Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions.

Nearly half of advanced melanoma patients do not achieve a clinical response with anti-programmed cell death 1 protein (PD1) therapy (i.e. primary resistance) or initially achieve a clinical response but eventually progress during or following further treatment (i.e. secondary resistance). A consensus definition for tumor resistance to anti-PD1 monotherapy was published by Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce (SITC) in 2020. A systematic literature review (SLR) of clinical trials and observational studies was conducted to characterize the proportions of advanced melanoma patients who have progressed on anti-PD1 therapies. The SLR included 55 unique studies and the SITC definition of primary resistance was applied to 37 studies that specified disease progression by best overall response. Median and range of patients with primary resistance in studies that specified first-line and second-line or higher anti-PD1 monotherapy was 35.50% (21.19-39.13%; n = 4 studies) and 41.54% (30.00-56.41%, n = 3 studies); median and range of patients with primary resistance in studies that specified first-line and second-line or higher combination therapy was 30.23% (15.79-33.33%; n = 6 studies), and 70.00% (61.10-73.33%; n = 3 studies). Primary resistance to anti-PD1 monotherapies and when in combination with ipilimumab are higher in patients receiving second-line or higher therapies, in patients with acral, mucosal, and uveal melanoma, and in patients with active brain metastases. The percentage of patients with primary resistance was generally consistent across clinical trials, with variability in resistance noted for observational studies. Limitations include applying the SITC definitions to combination therapies, where consensus definitions are not yet available. Future studies should highly consider utilizing the SITC definitions to harmonize how resistance is classified and facilitate meaningful context for clinical activity.

A Qualitative Systematic Review of Facilitators of and Barriers to Community Pharmacists-Led Anticoagulation Management Service.

OBJECTIVE: To identify the facilitators of and barriers to the implementation of Community Pharmacists-Led Anticoagulation Management Services (CPAMS). DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL Register of Controlled Trials were searched from inception until August 20, 2021. STUDY SELECTION AND DATA EXTRACTION: All abstracts proceeded to full-text review, which was completed by 2 reviewers. Data extraction was completed by a single reviewer and verified. Analysis was completed using best-fit framework synthesis. DATA SYNTHESIS: A total of 17 articles reporting on CPAMS from 6 jurisdictions were included: 2 Canadian provincial programs (Nova Scotia, Alberta), a national program (New Zealand), and 3 cities in the United Kingdom (Whittington and Brighton and Hove) and Australia (Sydney). Facilitators of CPAMS included convenience for patients, accessibility for patients, professional satisfaction for pharmacists, increased efficiency in anticoagulation management, improved outcomes, enhanced collaboration, and scalability. Barriers included perceived poor quality of care by patients, resistance by general practitioners, organizational limits, capping of the number of eligible patients, and cost. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The barriers and facilitators identified in this review will inform health policy makers on the implementation and improvement of CPAMS for patients and health care practitioners. CONCLUSION AND RELEVANCE: CPAMS has been implemented in 6 jurisdictions across 4 countries, with reported benefits and challenges. The programs were structurally similar in most jurisdictions, with minor variations in implementation. New anticoagulation management programs should consider adapting existing frameworks to local needs.

Immunogenicity and Safety of Reduced-Dose Intradermal vs Intramuscular Influenza Vaccines: A Systematic Review and Meta-analysis.

Importance: Low-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages. Objective: To compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages. Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020. Study Selection: All comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included. Data Extraction and Synthesis: Data were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted. Main Outcomes and Measures: Primary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events. Results: A total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses. Conclusions and Relevance: These findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.

Stirred suspension bioreactors maintain naïve pluripotency of human pluripotent stem cells.

Due to their ability to standardize key physiological parameters, stirred suspension bioreactors can potentially scale the production of quality-controlled pluripotent stem cells (PSCs) for cell therapy application. Because of differences in bioreactor expansion efficiency between mouse (m) and human (h) PSCs, we investigated if conversion of hPSCs, from the conventional "primed" pluripotent state towards the "naïve" state prevalent in mPSCs, could be used to enhance hPSC production. Through transcriptomic enrichment of mechano-sensing signaling, the expression of epigenetic regulators, metabolomics, and cell-surface protein marker analyses, we show that the stirred suspension bioreactor environment helps maintain a naïve-like pluripotent state. Our research corroborates that converting hPSCs towards a naïve state enhances hPSC manufacturing and indicates a potentially important role for the stirred suspension bioreactor's mechanical environment in maintaining naïve-like pluripotency.