In Sun Ryu

Prognostic Value of Preoperative Metabolic Tumor Volume and Total Lesion Glycolysis Measured by 18F-FDG PET/CT in Salivary Gland Carcinomas

Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from 18F-FDG PET/CT are emerging prognostic biomarkers in various human cancers. This study examined the prognostic value of these metabolic tumor parameters measured by pretreatment 18F-FDG PET/CT in patients with salivary gland carcinomas. Methods: Forty-nine patients with intermediate- or high-grade salivary gland carcinomas who underwent definitive surgery with or without radiotherapy or chemoradiotherapy were evaluated preoperatively by 18F-FDG PET/CT. Maximum standardized uptake values (SUVmax), MTV, and TLG were measured for each patient. Univariate and multivariate analyses were used to identify clinicopathologic and imaging variables associated with progression-free survival (PFS) and overall survival (OS). Univariate analyses included the following variables: age, sex, pT and pN classifications, overall pTNM stage, histologic grade, resection margin, tumor lymphovascular invasion and perineural invasion, postoperative adjuvant therapy, gross total volume, SUVmax, MTV, and TLG. Results: The 3-y PFS and OS rates for all study patients were 66.9% and 81.6%, respectively. The median SUVmax, MTV, and TLG were 5.1 (range, 1.7–21.5), 16.2 mL (1.0–115.1 mL), and 24.4 g (2.1–224.4 g), respectively. Univariate analyses showed that there were significant correlations between pT classification, pN classification, MTV, and TLG and both PFS and OS (P < 0.05). However, SUVmax was not associated with either PFS (P = 0.111) or OS (P = 0.316). Multivariate analyses revealed that MTV (P = 0.011; hazard ratio, 11.50; 95% confidence interval, 1.45–91.01) and TLG (P = 0.038; hazard ratio, 3.55; 95% confidence interval, 1.07–11.76) were independent variables for PFS. Conclusion: Pretreatment values of MTV and TLG are independent prognostic factors in patients with intermediate or high-grade salivary gland carcinomas.

Detection of the primary lesion in patients with cervical metastases from unknown primary tumors with narrow band imaging endoscopy: Preliminary report

We investigated whether the addition of narrow band imaging (NBI) to standard diagnostic workups could enhance the detection of primary lesions in patients with carcinoma of unknown primary (CUP).

Lymph node density as an independent predictor of cancer-specific mortality in patients with lymph node-positive laryngeal squamous cell carcinoma after laryngectomy.

We examined the prognostic value of lymph node density in predicting cancer‐specific mortality (CSM) for patients with lymph nodes positive (pN+) laryngeal squamous cell carcinoma (SCC) after laryngectomy.

Clinical outcomes of patients with salivary gland carcinomas preoperatively misdiagnosed as benign lesions.

We compared clinical outcomes between patients with salivary gland carcinomas preoperatively misdiagnosed as benign lesion and properly diagnosed as malignant lesion.

Can Response to Induction Chemotherapy Be a Predictive Marker for Ultimate Outcome in Hypopharyngeal Cancer

Objective. Induction chemotherapy (ICT) may reduce rates of distant metastases and enhance organ preservation and survival rates in patients with hypopharyngeal cancer. The authors compared survival data in patients who underwent chemoradiotherapy or surgery after ICT and investigated whether response to ICT is a predictive marker for outcome in patients with hypopharyngeal cancer. Study Design. Historical cohort study. Setting. Tertiary-care hospital. Subjects and Methods. The authors enrolled 97 patients (89 men, 8 women; mean age 61.2 years; range, 29-80 years) with previously untreated hypopharyngeal cancer who underwent ICT between January 1997 and December 2006 at Asan Medical Center. Disease-free survival (DFS), overall survival (OS), and laryngectomy-free survival (LFS) were analyzed. Results. At a mean follow-up of 38.0 months, the 3-year DFS and OS for all patients were 48.3% and 49.2%, respectively. The 3-year LFS rate of patients who underwent nonsurgical therapy (n = 85) after ICT was 48.0%. Only response to ICT was associated with DFS (P = .047), OS (P = .003), and LFS (P = .009) in multivariate analysis. When the authors compared survival data in patients who underwent surgical and nonsurgical treatments after ICT, they found that there was no statistical difference in terms of the 3-year DFS in partial response (42.9% vs 50.5%, P = .77) and nonresponse groups (50.0% vs 0%, P = .43) between the 2 treatment types. Conclusion. ICT permits assessment of tumor responsiveness and alters subsequent therapy accordingly. Response to ICT may be useful in the prediction of ultimate outcomes and organ conservation in patients with hypopharyngeal cancer.

Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer

OBJECTIVES PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers. MATERIAL AND METHODS We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model. RESULTS We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation. CONCLUSIONS Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.

Abstract 3348: Inhibition of MDMX by XI-011 induces p53-mediated apoptosis in head and neck cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Overexpression of MDM2 or MDMX inactivates the tumor-suppressive function of p53. Restoration of p53 function counteracting these p53 repressors can lead to in vivo tumor regression. Therefore, we evaluated whether the restoration of p53 function by a small-molecule p53 activator XI-011, a pseudouria derivative NSC146109, induce apoptosis in head-and-neck cancer (HNC). The effects of XI-011 treatment in four HNC cell lines were tested, individually or in combination with nutlin-3a, an inhibitor of MDM2-p53 interactions, and its growth suppression, cell-cycle arrest, and apoptosis were assessed. XI-011 induced accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. XI-011 showed maximal growth suppression in tumor cells with overexpression of MDMX and MDMX-dependent p53 degradation. With down-regulation of MDMX mRNA and protein levels, XI-011 upregulated expression of p21 and proapoptotic genes and promoted apoptosis in a dose-dependent manner. Notably, the apoptotic response was blocked by inhibition of p53 or MDMX gene expression, demonstrating the p53 and MDMX dependence of XI-011 effects. XI-011 decreased the viability of HNC cells expression low levels of MDMX in a less-efficient manner. Interestingly, in combination therapy, XI-011 synergistically acted with nutlin-3a to inhibit growth of HNC cells. Our data suggest that the MDMX inhibition and p53 functional restoration by XI-011 effectively induced cytotoxicity and apoptosis in cancer cells, an action that may offer a promising strategy for treating HNC. Citation Format: In Sun Ryu, Chang Hwan Ryu, Hyun Bae Park, Eunhye Kim, Jong-Lyel Roh. Inhibition of MDMX by XI-011 induces p53-mediated apoptosis in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3348. doi:10.1158/1538-7445.AM2013-3348

Abstract 1768: Enhanced cytotoxicity and apoptosis of cisplatin by p53-reactivating small molecule RITA in head and neck cancer

Overexpression of MDM2 inactivates the tumor suppressive function of p53 and a small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) disrupts the MDM2-p53 interaction. We evaluated whether the restoration of p53 function by RITA enhances cytotoxicity and apoptosis of cisplatin in head-and-neck cancer (HNC). RITA was tested in four human HNC cell lines differing in TP53 status. In vitro and in vivo growth suppression, cell cycle arrest, apoptosis after RITA treatment individually or in combination with cisplatin were assessed. RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing tumor cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA upregulated p21, BAX, and cleavage of caspase-3 but the p53-dependent apoptosis was blocked by pifithrin-μ. Strong induction of apoptosis rather than G2-phase arrest was observed along with increased dose of RITA. In combination therapy, RITA enhanced the growth inhibition and apoptosis of HNC by cisplatin in vitro and in vivo. Our data suggest that the restoration of p53 tumor suppressive function by RITA enhances cytotoxicity and apoptosis of cisplatin, which may offer an attractive strategy for treating HNC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1768. doi:1538-7445.AM2012-1768