Protocol for the stimulating β3-Adrenergic receptors for peripheral artery disease (STAR-PAD) trial: a double-blinded, randomised, placebo-controlled study evaluating the effects of mirabegron on functional performance in patients with peripheral arterial disease

Introduction: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. Methods and analysis: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. Ethics and dissemination: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes

Grafts for mesenterico-portal vein resections can be avoided during pancreatoduodenectomy

BACKGROUND: The aim of this study was to assess whether pancreatoduodenectomy (PD) and en bloc mesenterico-portal resection (PD-VR) could be performed with primary venous reconstruction, avoiding a vascular graft. In addition, the short-term surgical outcomes of this approach were compared with a standard PD (PD-VR). STUDY DESIGN: Two hundred twelve patients underwent PD between January 2004 and June 2011. Clinical data, operative results, pathologic findings, and postoperative outcomes were collected prospectively and analyzed. RESULTS: One hundred fifty patients (71%) had PD-VR and 62 patients underwent PD-VR. The majority (82%) of the venous reconstructions were performed with primary end-to-end anastomosis. Only 1 patient had synthetic interposition graft repair. The volume of intraoperative blood loss and the perioperative blood transfusion requirements were significantly greater, and the duration of the operation was significantly longer in the PD-VR group compared with the PD-VR group. There were no significant differences in the length of hospitalization, postoperative morbidity, or grades of complications between the 2 groups. Multivariate logistic regression identified American Society of Anesthesiologists score as the only predictor of postoperative morbidity. Fifty percent of patients with pancreatic adenocarcinoma (n=101) required VR. A significantly higher rate of positive resection margins (p< 0.001) was noted in the PD-VR subgroup compared with PD-VR subgroup. Furthermore, high intraoperative blood loss and neural invasion were predictive of a positive resection margin. CONCLUSIONS: Pancreatoduodenectomy with VR and primary venous anastomosis avoids the need for a graft and has comparable postoperative morbidity with PD-VR. However, it is associated with an increased operative time, higher intraoperative blood loss, and, for pancreatic ductal adenocarcinoma, a higher rate of positive resection margins compared with PD-VR

Adverse tumor biology associated with mesenterico-portal vein resection influences survival in patients with pancreatic ductal adenocarcinoma

Background: Although pancreatoduodenectomy (PD) with mesenterico-portal vein resection (VR) can be performed safely in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the impact of this approach on long-term survival is controversial. Patients and Methods: Analyses of a prospectively collected database revealed 122 consecutive patients with PDAC who underwent PD with (PD+VR) or without (PD-VR) VR between January 2004 and May 2012. Clinical data, operative results, and survival outcomes were analysed. Results: Sixty-four (53 %) patients underwent PD+VR. The majority (84 %) of the venous reconstructions were performed with a primary end-to-end anastomosis. Demographic and postoperative outcomes were similar between the two groups. American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss, and blood transfusion requirement were significantly greater in the PD+VR group compared with the PD-VR group. Furthermore, the tumor size was larger, and the rates of periuncinate neural invasion and positive resection margin were higher in the PD+VR group compared with the PD-VR group. Histological venous involvement occurred in 47 of 62 (76 %) patients in the PD+VR group. At a median follow-up of 29 months, the median overall survival (OS) was 18 months for the PD+VR group, and 31 months for the PD-VR group (p = 0.016). ASA score, lymph node metastasis, neurovascular invasion, and tumor differentiation were predictive of survival. The need for VR in itself was not prognostic of survival. Conclusions: PD with VR has similar morbidity but worse OS compared with a PD-VR. Although VR is not predictive of survival, tumors requiring a PD+VR have more adverse biological features