Combined IL-2, agonistic CD3 and 4-1BB stimulation preserve clonotype hierarchy in propagated non-small cell lung cancer tumor-infiltrating lymphocytes.

BACKGROUND: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) yielded clinical benefit in patients with checkpoint blockade immunotherapy-refractory non-small cell lung cancer (NSCLC) prompting a renewed interest in TIL-ACT. This preclinical study explores the feasibility of producing a NSCLC TIL product with sufficient numbers and enhanced attributes using an improved culture method. METHODS: TIL from resected NSCLC tumors were initially cultured using (1) the traditional method using interleukin (IL)-2 alone in 24-well plates (TIL 1.0) or (2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). TIL subsequently underwent a rapid expansion protocol (REP) with anti-CD3. Before and after the REP, expanded TIL were phenotyped and the complementarity-determining region 3 ß variable region of the T-cell receptor (TCR) was sequenced to assess the T-cell repertoire. RESULTS: TIL 3.0 robustly expanded NSCLC TIL while enriching for CD8+ TIL in a shorter manufacturing time when compared with the traditional TIL 1.0 method, achieving a higher success rate and producing 5.3-fold more TIL per successful expansion. The higher proliferative capacity and CD8 content of TIL 3.0 was also observed after the REP. Both steps of expansion did not terminally differentiate/exhaust the TIL but a lesser differentiated population was observed after the first step. TIL initially expanded with the 3.0 method exhibited higher breadth of clonotypes than TIL 1.0 corresponding to a higher repertoire homology with the original tumor, including a higher proportion of the top 10 most prevalent clones from the tumor. TIL 3.0 also retained a higher proportion of putative tumor-specific TCR when compared with TIL 1.0. Numerical expansion of TIL in a REP was found to perturb the clonal hierarchy and lessen the proportion of putative tumor-specific TIL from the TIL 3.0 process. CONCLUSIONS: We report the feasibility of robustly expanding a T-cell repertoire recapitulating the clonal hierarchy of the T cells in the NSCLC tumor, including a large number of putative tumor-specific TIL clones, using the TIL 3.0 methodology. If scaled up and employed as a sole expansion platform, the robustness and speed of TIL 3.0 may facilitate the testing of TIL-ACT approaches in NSCLC.

Home medicines reviews: a national survey of Australian accredited pharmacists’ health service time investment

Background: In Australia, polypharmacy and medication-related problems are prevalent in the community. Therefore, medicines safety initiatives such as the Home Medicines Review (HMR) service are critical to health care provision. While the evidence continues to expand around HMR service, little is known of accredited pharmacists’ experiences of HMR time investment. Objective: This study aimed to explore accredited pharmacists’ experiences of HMR practice regarding time investment in the study’s defined HMR Stages: 1 (initial paper-based assessment and review), 2 (in-home patient-accredited pharmacist consultation), and 3 (HMR report collation, generation, completion, and provision to the patient’s General Practitioner, including any liaison time). Methods: An electronic survey was developed and piloted by a panel of reviewers. Convenience sampling was used to distribute the final anonymous survey nationally via professional pharmacy organisations. Data were analyzed for frequency distributions and a chi-square test of independence was performed to evaluate any association between demographic variables relating to HMR time investment. Results: There was a total of 255 survey respondents, representing approximately 10% of national accredited pharmacist membership. The majority were experienced accredited pharmacists who had completed >100 HMRs (73%), were female (71%), and aged >40 years (60%). Regarding time investment for a typical instance of HMR, most spent: <30 minutes performing Stage 1 (46.7%), and 30-60 minutes performing Stage 2 (70.2%). In Stage 3, 40.0% invested 1-2 hours, and 27.1% invested 2-3 hours in HMR report collation and completion. Quantitative analysis revealed statistically significant (p=0.03) gender findings where females performed longer patient consultations than males (Stage 2) (AU)

Home medicines reviews: a national survey of Australian accredited pharmacists' health service time investment.

BACKGROUND: In Australia, polypharmacy and medication-related problems are prevalent in the community. Therefore, medicines safety initiatives such as the Home Medicines Review (HMR) service are critical to health care provision. While the evidence continues to expand around HMR service, little is known of accredited pharmacists' experiences of HMR time investment. OBJECTIVE: This study aimed to explore accredited pharmacists' experiences of HMR practice regarding time investment in the study's defined HMR Stages: 1 (initial paper-based assessment and review), 2 (in-home patient-accredited pharmacist consultation), and 3 (HMR report collation, generation, completion, and provision to the patient's General Practitioner, including any liaison time). METHODS: An electronic survey was developed and piloted by a panel of reviewers. Convenience sampling was used to distribute the final anonymous survey nationally via professional pharmacy organisations. Data were analyzed for frequency distributions and a chi-square test of independence was performed to evaluate any association between demographic variables relating to HMR time investment. RESULTS: There was a total of 255 survey respondents, representing approximately 10% of national accredited pharmacist membership. The majority were experienced accredited pharmacists who had completed >100 HMRs (73%), were female (71%), and aged >40 years (60%). Regarding time investment for a typical instance of HMR, most spent: <30 minutes performing Stage 1 (46.7%), and 30-60 minutes performing Stage 2 (70.2%). In Stage 3, 40.0% invested 1-2 hours, and 27.1% invested 2-3 hours in HMR report collation and completion. Quantitative analysis revealed statistically significant (p=0.03) gender findings where females performed longer patient consultations than males (Stage 2). More HMR career experience resulted in statistically significant (p=0.01) less time performing Stage 1 (initial paper-based assessment and review); with a trend to less time performing Stage 3 (HMR report writing). CONCLUSIONS: Accredited pharmacists invest significant time in performing comprehensive HMRs, especially during in-home patient consultations and during HMR report collation and completion. Their significant HMR time investment as medicines experts provides insight for program and workforce considerations and warrants further research to better understand their work processes for optimizing medicines use and improving health.

CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma.

INTRODUCTION: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. MATERIALS AND METHODS: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). RESULTS: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. CONCLUSION: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

Using the big five inventory to evaluate the personality traits of Australian pharmacists.

OBJECTIVES: Pharmacist personality traits may explain the incomplete uptake of extended scope pharmacy practice roles. The objective of this study was to explore the personality traits of Australian pharmacists using the Big Five Inventory (BFI). METHODS: A cross-sectional survey of Australian pharmacists was undertaken. Pharmacists were asked to complete a short demographic survey and the BFI, a 44-item survey that measures the Big Five personality traits: extraversion, agreeableness, conscientiousness, neuroticism and openness. Each trait can be scored out of a maximum of 5. The BFI and multivariate linear regression were used to assess associations between personality traits and demographic variables. KEY FINDINGS: A total of 122 responses were available for analysis. The majority of study participants were female (79.5%), were aged between 30 and 39 years (32.0%) and worked in hospital pharmacy (46.7%). Pharmacists scored (mean (standard deviation)) 3.4 (0.7) for extraversion, 3.9 (0.5) for agreeableness, 4.2 (0.5) for conscientiousness, 2.5 (0.8) for neuroticism and 3.5 (0.6) for openness. Associations were found between agreeableness and qualifications and location of pharmacy practice, neuroticism and working in a practice location (rural versus metropolitan) and age, and openness and practice location (rural versus metropolitan) and principle role in pharmacy. CONCLUSIONS: Pharmacists displayed high scores on the traits of extraversion, agreeableness, conscientiousness and openness and scored moderately on the trait of openness. Confirmation with a larger sample size and evaluation in the context of pharmacy practice change may assist in overcoming barriers to change in the pharmacy profession.

Pharmacist Compliance With Therapeutic Guidelines on Diagnosis and Treatment Provision.

Importance: Misuse and overselling of over-the-counter pharmaceuticals poses a major burden on both private and public health expenditures. Objective: To seek evidence on whether over-the-counter medication dispensing behavior complies or conflicts with the protocols indicated in practice standards and guidelines of a national professional pharmacy organization. Design, Setting, and Participants: This quality improvement study was undertaken in 205 pharmacies in the wider Brisbane, Australia, area. Two standardized patient (SP) scenarios were developed to evaluate noncompliant behavior. Data collection for scenario 1 was conducted between November 23 and December 9, 2016. Data collection for scenario 2 was conducted between September 1 and 28, 2017. A 2-sample test of proportions and a probit regression model were used to evaluate the likelihood of noncompliant treatments and overtreatments in each case scenario. Statistical analysis was performed from January 30 to June 21, 2018, and revised in May 2019. Main Outcomes and Measures: Outcomes were the observed likelihood of noncompliant treatments and overtreatments. Noncompliance is defined as treatments not complying with practice standards and guidelines set by the professional pharmacy society. Noncompliant treatments include undertreatment (patient did not receive necessary treatment) and overtreatments (patient was supplied with more than sufficient treatments) in both scenarios. Results: In scenario 1, 9 trained female SPs visited 89 pharmacies to request emergency hormonal contraception from pharmacy staff. In 45 cases, SPs reported having unprotected intercourse within the last 24 hours (case 1A), and in 44 cases, SPs reported having unprotected intercourse more than 72 hours ago (case 1B), which is past the efficacy threshold of over-the-counter emergency hormonal contraception. In scenario 2, 11 SPs (5 male and 6 female) visited 150 pharmacies (154 visits in total) to request treatment for family members or a partner with symptoms indicating bacterial conjunctivitis (case 2A; n = 73) or viral conjunctivitis (case 2B; n = 81). In scenario 1-dispensing emergency hormonal contraception when physician referral is recommended-21 of 44 pharmacists (47.7%) in case 1B violated the recommendation by selling the over-the-counter medication. With the inclusion of both no physician referral and emergency hormonal contraception sold, this rate increased to 79.5% (35 of 44 pharmacists). In scenario 2-1 case each of bacterial and viral conjunctivitis-overtreatment occurred in 55 of 154 cases (35.7%). In both scenarios, 140 of 243 pharmacies (57.6%) followed dispensing behavior compliant with the protocol, while 76 of 243 pharmacies (31.3%) involved some form of overtreatment or overselling of medication. Some evidence of an association between sex of SP and pharmacist was also found. Conclusions and Relevance: Although the market for dispensing over-the-counter medication in Australia is regulated, relatively high rates of overtreatment and some cases of undertreatment were observed in this study. Given the unintended adverse effects, including overuse of antibiotics and corticosteroids, these observations suggest the advisability of regulatory intervention ensuring compliance with professional protocols.

Health professional beliefs, knowledge, and concerns surrounding medicinal cannabis - A systematic review.

BACKGROUND: The number of jurisdictions allowing access to medicinal cannabis has been steadily increasing since the state of California introduced legislation in 1996. Although there is a high degree of legislative heterogeneity across jurisdictions, the involvement of a health professional is common among all. This places health professionals at the forefront of therapy, yet no systematic review of literature has offered insight into the beliefs, knowledge, and concerns of health professionals regarding medicinal cannabis. METHODS: Using a predetermined study protocol, PubMed, EMBASE, PsycINFO, CINAHL, and Scopus databases were searched for studies indexed up to the 1st August 2018. Pre-defined inclusion and exclusion criteria were applied uniformly. Screening for relevancy, full-text review, data extraction, and risk of bias were completed by two independent investigators. Risk of bias was assessed using CASP criteria (qualitative) and a modified domain-based risk assessment tool (quantitative). RESULTS: Of the 15,775 studies retrieved, 106 underwent full-text review and of these, 26 were included. The overall risk of bias was considered low across all included studies. The general impression was that health professionals supported the use of medicinal cannabis in practice; however, there was a unanimous lack of self-perceived knowledge surrounding all aspects of medicinal cannabis. Health professionals also voiced concern regarding direct patient harms and indirect societal harms. CONCLUSION: This systematic review has offered a lens through which to view the existing literature surrounding the beliefs, knowledge, and concerns of health professionals regarding medicinal cannabis. These results are limited, however, by the implicit common-sense models of behaviour utilised by the included studies. Before strategies can be developed and implemented to change health professional behaviour, a more thorough understanding of the factors that underpin the delivery of medicinal cannabis is necessary.

What can pharmacists do in general practice? A pilot trial.

BACKGROUND AND OBJECTIVES: Non-dispensing pharmacists are being suggested as a useful addition to the workforce in general practice. The aim of this study was to describe the activities of three general practice pharmacists over six months in a pilot trial. METHOD: Three general practices integrated a part-time (15.2-16 hours per week) non-dispensing pharmacist to be employed according to their individual skillset and local workplace needs. Each general practice pharmacist maintained a daily activity diary, which was subsequently analysed. RESULTS: The general practice pharmacists' activities were categorised as quality of practice (37%), administration (34%), medication review (19%) and patient education (11%). Within the quality of practice category, most time was spent conducting clinical audits (47%). Over the course of the six months, time spent on administration decreased, while time communicating with general practitioners (GPs) on clinical issues increased. DISCUSSION: The general practice pharmacists conducted a range of predominantly clinically related activities involving their expertise in the quality use of medications. Involvement in clinical activities to support GPs increased with time working in the practice. Randomised controlled trials are required to collect clinical outcomes and determine which activities conducted by pharmacists are most beneficial to Australian patients and GPs.

Stakeholder perspectives about general practice pharmacists in the Australian Capital Territory: a qualitative pilot study.

Previous studies have found that integrating non-dispensing pharmacists in general practice may improve patient safety, improve patient outcomes, deliver health system efficiencies and generate savings. However, the employment of pharmacists in general practice is not common in Australia. A naturalistic study was conducted in the Australian Capital Territory with three general practices, each employing a part-time pharmacist for 12 months. This study reports on stakeholder perspectives of the benefits, barriers and enablers for integrating pharmacists into general practice. Patients, practice staff and community pharmacists that had interacted with a practice pharmacist were asked to complete a self-administered questionnaire. Patient questionnaire respondents (n=44) reported that a practice pharmacist was beneficial and wanted to see this continue. Practice pharmacists were also perceived beneficial by primary healthcare employees surveyed (n=42). Opinions were further explored by individual semi-structured interviews (n=20). The qualitative data explored five themes: perception of the practice pharmacist, collaboration with doctors, pharmacist roles, sustainability and community pharmacy aspects. Patients welcomed improved understanding about their medication, whereas general practice staff appreciated pharmaceutical advice about patients with chronic conditions. Participants discussed options to fund practice pharmacists longer term, which was identified as the main barrier to widespread roll out.

Why does the need for medication become a barrier to breastfeeding? A narrative review.

PROBLEM: The need for medication during lactation can contribute to the early cessation of breastfeeding. BACKGROUND: Breastfeeding women may require medication for acute or chronic health conditions. For some women this need for medication can become a barrier to breastfeeding; this is despite the fact that the majority of medications are considered to be compatible with lactation. AIM: This narrative review aims to investigate factors relating to medicines safety that could contribute to medication unnecessarily becoming a barrier to breastfeeding. METHODS: A selective literature search using PubMed, Scopus and Google Scholar was conducted over a 6-month period using the search terms "breastfeeding", "lactation", "medication" and "information". Articles were assessed to identify whether they addressed the impact of medication use on the decision to breastfeed. FINDINGS: Fifty six articles were identified as having appropriate discussion about decision making for the safe use of medication during lactation. Themes identified included variable and conflicting safety advice for medicines; difficulty interpreting risks associated with medicine use; societal pressures faced by the breastfeeding woman; and the varied knowledge and training of health professionals involved in the care of breastfeeding women. CONCLUSION: Poor quality of information about medicine safety during lactation can contribute to confusion in giving recommendations. This confusion can result in early cessation of breastfeeding or insufficient health care for the breastfeeding woman.

The Australian rise of esomeprazole-was expenditure on samples a contributor?

BACKGROUND: Administrative data from the Australian Pharmaceutical Benefits Scheme (PBS) showed rapid growth of esomeprazole dispensing when it was launched. Australia has universal prescription medicine coverage (the PBS), which included esomeprazole from August 2002. Free samples of new medicines are commonly provided to doctors. OBJECTIVES: To determine if a relationship exists between marketing expenditure on samples and the dispensing rate for esomeprazole in Australia between June 2002 and September 2006. METHODS: Quarterly sample expenditures at product/brand level for proton pump inhibitors (PPIs) for Australian general practitioners were obtained for July 2002 to September 2006. Corresponding PBS dispensing data were obtained for all PPIs and converted to defined daily dose (DDD)/1000 population/day. Spending on samples was calculated as dollars per dispensed prescription and plotted against time on the Australian market. RESULTS: Total PPI usage increased from 34.2 to 50.8 DDD/1000 population/day over the study period. Expenditure on samples per dispensed prescription was higher when a PPI was new on the market and diminished over 5-6 years to a relatively constant level. The rapid decline in this ratio was demonstrated by a case study following esomeprazole from launch in Australia for almost 5 years clearly demonstrating the initial investment to drive sales. CONCLUSION: A relationship appears to exist between expenditure on esomeprazole samples and its usage in Australia. A high initial investment was followed by a rapid reduction in cost per prescription dispensed, predominantly due to growth in market share. This trend was consistent with other PPIs.