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JMIR Formative Research Mar 2024Web-based learning activities are key components of continuing medical education (CME) for health care professionals (HCPs). However, the published outcomes of web-based...
Assessing Knowledge, Competence, and Performance Following Web-Based Education on Early Breast Cancer Management: Health Care Professional Questionnaire Study and Anonymized Patient Records Analysis.
BACKGROUND
Web-based learning activities are key components of continuing medical education (CME) for health care professionals (HCPs). However, the published outcomes of web-based educational interventions for early breast cancer (EBC) are limited.
OBJECTIVE
This study aims to objectively assess knowledge, competence, and performance among HCPs following participation in 2 EBC-focused CME activities and to identify the remaining educational gaps.
METHODS
We developed 2 CME-accredited web-based educational activities addressing high-risk EBC, including integration of shared decision-making to optimize patient care (touchMDT) and stratification for early identification of high-risk patients and novel treatment strategies (touchPANEL DISCUSSION). Knowledge, competence, and performance were assessed before and after the activities against an expanded outcomes framework (levels 1-5) using self-reported questionnaires and an analysis of anonymized data extracted from patient records.
RESULTS
Six months after the launch of the activity, 7047 and 8989 HCP participants engaged with touchMDT and touchPANEL DISCUSSION, respectively. The overall satisfaction was 82% (a total score of 20.6 out of 25) for the touchMDT and 88% (a total score of 21.9 out of 25) for the touchPANEL DISCUSSION. For the evaluation of knowledge and competence (50 respondents before the activity and 50 learners after the activity), there was a significant increase in the mean number of correctly answered questions from pre- to postactivity (touchMDT: median 4.0, IQR 3.0-5.0 to median 5.5, IQR 4.0-7.0; mean 4.00, SD 1.39 to mean 5.30, SD 1.56 and touchPANEL DISCUSSION: median 4.0, IQR 4.0-5.0 to median 6.0, IQR 5.0-7.0; mean 4.32, SD 1.30 to mean 5.88, SD 1.49; both P<.001). A significant improvement in self-reported performance (50 respondents before the activity and 50 learners after the activity) was observed in a combined analysis of both activities (median 3.0, IQR 2.0-3.0 to median 4.0, IQR 3.0-5.0; mean 2.82, SD 1.08 to mean 4.16, SD 1.45; P<.001). Patient record analysis (50 respondents before the activity and 50 learners after the activity) showed that the HCPs used a range of measures to determine EBC recurrence risk and revealed no significant differences in adjuvant therapies used before and after the activity (P=.97 and P>.99 for Ki-67 <20% and Ki-67 ≥20% tumors, respectively). The remaining educational gaps included strategies for implementing shared decision-making in clinical practice and the use of genetic and biomarker testing to guide treatment selection.
CONCLUSIONS
Brief, web-based CME activities on EBC were associated with an improvement in HCP knowledge, competence, and self-reported performance and can help identify unmet needs to inform the design of future CME activities.
PubMed: 38512328
DOI: 10.2196/50931 -
Frontiers in Cellular and Infection... 2024Commercial foot-and-mouth disease (FMD) vaccines have limitations, such as local side effects, periodic vaccinations, and weak host defenses. To overcome these...
BACKGROUND
Commercial foot-and-mouth disease (FMD) vaccines have limitations, such as local side effects, periodic vaccinations, and weak host defenses. To overcome these limitations, we developed a novel FMD vaccine by combining an inactivated FMD viral antigen with the small molecule isoprinosine, which served as an adjuvant (immunomodulator).
METHOD
We evaluated the innate and adaptive immune responses elicited by the novel FMD vaccine involved both in vitro and in vivo using mice and pigs.
RESULTS
We demonstrated isoprinosine-mediated early, mid-term, and long-term immunity through in vitro and in vivo studies and complete host defense against FMD virus (FMDV) infection through challenge experiments in mice and pigs. We also elucidated that isoprinosine induces innate and adaptive (cellular and humoral) immunity via promoting the expression of immunoregulatory gene such as pattern recognition receptors [PRRs; retinoic acid-inducible gene (RIG)-I and toll like receptor (TLR)9], transcription factors [T-box transcription factor (TBX)21, eomesodermin (EOMES), and nuclear factor kappa B (NF-kB)], cytokines [interleukin (IL)-12p40, IL-23p19, IL-23R, and IL-17A)], and immune cell core receptors [cluster of differentiation (CD)80, CD86, CD28, CD19, CD21, and CD81] in pigs.
CONCLUSION
These findings present an attractive strategy for constructing novel FMD vaccines and other difficult-to-control livestock virus vaccine formulations based on isoprinosine induced immunomodulatory functions.
Topics: Animals; Mice; Swine; Foot-and-Mouth Disease; Inosine Pranobex; Adjuvants, Vaccine; Antibodies, Viral; Foot-and-Mouth Disease Virus; Adjuvants, Immunologic; Interleukins; Viral Vaccines; Immunity
PubMed: 38510965
DOI: 10.3389/fcimb.2024.1331779 -
JAAD International Jun 2024Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence...
BACKGROUND
Anti-Program-Death-1 (PD-1) is a standard adjuvant therapy for patients with resected melanoma. We hypothesized that there are discrepancies in survival, recurrence pattern and toxicity to adjuvant PD-1 between different ethnicities and melanoma subtypes.
OBJECTIVE
We performed a multicenter cohort study incorporating 6 independent institutions in Australia, China, Japan, and the United States. The primary outcomes were recurrence free survival (RFS) and overall survival (OS). Secondary outcomes were disease recurrence patterns and toxicities.
RESULTS
In total 534 patients were included. East-Asian/Hispanic/African reported significantly poorer RFS/OS. Nonacral cutaneous or melanoma of unknown primary reported the best RFS/OS, followed by acral, and mucosal was the poorest. Within the nonacral cutaneous or melanoma of unknown primary subtypes, East-Asian/Hispanic/African reported significantly poorer RFS/OS than Caucasian. In the multivariate analysis incorporating ethnicity/melanoma-subtype/age/sex/stage/lactate dehydrogenase/BRAF (v-Raf murine sarcoma viral oncogene homolog B)-mutation/adjuvant radiotherapy, East-Asian/Hispanic/African had independently significantly poorer outcomes (RFS: HR, 1.71; 95% CI, 1.19-2.44 and OS: HR, 2.34; 95% CI, 1.39-3.95), as was mucosal subtype (RFS: HR, 3.25; 95% CI, 2.04-5.17 and OS: HR, 3.20; 95% CI, 1.68-6.08). Mucosal melanoma was an independent risk factor for distant metastasis, especially liver metastasis. East-Asian/Hispanic/African had significantly lower incidence of gastrointestinal/musculoskeletal/respiratory/other-rare-type-toxicities; but higher incidences of liver toxicities.
LIMITATIONS
A retrospective study.
CONCLUSIONS
Ethnicity and melanoma subtype are associated with survival and recurrence pattern in melanoma patients treated with adjuvant anti-PD-1. Toxicity profile differs by ethnicity and may require a precision toxicity surveillance strategy.
PubMed: 38500872
DOI: 10.1016/j.jdin.2023.11.014 -
Frontiers in Immunology 2024, a gram-negative coccobacillus bacterium, can cause various infections in humans, including septic arthritis, diarrhea (traveler's diarrhea), gastroenteritis, skin and...
, a gram-negative coccobacillus bacterium, can cause various infections in humans, including septic arthritis, diarrhea (traveler's diarrhea), gastroenteritis, skin and wound infections, meningitis, fulminating septicemia, enterocolitis, peritonitis, and endocarditis. It frequently occurs in aquatic environments and readily contacts humans, leading to high infection rates. This bacterium has exhibited resistance to numerous commercial antibiotics, and no vaccine has yet been developed. Aiming to combat the alarmingly high infection rate, this study utilizes techniques to design a multi-epitope vaccine (MEV) candidate against this bacterium based on its aerolysin toxin, which is the most toxic and highly conserved virulence factor among the species. After retrieval, aerolysin was processed for B-cell and T-cell epitope mapping. Once filtered for toxicity, antigenicity, allergenicity, and solubility, the chosen epitopes were combined with an adjuvant and specific linkers to create a vaccine construct. These linkers and the adjuvant enhance the MEV's ability to elicit robust immune responses. Analyses of the predicted and improved vaccine structure revealed that 75.5%, 19.8%, and 1.3% of its amino acids occupy the most favored, additional allowed, and generously allowed regions, respectively, while its ERRAT score reached nearly 70%. Docking simulations showed the MEV exhibiting the highest interaction and binding energies (-1,023.4 kcal/mol, -923.2 kcal/mol, and -988.3 kcal/mol) with TLR-4, MHC-I, and MHC-II receptors. Further molecular dynamics simulations demonstrated the docked complexes' remarkable stability and maximum interactions, i.e., uniform RMSD, fluctuated RMSF, and lowest binding net energy. models also predict the vaccine will stimulate a variety of immunological pathways following administration. These analyses suggest the vaccine's efficacy in inducing robust immune responses against . With high solubility and no predicted allergic responses or toxicity, it appears safe for administration in both healthy and -infected individuals.
Topics: Humans; Artificial Intelligence; Aeromonas hydrophila; Diarrhea; Travel; Machine Learning; Vaccines; Epitopes, T-Lymphocyte; Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Bacterial Toxins; Pore Forming Cytotoxic Proteins
PubMed: 38495891
DOI: 10.3389/fimmu.2024.1369890 -
International Journal of Pharmaceutics Apr 2024The immunomodulatory properties of β-glucans have sparked interest among various medical fields. As vaccine adjuvants, glucan particles offer additional advantages as...
The immunomodulatory properties of β-glucans have sparked interest among various medical fields. As vaccine adjuvants, glucan particles offer additional advantages as antigen delivery systems. This study reported the immunomodulatory properties of glucan particles with different size and chemical composition. The effect of glucan microparticles (GPs) and glucan nanoparticles (Glu 130 and 355 NPs) was evaluated on human immune cells. While GPs and Glu 355 NPs demonstrated substantial interaction with Dectin-1 receptor on monocytes, Glu 130 NPs exhibited reduced activation of this receptor. This observation was substantiated by blocking Dectin-1, resulting in inhibition of reactive oxygen species production induced by GPs and Glu 355 NPs. Notably, monocyte-derived dendritic cells (moDCs) stimulated by Glu 355 NPs exhibited phenotypic and functional maturation, essential for antigen cross-presentation. The immunomodulatory efficacy was investigated using an autologous mixed lymphocyte reaction (AMLR), resulting in considerable rates of lymphocyte proliferation and an intriguing profile of cytokine and chemokine release. Our findings highlight the importance of meticulously characterizing the size and chemical composition of β-glucan particles to draw accurate conclusions regarding their immunomodulatory activity. This in vitro model mimics the human cellular immune response, and the results obtained endorse the use of β-glucan-based delivery systems as future vaccine adjuvants.
Topics: Humans; Glucans; Adjuvants, Immunologic; Adjuvants, Vaccine; beta-Glucans; Antigens
PubMed: 38490404
DOI: 10.1016/j.ijpharm.2024.123996 -
PloS One 2024The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor...
BACKGROUND
The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control).
METHODS AND ANALYSIS
This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy.
TRIAL REGISTRATION
The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.
Topics: Humans; Female; Breast Neoplasms; Receptors, Estrogen; Chemotherapy, Adjuvant; Neoadjuvant Therapy; Adjuvants, Immunologic; Gene Expression Profiling; Carcinoma; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic
PubMed: 38489298
DOI: 10.1371/journal.pone.0300339 -
Journal For Immunotherapy of Cancer Mar 2024Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study... (Randomized Controlled Trial)
Randomized Controlled Trial
Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: Outcomes in histopathologic subgroups from the randomized, double-blind, phase 3 KEYNOTE-716 trial.
BACKGROUND
Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics.
METHODS
Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm (median) vs ≥5 per mm), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present).
RESULTS
Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm and 0.57 (0.40 to 0.80) for ≥5 per mm; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS.
CONCLUSIONS
In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov, NCT03553836.
Topics: Humans; Adjuvants, Immunologic; Antibodies, Monoclonal, Humanized; Combined Modality Therapy; Melanoma; Skin Neoplasms; Adolescent; Adult
PubMed: 38485189
DOI: 10.1136/jitc-2023-007501 -
International Journal of Nanomedicine 2024Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and...
BACKGROUND
Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events.
METHODS
We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA.
RESULTS
Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations.
CONCLUSION
Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.
Topics: Humans; Rats; Animals; Methotrexate; Rats, Wistar; Arthritis, Rheumatoid; Nanoparticles; Inflammation; Arthritis, Experimental; Lipids; Diclofenac
PubMed: 38482519
DOI: 10.2147/IJN.S439359 -
Journal of Gastrointestinal Oncology Feb 2024Drug-induced pneumonia, especially immune-related adverse events, can sometimes be fatal, and it is crucial to seize the signs for early treatment. A clinical trial...
BACKGROUND
Drug-induced pneumonia, especially immune-related adverse events, can sometimes be fatal, and it is crucial to seize the signs for early treatment. A clinical trial (ATTRACTION-4) reported no cases of grade 4 or 5 pneumonia or interstitial lung disease associated with nivolumab plus S-1 and oxaliplatin. However, we encountered two cases of fatal pneumonia induced by this regimen.
CASE DESCRIPTION
The two patients were in their 70s, male and diagnosed gastric cancer with peritoneal dissemination. The patient of case 1 underwent surgery and adjuvant chemotherapy nine years before. The patient of case 2 was diagnosed unresectable 6 months before and chemo naïve. Both patients received nivolumab plus S-1 and oxaliplatin for the dissemination. The onset of both cases occurred after the fifth dose of the regimen, and the responses to corticosteroids were transient and limited. Computed tomography showed bilateral consolidation and ground-glass opacities, seemingly similar to an organizing pneumonia pattern. Acute and organizing stages of diffuse alveolar damage were detected histopathologically. Despite showing notable antitumor effects, both patients had indications of interstitial pneumonitis before admission, such as elevation of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) levels and slight lung opacity or respiratory symptoms approximately 10 days before admission.
CONCLUSIONS
Patients undergoing nivolumab plus S-1 and oxaliplatin should be closely followed up with imaging, evaluation of symptom including oxygen saturation, and serological marker analysis such as lactate dehydrogenase, CRP, and KL-6. Early detection of pneumonia leads to adequate cessation of chemotherapy and early treatment, and this can prevent severe adverse events.
PubMed: 38482223
DOI: 10.21037/jgo-23-511 -
Science Advances Mar 2024Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient...
Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.
Topics: Animals; Mice; Nanovaccines; Neoplasms; Nanoparticles; T-Lymphocytes, Cytotoxic; Melanoma; Antigens, Neoplasm; Adjuvants, Immunologic; Immunotherapy; Mice, Inbred C57BL
PubMed: 38478602
DOI: 10.1126/sciadv.adk2444