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American Society of Clinical Oncology... Jun 2024This article endeavors to navigate the clinical journey of bispecific antibodies (BsAbs), from elucidating common toxicities and management strategies to examining novel... (Review)
Review
This article endeavors to navigate the clinical journey of bispecific antibodies (BsAbs), from elucidating common toxicities and management strategies to examining novel agents and broadening access in community health care. These drugs, commonly through T-cell activation, result in shared adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Variations in target antigens and designs, however, might introduce unique toxicities for different BsAbs, warranting specific management approaches. Recent US Food and Drug Administration approvals of BsAbs targeting CD3 T cells linked to CD20 for non-Hodgkin lymphoma and to B-cell maturation antigen or GPRC5D for multiple myeloma have transformed the treatment landscape for hematologic malignancies. Emerging new agents promise further enhancement and safety, exploring novel antigen targets, innovative structures such as trispecific antibodies, and the engagement of diverse immune cells. Simultaneously, the expansion of BsAbs into community practices is underway, demanding a multifaceted strategy that encompasses educational initiatives, operational adaptations, and collaborative frameworks. This ensures comprehensive treatment access, allowing every patient, irrespective of geographical or socioeconomic status, to benefit from these advancements in cancer therapy.
Topics: Humans; Antibodies, Bispecific; Multiple Myeloma; Lymphoma; Antineoplastic Agents, Immunological
PubMed: 38935881
DOI: 10.1200/EDBK_433516 -
Emerging Microbes & Infections Dec 2024Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral...
Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (= 0.048) and 96 (= 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770). ClinicalTrials.gov identifier: NCT04098770. ClinicalTrials.gov identifier: NCT02651376.
Topics: Humans; Male; Female; Adult; Middle Aged; Immunotherapy, Adoptive; Immunocompromised Host; HLA Antigens; Acquired Immunodeficiency Syndrome; Treatment Outcome; AIDS-Related Opportunistic Infections; Transplantation, Homologous; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count
PubMed: 38935839
DOI: 10.1080/22221751.2024.2364744 -
PloS One 2024Health technology assessment uses a multidisciplinary approach to support health benefits package design towards universal health coverage. The evidence-informed... (Review)
Review
Health technology assessment for sexual reproductive health and rights benefits package design in sub-Saharan Africa: A scoping review of evidence-informed deliberative processes.
BACKGROUND
Health technology assessment uses a multidisciplinary approach to support health benefits package design towards universal health coverage. The evidence-informed deliberative process framework has been used alongside Health technology assessment to enhance stakeholder participation and deliberations in health benefits package design. Applying the evidence-informed deliberative framework for Health assessment could support the morally diverse sexual reproductive health and rights (SRHR) benefits package design process. However, evidence on participation and deliberations for stakeholders in health technology assessment for SRHR benefits package design has not been curated in sub-Saharan Africa. This study synthesises literature to fill this gap.
METHODS
This scoping review applies the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews, and deductive analysis following the evidence-informed deliberative processes framework. The search strategy uses the Guttmacher-Lancet Commission-proposed comprehensive definition of SRHR and the World Health Organisation's universal health coverage compendium of SRHR interventions to generate search terms. Six databases and biographical hand searches were used to identify studies in Sub-Saharan Africa from 1994.
RESULTS
A total of 14 studies met the inclusion criteria. Evidence for yearly public budgets and explicit SRHR health technology assessment processes was not found. In 12 of the studies reviewed, new advisory committees were set up specifically for health technology assessment for SRHR priority-setting and benefits package design. In all decision-making processes reviewed, the committee member roles, participation and deliberations processes, and stakeholder veto powers were not clearly defined. Patients, the public, and producers of health technology were often excluded in the health technology assessment for the SRHR benefits package design. Most health technology assessment processes identified at least one decision-making criterion but failed to use this in their selection and appraisal stages for SRHR benefits design. The identification, selection, and scoping stages in health technology assessment for SRHR were non-existent in most studies. In 11 of the 14 processes of the included studies, stakeholders were dissatisfied with the health policy recommendation from the appraisal process in health technology assessment. Perceived benefits for evidence-informed deliberative processes included increased stakeholder engagement and fairness in decision-making.
CONCLUSION
To support the integration of diverse social values in health technology assessment for fairer SRHR benefits package design, evidence from this review suggests the need to institutionalise health technology assessment, establish prioritisation decision criteria, involve all relevant stakeholders, and standardise the process and assessment methodological approaches.
Topics: Africa South of the Sahara; Humans; Technology Assessment, Biomedical; Reproductive Health; Sexual Health
PubMed: 38935794
DOI: 10.1371/journal.pone.0306042 -
PloS One 2024Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account....
Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.
Topics: Animals; Aniline Compounds; Acrylamides; Afatinib; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mice; Humans; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Xenograft Model Antitumor Assays; ErbB Receptors; Quinazolines; Piperazines; Female; Indoles; Pyrimidines
PubMed: 38935790
DOI: 10.1371/journal.pone.0304914 -
PloS One 2024Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in...
Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7-18 years) while they performed n-back tasks. Blood-oxygenation level-dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD.
Topics: Humans; Hydroxyurea; Anemia, Sickle Cell; Memory, Short-Term; Child; Adolescent; Male; Female; Magnetic Resonance Imaging; Antisickling Agents; Brain; Case-Control Studies
PubMed: 38935785
DOI: 10.1371/journal.pone.0296196 -
PloS One 2024Although breast cancer has a markedly higher incidence in developed countries, seven out of ten deaths occur in developing countries, including Ethiopia. However, there...
BACKGROUND
Although breast cancer has a markedly higher incidence in developed countries, seven out of ten deaths occur in developing countries, including Ethiopia. However, there is a limited information on the quality of life (QoL) among breast cancer patients in Ethiopia, notably in the Amhara region. Therefore, this study aimed to assess the QoL and its associated factors among patients with breast cancer in the Amhara Region, Ethiopia.
METHODS
An institutional based cross-sectional study was conducted from 25th March 2019 to 7th July 2019. A systematically selected sample of 256 breast cancer patients were participated in the study. A standardized interviewer-administered Amharic version questionnaire was used to collect the data. We used the European Organization for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ C30) and breast cancer supplementary measure (QLQ-BR23) to measure QoL. The data were analyzed by SPSS version 23. A binary logistic regression model was fitted to identify the predictors of QoL. The adjusted odds ratio (AOR) with a 95% confidence interval (CI) was reported to show the strength of the association.
RESULTS
Sixty-eight percent of breast cancer patients had poor QoL (68.4%; 95% CI: 62.5-73.8). The mean score of QoL was 70.6 (standard deviation (SD) ±13.9; 95% CI: 69.0-72.4). All functional component scores were less than 75 on the symptom scale. Diarrhea (11.6), constipation (17.5), and dyspnea (24.7) were less noticeable symptoms. Being out of marriage (AOR = 2.59, 95% CI: 1.32-5.07), being poor (AOR = 2.39, 95%CI: 1.32-5.03), being non-housewife (AOR = 3.25, 95% CI: 1.16-7.22), and being complaints of dyspnea (AOR = 3.48, 95% CI: 1.79-6.79), and insomnia (AOR = 2.03, 95% CI: 1.05-3.91) were significantly associated with QoL.
CONCLUSIONS
The proportion of poor QoL among breast cancer patients was high. Health care professionals should give attention to breast cancer patients who are out of marriage, poor and non-housewife while offering the recommended treatment courses.
Topics: Humans; Quality of Life; Ethiopia; Female; Breast Neoplasms; Cross-Sectional Studies; Middle Aged; Adult; Surveys and Questionnaires; Aged
PubMed: 38935776
DOI: 10.1371/journal.pone.0305263 -
PloS One 2024The Coronavirus Disease 2019 (COVID-19) has caused a global health crisis. Mortality predictors in critically ill patients remain under investigation. A retrospective...
The Coronavirus Disease 2019 (COVID-19) has caused a global health crisis. Mortality predictors in critically ill patients remain under investigation. A retrospective cohort study included 201 patients admitted to the intensive care unit (ICU) due to COVID-19. Data on demographic characteristics, laboratory findings, and mortality were collected. Logistic regression analysis was conducted with various independent variables, including demographic characteristics, clinical factors, and treatment methods. The study aimed to identify key risk factors associated with mortality in an ICU. In an investigation of 201 patients comprising non-survivors (n = 80, 40%) and Survivors (n = 121, 60%), we identified several markers significantly associated with ICU mortality. Lower Interleukin 6 and White Blood Cells levels at both 24- and 48-hours post-ICU admission emerged as significant indicators of survival. The study employed logistic regression analysis to evaluate risk factors for in-ICU mortality. Analysis results revealed that demographic and clinical factors, including gender, age, and comorbidities, were not significant predictors of in-ICU mortality. Ventilator-associated pneumonia was significantly higher in Survivors, and the use of antibiotics showed a significant association with increased mortality risk in the multivariate model (OR: 11.2, p = 0.031). Our study underscores the significance of monitoring Il-6 and WBC levels within 48 hours of ICU admission, potentially influencing COVID-19 patient outcomes. These insights may reshape therapeutic strategies and ICU protocols for critically ill patients.
Topics: Humans; COVID-19; Male; Female; Critical Illness; Middle Aged; Prognosis; Aged; Retrospective Studies; Intensive Care Units; Risk Factors; Interleukin-6; SARS-CoV-2; Adult; Hospital Mortality; Pneumonia, Ventilator-Associated; Logistic Models; Leukocyte Count
PubMed: 38935767
DOI: 10.1371/journal.pone.0302248 -
PloS One 2024At some point in their career, many healthcare workers will experience psychological distress associated with being unable to take morally or ethically correct action,...
OBJECTIVE
At some point in their career, many healthcare workers will experience psychological distress associated with being unable to take morally or ethically correct action, as it aligns with their own values; a phenomenon known as moral distress. Similarly, there are increasing reports of healthcare workers experiencing long-term mental and psychological pain, alongside internal dissonance, known as moral injury. This review examined the triggers and factors associated with moral distress and injury in Health and Social Care Workers (HSCW) employed across a range of clinical settings with the aim of understanding how to mitigate the effects of moral distress and identify potential preventative interventions.
METHODS
A systematic review was conducted and reported according to recommendations from Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were conducted and updated regularly until January 2024 on 2 main databases (CENTRAL, PubMed) and three specialist databases (Scopus, CINAHL, PsycArticles), alongside hand searches of study registration databases and other systematic reviews reference lists. Eligible studies included a HSCW sample, explored moral distress/injury as a main aim, and were written in English or Italian. Verbatim quotes were extracted, and article quality was assessed via the CASP toolkit. Thematic analysis was conducted to identify patterns and arrange codes into themes. Specific factors like culture and diversity were explored, and the effects of exceptional circumstances like the pandemic.
RESULTS
Fifty-one reports of 49 studies were included in the review. Causes and triggers were categorised under three domains: individual, social, and organisational. At the individual level, patients' care options, professionals' beliefs, locus of control, task planning, and the ability to make decisions based on experience, were indicated as elements that can cause or trigger moral distress. In addition, and relevant to the CoVID-19 pandemic, was use/access to personal protection resources. The social or relational factors were linked to the responsibility for advocating for and communication with patients and families, and professionals own support network. At organisational levels, hierarchy, regulations, support, workload, culture, and resources (staff and equipment) were identified as elements that can affect professionals' moral comfort. Patients' care, morals/beliefs/standards, advocacy role and culture of context were the most referenced elements. Data on cultural differences and diversity were not sufficient to make assumptions. Lack of resources and rapid policy changes have emerged as key triggers related to the pandemic. This suggests that those responsible for policy decisions should be mindful of the potential impact on staff of sudden and top-down change.
CONCLUSION
This review indicates that causes and triggers of moral injury are multifactorial and largely influenced by the context and constraints within which professionals work. Moral distress is linked to the duty and responsibility of care, and professionals' disposition to prioritise the wellbeing of patients. If the organisational values and regulations are in contrast with individuals' beliefs, repercussions on professionals' wellbeing and retention are to be expected. Organisational strategies to mitigate against moral distress, or the longer-term sequalae of moral injury, should address the individual, social, and organisational elements identified in this review.
Topics: Humans; Health Personnel; Morals; Social Workers; Qualitative Research; COVID-19; Psychological Distress; Stress, Psychological
PubMed: 38935754
DOI: 10.1371/journal.pone.0303013 -
PloS One 2024Colorectal cancer (CRC) is the third most common malignancy cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) promotes cancer...
Colorectal cancer (CRC) is the third most common malignancy cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) promotes cancer metastasis and a tumour-based Glasgow EMT score was associated with adverse clinical features and poor prognosis. In this study, the impact of using the established five tumour-based EMT markers consisting of E-cadherin (E-cad), β-catenin (β-cat), Snail, Zeb-1, and Fascin in combination with the stromal periostin (PN) on the prediction of CRC patients' prognosis were invesigated. Formalin-fixed paraffin-embedded tissues of 202 CRC patients were studies the expressions of E-cad, β-cat, Snail, Zeb-1, Fascin, and PN by immunohistochemistry. Individually, cytoplasmic Fascin (Fc), cytoplasmic Snail (Sc), nuclear Snail (Sn), stromal Snail (Ss), and stromal PN (Ps) were significantly associated with reduced survival. A combination of Ps with Fc, Fs, and Sn was observed in 2 patterns including combined Fc, Fs, and Ps (FcFsPs) and Fc, Sn, and Ps (FcSnPs). These combinations enhanced the prognostic power compared to individual EMT markers and were independent prognostic markers. As the previously established scoring method required five markers and stringent criteria, its clinical use might be limited. Therefore, using these novel combined prognostic markers, either FcFsPs or FcSnPs, may be useful in predicting CRC patient outcomes.
Topics: Humans; Colorectal Neoplasms; Snail Family Transcription Factors; Cell Adhesion Molecules; Prognosis; Female; Male; Middle Aged; Carrier Proteins; Microfilament Proteins; Epithelial-Mesenchymal Transition; Aged; Biomarkers, Tumor; Adult; Cadherins; Transcription Factors; beta Catenin; Aged, 80 and over; Periostin
PubMed: 38935747
DOI: 10.1371/journal.pone.0304666 -
PloS One 2024Among the consequences of systemic racism in health care are significant health disparities among Black/African American individuals with comorbid physical and mental...
Among the consequences of systemic racism in health care are significant health disparities among Black/African American individuals with comorbid physical and mental health conditions. Despite decades of studies acknowledging health disparities based on race, significant change has not occurred. There are shockingly few evidence-based antiracism interventions. New paradigms are needed to intervene on, and not just document, racism in health care systems. We are developing a transformative paradigm for new antiracism interventions for primary care settings that integrate mental and physical health care. The paradigm is the first of its kind to integrate community-based participatory research and systems science, within an established model of early phase translation to rigorously define new antiracism interventions. This protocol will use a novel application of systems sciences by combining the qualitative systems sciences methods (group model building; GMB) with quantitative methods (simulation modeling) to develop a comprehensive and community-engaged view of both the drivers of racism and the potential impact of antiracism interventions. Community participants from two integrated primary health care systems will engage in group GMB workshops with researchers to 1) Describe and map the complex dynamic systems driving racism in health care practices, 2) Identify leverage points for disruptive antiracism interventions, policies and practices, and 3) Review and prioritize a list of possible intervention strategies. Advisory committees will provide feedback on the design of GMB procedures, screen potential intervention components for impact, feasibility, and acceptability, and identify gaps for further exploration. Simulation models will be generated based on contextual factors and provider/patient characteristics. Using Item Response Theory, we will initiate the process of developing core measures for assessing the effectiveness of interventions at the organizational-systems and provider levels to be tested under a variety of conditions. While we focus on Black/African Americans, we hope that the resulting transformative paradigm can be applied to improve health equity among other marginalized groups.
Topics: Humans; Primary Health Care; Health Equity; Racism; Black or African American; Community-Based Participatory Research; Healthcare Disparities; Antiracism
PubMed: 38935743
DOI: 10.1371/journal.pone.0306185