An open-label, single-arm pilot study of EUS-guided brachytherapy with phosphorus-32 microparticles in combination with gemcitabine +/- nab-paclitaxel in unresectable locally advanced pancreatic cancer (OncoPaC-1): Technical details and study protocol.

Current treatment options for patients with unresectable locally advanced pancreatic cancer (LAPC) include chemotherapy alone or followed by chemoradiation or stereotactic body radiotherapy. However, the prognosis for these patients remains poor, with a median overall survival <12 months. Therefore, novel treatment options are needed. Currently, there is no brachytherapy device approved for pancreatic cancer treatment. Hereby, we present the protocol of a prospective, multicenter, interventional, open-label, single-arm pilot study (OncoPac-1, Clinicaltrial.gov-NCT03076216) aiming to determine the safety and efficacy of Phosphorus-32 when implanted directly into pancreatic tumors using EUS guidance, for patients with unresectable LAPC undergoing chemotherapy (gemcitabine ± nab-paclitaxel).

Determination of caprolactam and residual vinyl caprolactam monomer in soluplus by mixed mode gel permeation chromatography.

Soluplus, a graft copolymer of polyethylene glycol, vinyl caprolactam and vinyl acetate, is designed to solubilize poorly soluble active pharmaceutical ingredients. A straightforward aqueous gel permeation chromatography method that exploits both size exclusion and adsorption modes of separation was used to separate and quantify the related residual vinyl caprolactam monomer and caprolactam impurity present in Soluplus. This methodology offers a single step analysis of caprolactam and the residual vinyl caprolacatam monomer, yielding similar results to reversed-phase chromatography measurements, which are time-consuming and may involve multi-step sample preparation. The results of this study demonstrate that gel permeation chromatography provides a viable option to traditional reversed-phase chromatography in the quantitative analysis of residual caprolactam and vinyl caprolactam monomers and can be extended to other monomer-polymeric systems.

Application of iChemExplorer in pharmaceutical pH stress testing.

pH stress testing is an integral part of pharmaceutical stress testing and is a regulatory requirement for validating a stability indicating analytical method and elucidating degradation products and degradation pathways. This paper reports the results of an evaluation of iChemExplorer (ICE) for drug substance and drug product pH stress testing in comparison with the conventional (manual) approach. ICE is a simple and inexpensive technology, and through real case studies it was demonstrated that ICE is an efficient and "fit-for-purpose" alternative in conducting pharmaceutical pH stress testing. In addition, when using a non-isothermal ICE protocol, it is feasible to estimate the pH degradation kinetics (e.g., E(a)) using the ICE software.

Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A.

An in silico screen of the NIH Molecular Library Small Molecule Repository (MLSMR) of ∼350000 compounds and confirmatory bioassays led to identification of chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogues of 1 uncovered two compounds, talaroderxines A (2) and B (3), with improved activity. These are the first fungal metabolites reported to exhibit BoNT/A inhibitory activity.

Prognostic impact of types of atrial fibrillation in acute coronary syndromes.

Atrial fibrillation (AF) has been established as an independent predictor of long-term mortality after acute myocardial infarction. However, this is less well defined across the whole spectrum of acute coronary syndromes (ACSs). The Acute Coronary Syndrome Prospective Audit is a prospective multicenter registry with 12-month outcome data for 3,393 patients (755 with ST-segment elevation myocardial infarction, 1942 with high-risk non-ST-segment elevation ACS [NSTE-ACS], and 696 with intermediate-risk NSTE-ACS). A total of 149 patients (4.4%) had new-onset AF and 387 (11.4%) had previous AF. New-onset AF was more, and previous AF was less frequent in those with ST-segment elevation myocardial infarction than in those with high-risk NSTE-ACS or intermediate-risk NSTE-ACS (p <0.001). Compared to patients without arrhythmia, patients with new-onset AF and previous AF were significantly older and had more high-risk features at presentation (p <0.004). Patients with new-onset AF more often had left main coronary artery disease, resulting in a greater rate of surgical revascularization (p <0.001). Only new-onset AF resulted in adverse in-hospital outcomes (p <0.001). Only patients with previous AF had greater long-term mortality (hazard ratio 1.42, p <0.05). New-onset AF was only associated with a worse long-term composite outcome (hazard ratio 1.66, p = 0.004). However, the odds ratio for the composite outcome was greatest for patients with new-onset AF with intermediate-risk NSTE-ACS (odds ratio 3.9, p = 0.02) than for those with high-risk NSTE-ACS (odds ratio 2.0, p = 0.01) or ST-segment elevation myocardial infarction (odds ratio 1.4, p = 0.4). In conclusion, new-onset AF was associated with worse short-term outcomes and previous AF was associated with greater mortality even at long-term follow-up. The prognostic burden of new-onset AF differed with the type of ACS presentation.

Treatment disparities and effect on late mortality in patients with diabetes presenting with acute myocardial infarction: observations from the ACACIA registry.

OBJECTIVES: To compare the use of evidence-based pharmacological and invasive treatments and 12-month mortality rates between patients with and without diabetes who present with acute myocardial infarction (MI), and to explore the relationship between these treatments and late clinical outcomes. DESIGN AND SETTING: Prospective, nationwide multicentre registry: the Acute Coronary Syndrome Prospective Audit (ACACIA). PATIENTS: Patients presenting to 24 metropolitan and 15 non-metropolitan hospitals with acute coronary syndrome (ACS) and a final discharge diagnosis of acute MI between November 2005 and July 2007. MAIN OUTCOME MEASURE: All-cause mortality at 12 months. RESULTS: Nearly a quarter of 1744 patients with a final diagnosis of acute MI had a history of diabetes on presentation. Patients with diabetes were older, with a greater prevalence of comorbidities than non-diabetic patients, and were less likely to be treated at discharge with evidence-based medications (aspirin, clopidogrel, a statin and/or a beta-blocker) or to receive early invasive procedures. After adjusting for baseline characteristics and therapeutic interventions, diabetes at presentation was independently associated with a higher mortality at 12 months after MI (hazard ratio, 1.79; 95% CI, 1.18-2.72; P=0.007). Early invasive management and discharge prescription of guideline-recommended medications were associated with a significantly reduced hazard of mortality at 12 months. CONCLUSION: Patients with diabetes have a higher risk than non-diabetic patients of late mortality following an acute MI, yet receive fewer guideline-recommended medications and early invasive procedures. Increased application of proven pharmacotherapies and an early invasive management strategy in patients with diabetes presenting with ACS might improve their outcomes. STUDY PROTOCOL NUMBER (SANOFI-AVENTIS): PML-0051.

Invasive management and late clinical outcomes in contemporary Australian management of acute coronary syndromes: observations from the ACACIA registry.

OBJECTIVE: To describe the impact of invasive management on 12-month survival among patients with suspected acute coronary syndrome (ACS) in Australia. DESIGN AND SETTING: Prospective nationwide multicentre registry. PATIENTS: Patients presenting to 24 metropolitan and 15 non-metropolitan hospitals with ST-segment-elevation myocardial infarction (STEMI), and high-risk and intermediate-risk non-ST-segment-elevation ACS (NSTEACS) between 1 November 2005 and 31 July 2007. MAIN OUTCOME MEASURES: Death, myocardial infarction (MI) or recurrent MI, revascularisation and stroke at 12 months. RESULTS: Among 3402 patients originally enrolled, vital status at 12 months was available for 3393 (99.7%). Patients from non-metropolitan areas (810) constituted 23.9% of patients. Early invasive management was more commonly undertaken among patients with STEMI (STEMI, 89.7% v non-STEMI, 70.8% v unstable angina, 44.8% v stable angina, 35.8%; P<0.001). Factors most associated with receiving invasive management included admission with suspected STEMI or high-risk NSTEACS, being male and the hospital having an onsite cardiac surgical service. Overall mortality by 12 months among patients with STEMI, non-STEMI, unstable angina and stable angina was 8.0%, 10.5%, 3.3%, and 3.7% (P<0.001), respectively. After adjusting for a propensity model predicting early invasive management and other known confounders, early invasive management was associated with a 12-month mortality hazard ratio of 0.53 (95% CI, 0.34-0.84, P=0.007). CONCLUSIONS: A substantial burden of late morbidity and mortality persists among patients with ACS within contemporary Australian clinical practice. Under-use of invasive management may be associated with an excess in 12-month mortality, suggesting the need for more use of invasive management among these patients.