Emily Light

Infiltrating lymphocytes and human papillomavirus-16–associated oropharyngeal cancer†‡§

Human papillomavirus‐16 (HPV‐16)–associated carcinoma of the oropharynx has a favorable prognosis. Such patients have elevated CD8+ T‐lymphocyte levels that correlate with response to chemotherapy and survival. Tumor‐infiltrating lymphocyte (TIL) subpopulations were assessed in pretreatment biopsies from a prospective patient cohort to determine if TIL subsets differed by HPV status, clinical factors, or patient outcome or correlated with peripheral blood T‐cell levels.

Correlation of Cellular Immunity With Human Papillomavirus 16 Status and Outcome in Patients With Advanced Oropharyngeal Cancer

OBJECTIVE to determine whether the favorable outcome associated with human papillomavirus (HPV) 16-positive oropharyngeal cancer is related to a patients adaptive immunity. SETTING academic medical center. PATIENTS forty-seven of 66 previously untreated patients (6 of 20 patients with stage III and 41 of 46 with stage IV cancer) in a prospective clinical trial of chemoradiotherapy. INTERVENTION all patients were treated with a single course of neoadjuvant chemotherapy followed by either surgery (for nonresponders) or chemoradiotherapy. MAIN OUTCOME MEASURES pretreatment levels (percentages and absolute counts) of CD3, CD4, CD8, natural killer, and B cells and overall white blood cell counts were measured by flow cytometry. Correlations of subsets with HPV-16 status, tumor subsite, cancer stage, T class, N class, smoking status, performance status, sex, response to chemoradiotherapy, p53 mutation type, epidermal growth factor receptor expression, and disease-specific and overall survival were determined. RESULTS after a median follow-up of 6.6 years, improved survival was associated with an elevated percentage of CD8 cells (P = .04), a low CD4:CD8 ratio (P = .01), low epidermal growth factor receptor expression (P = .002), and HPV status (P = .02). The percentage of CD8 cells was significantly higher (P = .04) and the CD4:CD8 ratio was significantly lower (P = .02) in HPV-16-positive patients. A higher percentage of CD8 cells was associated with response to induction chemotherapy (P = .02) and complete tumor response after chemoradiotherapy (P = .045). CONCLUSION these findings confirm previous correlations of outcome with circulating CD8 cell levels and support the conjecture that improved adaptive immunity may play a role in the favorable prognosis of patients with HPV-16-positive cancers.

Matted nodes: Poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status

Despite better prognosis, there is a group of oropharyngeal squamous cell carcinoma (SCC) human papillomavirus (HPV)+ patients who experience treatment failure and succumb to distant metastasis.

Pretreatment dietary patterns, weight status, and head and neck squamous cell carcinoma prognosis

BACKGROUND Few studies have evaluated the association of diet and weight status with head and neck cancer outcomes. OBJECTIVE The purpose of this study was to determine whether pretreatment dietary patterns and weight status are associated with head and neck cancer prognosis. DESIGN This was a longitudinal study of 542 patients with newly diagnosed head and neck cancer who completed food-frequency questionnaires and health surveys before treatment. Clinical data were abstracted from medical records and the Social Security Death Index. Dietary patterns were identified by using principal component analysis. Cox proportional hazard models were used to examine the association of derived dietary patterns (fit by quintiles of exposure) and weight status with time to recurrence and survival, with control for covariates. RESULTS During the study period, there were 229 deaths and 184 recurrences. Two dietary patterns were identified: a whole-foods pattern (characterized by high intakes of vegetables, fruit, fish, poultry, and whole grains) and a Western pattern (characterized by high intakes of red and processed meats, refined grains, potatoes, and French fries). In multivariable analyses, significantly fewer deaths were observed in subjects most adherent to the whole-foods pattern (HR: 0.56; 95% CI: 0.34, 0.92; P-trend = 0.01). Subjects classified as overweight or obese had significantly fewer deaths (HR: 0.65; 95% CI: 0.49, 0.85; P = 0.001) and recurrences (HR: 0.70; 95% CI: 0.52, 0.95; P = 0.02) than did normal-weight or underweight subjects. CONCLUSION Consumption of a diet rich in vegetables, fruit, fish, poultry, and whole grains and being overweight before diagnosis with head and neck cancer are associated with a better prognosis.

Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2 and IL-6

Purpose: Invasion is the critical step in progression of a precancerous lesion to squamous cell carcinoma of the head and neck (HNSCC). Invasion is regulated by multiple proinflammatory mediators. Tristetraprolin (TTP) is an mRNA-degrading protein that regulates multiple proinflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated. Experimental Design: Using complementary approaches, we modulated TTP and altered expression of interleukin (IL)-6 and matrix metalloproteinase (MMP) 2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the oral-cancer-equivalent (OCE) three-dimensional model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies. Results: Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of HNSCC, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen-activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3′-untranslated region (UTR). High IL-6 and MMP9 are prognostic for poor clinical outcomes in patients with HNSCC. Conclusions: Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in HNSCC to concurrently suppress multiple mediators of invasion. Clin Cancer Res; 19(5); 1169–79. ©2012 AACR.

Sensitization of Head and Neck Cancer to Cisplatin Through the Use of a Novel Curcumin Analog

OBJECTIVE To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin. DESIGN Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC(50)) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined. RESULTS The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin. CONCLUSIONS FLLL32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.

Preoperative topical antimicrobial decolonization in head and neck surgery

Surgical site infections (SSIs) are an important cause of morbidity and mortality after head and neck surgery. Our primary objective was to determine the efficacy of preoperative topical antimicrobial decolonization before head and neck surgery.

Higher Micronutrient Intake Is Associated With Human Papillomavirus-Positive Head and Neck Cancer: A Case-Only Analysis

No studies have investigated dietary differences between head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV)-positive tumors and patients with HPV-negative tumors. This study was designed to investigate the relationship between diet and HPV status in HNSCC patients. Cases of HNSCC were recruited from 2 clinical centers participating in the University of Michigan Head and Neck Specialized Program of Research Excellence (SPORE). HPV tissue genotyping was performed, and epidemiological and dietary data collected. Multivariable logistic regression tested whether pretreatment consumption of 12 selected micronutrients was significantly associated with HPV-positive status in 143 patients newly diagnosed with cancer of the oral cavity or pharynx. After controlling for age, sex, body mass index, tumor site, cancer stage, problem drinking, smoking, and energy intake, significant and positive associations were observed between vitamin A, vitamin E, iron, β-carotene, and folate intake and HPV-positive status (P trend < 0.05), suggesting that diet may be a factor in the improved prognosis documented in those with HPV-positive HNSCC. Dietary differences by HPV status should be considered in prognostic studies to better understand the influence of diet on HNSCC survival.

Clinical and Pathologic Predictors of Recurrence and Survival in Spindle Cell Squamous Cell Carcinoma

Objective. To determine clinicopathologic predictors of recurrence and survival in patients with spindle cell squamous cell carcinoma (SpSCC). Study Design. Historical cohort study. Setting. Tertiary care hospital. Subjects and Methods. Forty-eight patients (mean age, 65.2 years; 35 men, 13 women) who underwent definitive treatment for pathologically confirmed SpSCC between 1987 and 2009 were identified and reviewed. The main outcome measures were time to recurrence and overall survival, while controlling for clinical and pathologic parameters (age, sex, TNM classification, stage, tumor subsite, smoking status, treatment modality, margin status). Results. Of 48 patients, there were 25 oral cavity, 15 laryngeal, 7 oropharyngeal, and 1 maxillary sinus tumors. Treatment included surgery in 32, radiation in 9, and concurrent chemoradiation in 7 patients. The 3-year overall survival for the cohort was 62% with a median follow-up of 59 months; 52.1% (25/48) of patients developed a recurrence, and 88% (22/25) recurred locally or locoregionally. Recurrence occurred within 2 years in 72% (18/25) of patients. Age, sex, initial T and N classification, overall stage, tumor subsite, smoking status, treatment modality, and margin status were not predictive of recurrence or overall survival. Conclusion. Patients with SpSCC are at high risk of developing locoregional recurrence, but no measured clinical or pathologic parameter was predictive of survival. Although overall survival is similar to that of patients with conventional SCC, closer follow-up should be considered in these patients to allow earlier detection and treatment of these locally aggressive tumors.

Metronomic Dosing of BH3 Mimetic Small Molecule Yields Robust Antiangiogenic and Antitumor Effects

Bcl-2 is an antiapoptotic protein that has also been found to function as a proangiogenic signaling molecule. Improvements in antiangiogenic therapy can be engendered by metronomic dosing. Thus, we hypothesized that BH3-mimetic drugs that antagonize Bcl-2 family proteins may exert a greater efficacy when dosed metronomically. To examine this hypothesis, we employed AT101, an orally available and well-tolerated BH3-mimetic drug that has been established as effective. In a mouse xenograft model of human squamous cell carcinomas (SCC) that includes a humanized vasculature, we explored the effects of docetaxel in combination with either daily (metronomic) or weekly (bolus) doses of AT101. In addition, we explored the effect of single or combination therapy on angiogenesis and survival of endothelial or SCC cells in vitro. Metronomic AT101 therapy increased mouse survival, decreased tumor mitotic index, and decreased tumor microvessel density, compared with bolus therapy. Therapeutic potentiation was achieved by similar overall drug exposure and without altering systemic toxicities. Combinations of AT101 and docetaxel produced additive toxicity in both endothelial and SCC tumor cells. Notably, subapoptotic concentrations of AT101 potently inhibited the angiogenic potential of endothelial cells. Taken together, our findings unveil the efficacious benefits that can be achieved by metronomic delivery of BH3-mimetic drugs, in particular suggesting that SCC patients with might benefit from low-dose continuous administration of these drugs.