Local and systemic Curcumin C3 complex inhibits 4NQO-induced oral tumorigenesis via modulating FGF-2/FGFR-2 activation.

Head and Neck Squamous cell carcinoma (HNSCC) can be characterized by synchronous tumors in the upper aerodigestive tract. Second primary tumors as a result of field cancerization are a significant problem amongst patients with risk factors for HNSCC, indicating a need for chemo preventive agents. We investigated the efficacy of local and systemic Curcumin C3 complex (C3); a purified mixture of Curcumin, bisdemethoxy Curcumin and demethoxy Curcumin as a chemo preventative agent in 4-nitroquinoline-1-oxide (4NQO)-induced tumorigenesis in mice. The effect of local C3 application was compared to C3 administered orally and in combination with systemic administration. C57Bl/6 mice were administered 4NQO (50 µg/ml) in the drinking water for 16 weeks. At 12 weeks, mice were subjected to daily treatment with either vehicle (control), or 15 mg C3 complex by local delivery, gavage, or combined local and gavage for 28 days (16 week time point), and followed up to 22 weeks. Compared to local and oral systemic C3 administration, combination of local and systemic application significantly decreased multiplicity of 4NQO-induced preneoplastic and neoplastic lesions (p<0.05). Treatment with C3 correlated with a decrease in cell proliferation compared to the 4NQO group. Further, pre-treatment with C3 complex significantly attenuated 4NQO induced expression of basic fibroblast growth factor (FGF-2) and its cognate receptor FGFR-2, suggesting an important role of FGF-2/FGFR-2 axis in chemoprevention of HNSCC (p<0.05). Our findings suggest that a combination of local and systemic C3 complex could effectively target proliferation and inhibit 4NQO-induced tumorigenesis via modulation of the FGF-2/FGFR-2 axis as a mechanism for its efficacy.

Sildenafil Transiently Delays Early Alveolar Healing of Tooth Extraction Sockets.

Bone is a unique tissue that has the ability to repair itself and return to full function. Bone regeneration is a well synchronized biological process that recapitulates embryonic bone development. The establishment of a functional vascular supply has been shown to be essential for proper ossification of newly deposited bone, and impaired angiogenesis as in advanced age, diabetes, and anti-cancer treatments affect bone repair. Endothelial Guanosine, 3', 5'-Cyclic Monophophate(cGMP) is known to support angiogenesis, and sildenafil, a Phosphodiesterase 5 (PDE5) antagonist, prevents cGMP hydrolysis and thereby, promotes the formation of new blood vessels. Since the development of functional vascular networks is critical to bone repair, we investigated the effects of sildenafil on early alveolar bone regeneration following exodontia. Our results demonstrate that per-oral administration of sildenafil (10 mg/kg/day) in rats delays the dissolution and replacement of the sanguine clot with granulation tissue. As a result, the number of replicating cells, a hallmark of regenerating tissue, observed on day 4 was remarkably lower in sildenafil-treated animals than their control counterparts (mean±SD; control: 47.35±9.21; sildenafil: 11.47±5.14). Similarly, cells expressing transcription factor Cbfa-1/Runx2 and osteopontin, markers of differentiating osteoblasts, were fewer in treated animals (mean±SD; control: 83.18 ± 4.60; sildenafil: 13.77 ± 4.63). Treatment with hydrolysis-resistant cyclic GMP (cGMP) showed findings similar to sildenafil-treated animals suggesting a negative impact of cGMP on early inflammatory phase of bone healing. However, histological differences were not significant between the 2 groups on day 8. Based on these findings, we conclude that sildenafil temporarily retards early events in alveolar bone healing.

Biomarker and Pathologic Predictors of Cutaneous Squamous Cell Carcinoma Aggressiveness.

OBJECTIVE: Aggressive cutaneous squamous cell carcinoma (cSCC) patients are at increased risk of metastasis. Currently, there are no accepted criteria or biomarkers for reliably predicting individuals at risk for recurrence and metastasis. Our objective is to determine if pS6 and pERK can predict cSCC aggressiveness and to identify primary tumor characteristics that may predict parotid metastasis. STUDY DESIGN: Retrospective case series. SETTINGS: Tertiary care center. SUBJECTS AND METHODS: An Institutional Review Board-approved retrospective review was performed for patients with facial cSCC, with and without metastasis to the parotids. Subjects for the study were identified through the Louisiana Tumor Registry, Veterans Medical Records, and LSU Health-Shreveport pathology database. Tumor specimens from patients with cSCC and cSCC with parotid metastasis were analyzed for pERK and pS6 expression through immunohistochemistry. To identify risk factors for tumor aggressiveness, multiple logistic regression analysis was used to evaluate patients with cSCC that was metastatic to the parotid and managed surgically. RESULTS: cSCC with parotid metastasis specimens exhibited significantly higher average pS6 but not pERK positivity than those from cSCC without metastasis (P < .05). Primary lesion-positive margins (P < .01), size of the skin tumor (P < .01) and degree of tumor differentiation (P < .01) were significantly associated with parotid metastasis. CONCLUSION: Surgical history of cSCC, primary lesion-positive margins, degree of differentiation, and lesion size together with pS6 positivity appear to be predictors of cSCC aggressiveness and should prompt increased monitoring or elective parotidectomy.

Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells.

Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS-SV-AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS-SV-AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells.

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia.

Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the United States due to high exposure to ultraviolet B (UVB) radiation. In our previous studies, Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling that play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against acute UVB-induced hyperproliferation by targeting the mTOR and FGFR signaling pathways. Pretreatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced cell proliferation, progression and colony formation, mTORC1 and mTORC2 activation, and FGFR2 phosphorylation in the promotion-sensitive JB6 cells epithelial cells. Further, FGFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to UVB (180 mj/cm(2)) significantly attenuated UVB-induced mTORC1, mTORC2, and FGFR2 activation. To further assess the role of FGFR in UVB-induced hyperproliferation, SKH-1 mice were pretreated with AZD4547 (5 mg/kg/b.w.); a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (180 mj/cm(2)). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer.

Enhanced Systemic Bioavailability of Curcumin Through Transmucosal Administration of a Novel Microgranular Formulation.

BACKGROUND/AIM: Curcumin is a promising nutraceutical for chemoprevention of head and neck squamous cell carcinoma (HNSCC). Capsular formulations of curcumin demonstrate low systemic bioavailability. We aimed to determine if curcumin levels were higher in healthy volunteers and cancer patients with microgranular curcumin that allows for transmucosal absorption and identify a consistent biomarker. PATIENTS AND METHODS: Eight healthy volunteers and 15 HNSCC patients completed the trials. Serum levels of curcumin were measured by HPLC. Biological activity of curcumin was assessed with Multiplex Immunoassay and immunohistochemistry. RESULTS: We achieved higher serum levels of curcumin compared to trials using capsular formulation. In cancer patients a significant decrease in expression of fibroblast growth factor-2 (FGF-2) in post-biopsy samples and decreased serum levels of FGF-2, granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-17 (IL-17) (p<0.05) was observed. CONCLUSION: Transmucosal administration of microgranular curcumin leads to enhanced curcumin bioavailability that is associated with significant biological effects.

4,4'-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats.

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4'-Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2-hydroxyestradiol (2-OHE1)/16α-hydroxyestrogen (16α-OHE1). In females, ET-1,[Formula: see text] , and 2-OHE1/16α-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM-induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis.

Association between human papilloma virus/Epstein-Barr virus coinfection and oral carcinogenesis.

BACKGROUND: The recent epidemic of head and neck squamous cell carcinomas associated with human papilloma virus (HPV) has not addressed its association with lymphoid tissue in the oropharynx or the potential role of Epstein-Barr virus (EBV)/HPV coinfection. METHODS: The prevalence of HPV and EBV infection/coinfection and CD21 mRNA expression were determined in normal and cancerous tissues from the oropharynx using in situ hybridization (ISH), p16, and quantitative reverse transcriptase PCR (qRT-PCR). The effects of coinfection on tumorigenicity were evaluated using proliferation and invasion assays. RESULTS: Normal oropharynx, tonsil, non-cancer base of tongue (BOT), and BOT from sleep apnea patients demonstrated EBV positivity ranging from 7% to 36% depending on the site and methods of detection used (qRT-PCR or ISH). Among non-malignant BOT samples, HPV positivity was noted only in 20%. The percent of tonsil and BOT cancers positive for HPV (up to 63% and 80%, respectively) or coinfected with HPV/EBV (up to 25% and 70%, respectively) were both significantly associated with cancer status. Notably, HPV/EBV coinfection was observed only in malignant tissue originating in lymphoid-rich oropharynx sites (tonsil, BOT). CD21 mRNA (the major EBV attachment receptor) was detected in tonsil and BOT epithelium, but not in soft-palate epithelium. Coinfected cell lines showed a significant increase in invasiveness (P < 0.01). CONCLUSIONS: There is a high prevalence of HPV/EBV infection and coinfection in BOT and tonsil cancers, possibly reflecting their origins in lymphoid-rich tissue. In vitro, cells modeling coinfection have an increased invasive potential.

Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models.

BACKGROUND: Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood. METHODS: Lymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. RESULTS: Rapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines. CONCLUSIONS: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR-2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes.

Recombinant AAV9-TLK1B administration ameliorates fractionated radiation-induced xerostomia.

Salivary glands are highly susceptible to radiation, and patients with head and neck cancer treated with radiotherapy invariably suffer from its distressing side effect, salivary hypofunction. The reduction in saliva disrupts oral functions, and significantly impairs oral health. Previously, we demonstrated that adenoviral-mediated expression of Tousled-like kinase 1B (TLK1B) in rat submandibular glands preserves salivary function after single-dose ionizing radiation. To achieve long-term transgene expression for protection of salivary gland function against fractionated radiation, this study examines the usefulness of recombinant adeno-associated viral vector for TLK1B delivery. Lactated Ringers or AAV2/9 with either TLK1B or GFP expression cassette were retroductally delivered to rat submandibular salivary glands (10(11) vg/gland), and animals were exposed, or not, to 20 Gy in eight fractions of 2.5 Gy/day. AAV2/9 transduced predominantly the ductal cells, including the convoluted granular tubules of the submandibular glands. Transgene expression after virus delivery could be detected within 5 weeks, and stable gene expression was observed till the end of study. Pilocarpine-stimulated saliva output measured at 8 weeks after completion of radiation demonstrated >10-fold reduction in salivary flow in saline- and AAV2/9-GFP-treated animals compared with the respective nonirradiated groups (90.8% and 92.5% reduction in salivary flow, respectively). Importantly, there was no decrease in stimulated salivary output after irradiation in animals that were pretreated with AAV2/9-TLK1B (121.5% increase in salivary flow; p<0.01). Salivary gland histology was better preserved after irradiation in TLK1B-treated group, though not significantly, compared with control groups. Single preemptive delivery of AAV2/9-TLK1B averts salivary dysfunction resulting from fractionated radiation. Although AAV2/9 transduces mostly the ductal cells of the gland, their protection against radiation assists in preserving submandibular gland function. AAV2/9-TLK1B treatment could prove beneficial in attenuating xerostomia in patients with head and neck cancer undergoing radiotherapy.

Topical curcumin-based cream is equivalent to dietary curcumin in a skin cancer model.

Skin squamous cell carcinoma (SCC), the most common cancer in the USA, is a growing problem with the use of tanning booths causing sun-damaged skin. Antiproliferative effects of curcumin were demonstrated in an aggressive skin cancer cell line SRB12-p9 (P < 0.05 compared to control). Topical formulation was as effective as oral curcumin at suppressing tumor growth in a mouse skin cancer model. Curcumin at 15 mg administered by oral, topical, or combined formulation significantly reduced tumor growth compared to control (P = 0.004). Inhibition of pAKT, pS6, p-4EBP1, pSTAT3, and pERK1/2 was noted in SRB12-p9 cells post-curcumin treatment compared to control (P < 0.05). Inhibition of pSTAT3 and pERK1/2 was also noted in curcumin-treated groups in vivo. IHC analysis revealed human tumor specimens that expressed significantly more activated pERK (P = 0.006) and pS6 (P < 0.0001) than normal skin samples. This is the first study to compare topical curcumin to oral curcumin. Our data supports the use of curcumin as a chemopreventive for skin SCC where condemned skin is a significant problem. Prevention strategies offer the best hope of future health care costs in a disease that is increasing in incidence due to increased sun exposure.

The value of duplicate slides on atypical squamous cells, cannot exclude high-grade intraepithelial lesion.

Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) category was added to the 2001 Bethesda System. ASC-H accounts for a small percentage (0.2-0.6%) of abnormal Pap smears and includes heterogenous group of lesions. There are more high-grade cervical lesions (30-50%) in ASC-H than ASC-US (10-15%). An accurate Pap diagnosis is crucial for appropriate patient follow-up and treatment. A total of 43 consecutive ASC-H cases were collected from October 2007 to March 2008, and all duplicate and the original slides were reviewed blindly at the end of the study. On review of the duplicate Pap slides, 18 cases had diagnostic SIL cells (15 HSIL, 2 LSIL with ASC-H, and 1 LSIL). The duplicate slides could have potentially changed 18 (41.9%) ASC-H diagnoses to a more definitive SIL diagnosis. On review of the original Pap slides, 8 of these 18 cases also had HSIL cells. Twenty-one follow-up cervical biopsies (21/43, 48.8%) showed 12 CIN 2/3, 4 CIN 1, 1 VAIN 1, 2 cervical polyps, 1 negative for dysplasia, and 1 insufficient for diagnosis. The CIN 2/3 rate was 57.1% (12/21) based on the original ASC-H Pap diagnosis. The CIN 2/3 rates were 80% (8/10) with SIL cells on duplicate slides and 36.4% (4/11) without SIL cases on duplicate slides. Our study suggested that duplicate slides were very useful for further classification of ASC-H, but other ancillary tests might be necessary for some cases. We propose a systematic approach using combined duplicate slides and reflex HPV testing to further classify ASC-H.

Analysis of eIF4E and 4EBP1 mRNAs in head and neck cancer.

OBJECTIVES/HYPOTHESIS: The eukaryotic translation initiation factor 4E (eIF4E) in conjunction with its binding protein, 4EBP1, regulates the translation of cap-dependent mRNAs. An aberrant increase in eIF4E shifts the balance in favor of translation of transcripts that promote cell proliferation and malignancy. eIF4E protein is commonly elevated in head and neck squamous cell carcinomas (HNSCC), and its overexpression is associated with increased recurrence. An underlying mechanism for eIF4E overexpression is gene amplification, and we wanted to determine whether eIF4E mRNA could serve as a prognostic maker of HNSCC. METHODS: Tumor specimens from 26 HNSCC patients and oral tissues from 17 control subjects were examined for eIF4E and 4EBP1 by semiquantitative RT-PCR and correlated with clinical and pathologic findings. RESULTS: Unlike eIF4E mRNA alone, expression of eIF4E relative to 4EBP1 was a more precise predictor of HNSCC and its progression (P < .01, Wilcoxon rank sum test). Eight of 26 patients (31%) had elevated eIF4E:4EBP1 (4E:4EBP1; >25), and 7 of these (87.5%) had recurrence. Alternately, from 18 patients with low 4E:4EBP1 (<25; 69%), only 5 patients had recurrence (30.1%). To determine the probability of no recurrence, Kaplan-Meier analysis showed significantly poor disease-free survival in patients with elevated 4E:4EBP1 than those with low ratios (P < .01, log rank test). CONCLUSIONS: Elevated 4E:4EBP1 significantly correlated with increased disease recurrence. Because 4EBP1 modulates eIF4E activity, our results highlight the importance of incorporating a joint analysis of eIF4E and 4EBP1 mRNAs in HNSCC patient care decisions.

Teenage cervical screening in a high risk American population.

BACKGROUND: The new 2009 ACOG guideline for cervical cytology screening changed the starting age to 21 years regardless of the age of onset of sexual intercourse. However, many recent studies have shown a dramatic increase in the incidence of cervical epithelial abnormalities among adolescents within the past two decades. MATERIALS AND METHODS: For this study, the reports of 156,342 cervical cytology were available of which 12,226 (7.8%) were from teenagers. A total of 192 teenagers with high grade intraepithelial lesion (HSIL) cervical cytology were identified. The ages ranged from 13 to 19 years with a mean of 17.7 years and a median of 18 years. Among them, 31.3% were pregnant, 12.0% were postpartum, and 13.5% were on oral contraceptive. Ninety-eight had prior cervical cytology. RESULTS: The teenagers had statistically significant higher detection rates of overall abnormal cervical cytology (23.6% vs. 6.6%, P = 0), with 15.4% vs. 3.2% (P = 0) of low grade intraepithelial lesion (LSIL) and 1.8% vs. 1.0% (P = 2.56 × 10(-13) ) of HSIL compared to women ≥20 years. The teenage group had the highest abnormal cytology among all age groups. The LSIL/HSIL ratio was 8.5:1 for teenagers and 3.1:1 for women ≥20 years. A total of 131 teenagers had cervical biopsies within 12 months of the HSIL cytology, with diagnoses of 39 CIN 3, 1 VAIN 3, 15 CIN 2, 62 CIN 1, and 14 had a negative histology (CIN 0). Only in 19 of these 39 women, the CIN 2/3 lesion proved to be persistent. CONCLUSION: We conclude that cytology screening of high risk teenagers is effective in detecting CIN 2/3 lesions. Moreover, treatment and careful follow-up can be realized.

Curcumin inhibits skin squamous cell carcinoma tumor growth in vivo.

OBJECTIVE: Squamous cell carcinoma (SCCa) has increased from 4% to 10% over 4 decades, stimulating interest in developing novel agents that slow sun-damaged skin progression. This is the first study evaluating the naturally occurring bioactive food compound curcumin on skin cancer xenografts. Low bioavailability of curcumin has slowed its transition to clinical trials. It is hypothesized that curcumin has growth-inhibitory effects through the TOR pathway and chemopreventive potential in skin SCCa where local application could bypass bioavailability problems. STUDY DESIGN: A randomized experimental animal and laboratory study. SETTING: Louisiana State University Health Sciences Center, Shreveport, Louisiana. SUBJECTS AND METHODS: SCID mice were pretreated with 0, 5, or 15 mg of curcumin (n = 8 per group), 3 days prior to injecting 106 SRB12-p9 skin SCCa cells in each flank, and were gavaged daily thereafter. Tumor volumes were measured and tumors were harvested on day 24 when mice were sacrificed. Immunohistochemical analysis of pS6 expression (n = 3 per group) and tumor volumes in the 3 groups were compared using 1-way analysis of variance and pairwise comparisons were determined with the Tukey t test if overall comparisons were significant. RESULTS: Tumor volume increased 2.3 times faster in control mice compared with the group receiving 15 mg of curcumin (P = .0003). A significant difference in average tumor volumes was seen (P = .0012), especially with treatment of 15 mg of curcumin compared with control P = .0003). Curcumin inhibited S6 phosphorylation (P = .0027), suggest-ing inhibition of the MTOR pathway. CONCLUSION: Curcumin appears to inhibit skin SCCa growth and blocks tumor progression by inhibiting pS6 even when gavage is used to deliver curcumin, indicating even more significant effects in future experiments with local application.

Human papillomavirus in metastatic lymph nodes from unknown primary head and neck squamous cell carcinoma.

OBJECTIVE: Determine human papillomavirus (HPV) incidence in unknown primary squamous cell carcinomas (SCCa) of the head and neck and assess if HPV status influenced survival. STUDY DESIGN: Historical cohort study. SETTING: Tertiary care center. SUBJECTS: Patients with unknown primary SCCa despite a complete workup who underwent neck dissection or excisional biopsy and postoperative comprehensive ± chemoradiotherapy between 2002 and 2009. METHODS: HPV fluorescence in situ hybridization (FISH) and p16(INK4a) immunohistochemistry (p16 IHC) were performed. Results were compared with survival, age, race, gender, tobacco use, alcohol use, and nodal stage. RESULTS: Twenty-five patients met the inclusion criteria, of whom 88% were >10 pack year tobacco users. Twenty-eight percent were HPV-positive defined by both p16+ and FISH+. Five-year overall survival was 66.7% in HPV-positive and 48.5% in HPV-negative patients (P = .35). Similarly, 5-year disease-free survival rates were 66.7% in HPV-positive and 48.5% in HPV-negative patients (P = .54). All 3 HPV-positive nonsmokers were survivors, but this was not significant because of the small sample size (P > .05). No other characteristics were associated with survival (P > .05). CONCLUSION: Twenty-eight percent of metastatic lymph nodes from occult primary tumors were HPV positive. There was no survival difference associated with HPV status. Most of the HPV-positive patients in this study were tobacco users who had similar survival to HPV-negative patients, so caution should be used in interpreting HPV status in these patients.

Chemokine receptor CXCR4 overexpression predicts recurrence for hormone receptor-positive, node-negative breast cancer patients.

BACKGROUND: The expected outcome for hormone receptor-positive, node-negative patients should be favorable. However, some patients do develop metastatic disease and the mechanism for this observation is poorly understood. CXCR4 is a chemokine receptor that has been implicated to play a pivotal role in breast cancer growth and metastasis. Its predictive role has not been fully evaluated. We determined to see whether CXCR4 can predict outcome in this subset of patients. METHODS: We accrued and analyzed data from 101 patients with hormone receptor-positive, node-negative breast cancers. The CXCR4 level was detected using Western blots and its level was defined as either low (<6.6-fold) or high (≥6.6-fold). Primary end points were systemic cancer recurrence and death. Statistical analysis performed included Spearman's correlation, Kaplan-Meier survival analysis, and Cox proportional hazard model. RESULTS: Although benign breast tissues had an undetectable level of CXCR4, all 101 cancer specimens had overexpressed CXCR4 (mean 6.4 ± 3.4-fold). There were 79 patients in the low CXCR4 group and 22 patients in the high CXCR4 group. High CXCR4 overexpression was predictive of both cancer recurrence (P = .002) and overall survival (P = .0012). CONCLUSION: High CXCR4 overexpression in primary tumors was predictive of worse outcomes in hormone receptor-positive, node-negative breast cancer patients.

Trimodal therapy for inflammatory breast cancer: a surgeon's perspective.

Inflammatory breast cancer (IBC) is a rare and most aggressive form of breast cancer. The onset and progression of disease are rapid; diagnosis must be made expediently to initiate treatment quickly. In this review, the clinical presentation, trimodal therapy, surgical principles and a brief summary of the Louisiana State University at Shreveport experience with IBC are presented. With this aggressive approach, 5-year survival of better than 40-50% can be expected. This represents a substantive improvement in clinical outcome for IBC patients compared with 30 years ago.

Fine needle aspiration of parapharyngeal space adult rhabdomyoma: a case report.

BACKGROUND: Rhabdomyomas are rare benign tumors of striated muscle and include cardiac and extracardiac types. Extracardiac rhabdomyomas are divided in three subtypes (adult, fetal, genital). The adult type is usually found in the head and neck regions of elderly persons. Misinterpretations in initial diagnosis of adult rhabdomyomas on fine needle aspiration have been reported. CASE: A 64-year-old man presented with gurgling and difficulty swallowing for approximately 3 months. Computed tomography and magnetic resonance imaging showed a 5.8-cm solid mass located in the right parapharyngeal space. Fine needle aspiration smears were cellular, showing cohesive clusters of cells with scattered individual cells. Cells had abundant eosinophilic glassy cytoplasm, peripherally placed round nuclei, and prominent nucleoli. Many traversing vessels were noted, but cross-striations were not seen. The cell block demonstrated clusters of cells with abundant eosinophilic granular cytoplasm, some with clear and/or vacuolated cytoplasm, and possible cross-striations. Tumor cells were positive for desmin. The lesion closely resembled normal muscle tissue. Electron microscopy showed many cells containing actin and myosin filaments with Z-band material. CONCLUSION: Correct diagnosis can be achieved with a combination of awareness of the lesion, familiarity with the characteristic cytologic features, and application of appropriate immunohistochemistry markers. Classic electron microscopic findings can support the diagnosis.