controlled gene expression relies on two components: (i) a tetracycline-responsive transactivator (tTA) that is, a fusion of E. Coli tet repressor to the transactivation domain of VP16 protein of herpes simplex virus, and (ii) a tTA-dependent promoter consisting of a minimal RNA polymerase II promoter fused to tet operator sequences. By using a reverse tTA, which becomes transcriptionally active only when bound to tetracycline or its derivatives, expression of a target gene can be induced by administration of tetracycline or doxycycline. In recent years, several transgenic mouse models with overexpression or inactivation of cancer-related genes using the CreLoxP technology have been used to study the initiation, development and metastasis of epidermal/cutaneous squamous cell carcinoma (SCC). However, the use of these animal model systems for the study of head and neck squamous cell carcinoma (HNSCC) is still in its infancy. Studies of several major cancer-related genes in HNSCC carcinogenesis using transgenic models are discussed below. Squamous epithelia of the upper airway as well as a variety of human tumors show abnormal overexpression of cyclin D1. Nakagawa et al. used an Epstein–Barr virus (EBV) ED-L2 promoter in a construct to target human cyclin D1 in transgenic mice. They observed the expression of the cyclin D1 transgene in oral and esophageal epithelia and a phenotype that showed mild dysplasia by 6–12 months, with progression to moderate– severe dysplasia by 15–16 months. Overexpression of PCNA and abnormalities in cyclin-dependent kinase-4, EGFR and p53 during early HNSCC carcinogenesis were also demonstrated, but no evidence of cancer was noted. Cross breeding the cyclin D1 expressing mice with p53 knockout mice, however, led to the development of mice with histologic evidence of invasive oral cancer, suggesting that cyclin D1 requires cofactors to cause malignant epithelial transformation. The TP53 tumor suppressor gene is mutated in over 50% of human cancers and is considered a central event in the progression of human malignancies. Mice with heterozygous knockout or mutations in the TP53 tumor suppressor gene show a high sensitivity to a variety of carcinogens and, thus, provide relevant tumor models to study carcinogenicity of pharmaceutical agents. However, there is a paucity of studies specific to HNSCC using this model. Nishikawa et al. showed a high susceptibility of p53 (1/2) knockout mice to esophageal carcinogenesis after administration of N-dibutylnitrosamine (DBN) in their drinking water for 8 weeks. This was likely attributed to early mutations of the residual TP53 allele and increased cellular proliferation in the target organs. Mutations in the K-ras and H-ras genes have been reported in HNSCC to be between 30 and 50% depending on geographical region. However, the role of –ras genes in HNSCC carcinogenesis is still debatable. Vitale-Cross et al. (2004) engineered transgenic mice carrying the tetracycline-inducible system (tet-on receptor) targeted to the basal layer of stratified epithelium, which includes the epithelial stem cells, by crossing with mice expressing the K-ras (G12D) oncogene under the control of tet-regulated responsive elements. Progeny animals developed lesions ranging from hyperplasias, papillomas and dysplasias to metastatic carcinomas in epithelia from skin, oral mucosa, salivary glands, tongue, esophagus and uterine cervix. The most noticeable lesions, however, were invasive squamous carcinomas of the skin and oral mucosa, suggesting that expression of K-ras oncogenes in epithelial compartments containing stem cells may be sufficient to promote squamous carcinogenesis. Importantly, Caulin et al. developed a novel system based on the generation of transgenic mice that express an inducible Cre recombinase under the control of a promoter specific for stratified epithelia. They fused Cre to a deletion mutant of the human progesterone receptor (PR), which fails to bind progesterone, but can be activated by progesterone antagonists, such as RU486. This fusion protein (CrePR1) is sequestered in the cytoplasm. After activation with RU486, CrePR1 translocates to the nucleus, where it mediates the excision of DNA sequences flanked by LoxP sites. In this matter, they generated mice that express CrePR1 under the control of the K5 or K14 pro-

Lipoma and liposarcoma of the larynx: case reports and literature review

OBJECTIVE Two cases of laryngeal lipomatous tumors are presented. Their diagnoses and management are discussed and contrasted. METHODS Case report and literature review. RESULTS Patient 1 is a 58 year old male presenting with five years of progressive shortness of breath, dysphagia, and globus sensation. Clinical exam and imaging study showed a 3.5 cm hypodense laryngeal mass, and he underwent transoral robotic-assisted surgery for complete excision. Final pathology revealed a well-differentiated liposarcoma. Patient 2 is a 79 year old female presenting with one year of non-progressive hoarseness and globus sensation. Clinical examination and imaging study revealed a 1.8 cm hypodense laryngeal mass. Transoral endoscopic complete excision of the submucosal mass was performed. Final pathology revealed benign spindle-cell lipoma. CONCLUSION Liposarcoma and lipoma may present with similar symptomatology, clinical, and imaging findings. Pathology evaluation is of utmost importance for definitive diagnosis. Therefore, diagnosis and treatment of laryngeal lipomatous lesions are best accomplished with complete excision of the mass.

Human papillomavirus–induced oropharyngeal cancer in Hispanics in the United States

Determine disparities in survival outcome and clinical presentation between Hispanic and non‐Hispanic white patients with human papillomavirus–positive oropharyngeal squamous cell carcinoma.

Head and Neck Cancer

Head and Neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide. They include cancers of the oral cavity, oropharynx and larynx. Major risks factors for head and neck squamous cell carcinoma include tobacco and alcohol use. In the past decade, our understanding of Human Papillomavirus (HPV) in the development of oropharyngeal squamous cell carcinoma is significantly changing our diagnostic and therapeutic modalities. However, the complex molecular genetic events leading to the development of HNSCC are still not clearly understood.