Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers

Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells

Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound

Differences in presentation, management and outcomes in women and men presenting to an emergency department with possible cardiac chest pain

Background Research suggests that female patients with acute coronary syndrome (ACS) experience delays in emergency department (ED) management and are less likely to receive guideline-based treatments and referrals for follow-up testing. Women are often found to have poorer clinical outcomes in comparison to men. This study aimed to assess current sex differences in the presentation, management and outcomes of patients with undifferentiated chest pain presenting to a tertiary ED. Methods Data were analysed from two prospective studies conducted at a single Australian site between 2007 and 2013. Eligible patients were those of 18 years of age or older presenting with at least five minutes of chest pain or other symptoms for which the treating physician planned to investigate for possible ACS. Characteristics of presenting symptoms, ED time measures, rates of follow-up testing and outcomes including 30-day ACS and mortality were measured and compared between male and female patients. Results Of 2349 (60% men) patients presenting with chest pain, ACS was confirmed within 30 days in 153 men and 51 women. Presenting symptoms were similar in men and women with confirmed ACS. Time from symptom onset to ED presentation, time spent in the ED and total time in hospital were similar between the sexes. Male and female patients underwent similar rates of follow-up provocative testing. Females were significantly less likely to undergo coronary angiography; after adjustment for clinical factors, the odds of undergoing angiography were 1.8 (95% CI: 1.36–2.40) times higher for men than women. Of those undergoing coronary angiography within 30 days, a smaller proportion of women, compared to men, received revascularisation. Within 30 days, three (0.2%) male and one (0.1%) female patient died. Conclusion Minimal sex differences were observed in the contemporary emergency management of patients presenting with suspected ACS, and 30-day outcomes were similarly low in men and women despite lower rates of subsequent coronary angiography and revascularisation in women. Further study is required to replicate these results in different hospital systems and cultural settings. Keywords Chest pain; Emergency; Acute coronary syndrome; Se

Agreement between patient-reported and cardiology-adjudicated medical history in patients with possible ischemic chest pain: an observational study

Obtaining an accurate medical history is essential in the assessment of patients, particularly in emergency department (ED) patients with acute chest pain, as there can be a time imperative for diagnosis and commencement of treatment. We aimed to evaluate reliability of patient-reported compared with physician-adjudicated medical history by assessing patient's recall and communication of personal events and its influence on the accuracy of the medical history.A total of 776 patients presenting at ED with suspected cardiac chest pain were recruited. Data collection included self-reported patient history, electrocardiogram testing, and troponin I measurements. Independent assessment of risk factors and medical history was adjudicated by cardiologists. Diagnosis of acute coronary syndrome (ACS) at 30 days after presentation was assessed. Cohen's kappa measured patient-cardiologist agreement. Cardiologist adjudicated events were taken as true to assess accuracy.A total of 83 participants (10.7%) were diagnosed with ACS at 30 days after presentation. "Previous coronary artery bypass grafting" showed highest agreement (K = 1.00) between patient-reported and cardiologist-adjudicated events. Lowest agreement between patient-reported and cardiologist-adjudicated events was found for "prior ventricular dysrhythmia" (K = 0.33). Accuracy of reported "prior congestive heart failure" differed significantly between patients with and without diagnosed ACS at 30 days (92.8% and 97.5%, respectively).Accuracy of patient's recall and communication of medical history and risk factors was substantial but not perfect in the assessment of patients with ACS in the ED context. Our study reinforces the importance in the utilization of medical records and collateral information to address possible discrepancies in the medical history and improve patient care

Cost and outcomes of assessing patients with chest pain in an Australian emergency department

Free to read on journal website (may need to create free account first) Objectives: We sought to characterise the demographics, length of admission, final diagnoses, long-term outcome and costs associated with the population who presented to an Australian emergency department (ED) with symptoms of possible acute coronary syndrome (ACS). Design, setting and participants: Prospectively collected data on ED patients presenting with suspected ACS between November 2008 and February 2011 was used, including data on presentation and at 30 days after presentation. Information on patient disposition, length of stay and costs incurred was extracted from hospital administration records. Main outcome measures: Primary outcomes were mean and median cost and length of hospital stay. Secondary outcomes were diagnosis of ACS, other cardiovascular conditions or non-cardiovascular conditions within 30 days of presentation. Results: An ACS was diagnosed in 103 (11.1%) of the 926 patients recruited. 193 patients (20.8%) were diagnosed with other cardiovascular-related conditions and 622 patients (67.2%) had non-cardiac-related chest pain. ACS events occurred in 0 and 11 (1.9%) of the low-risk and intermediate-risk groups, respectively. Ninety-two (28.0%) of the 329 high-risk patients had an ACS event. Patients with a proven ACS, high-grade atrioventricular block, pulmonary embolism and other respiratory conditions had the longest length of stay. The mean cost was highest in the ACS group ($13 509; 95$11 794–$15 223) followed by other cardiovascular conditions ($7283; 95% CI, $6152–$8415) and non-cardiovascular conditions ($3331; 95$2976–$3685). Conclusions: Most ED patients with symptoms of possible ACS do not have a cardiac cause for their presentation. The current guideline-based process of assessment is lengthy, costly and consumes significant resources. Investigation of strategies to shorten this process or reduce the need for objective cardiac testing in patients at intermediate risk according to the National Heart Foundation and Cardiac Society of Australia and New Zealand guideline is required