Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial.

INTRODUCTION: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. METHODS AND ANALYSIS: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication. TRIAL REGISTRATION NUMBER: jRCT2031210046.

Effects of outdoor housing of piglets on behavior, stress reaction and meat characteristics.

Well-designed housing systems are important from the viewpoint of animal welfare and improvement of meat production. In this study, we investigated the effects of outdoor housing of pigs on their behavior, cortisol levels, and meat characteristics. Two groups that were born and raised in a spacious outdoor pen (4×10 m for every two sows) or a minimum-sized standard pen in a piggery (1.9×2.2 m for every sow) were studied. When their behaviors at the age of 2 to 3 wk were observed, the number of rooting episodes tended to be larger (p = 0.0509) and the total time of rooting tended to be longer (p = 0.0640) in the outdoor-housed piglets although the difference was not significant. Basal salivary cortisol levels of the outdoor piglets at the age of 4 wk were significantly lower than those of the indoor piglets (5.0±0.59 ng/ml vs. 11.6±0.91 ng/ml, 30 min after treatment), although their plasma cortisol levels were similar (53.3±3.54 ng/ml vs. 59.9±4.84 ng/ml, 30 min after treatment). When the ears were pierced at weaning, plasma and salivary cortisol levels were increased in both groups, even at 15 min after piercing. However, the increase in the outdoor-housed group was significantly less than that in the indoor-housed group. Throughout their lives, body weight and daily gain of the pigs were not significantly different between the two groups. In a meat taste preference test taken by 20 panelists, saltiness, flavor, and color of the outdoor-housed pork were found to be more acceptable. Moreover, when an electronic taste-sensing device was utilized, the C00 and CPA-C00 outputs (3.78±0.07 and -0.20±0.023), which correspond to compounds of bitterness and smells, respectively, were significantly lower in the outdoor-housed pork (5.03±0.16 and -0.13±0.009). Our results demonstrate that the outdoor housing system for piglets induces natural behaviors such as rooting and suppresses the strongest stress reaction of piglets, which could be important for animal welfare. Moreover, the outdoor housing system might change muscle characteristics and improve pork bitterness, flavor, and color. These changes may be preferred by consumers, increasing the sale of these meats.