Cato Chan

Galectin-1 mediates radiation-related lymphopenia and attenuates NSCLC radiation response.

Purpose: Radiotherapy can result in lymphopenia, which has been linked to poorer survival. Here, we test the hypothesis that radiotherapy-induced lymphopenia is mediated by a tumor-secreted factor, Galectin-1 (Gal-1), which possesses T-cell proapoptotic activities. Experimental Design: Matched Gal-1 wild-type (WT) or null mice were implanted with Lewis lung carcinoma (LLC-1) that either expressed Gal-1 or had Gal-1 stably downregulated. Tumors were irradiated locally and circulating Gal-1 and T cells were measured. Tumor growth, lung metastasis, intratumoral T-cell apoptosis, and microvessel density count were quantified. Thiodigalactoside (TDG), a Gal-1 inhibitor, was used to inhibit Gal-1 function in another group of mice to validate the observations noted with Gal-1 downregulation. Lymphocyte counts, survival, and plasma Gal-1 were analyzed in cohorts of radiotherapy-treated lung [non–small cell lung cancer (NSCLC)] and head and neck cancer patients. Results: LLC irradiation increased Gal-1 secretion and decreased circulating T cells in mice, regardless of host Gal-1 expression. Inhibition of tumor Gal-1 with either shRNA or thiodigalactoside ablated radiotherapy-induced lymphopenia. Irradiated shGal-1 tumors showed significantly less intratumoral CD8+ T-cell apoptosis and microvessel density, which led to marked tumor growth delay and reduced lung metastasis compared with controls. Similar observations were made after thiodigalactoside treatment. Radiotherapy-induced lymphopenia was associated with poorer overall survival in patients with NSCLC treated with hypofractionated radiotherapy. Plasma Gal-1 increased whereas T-cell decreased after radiation in another group of patients. Conclusions: Radiotherapy-related systemic lymphopenia appeared to be mediated by radiotherapy-induced tumor Gal-1 secretion that could lead to tumor progression through intratumoral immune suppression and enhanced angiogenesis. Clin Cancer Res; 20(21); 5558–69. ©2014 AACR.

Concurrent cetuximab versus platinum-based chemoradiation for the definitive treatment of locoregionally advanced head and neck cancer.

The purpose of this study was to present our experience utilizing cetuximab and platinum‐based concurrent chemoradiotherapy for the definitive treatment of head and neck squamous cell carcinoma (HNSCC).

A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth

Purpose: To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo. Experimental Design: Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS). Results: Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group. Conclusion: Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia. Clin Cancer Res; 19(16); 4455–64. ©2013 AACR.

Salvage Treatment for Locally Recurrent Nasopharyngeal Carcinoma (NPC)

Background:It is important to determine the outcomes of retreatment in patients with locally recurrent nasopharyngeal carcinoma. Methods:We reviewed the records of patients treated for local recurrence at Stanford and Shantou Universities. The end points were local relapse-free survival (LRFS) and overall survival after retreatment. Results:Fifty-six patients from Stanford and 98 from Shantou qualified. For the Stanford patients, 33 had surgery alone (S group), 12 had surgery plus radiotherapy±chemotherapy (CMT group), and 22 had radiotherapy±chemotherapy (RT Stanford group). All Shantou patients received radiotherapy±chemotherapy (RT Shantou group). The 5-year LRFS rates were: 57% for S group, 25% for CMT group, 53% for RT Stanford group, and 41% for RT Shantou group (P>0.05) for rT1-2 tumors; they were 29% for S group, 25% for CMT group, 39% for RT Stanford group, and 9% for RT Shantou group for rT3-4 tumors (P>0.05). For RT patients, 5-year overall survival rates were 49% for Stanford and 25% for Shantou patients (P=0.026). Conclusions:Similar and durable LRFS rates were attained for both S and RT groups when stratified by rT-stage.

Long-term outcomes of surgery followed by radiation therapy for minor salivary gland carcinomas.

Postoperative radiation therapy is often used in patients with high‐risk salivary gland carcinomas. In this study we evaluated the outcomes and prognostic factors in patients with minor salivary gland cancers treated with adjuvant radiation therapy.

Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase Inhibitors by Multimodality Molecular Imaging in Living Subjects

Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(α/β)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21(waf1) upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control-treated mice as determined by BLI. Small animal (18)F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor.

Radiotherapy for nonadenoid cystic carcinomas of major salivary glands

PURPOSE To report outcomes in patients treated with postoperative radiotherapy for nonadenoid cystic carcinomas of the major salivary glands. MATERIALS AND METHODS From 1998-2011, 37 patients with nonadenoid cystic carcinomas of the major salivary gland underwent postoperative radiotherapy. The median radiation dose was 60 Gy (range, 45-70 Gy). TNM distribution included T1-2 (n=16, 44%), T3-T4 (n=21, 56%), N0 (n=19, 51%), and N+ (n=18, 49%). Histologies included adenocarcinoma (n=13, 35%), squamous cell carcinoma (n=8, 22%), mucoepidermoid carcinoma (n=8, 22%), and other (n=8, 21%). Median follow-up was 4.7 years for all patients (range, 0.3-14.1 years) and 5.0 years for living patients (range, 1.2-12.2 years). RESULTS Five-year local-regional control, overall survival (OS), and cancer-specific survival (CSS) were 97%, 76%, and 84%. On univariate analysis, OS was significantly worse for patients ≥65 years old (p=0.04). CSS was significantly worse for positive perineural invasion (p=0.02), extraparenchymal extension (p=0.04), and in patients who received no chemotherapy (p=0.02). Doses >60 Gy was significantly worse for OS (p=0.003) and CSS (p=0.003), although these patients had higher TNM (>T2, p=0.01) and trended towards a higher rate of extraparenchymal extension (p=0.08). Four patients (11%) developed ≥grade 2 toxicities; 3 patients developed early toxicities and one patient developed late toxicities. CONCLUSIONS Radiotherapy for salivary gland tumors provides excellent local-regional control when combined with surgery. Distant metastasis is the predominant pattern of failure, although chemotherapy seemed to improve cancer-specific survival.

Radiologic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status

Radiation of retropharyngeal nodes (RPN) results in increased toxicities. This study assessed characteristics associated with RPN involvement in 165 oropharynx cancer patients. Factors associated with involvement were stage N2c-3 disease and stage N2b disease with either advanced T-stage, ⩾3 involved cervical LN, and ⩾1 involved contralateral LN, or lateral/posterior subsites.

Feasibility of optimizing intensity‐modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes

Abstract We prospectively investigated the feasibility of IMRT treatment plan optimization based on dosimeter measurements of lateral tongue mucosal dose adjacent to the dental fillings and evaluated dose‐toxicity relationship and factors affecting oral mucositis (OM) in head and neck cancer patients. Twenty‐nine head and neck cancer patients with metallic dental fillings who were scheduled to undergo fractionated external beam radiation therapy (RT) ± chemotherapy were enrolled. The lateral tongue dose was measured and if the calculated dose for the entire treatment was ≥35 Gy, a re‐plan was generated to reduce the lateral tongue mucosal dose. OM was graded weekly according to Common Terminology Criteria for Adverse Events version 4.0 and the patients completed the Oral Mucositis Weekly Questionnaire‐Head and Neck Cancer. The result showed that it was not feasible to optimize the IMRT plan based on measured tongue dose in most of the patients who needed re‐plan as re‐planning compromised the target coverage in 60% of these patients. The duration of grade (Gr) 2 OM was correlated with measured lateral tongue dose (P = 0.050). Concurrent cetuximab was significantly associated with faster onset of Gr2 OM than concurrent cisplatin (P = 0.006) and with longer duration of OM (P = 0.041) compared to concurrent cisplatin or IMRT‐alone. The pattern of reported pain over time was significantly different for each treatment type (RT and cetuximab, RT and cisplatin and RT‐alone) and depending on the dose level (P = 0.006). In conclusion, optimizing the IMRT plan based on measured lateral tongue dose was not feasible. Measured lateral tongue dose was significantly correlated with longer duration of OM ≥Gr2, and concurrent cetuximab was associated with earlier onset and longer duration of OM ≥Gr2.

Hearing evaluation of patients with head and neck cancer: Comparison of Common Terminology Criteria for Adverse Events, Brock and Chang adverse event criteria in patients receiving cisplatin: Comparison of adverse event criteria with cisplatin

Purpose To compare CTCAE, Brock and Chang hearing loss (HL) grading in HNCP receiving CDDP. Endpoints were baseline distribution of HL, inter-observer consistency, and sensitivity to HL following CDDP treatment.The purpose of this study was to compare Common Terminology Criteria for Adverse Events (CTCAE), Brock and Chang hearing loss grading in patients with head and neck cancer receiving cis‐diamminedichloroplatinum (CDDP). Endpoints were baseline distribution of hearing loss, interobserver consistency, and sensitivity to hearing loss after CDDP treatment.