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Received 11 November 2008/Returned for modification 2 February 2009/Accepted 14 August 2009 Previous studies have demonstrated that c-Src tyrosine kinase interacts specifically with ErbB2, but not with other members of the epidermal growth factor receptor (EGFR) family. To identify the site of interaction, we recently used a chimeric EGFR/ErbB2 receptor approach to show that c-Src requires the kinase region of ErbB2 for binding. Here, we demonstrate that retention of a conserved amino acid motif surrounding tyrosine 877 (referred to here as EGFR YHAD ) is sufficient to confer binding to c-Src. Surprisingly the association of c-Src was not dependent on its SH2 or SH3 domain or on the phosphorylation or kinase activity of the receptor. We further show that the chimeric EGFRs that contain the Y877 motif are transforming in vitro and in vivo following ligand stimulation. Transformation was also partially dependent on sustained activation of Stat3. Finally, we demonstrate that EGFRs with mutations in the catalytic domain, originally identified in lung cancer and conferring increased sensitivity to gefitinib and erlotinib, two EGFR kinase inhibitors, gained the capacity to bind c-Src. Moreover, transformation by these EGFR mutants was inhibited by Src inhibitors regardless of their sensitivities to gefitinib and erlotinib. These observations have important implications for understanding the molecular basis for resistance to EGFR inhibitors and implicate c-Src as a critical signaling molecule in EGFR mutant-induced transformation.

Most asthma patients prescribed maintenance asthma therapies still experience periods of asthma worsenings characterized by daytime or night-time symptoms, or an increased need for rescue medication. In fact, these episodes are highly prevalent even in patients with well-controlled disease. Published literature suggests that asthma worsenings likely represent a window of opportunity during which patients could intervene early to prevent exacerbations or further deterioration of asthma symptoms. However, current evidence suggests that most patients fail to respond or to self-manage appropriately during these periods.To address the issue of asthma worsenings, an interdisciplinary committee of respirologists, allergists, family physicians, pharmacists and certified asthma educators from across Canada developed a practical definition of asthma worsenings and provided approaches to the prevention and management of these episodes based on current literature. To date, combination inhaled corticosteroid/long-acting beta-agonist therapy, particularly single inhaler maintenance and reliever therapy, appears to be an effective strategy for preventing asthma worsenings and exacerbations. Addressing the potential barriers to appropriate patient self-management of asthma worsenings, such as failure to adequately identify and respond to worsenings, low expectations for controlling asthma, low health literacy and poor patient-health care professional communication, are also critical to the successful prevention and management of these episodes. Finally, an interdisciplinary team approach involving patients and their families, certified asthma educators, primary care physicians, pharmacists and specialists is likely to have the greatest impact on the identification, prevention and management of asthma worsenings.

Objectives To identify the antitumor activity and wound-healing effect of docetaxel delivered in the surgical tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). Design Control and experimental series. Setting Academic medical center. Subjects BALB/c and severe combined immunodeficiency mice. Intervention Intrawound (IW) docetaxel therapy was tested in 3 HNSCC xenograft and 2 taxane-resistant models. Intratumoral (IT) docetaxel therapy was further tested in the 2 taxane-resistant models. Main Outcome Measures Tumor size, survival, and wound toxic effects were measured. The effect of docetaxel on various factors involved in wound healing and tumor growth within the surgical tumor microenvironment was also analyzed. Results In a pilot study using BALB/c mice, IW docetaxel therapy was not associated with problems in wound healing. Using the HN6, HN12, and HN30 HNSCC xenograft model, IW docetaxel prevented tumor growth and improved survival when compared with controls. No local or systemic toxic effect or wound-healing problem was noted. Using taxane-resistant xenograft lung cancer (H460/T800) and syngeneic salivary cancer (BALB/c mucoepidermoid carcinoma) models, IW therapy did not delay tumor growth. An antitumor effect was detected with repeated docetaxel injections in the H460/T800 taxane-resistant model but not in the BALB/c mucoepidermoid carcinoma model. Docetaxel inhibited the expression of growth factors and receptors in tumor cells; however, it did not inhibit the level of wound-healing growth factors in the surgical tumor microenvironment. Conclusions These preclinical results support further testing of IW docetaxel treatment in HNSCC. Docetaxel appears to exert antitumor activity without affecting factors involved in wound healing in the tumor microenvironment.

Purpose The aim of this study is to determine the ability of intratumorally delivered docetaxel to enhance the antitumor activity of adenovirus-mediated delivery of p53 (Ad-p53) in murine head and neck cancer xenograft model. Materials and methods A xenograft head and neck squamous cell carcinoma mouse model was used. Mice were randomized into 4 groups of 6 mice receiving 6 weeks of biweekly intratumoral injection of ( a ) diluent, ( b ) Ad-p53 (1 × 10 10 viral particles per injection), ( c ) docetaxel (1 mg/kg per injection), and ( d ) combination of Ad-p53 (1 × 10 10 viral particles per injection) and docetaxel (1 mg/kg per injection). Tumor size, weight, toxicity, and overall and disease-free survival rates were determined. Results Intratumoral treatments with either docetaxel alone or Ad-p53 alone resulted in statistically significant antitumor activity and improved survival compared with control group. Furthermore, combined delivery of Ad-p53 and docetaxel resulted in a statistically significant reduction in tumor weight when compared to treatment with either Ad-p53 or docetaxel alone. Conclusion Intratumoral delivery of docetaxel enhanced the antitumor effect of Ad-p53 in murine head and neck cancer xenograft model. The result of this preclinical in vivo study is promising and supports further clinical testing to evaluate efficacy of combined intratumoral docetaxel and Ad-p53 in treatment of head and neck cancer.

6011 Background: Quality of head and neck surgery has thus far focused on adherence to clinical national guidelines and margin status. For other solid tumors, an association has been found between ...

119 Background: Radiotherapy (RT) interruptions have a negative impact on outcomes in many epithelial malignancies treated with definitive RT. The purpose of this study was to analyze the impact of RT duration on outcomes in patients (pts) with esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Pts treated with definitive CRT on RTOG trials 8501 and 9405 were included. Separate analyses were performed in pts receiving standard dose (SD-CRT; 50 Gy + 5FU + cisplatin) and high dose (HD-CRT; 64.8 Gy + 5FU + cisplatin) CRT. Local (LF) and regional (RF) failure were estimated by the cumulative incidence method. Disease-free (DFS) and overall (OS) survival were estimated by the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were utilized to examine for correlation between RT duration (< vs. ≥ median) with LF, RF, DFS and OS. Results: In the SD-CRT cohort (n=235), 96 pts (41%) had ≥ 1 RT interruption for a median of 3 (IQR 1-6) days. The median RT duration was 39 (IQR 37-43) days. In UVA and MVA, RT duration was not associated with LF, RF, DFS, or OS. Estimated outcome rates are in the table. In the HD-CRT cohort (n=107), 64 pts (60%) had ≥ 1 RT interruption for a median of 3.5 (IQR 2-7.5) days. The median RT duration was 52 (IQR 50-57) days. In UVA, RT duration ≥ 52 days was associated with a 33% reduction in risk of DFS failure (HR=0.66, 95% CI [0.44-0.98], p=0.039) and a 29% reduction in risk of death (HR=0.71, 95% CI [0.48-1.06], p=0.09). When excluding the 25 pts with RT dose < 64.8 Gy, RT duration was not associated with DFS or OS. Conclusions: In pts with esophageal cancer receiving definitive SD-CRT, an association between RT duration and outcomes was not observed. In pts receiving HD-CRT, longer RT duration was associated with improved DFS, which may have been due to a significant number of deaths at RT dose < 64.8 Gy. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422. Clinical trial information: NCT00002631. [Table: see text]

Using surrogate models in place of high fldelity engineering simulations can help reduce design cycle times and cost by enabling rapid analysis of alternative designs. Surrogate models can also be used in a deliverable product as an e‐cient replacement for large lookup tables or as a soft sensor to predict quantities than cannot be directly measured. Many difierent surrogate modeling techniques exist, including new commercial technologies, each with difierent capabilities and pitfalls. The goal of this research is to aid the designer in selecting the appropriate surrogate model by comparing two popular techniques, second order regression and kriging, along with a new commercial application called Datascape. The three difierent modeling techniques are compared on model accuracy, computational e‐ciency, robustness, transparency, and ease of use. The comparisons were done using three test problems: an Earth-Mars transfer orbit problem, the analytic Shekel function, and a low Earth orbit three-satellite constellation design problem. It was found that kriging models performed the best when the sample data used to build the models was sparse, when larger sample sets were used Datascape produced more accurate models.

Background. Postopertative adjuvant chemoradio- therapy recently became an established modality for patients with selected high-risk locally advanced head and neck cancers. The optimal treatment of unknown primary squamous cell cancer of the head and neck (SCCHN) continues to be controversial, since major randomized studies excluded those patients. Methods. We conducted a retrospective review of patients treated during 1995 to 2002 for unknown primary SCCHN. All patients were treated with a neck dissection followed by con- current high-dose cisplatin (100 mg/m 2 ) and bilateral neck radiotherapy. Results. Thirty-seven patients were identified with nodal dis- ease distribution of N1 (5%), N2a (22%), N2b (41%), N2c (8%), N3 (22%), and Nx (3%). Modified neck dissection was done on the majority (30/37 ¼ 81%) of patients. With a median follow-up of 42 months among the survivors, very few patients had re- gional recurrence (5%) or distant failure (11%), and 89% of patients were alive. The actuarial 5-year overall survival rate could not be estimated because there were no deaths beyond 20 months after surgery. Substantial yet acceptable acute and late morbidities were demonstrated in this cohort of patients. Conclusions. Postoperative chemoradiotherapy is of poten- tial benefit to patients with unknown primary SCCHN by improv- ing survival and reducing failures. This treatment warrants further prospective evaluation. V C 2006 Wiley Periodicals, Inc. Head Neck 28: 1090-1098, 2006

Purpose BMS-275183 is an orally bioavailable taxane that has antitumor activity in preclinical cancer models. However, limited BMS-275183 studies have been performed in head and neck squamous cell carcinoma (HNSCC) cell lines. The purpose of this study is to identify the biological activity of BMS-275183 on HNSCC. Materials and Methods Head and neck squamous cell carcinoma cell lines, HN6, HN12, and HN30, were exposed to BMS-275183. BMS-275183–induced growth suppression, cell-cycle arrest, and apoptosis were measured. Then, expression of selected proteins that were induced by BMS-275183 was determined by Western blot analysis. Results BMS-275183 suppressed proliferation and induced G2M arrest and apoptosis in all HNSCC cell lines tested. BMS-275183 altered the expression of cell-cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and p27 was decreased and increased, respectively, in all HNSCC cell lines. Cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) were increased in HN6 and HN12 cells. epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) expression were decreased by BMS-275183 in HN6 and HN30 cell lines, whereas phosphorylated epidermal growth factor receptor (pEGFR) was decreased in only HN6 cells. Conclusions BMS-275183 induced cellular apoptosis, cell-cycle arrest, and altered gene expression in HNSCC via molecular pathways similar to other taxanes. These preclinical experiments suggest that BMS-275183 may be useful in treating HNSCC and that the aforementioned genes can potentially be used as surrogate end-point biomarkers.

Purpose This multicentered phase III trial was designed to compare an emulsion containing trolamine against the usual supportive care within each participating institution for patients with head and neck cancer undergoing radiation therapy. Patients and Methods Patients with biopsy-proven squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to one of the following treatments: prophylactic trolamine emulsion, interventional trolamine emulsion, or declared institutional preference. The primary outcome was the reduction in grade 2 or higher skin toxicity, as per National Cancer Institute Common Toxicity Criteria version 2.0. Secondary outcomes included patient-reported quality of life (QOL). Results From October 2000 to April 2002, 547 patients from 51 institutions were entered onto the trial. The average age was 59 years. Patients were predominately male (79%) and most continued to use tobacco products (52%). The rates of grade 2 or higher radiation dermatitis were 79%, 77%, and 79% in the prophylactic, interventional, and institutional preference arms of the study, respectively. No significant differences in QOL were found. Conclusion The results of this trial demonstrate no advantage for the use of trolamine in reducing the incidence of grade 2 or higher radiation dermatitis or improving patient-reported QOL. The use of 15 different local standards of care highlights the need to continue research that will result in evidence-based recommendations to reduce the burden of radiation dermatitis.

A family history of food allergy can cause anxiety in parents. This may prevent food introduction in their children. Current guidelines recommend skin testing only when there is a reaction to a food in that specific patient. When there is a family history of food allergy, parents frequently ask their physicians for food testing of their children prior to introduction of specific foods. We conducted this study to determine whether allergy skin testing reduces anxiety levels in parents thereby leading to food introduction. Methods The parents of 50 children with a family history of food allergy completed a Visual Analog Score (VAS) to estimate their anxiety to give their children the specific food of concern. Previously, the children had not eaten the food. The VAS scores were recorded pre- and post-skin testing on a scale from 0 to 10. The likelihood of food introduction pre- and post-skin testing was estimated. Results The mean age of the children was 3.6 years; the majority were males (62%). Approximately 58% of patients’ parents, 38% siblings and 4% other relatives had food allergy. Most children (78%) had family history of a single food allergen and 60% had a family history of allergy to peanuts. All children tested negative for the food allergen of concern. Mean VAS was statistically different pre- and post-skin testing (pre VAS mean= 7.83 vs post VAS mean = 2.15; p=

Background Tourette's syndrome is a relatively common disorder that may present as a spectrum that can include both motor and behavioral features. Methods We report four patients referred to allergists to rule out atopy as a reason for their presumed respiratory symptoms who were subsequently found to have Tourette's syndrome. A review of the literature was also performed using MEDLINE. Results The symptoms of Tourette's syndrome may overlap those associated with allergy involving the respiratory tract. There is little published information on the association of Tourette's syndrome with atopy. Conclusions Allergists should be aware of Tourette's syndrome and the variable clinical spectrum of this disorder as Tourette's syndrome patients may be referred prior to the diagnosis of Tourette's syndrome.

Purpose: This is a pilot study to identify changes in gene and protein expressions after treatment with docetaxel in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). Methods: Two cisplatin-resistant HNSCC cell lines, HN30 and HN12, were treated with either docetaxel or cisplatin. After 48 hours, differential gene expression between the two treatment groups (docetaxel-treated cells and cisplatin-treated cells) was analyzed using cDNA microarray. Differential protein expression between these two treatment groups was determined using PowerBlot and Western Blot analysis Results: A total of 150 genes and proteins were found to have differential expression patterns in HNSCC after treatment with docetaxel versus cisplatin. Many of these differentially expressed genes and proteins were involved in the cell cycle (decreased E2F), apoptosis (increased bax), angiogenesis (increased thrombospondin), and signal transduction (decreased epidermoid growth factor receptor) regulatory pathways. Conclusions: Gene and protein expression are different and distinct between cells treated with docetaxel and cells treated with cisplatin. This finding provides evidence that different molecular pathways leading to cell death are targeted by docetaxel and cisplatin. Future studies focusing on these differentially expressed genes and proteins may improve our understanding, at the molecular level, of the mechanisms responsible for docetaxel-induced apoptosis in cisplatin-resistant HNSCC. Furthermore, these differentially expressed genes and proteins can be exploited as useful surrogate endpoint biomarkers in future clinical trials using docetaxel.

c-Src associates with and is activated by the ErbB-2 receptor tyrosine kinase, but is unable to bind the EGFR. Although c-Src has been found to interact directly and specifically with the ErbB-2 receptor, the significance of this interaction is unclear. Using both chimeric receptor and site-directed mutagenesis approaches, the region of interaction of c-Src on ErbB-2 was identified. Significantly, EGFR could be converted into a receptor capable of binding c-Src by replacement of a catalytic domain of ErbB-2. We further demonstrated that MDCK cells that express mutant EGFR that are competent in c-Src recruitment lose epithelial polarity in organoid cultures, whereas cells overexpressing the wild-type EGFR retain a polarized phenotype. ErbB-2-dependent activation of c-Src results in disruption of epithelial cell-cell contacts leading to cell dispersal that correlates with the re-localization of phospho-MAPK to focal adhesions. Taken together, these observations suggest that recruitment of c-Src to these closely related EGFR family members plays a critical role in modulating cell polarity.

Top of pageAbstract The c-Src tyrosine kinase has been implicated to play an integral role in modulating growth factor receptor, integrin and steroid receptor function. One class of steroid receptors that c-Src modulates is the estrogen receptor (ER). Although there is strong biochemical evidence supporting a role for c-Src in ER signaling, the consequence of this association is unclear at the biological level. To explore the significance of c-Src in ER signaling, we studied the development of various reproductive organs that are dependent on ER in c-Src-deficient mice. We show that the loss of the c-Src tyrosine kinase correlates with defects in ductal development as well as in uterine and ovarian development. Genetic and biochemical analyses of c-Src-deficient mammary epithelial cells also revealed defects in the ability of mammary epithelial cells to activate a number of signaling pathways in response to exogenous estrogen stimulation. Taken together, these studies demonstrate that c-Src plays a role in ER signaling in vivo. Keywords: estrogen receptor, c-Src, mammary gland

Dok-R has previously been shown to associate with the epidermal growth factor receptor (EGFR) and become tyrosine phosphorylated in response to EGF stimulation. The recruitment of Dok-R to the EGFR, which is mediated through its phosphotyrosine binding (PTB) domain, results in attenuation of mitogen-activated protein kinase (MAPK) activation. Dok-R's ability to attenuate EGF-driven MAPK activation is independent of its ability to recruit rasGAP, a known attenuator of MAPK activity, suggesting an alternate Dok-R-mediated pathway. Herein, we have determined the structural determinants within Dok-R that are required for its ability to attenuate EGF signaling and to associate with c-Src and with the Src family kinase (SFK)-inhibitory kinase, Csk. We demonstrate that Dok-R associates constitutively with c-Src through an SH3-dependent interaction and that this association is essential to Dok-R's ability to attenuate c-Src activity and diminish MAPK and Akt/PKB activity. We further illustrate that EGF-dependent phosphorylation of Dok-R requires SFK activity and, more specifically, that SFK-dependent phosphorylation of tyrosine 402 on Dok-R facilitates the inducible recruitment of Csk. We propose that recruitment of Csk to Dok-R serves to bring Csk to c-Src and down-regulate its activity, resulting in a concomitant attenuation of MAPK and Akt/PKB activity. Furthermore, we demonstrate that Dok-R can abrogate c-Src's ability to protect the breast cancer cell line SKBR3 from anoikis and that an association with c-Src and Csk is required for this activity. Collectively these results demonstrate that Dok-R acts as an EGFR-recruited scaffolding molecule that processively assembles c-Src and Csk to attenuate signaling from the EGFR.

Background Radiation therapy yields a 2-year local control rate of 80% to 90% in early laryngeal squamous cell carcinoma. However, a subset of early laryngeal cancers has a significantly higher rate of local recurrence and lower rate of overall survival. Objective The objective of this study was determine the prognostic significance of p53, p27, and p21 expression in patients with early laryngeal cancer. Methods Expression of p53, p27, and p21 proteins in pretreatment biopsies from sixty-eight patients was analyzed by using immunohistochemistry. Low (≤10% cells) and high (>10% cells) levels of expression were measured. All patients were newly diagnosed and treated with external beam radiation. Other contributing factors were also studied, such as age, sex, race, tumor site, and stage. Results Forty (58.8%) and 28 (41.2%) lesions were staged as T1 and T2, respectively, whereas 16 (23.5%) and 52 (76.5%) were located in the supraglottis and glottis, respectively. Overexpression of p27, p53, and p21 was found in 36.7%, 60.6%, and 60% of cases, respectively. Overexpression of p27 was found to be a significant predictor of recurrence by multivariate analysis (RR 3.3, P = .017). Overexpression of p21 and/or p53 was not predictive of recurrence. No factor predicted disease specific or nonspecific overall survival. Conclusion Our results indicate the significance of p27 overexpression as an indicator of recurrence in patients with early laryngeal squamous cell carcinoma.

Objective To determine the prognostic significance of p53 and fragile histidine triad (FHIT) expression in advanced oropharyngeal squamous cell carcinoma. Study design A retrospective collection of clinical data was correlated with the protein expression. Method The expression of p53 and FHIT in specimens from patients with previously untreated advanced squamous cell carcinoma of the oropharynx was determined by immunohistochemistry. The expression of p53 and FHIT was statistically correlated with survival outcome. The primary endpoints were overall survival and disease-free survival. Results Thirty-four patients were analyzed in this study. Overexpression of p53 was observed in 41.2% (14/34) of tumors and was associated with a trend toward an improved overall survival using univariate ( P = .1088, risk ratio [RR] = 0.503) and multivariate ( P = .1533, RR = 0.470) analyses. Marked reduction or complete absence of FHIT expression was observed in 57.6% (19/33) of tumors. Patients with tumors showing no reduction in FHIT expression had a lower overall survival using univariate ( P = .04, RR = 2.27) and multivariate ( P = .013, RR = 4.41) analyses. Conclusion Overexpression of p53 predicted a trend toward an improved prognosis, whereas no reduction in FHIT expression predicted a significantly poorer outcome in patients with advanced oropharyngeal cancer.

We present the clinical and histopathologic findings of a 38-year-old woman recently diagnosed with sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid (SMECE). This case is of particular interest because of its extremely aggressive clinical course. After total thyroidectomy, there was extensive bilateral thyroid lobe involvement with extension into perithyroidal soft tissues and the modified radical neck dissection contained 35 of 35 positive lymph nodes. This patient underwent 2 further surgeries; the first was a second right neck and supraclavicular surgery for lymph node metastases in which 8 of 11 were positive, followed a few months later by posterior neck surgery in which multiple lymph nodes were positive. Tumor was also documented by histological review from a right axillary lymph node. Imaging evidence of tumor in the lungs and liver was also present. Establishing the correct diagnosis of SMECE involves an awareness of the cyto- and histomorphologic features of this rare malignancy. As evidence that the biologic behavior of this neoplasm may well be more aggressive than previously considered, we briefly present the clinical and biologic course of this patient's neoplasm and a review of the literature.

Objective: To report a case of thrombocytopenia and a case of neutropenia, both associated with the use of diclofenac. Case Summaries: A 63-year-old woman was receiving diclofenac for osteoarthritis. During a hospital admission for pneumonia, she was found to have severe thrombocytopenia. Diclofenac therapy was stopped and the thrombocytopenia resolved. Several months later she was inadvertently treated with diclofenac by another physician and again experienced thrombocytopenia, which again resolved on discontinuation of the drug and has not recurred since. A 72-year-old man was receiving diclofenac for 9 months for osteoarthritis. He was then found to have asymptomatic neutropenia. Diclofenac therapy was stopped and the neutropenia resolved with no other intervention. He was not rechallenged. Discussion: Severe thrombocytopenia and neutropenia are extremely rare adverse reactions to diclofenac. To date, there is only 1 case of each that is well documented and supported in the literature. Conclusions: Severe thrombocytopenia and neutropenia are potential serious adverse effects of the use of diclofenac. Patients who are receiving diclofenac and develop symptoms of either thrombocytopenia or neutropenia should have a complete blood count, and if this diagnosis is confirmed, the drug therapy should be stopped.

Publisher Summary This chapter focuses on two head and neck cancers: cervical lymphadenopathy from an undetectable primary source and adenoid cystic carcinomas (ACC) that have unusual natural histories. Although cervical lymphadenopathy is a common presentation of malignant tumor in the head and neck area, in –4% of the patients, the primary tumor cannot be identified following extensive diagnostic workup. The most common age of this undetectable primary source at presentation is 50 to 60 years old, and the male-to-female ratio is 3:1. The most commonly involved nodal group is jugulodiagastric and midjugular, which are involved in about 60% of the patients, where squamous cell and undifferentiated carcinoma accounts for 70–80% of histology. The most common site of ACC is in the salivary glands, especially in minor salivary glands. ACC comprises 2–5% of all tumors of the salivary glands, and it is the most common malignancy of the minor salivary glands. The most common age at presentation is 50 to 60 years old with no predilection for either gender. The most common presenting symptom is a painless mass, often enlarging rapidly but presenting indolently for years prior to presentation. Pain is a relatively uncommon symptom and may indicate the involvement of deep structures. ACC has a high rate of local recurrence and distant metastasis despite aggressive initial local treatment. It is believed to originate from the reserve epithelial cells in the intercalated ducts, which can differentiate into epithelial and myoepithelial cell forms.

Purpose To characterize in vivo features of HPV-immortalized and carcinogen transformed oral keratinocytes. Methods The growth and squamous differentiation of IHGK (immortalized human gingival keratinocyte with HPV), IHGKN [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)]-carcinogen transformed keratinocytes, and two head and neck squamous cell carcinoma (HNSCC) cell lines, HN30 and HN12, were tested by injecting these cells into SCID mice. The growth, histological features, and expression of PCNA, Involucrin, and high molecular weight keratin of the tumors formed were compared among these cell lines. Results All cell lines formed a palpable lesion at 2 weeks; however, only HN30 continued to grow. IHGK and IHGKN cells formed palpable nodules within 2 weeks with no further growth after 4 to 5 weeks, and no regression of the nodule was noted at 12 weeks. HN12 cells did not form tumor nodules unless these cells were co-injected with immortalized fibroblasts. Both IHGK and IHGKN cells formed a well-circumscribed epithelial lesion with islands of differentiated squamous cells bound by a myxoid matrix. Nests of basal-horny squamous cells centrally differentiated into anucleate squamous cells. IHGK and IHGKN nodules had more squamous differentiation than HN12 and HN30 and further differentiated over time. IHGK and IHGKN cells expressed differentiation (involucrin and high molecular weight keratin) and proliferation (PCNA) markers that suggest that IHGK and IHGKN behave as well-differentiated squamous lesions when compared with malignant HN12 and HN30 nodules. IHGK and IHGKN cells showed an initial growth phase followed by terminal differentiation, and then a phase characterized by regression and host inflammatory stage. Conclusions The growth, histology, and expression of differentiation and proliferation markers of IHGK and IHGKN lesions into SCID mice demonstrate that these cells are endowed with a limited malignant potential. Our in vivo model with these intermediate cell lines can provide a short-term analysis for studying the biology of HNSCC progression and the activity of chemoprevention agents.

Background Auriculotemporal syndrome (AS) is an uncommon disorder that may present with facial erythema with chewing food. Methods We report a patient referred to an allergist to rule out allergy as a reason for food-associated bilateral facial flushing. She was subsequently found to have bilateral AS. Results The symptoms of AS may overlap those associated with food allergy. There are only a few published cases of bilateral AS. Conclusions Allergists should be aware of bilateral AS and the clinical spectrum of this disorder as AS patients may be referred to allergists to rule out food allergy.

The purpose of this study was to evaluate the biological mechanisms of docetaxel (TXT) on salivary gland carcinoma.The effects of TXT on a spontaneous murine salivary carcinoma were determined. Proliferation, cell cycle regulation, connexin43 expression, gap-junctional intercellular communication, apoptosis, and Fas receptor (FasR) expression were measured.We characterized a spontaneous mouse salivary gland carcinoma (SGC1). SGC1 is a poorly differentiated carcinoma that originated from the parotid gland of a BALB/c mouse. SGC1 cells were cultured and found to be immortal past 30 passages. Initially, cells formed tumor nodules in severe combined immunodeficient (SCID) mice. Afterward, SGC1 cells that were subcultured from SCID tumors readily formed colonies in soft agar and were highly tumorigenic in SCID mice and immune-competent BALB/c hosts. Dose response for TXT with respect to growth suppression, G(2)-M cell cycle arrest, and apoptosis was found. Induction of apoptosis by TXT coincided with an increase in cell surface FasR expression. Up-regulation of FasR with lower doses of TXT rendered cells susceptible to FasR agonist antibody-mediated apoptosis. In the absence of TXT, anti-FasR antibodies were completely without effect, suggesting that TXT is critical for priming apoptosis mediated through the Fas pathway. In addition, gap-junctional intercellular communication was augmented by TXT in SGC1 cells concomitant with increased connexin43 expression and membrane localization.We have identified several novel targets of TXT that contribute to its antitumor activity in poorly differentiated salivary gland carcinoma. These results suggest that TXT may be appropriate for additional in vivo studies and clinical trials in patients with salivary cancers.

BACKGROUND: Recent results of R9802 (Buckner et al; J Clin Oncol 32:5s, 2014 (suppl; abstr 2000)) demonstrated that PCV given with RT at the time of initial diagnosis prolongs both progression-free survival (PFS) and overall survival (OS) for all patients enrolled in the trial. Herein, we report the impact of treatment on PFS and OS based upon specific histologic type. METHODS: Eligibility criteria included age 40 with any extent of resection, and supratentorial grade ll oligodendroglioma (O), oligo-astrocytoma (OA), or astrocytoma (A). Patients were stratified by age, histology, Karnofsky Performance Status, and presence versus absence of contrast enhancement on the preoperative imaging study and randomized to RT alone (54 Gy in 30 fractions) or RT followed by 6 cycles of PCV chemotherapy. In an exploratory analysis, we used the log rank test to compare survival and progression free survival (PFS) distributions for each histologic type. RESULTS: 251 eligible patients were accrued from 1998 to 2002: 107 had O, 79 had OA, and 65 had A. In total, 67% have progressed and 55% have died. Median PFS (RT vs. RT + PCV) overall, O, OA, and A, respectively, are 4.0 vs 10.4 (p < 0.001); 6.0 vs not reached (NR) (p < 0.001); 3.0 vs 8.9 (p = 0.01); and 1.8 vs 3.7 (p = 0.06) years. Median survival times (RT vs. RT + PCV) overall, O, OA, and A, respectively, are 7.8 vs 13.3 (p = 0.002); 10.8 vs NR (p = 0.008); 5.9 vs 11.4 (p = 0.05); and 4.4 vs 7.7 (p = 0.31) years. CONCLUSIONS: For grade 2 glioma patients with less than gross total tumor resection or >40 years of age, PCV + RT prolongs both OS and PFS compared with RT alone. The observed benefit is most definitive for O and OA patients.

Background Epinephrine auto-injectors are the standard first aid treatment for anaphylaxis. Intramuscular delivery into the anterolateral aspect of the thigh is recommended for optimal onset of action of epinephrine. The most frequently prescribed auto-injector in North America and Canada is the EpiPen®, which has a needle length of 15.2 mm. Currently, it is unknown whether this needle length is adequate for intramuscular delivery of epinephrine in adult patients at risk of anaphylaxis. Methods One hundred consecutive adult patients with confirmed food allergy requiring an epinephrine auto-injector were recruited. Skin to muscle depth (STMD) at the right mid-anterolateral thigh was measured using ultrasound under minimal (min) and maximum (max) pressure. The EpiPen® needle length was considered adequate if STMDmax was ≤15.2 mm. Baseline characteristics including age, gender, ethnicity, and body mass index (BMI) were compared in patients with STMDmax ≤15.2 mm vs. >15.2 mm. Results The EpiPen® needle length of 15.2 mm was inadequate for intramuscular delivery in 19 of the 100 enrolled patients (19%), all of whom were female; 28% of women had a STMDmax >15.2 mm. The mean STMDmax in the ≤15.2-mm and >15.2-mm groups were 9 ± 4 mm and 20 ± 4 mm, respectively (p = 0.0001). Linear regression analysis found BMI to be significantly associated with STMDmax after adjusting for age (p

2000 Background: Early results of R9802 (Shaw et al: J Clin Oncol. 2012; 30(25):3065-70) demonstrated that PCV given with RT at the time of initial diagnosis prolongs progression-free survival (PFS...

Background Allergic rhinitis (AR) has been estimated to affect approximately 20–25% of Canadians. [1] Management of AR encompasses allergen avoidance, use of symptomatic medications, and allergen immunotherapy for patients unresponsive to other pharmacotherapy. [2,3] This study was conducted to characterize patients receiving subcutaneous immunotherapy (SCIT) and the SCIT administration process in Canada and the United States; Canadian results are presented. Methods A multi-center, prospective, observational study was conducted at 5 allergy clinics in Quebec and Ontario and 1 primary care clinic in Quebec from March-September 2012. Patients ≥6 years who were scheduled for SCIT on study days were invited to participate in the study. Patients enrolled in a clinical trial, receiving sublingual immunotherapy or allergic only to insect venom, latex, food, or drugs were excluded. Site and patient-specific information were captured via direct observation, questionnaires, and medical chart review. Costs were estimated from time and supply observation and query. Results A total of 294 patients were enrolled with a mean age of 44 years (4%

Background Epinephrine delivered by an auto-injector to the anterolateral aspect of the thigh is the standard of care for the emergency treatment of anaphylaxis. For most pediatric patients in Canada, the EpipenJr is prescribed, which has a needle length of 12.7mm. The route of epinephrine administration affects its onset of action, and intramuscular delivery is recommended for rapid absorption. If epinephrine is injected subcutaneously, the absorption will be slower. Conversely, if it is injected into the bone, the absorption will be unpredictable. There are no published clinical studies assessing whether the needle length of the EpipenJr is adequate to deliver epinephrine intramuscularly in pediatric patients at risk of anaphylaxis.

Amplification of the Neu (ErbB-2 or HER-2) receptor tyrosine kinase occurs in 20 to 30% of human mammary carcinomas, correlating with a poor clinical prognosis. We have previously demonstrated that four (Y1144 Y1201, Y1227 and Y1253) of the five known Neu autophosphorylation sites can independently mediate transforming signals. The transforming potential of two of these mutants correlates with their capacity to recruit Grb2 directly to Y1144 (YB) or indirectly through Shc to Y1227 (YD). Here, we demonstrate that these transformation-competent neu mutants activate extracellular signal-regulated kinases and stimulate Ets-2-dependent transcription. Although the transforming potential of three of these mutants (YB, YD, and YE) was susceptible to inhibition by Rap1A, a genetic antagonist of Ras, the transforming potential of YC was resistant to inhibition by Rap1A. To further address the significance of these ErbB-2-coupled signaling molecules in induction of mammary cancers, transgenic mice expressing mutant Neu receptors lacking the known autophosphorylation sites (NYPD) or those coupled directly to either Grb2 (YB) or Shc (YD) adapter molecules were derived. In contrast to the NYPD strains, which developed focal mammary tumors after a long latency period with low penetrance, all female mice derived from YB and YD strains rapidly developed mammary tumors. Although female mice from several independent YB or YD lines developed mammary tumors, the YB strains developed lung metastases at substantially higher rates than the YD strains. These observations argue that Grb2 and Shc play important and distinct roles in ErbB-2/Neu-induced mammary tumorigenesis and metastasis.

Objectives. To define the patient-reported complications after cryoablation therapy for prostate cancer and to compare these results to previously published patient-reported complications for radical prostatectomy and external beam irradiation. Methods. A questionnaire similar to previously published patient-reported complication studies was sent to the first 290 patients treated by cryoablation therapy at our institution. The questionnaire was returned by 267 patients. Forty-four patients were excluded from analysis because of prior irradiation, transurethral prostatectomy, or cryoablation, resulting in a study group of 223 patients. Results. Of the 208 patients with good urinary control preoperatively, 9 (4.3%) patients used incontinence pads after cryoablation. Seven of the 8 patients who used one pad daily reported leakage of only a few drops. Impotency, defined as an inability to obtain erections adequate for vaginal penetration, occurred in 85% of men who were potent preoperatively. Urethrorectal fistula occurred in 1 patient (0.4%). Bladder outlet obstruction caused by stricture or sloughed necrotic prostatic tissue required dilation or transurethral resection in 10% of patients. Scrotal swelling, penile tingling, and pelvic pain occurred in 18%, 15%, and 12% of patients, respectively; typically, these resolved spontaneously within 3 months. Conclusions. Patient-reported complications for cryoablation compared favorably to those reported for radical prostatectomy and external beam irradiation. Patient satisfaction was high; 96% of patients reported that they would choose cryosurgery as a treatment option again.

It has previously been shown that a single intracisternal inoculum of AlCl3 in young adult New Zealand white rabbits will induce a dose-dependent phosphatase resistance of the high molecular weight neurofilament protein (NFH) that is proportionate to the extent of neurofilamentous inclusion formation (Strong and Jakowec, 1994). To determine if the potential for dissolution of aluminum-induced neurofilamentous inclusions was dependant on the degree of NFH phosphatase resistance, we have examined NFH phosphatase sensitivity in a reversible chronic model of aluminum neurotoxicity. Rabbits receiving repeated intracisternal inoculums of 100 μg AlCl3 at 28 day intervals until day 267 develop spinal motor neuron perikaryal and neuroaxonal neurofilamentous aggregates in a Stereotypic, dose-dependent fashion. In the rabbits receiving inoculums until day 156 with survival until day 267 without further aluminum exposure, neuroaxonal spheroids remained prominent while perikaryal inclusions largely resolved. Immunoreactivity to a monoclonal antibody recognizing phosphorylated NFH (SMI 31) was abolished in perikaryal aggregates at each time interval by dephosphorylation with bovine alkaline phosphatase. However, neuroaxonal spheroids maintained their immunoreactivity. Using time-course dephosphorylation studies of spinal cord homogenates, we observed a significant reduction in the rate of dephosphorylation of NFH following 267 days of AlCl3 exposure (P < 0.05). These observations suggest that neuroaxonal spheroids contain phosphatase-resistant NFH isoforms and that the potential for resolution of intraneuronal neurofilamentous inclusions correlates with the susceptibility of NF within these inclusions to enzymatic dephosphorylation.

the 13 patients who developed DM, the LN levels involved were: Level I (3 pts), Level II (12 pts), Level III (8 pts), Level IV (7 pts), Level V (6 pts) and RP group (2 pts). Hence, the risk of DM stratified based on each LN level was calculated as follows: Level I (33%), Level II (20%), Level III (20%), Level IV (39%), Level V (46%) and RP group (33%). The 3 patients with DM who had Level I LN involved had extra-oral cavity primaries with multi-level involvement (Supraglottic Larynx “level I-V”, Base of Tongue ”Levels I,III,IV” and Tonsil “Level I-II”). The most common site for DM was lung (8 pts), followed by bones (5), liver (2) and brain (1). Conclusions: Patients with HNSCC who have involved Lymph Node levels IV, V or RP group are associated with 33-46% risk of DM on this cohort and should be considered to be further assessed for the role of adjuvant systemic therapy. Author Disclosure: H. AlHussain: None. I. Busca: None. L. Eapen: None. S. El-Sayed: None.

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p

e16019 Background: After the failure of first line palliative chemotherapy in recurrent non-resectable or metastatic head and neck squamous-cell carcinoma (HNSCC), there is no standard of care treatment that improves survival or quality of life. Both, methotrexate and cetuximab have single agent activity in metastatic HNSCC. We are presenting our institutional experience in using unique combination chemotherapy with methotrexate plus cetuximab (MC). Methods: Retrospectively, single institution’s charts were reviewed from 2004-2010, all patients have documented recurrent non-resectable or metastatic HNSCC. Patients received weekly IV methotrexate 25 mg/m2 plus IV cetuximab 250 mg/m2. Each cycle is 4 weeks treatments. Patients who completed at least 2 cycles were included. Patients can receive MC as first line if they have poor performance status. Treatment was continued until progression. Results: Total of 39 patients were included, 27 male and 12 female. Median patients’ age was 57 years old. 35 patients received methotrexate plus cetuximab (MC) after failure of prior line of palliative chemotherapy. 17, 10 and 8 patients received MC as second, third and fourth line therapy, respectively. 4 patients received MC as 1st line because they were not candidate for more aggressive therapy. The average received number of weekly treatments was 31 (8-95) and average number of cycles was 7 (2-23). Prior chemotherapy regimens include taxanes, platinum, 5-flurouracil, and gemcitabin. 13 patients received prior cetuximab as single agent or in combination. Median progression free survival was 7.1 months and overall survival was 9.8 months. Considering the line of therapy, the median survival was 6.9, 10.1, 13.5 and 9.9 months for patients received MC as 1st, 2nd , 3rd and 4th line of therapy respectively (P= 0.356). Grade 1 and 2 skin rash and hypomagnesimia were observed in 47% and 36% of patients. Conclusions: Methotrexate plus cetuximab is a well tolerated regimen with a significant survival benefit. Prospective well designed studies are warranted in order to evaluate this regimen as a second line palliative therapy for patients with advanced non-curable head and neck squamous cell carcinoma.

5534 Notice of Retraction: "Phase II study of biweekly dose-intense docetaxel plus gemcitabine (GEM/DOC) in patients with recurrent locoregional or metastatic head and neck squamous cell carcinoma." ASCO's Confidentiality Policy requires that abstracts be considered confidential and embargoed from the time of submission until the findings have been publicly released in conjunction with the ASCO Annual Meeting. Abstract 5534, published in the 2012 Annual Meeting Proceedings Part I, a supplement to the Journal of Clinical Oncology, violated this policy and has been retracted from publication and presentation at the 2012 ASCO Annual Meeting. Background: Patients with metastatic head and neck squamous cell carcinoma (HNSCC) have a poor prognosis, limited treatment options, and median survival of 6 to 9 months. Docetaxel and gemcitabine have both shown activity in HNSCC. The optimal combination, dosing, and scheduling of both drugs is, however, unknown. Thus, we investigated the efficacy and safety of biweekly dose intense GEM/DOC in patients with recurrent locoregional or metastatic HNSCC. Methods: An open-label, single-institution, single-arm, phase II study was conducted for patients who were previously treated with no more than two cytotoxic regimens. The patients received docetaxel (60 mg/m2IV) and gemcitabine (3000 mg/m2 IV) on day 1. The treatments were repeated every 14 days (one cycle), until disease progression or unacceptable toxicity. The primary end point was response rate. RECIST-defined response was evaluated every 4 cycles and toxicities were evaluated at each cycle. Results: A total of 36 patients were enrolled (M:F 26:10; median age (range), 60 years (46-79); performance status 0-1) , 29 of whom were response-evaluable. The patients received a median of 4 cycles (range 0-24). Of these 29 patients, none achieved complete response (CR) and 6 demonstrated a partial response (PR). Thus, the overall response rate was 21% (95% confidence interval [CI], 0.10 – 0.38). Ten patients had stable disease (SD), resulting in tumor control (CR or PR or SD) in 16 of 29 patients (55%), whereas 13 patients (45%) had disease progression. The median response duration was 3.2 months (80% CI: 2.0 – 6.1 months). For all 36 patients, the median overall survival was 4.2 months (95% CI: 2.4 – 7.0 months). Myelosuppression was the most common adverse event. Grade 3-4 neutropenia and anemia were observed in 10 (30%) and 13 (39%) patients, respectively. None of these patients, however, had febrile neutropenia or bleeding events, and there were no treatment-related deaths. Conclusions: The combination of biweekly dose intense GEM/DOC was tolerable and active regimen in patients with recurrent locoregional or metastatic HNSCC. Our findings warrant further investigation in a larger patient population.

96 Background: RTOG 9413 demonstrated that NHT+WPRT improved progression-free survival (PFS) compared to NHT+PORT, WPRT+AHT and PORT+AHT. We update primary and secondary endpoints (SE): biochemical failure (BF), time to metastasis (Mets), prostate specific survival (PSS) and overall survival (OS). Methods: RTOG 9413 opened on April 1, 1995, and closed on June 1, 1999, with 1275 eligible pts who were required to have a risk of lymph node (LN) involvement >15% but LN-positive pts were ineligible. They were stratified by T Stage, GS (30 vs < 30ng/ml) and randomized to PORT +/- WPRT to 70 Gy and NHT or AHT. Hormonal therapy (HT) consisted of flutamide, and leuprolide or goserelin, monthly x 4 mos, beginning 2 mos before RT and continued until RT is completed (NHT) or beginning at the completion of RT (AHT). For this analysis PFS was defined as the first occurrence of local/regional or LN progression, Mets, BF (PSA nadir+2ng/mL), or death from any cause. PSS is defined as a death due to prostate cancer, treatment toxicity or unknown causes with local progression, Mets or BF. Results: For the entire cohort WPRT or NHT did not appear to improve any endpoint compared with PORT or AHT, (although there was a trend for improvement in regional failure for WPRT vs PORT, (p=0.07)). However, there were complex sequence/volume dependent interactions between HT and RT and statistically significant differences between the 4 arms in PFS (p=0.03). There was a trend for NHT+WPRT to improved PFS compared to NHT+PO (p=0.07) and WPRT+AHT (p=0.04). NHT+WPRT was associated with an increased risk of late GI toxicity, 5% compared to 0.6%, 2% and 2% for NHT+PORT, WPRT+AHT and PORT+AHT (p Conclusions: The failure to improve SE or definitively impact PFS may reflect sample size, pt selection, and inadequate RT doses. RTOG 0924 will test the hypotheses that modern techniques and doses will improve OS without increasing late toxicity.

Background Allergen immunotherapy (IT) is a key component of allergy practice, however fellows state that there is inadequate IT exposure during their training. In response, the Canadian Society of Allergy and Clinical Immunology (CSACI) unveiled the first ever IT Training Manual for fellows-in-training at the annual 2010 CSACI meeting. The manual was distributed during a faculty-led teaching session. This was a pilot investigation to determine the perspectives of fellows in training about the IT training manual. Methods Canadian fellows-in-training in Allergy and Clinical Immunology (list derived from CSACI) were contacted via email to complete a survey (using survey monkey), both quantitative (Likert scales) and qualitative, to assess their opinion on the faculty-led session on IT and the IT Training Manual. Results Sixty-nine Canadian fellows-in-training were invited to complete the survey and 16 (23%). Fifty-four percent of 13 respondents were in their first year of fellowship. Seven respondents (58% of 12 respondents) attended the 2010 CSACI fellow-in-training session and received the IT Training Manual. One respondent commented that it was “more information than we've had in all of our fellowship!” The same 7 respondents “somewhat liked” or “liked” the large group format, but felt that the experience could be improved in the future with the addition of cased-based learning in smaller groups. One respondent commented that “as in intro, it was good in a larger setting.” All 7 respondents felt that their understanding of IT was positively impacted by the faculty-led session. Eighty-six percent of 7 respondents indicated that the Training Manual “somewhat impacted” to “very much impacted” their understanding of IT. One commenter stated that “it is the basis of my knowledge thus far.” Most respondents (86%) preferred the current paper booklet format of the IT Training Manual. Conclusions The results of this pilot survey demonstrate that some fellows-in-training found the faculty-led session on IT and the IT Training Manual useful. Future studies will help to further elucidate the utility of these 2 educational interventions.

Background Allergen immunotherapy (IT) is a key component of allergy practice of allergy. Canadian fellows-in-training have expressed concern that they receive inadequate exposure to IT in their training programs. Methods Canadian fellows-in-training in Allergy and Clinical Immunology, identified through the Canadian Society of Allergy and Clinical Immunology (CSACI), were contacted via email to complete a pilot survey (using survey monkey) to assess their exposure to, experience with, and comfort level in using IT. Results Sixty-nine Canadian fellows-in-training were invited to complete the survey and 16 (23%) completed at least part of the survey. Fifty-four percent of 13 respondents were in their first year of fellowship. Fifty percent of 12 respondents were internal medicine trained. Eighty-three percent of 12 respondents acknowledged exposure to IT during their training. Eighty percent of 10 respondents had previously written a prescription for IT; 71% and 43% of 7 respondents had written 1 to 5 prescriptions for aeroallergen and stinging venom IT, respectively. Only 50% of 12 respondents felt comfortable prescribing IT. The most common reason cited was lack of experience; however, one respondent wrote that he/she would feel uncomfortable prescribing IT without using the standardized hospital IT form. Sixty-seven percent of 12 respondents had previously administered IT to a patient. Sixteen percent of 12 respondents felt uncomfortable administering IT due to lack of experience. Fifty percent of 12 respondents had treated a patient having an allergic reaction to IT and 100% of these same respondents felt "somewhat comfortable" to "very comfortable" in responding to an allergic reaction to IT. Seventy-five percent of 12 respondents agreed that a formal clinical rotation in IT would be helpful. Conclusions The results of this pilot survey demonstrate that Canadian fellows-in-training in Allergy and Clinical Immunology are not receiving adequate exposure and training in IT. Future studies will help to explore this subject in more detail.

Background Cow’s milk and hen’s egg are the most frequently encountered food allergens in the pediatric population. Skin prick testing (SPT) with commercial extracts followed by an oral food challenge (OFC) are routinely performed in the diagnostic investigation of these children. Recent evidence suggests that milk-allergic and/or egg-allergic individuals can often tolerate extensively heated (EH) forms of these foods. This study evaluated the predictive value of a negative SPT with EH milk or egg in determining whether a child would tolerate an OFC to the EH food product. Methods Charts from a single allergy clinic were reviewed for any patient with a negative SPT to EH milk or egg, prepared in the form of a muffin. Data collected included age, sex, symptoms of food allergy, co-morbidities and the success of the OFC to the muffin. Results Fifty-eight patients had negative SPTs to the EH milk or egg in a muffin and underwent OFC to the appropriate EH food in the outpatient clinic. Fifty-five of these patients tolerated the OFC. The negative predictive value for the SPT with the EH food product was 94.8%. Conclusions SPT with EH milk or egg products was predictive of a successful OFC to the same food. Larger prospective studies are required to substantiate these findings.

Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone. The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure that the lowest effective ICS doses are being utilized to control asthma symptoms, and by choosing an ICS medication with minimal adrenal effects. Screening for AS should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of prolonged oral corticosteroid use. Cases of AS should be managed in consultation with a pediatric endocrinologist whenever possible. In patients with proven AS, stress steroid dosing during times of illness or surgery is needed to simulate the protective endogenous elevations in cortisol levels that occur with physiological stress. This article provides an overview of current literature on AS as well as practical recommendations for the prevention, screening and management of this serious complication of ICS therapy.

5558 Background: Induction chemotherapy (IC) is regaining its rule in the management of locally advanced head and neck squamous cell carcinoma (LAHNSCC). IC is a successful strategy for organ preservation, improves clinical response and reduces distant relapse, but it adds considerable morbidity and mortality. While large randomized trials comparing IC followed by chemo-radiotherapy with chemo-radiotherapy alone are ongoing, we are assessing the patient’s compliance to complete radiotherapy after IC. Methods: Retrospectively the medical records of patients with LAHNSCC, who were planned to receive IC followed by concurrent chemo-radiotherapy, were reviewed. Patients are considered compliant when they complete thirty five fractions of radiotherapy. Non-compliant is defined as; less than thirty fractions of radiation or more than one week interruption of radiation. Results: Seventy two patients were included, sixty one male and eleven female. IC regimens were cisplatin and 5-flurouracil (PF) in fifty one pa...

5507 Background: Data of patients with stage III-IV HNC accrued in a phase III trial of cisplatin (CDDP) plus an accelerated concomitant boost (AFX-C, 72 Gy/6 W) versus standard fractionation (SFX, 70 Gy//7 W) was analyzed with emphasis on the impact of radiotherapy (RT) and CDDP intensity. Methods: Patients had good status (Zubrod 0-1) and predefined blood chemistry range. Therapies were AFX-C + CDDP x2 or SFX + CDDP x3 (100 mg/m2, q3W). Results: Of 743 enrolled, 721 were analyzable. There was no difference in the primary endpoint (5-Y survival: 59% vs. 56%; HR: 0.90, 0.72-1.13; p=0.18). Other endpoints were assessed in 656 patients (AFX-C: 333; SFX: 323) receiving 64-76 Gy in 35-63 days and 1-3 CDDP doses. Table shows the combined effects of RT and CDDP regimens on outcome and toxicity. As a continuous variable, each day of RT delay compromised OS, PFS, and LRP by 5%, 4%, and 4% (p=0.001, 0.006, and 0.02), respectively. Conclusions: RT duration and CDDP dose affected survival significantly. CDDP improve...

6053 Background: In advanced head and neck squamous cell carcinoma (HNSCC), the five-year survival rate is less than 40%. Although the efficacy and tolerability of continuous IV 5-Fluorouracil (5FU) therapy has been established in HNSCC, the feasibility and tolerability of long-term therapy of oral capecitabine has not been established in HNSCC. Our primary objective is to assess the feasibility of treating patients with squamous cell carcinoma of the head and neck (HNSCC) with adjuvant Capecitabine after undergone definitive treatment. The secondary objectives are to estimate time to recurrence, local-regional control and survival rates along with incidence of second primary tumors. Methods: Eligible patients with newly diagnosed locally advanced HNSCC received capecitabine 1,000 mg orally once daily for one year, after undergone definitive treatment. Patients’ compliance with oral capecitabine as will as the side effects profile was evaluated on monthly basis over the first 12 months. Feasibility, survival, progression and progression free survival were measured over 36 months. Results: Thirty five patients were enrolled in the study. 17 patients had stage IV b, 7 had stage III, and 5 had unknown primary HNSCC. All but one took at least 60% of dispensed tablets. Twenty six patients completed at least 7 months of capecitabine. Sixteen patients completed at least 10 month of capecitabine. Two years overall survival rate was 97%. Three years progression free survival was 86%. Conclusions: Adjuvant capecitabine in locally advanced HNSCC is a feasible approach with minimum side effects. A favorable 3-year progression-free survival was found as compare to historical results. We recommend a randomized phase III trail to examine the effect of one year of adjuvant capecitabine versus placebo in locally advanced HNSCC after definitive treatment. No significant financial relationships to disclose.