Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials.

BACKGROUND: Retrospective studies have suggested a potential risk of hyperprogressive disease (HPD) in patients receiving immune checkpoint inhibitors (ICIs). We compared the incidence of HPD during treatment with nivolumab±ipilimumab versus natural tumor progression with placebo in post hoc analyses of two randomized, double-blind clinical trials. METHODS: ATTRACTION-2 randomized patients with advanced gastric or gastroesophageal junction cancer (GC/GEJC) and progression on ≥2 prior regimens to nivolumab 3 mg/kg Q2W or placebo. CheckMate 451 randomized patients with extensive-disease small cell lung cancer (ED SCLC) and ongoing complete/partial response or stable disease after first-line chemotherapy to nivolumab 240 mg Q2W, nivolumab 1 mg/kg+ipilimumab 3 mg/kg Q3W for four doses then nivolumab 240 mg Q2W, or placebo. Patients receiving ≥1 dose of study drug and with tumor scans at baseline and the first on-treatment evaluation were included in the HPD analyses. HPD definitions were ≥20%, ≥50%, and ≥100% increase in target lesion sum of the longest diameters (SLD) at the first on-treatment assessment. RESULTS: In the ATTRACTION-2 HPD-evaluable population, 243 patients received nivolumab and 115 placebo. Fewer patients receiving nivolumab versus placebo had increases in SLD ≥20% (33.7% vs 46.1%) and ≥50% (6.2% vs 11.3%); similar proportions had increases in SLD ≥100% (1.6% vs 1.7%). In the CheckMate 451 HPD-evaluable population, 177 patients received nivolumab, 179 nivolumab+ipilimumab, and 175 placebo. Fewer patients receiving nivolumab or nivolumab+ipilimumab versus placebo had increases in SLD ≥20% (27.1%, 27.4% vs 45.7%), ≥50% (10.2%, 11.2% vs 22.3%), and ≥100% (2.8%, 2.8% vs 6.3%). CONCLUSIONS: Nivolumab±ipilimumab was not associated with an increased rate of progression versus placebo in patients with GC, GEJC, or ED SCLC, suggesting that previous reports of HPD may reflect the natural disease course in some patients rather than ICI-mediated progression. TRIAL REGISTRATION NUMBER: NCT02538666; NCT02267343.

Assessment of Brain Functional Activity Using a Miniaturized Head-Mounted Scanning Photoacoustic Imaging System in Awake and Freely Moving Rats.

Understanding the relationship between brain function and natural behavior remains a significant challenge in neuroscience because there are very few convincing imaging/recording tools available for the evaluation of awake and freely moving animals. Here, we employed a miniaturized head-mounted scanning photoacoustic imaging (hmPAI) system to image real-time cortical dynamics. A compact photoacoustic (PA) probe based on four in-house optical fiber pads and a single custom-made 48-MHz focused ultrasound transducer was designed to enable focused dark-field PA imaging, and miniature linear motors were included to enable two-dimensional (2D) scanning. The total dimensions and weight of the proposed hmPAI system are only approximately 50 × 64 × 48 mm and 58.7 g (excluding cables). Our ex vivo phantom experimental tests revealed that a spatial resolution of approximately 0.225 mm could be achieved at a depth of 9 mm. Our in vivo results further revealed that the diameters of cortical vessels draining into the superior sagittal sinus (SSS) could be clearly imaged and continuously observed in both anesthetized rats and awake, freely moving rats. Statistical analysis showed that the full width at half maximum (FWHM) of the PA A-line signals (relative to the blood vessel diameter) was significantly increased in the selected SSS-drained cortical vessels of awake rats (0.58 ± 0.17 mm) compared with those of anesthetized rats (0.31 ± 0.09 mm) (p < 0.01, paired t-test). In addition, the number of pixels in PA B-scan images (relative to the cerebral blood volume (CBV)) was also significantly increased in the selected SSS-drained blood vessels of awake rats (107.66 ± 23.02 pixels) compared with those of anesthetized rats (81.99 ± 21.52 pixels) (p < 0.01, paired t-test). This outcome may result from a more active brain in awake rats than in anesthetized rats, which caused cerebral blood vessels to transport more blood to meet the increased nutrient demand of the tissue, resulting in an obvious increase in blood vessel volume. This hmPAI system was further validated for utility in the brains of awake and freely moving rats, showing that their natural behavior was unimpaired during vascular imaging, thereby providing novel opportunities for studies of behavior, cognition, and preclinical models of brain diseases.

In Vivo Assessment of Hypoxia Levels in Pancreatic Tumors Using a Dual-Modality Ultrasound/Photoacoustic Imaging System.

Noninvasive anatomical and functional imaging has become an essential tool to evaluate tissue oxygen saturation dynamics in preclinical or clinical studies of hypoxia. Our dual-wavelength technique for photoacoustic (PA) imaging based on the differential absorbance spectrum of oxyhemoglobin (oxy-Hb) and deoxyhemoglobin (deoxy-Hb) can quantify tissue oxygen saturation using the intrinsic contrast property. PA imaging of tissue oxygen saturation can be used to monitor tumor-related hypoxia, which is a particularly relevant functional parameter of the tumor microenvironment that has a strong influence on tumor aggressiveness. The simultaneous acquisition of anatomical and functional information using dual-modality ultrasound (US) and PA imaging technology enhances the preclinical applicability of the method. Here, the developed dual-modality US/PA system was used to measure relative tissue oxygenation using the dual-wavelength technique. Tissue oxygen saturation was quantified in a pancreatic tumor mouse model. The differences in tissue oxygenation were detected by comparing pancreatic samples from normal and tumor-bearing mice at various time points after implantation. The use of an in vivo pancreatic tumor model revealed changes in hypoxia at various stages of tumor growth. The US/PA imaging data positively correlated with the results of immunohistochemical staining for hypoxia. Thus, our dual-modality US/PA imaging system can be used to reliably assess and monitor hypoxia in pancreatic tumor mouse models. These findings enable the use of a combination of US and PA imaging to acquire anatomical and functional information on tumor growth and to evaluate treatment responses in longitudinal preclinical studies.

Management of gastric cancer in Asia: resource-stratified guidelines.

Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries.

Pharmacoeconomic analysis of capecitabine versus 5-fluorouracil/leucovorin as adjuvant therapy for stage III colon cancer in Taiwan.

OBJECTIVES: To assess the cost-effectiveness of oral capecitabine compared with intravenous bolus 5-fluorouracil/leucovorin (5-FU/LV) in the adjuvant treatment of stage III colon cancer in Taiwan from payer (Bureau of National Health Insurance [BNHI]) perspectives. METHODS: A health state-transition model was developed to estimate the incremental costs and effectiveness of capecitabine versus 5-FU/LV. The time horizons studied were: treatment duration (24 weeks) plus 36 months, 48 months, 60 months, 120 months, and lifetime. Costs were expressed in Taiwanese new dollars (NT$). Clinical outcomes, medical resource use, and utilities were extracted from published sources. Unit costs were estimated from BNHI fee schedules, published sources, and local expert opinion. Outcomes and future costs were discounted at 3%. Cost-effectiveness was expressed as cost per quality-adjusted life-month (QALM). The effects of uncertainty were explored through a one-way sensitivity analysis. RESULTS: For the 24-week time period, drug acquisition costs were higher for capecitabine than 5-FU/LV (NT$114,405 vs. NT$4,904 per patient); however, these were offset by the higher administration costs of 5-FU/LV (NT$2,573 vs. NT$204,201 per patient). Overall direct costs for the 24-week treatment period were less with capecitabine than 5-FU/LV (NT$129,327 vs. NT$233,873 per patient). Cost savings with capecitabine were also evident when longer time horizons were considered. Over a lifetime, the projected survival benefit for capecitabine was 7 QALMs. CONCLUSIONS: From the perspectives of the BNHI and society in Taiwan, capecitabine not only saves costs but also improves health outcomes compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer.

Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009.

Asia has a disproportionately large share of the world's hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.

Effect of thalidomide in hepatocellular carcinoma: assessment with power doppler US and analysis of circulating angiogenic factors.

PURPOSE: To prospectively evaluate the feasibility of using power Doppler ultrasonography (US) and measurement of circulating angiogenic factors to assess the antiangiogenic effect of thalidomide in hepatocellular carcinoma. MATERIALS AND METHODS: The Ethics Committee of the National Taiwan University Hospital approved the study, and all patients gave prior written informed consent. Evaluation of response to thalidomide treatment was based on findings at computed tomography (CT) and change in serum alpha-fetoprotein level. Tumor vascularity index was evaluated with power Doppler US in patients with advanced hepatocellular carcinoma treated with 200-300 mg/d thalidomide. Serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and placental growth factor were measured with enzyme-linked immunoassay. The chi(2) test or Fisher exact test was used for categorical variables, and the nonparametric Mann-Whitney test was used for numeric variables. A P value of less than .05 was considered to indicate a statistically significant difference. RESULTS: Of 47 patients enrolled in the study who had disease that was bidimensionally assessable on CT scans, 44 were assessable for tumor response. Of the 44 evaluated, five were classified as showing objective response (responders): One each showed a complete and a partial response according to World Health Organization criteria, and three had a decrease in alpha-fetoprotein level by more than 50% and stable disease for 10.4, 5.3, or 3.5 months. The pretreatment vascularity index was significantly higher in responders (median, 7.42; range, 2.99-13.90) than in nonresponders (median, 2.15; range, 0-25.36) (P = .03). Four of five responders had a significant decrease in vascularity index with thalidomide. Serum levels of angiogenic factors did not differ significantly between responders and nonresponders. CONCLUSION: Higher vascularity index may be associated with a better chance of response to thalidomide in patients with advanced hepatocellular carcinoma. Serum levels of circulating angiogenic factors do not appear to be clinically useful as an indicator of response.