Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Matrix metalloproteinases 2 and 9 as diagnostic markers in the progression to Chagas cardiomyopathy.

BACKGROUND: Infection with the Trypanosoma cruzi parasite is endemic in parts of Central and South America. Approximately 30% of those infected develop Chagas cardiomyopathy, the most common cause of heart failure in this region. No suitable biomarker is available that reflects the evolution of the disease. Although there is substantial evidence of a strong inflammatory reaction following infection that could activate matrix metalloproteinases (MMPs), their role in the development of Chagas cardiomyopathy is unknown. METHODS: A cross-sectional study was conducted in Bucaramanga, Colombia, from 2002 to 2006, including 144 patients at different stages of Chagas disease and 44 control patients. The potential enzyme activities of MMP-2 and MMP-9 in plasma samples were determined by gelatin zymography. Clinical data including T cruzi serology, electrocardiograms, and echocardiograms were recorded for all patients. RESULTS: Densitometric analysis of potential enzyme activities in plasma samples showed a significant increase of 72-kd MMP-2 (P < .001) and 92-kd MMP-9 (P < .001) in T cruzi seropositive patients compared with control subjects. Matrix metalloproteinase 9 showed significantly increased activity in patients with abnormal electrocardiogram (P < .004) and with dilated cardiomyopathy compared (P < .001) with controls. Analysis of the MMP-2 and MMP-9 results in relation to clinical data revealed that abnormal heart relaxation correlated positively with high MMP-2 levels in patients with dilated cardiomyopathy (r = 0.75, P < .01). CONCLUSIONS: Plasma MMP-2 and MMP-9 both appear to be useful biomarkers for detecting the advent and progression of cardiomyopathy in T cruzi-infected individuals.

Anesthesia interventions that alter perioperative mortality: a scoping review.

BACKGROUND: With over 230 million surgical procedures performed annually worldwide, better application of evidence in anesthesia and perioperative medicine may reduce widespread variation in clinical practice and improve patient care. However, a comprehensive summary of the complete available evidence has yet to be conducted. This scoping review aims to map the existing literature investigating perioperative anesthesia interventions and their potential impact on patient mortality, to inform future knowledge translation and ultimately improve perioperative clinical practice. METHODS: Searches were conducted in MEDLINE, EMBASE, CINAHL, and the Cochrane Library databases from inception to March 2015. Study inclusion criteria were adult patients, surgical procedures requiring anesthesia, perioperative intervention conducted/organized by a professional with training in anesthesia, randomized controlled trials (RCTs), and patient mortality as an outcome. Studies were screened for inclusion, and data was extracted in duplicate by pairs of independent reviewers. Data were extracted, tabulated, and reported thematically. RESULTS: Among the 10,505 publications identified, 369 RCTs (n = 147,326 patients) met the eligibility criteria. While 15 intervention themes were identified, only 7 themes (39 studies) had a significant impact on mortality: pharmacotherapy (n = 23), nutritional (n = 3), transfusion (n = 4), ventilation (n = 5), glucose control (n = 1), medical device (n = 2), and dialysis (n = 1). CONCLUSIONS: By mapping intervention themes, this scoping review has identified areas requiring further systematic investigation given their potential value for reducing patient mortality as well as areas where continued investment may not be cost-effective given limited evidence for improving survival. This is a key starting point for future knowledge translation to optimize anesthesia practice.

Matrix metalloproteinases: control of vascular function and their potential role in preeclampsia.

Preeclampsia is a pregnancy specific disorder characterised by hypertension and proteinuria occurring after the twentieth week of gestation. Preeclampsia induced hypertension is the result of increased vascular reactivity and endothelial dysfunction, however, the mechanisms underlying this state remain elusive. One possible mediator may be the matrix metalloproteinases (MMPs), a family of proteinases typically recognized for long term tissue remodelling. This review examines the evidence suggesting a role for MMPs in acutely regulating vascular function. Studies have shown that MMPs can activate vasoconstrictors (e.g. endothelin), inactivate vasodilators (e.g. calcitonin gene related peptide) and transactivate cell surface receptors responsible for vasoconstriction (e.g. epidermal growth factor receptor). The potential role of these proteinases in preeclampsia will then be discussed.

Guidance on assessing the methodological and reporting quality of toxicologically relevant studies: A scoping review.

Assessments of methodological and reporting quality are critical to adequately judging the credibility of a study's conclusions and to gauging its potential reproducibility. To aid those seeking to assess the methodological or reporting quality of studies relevant to toxicology, we conducted a scoping review of the available guidance with respect to four types of studies: in vivo and in vitro, (quantitative) structure-activity relationships ([Q]SARs), physico-chemical, and human observational studies. Our aims were to identify the available guidance in this diverse literature, briefly summarize each document, and distill the common elements of these documents for each study type. In general, we found considerable guidance for in vivo and human studies, but only one paper addressed in vitro studies exclusively. The guidance for (Q)SAR studies and physico-chemical studies was scant but authoritative. There was substantial overlap across guidance documents in the proposed criteria for both methodological and reporting quality. Some guidance documents address toxicology research directly, whereas others address preclinical research generally or clinical research and therefore may not be fully applicable to the toxicology context without some translation. Another challenge is the degree to which assessments of methodological quality in toxicology should focus on risk of bias - as in clinical medicine and healthcare - or be broadened to include other quality measures, such as confirming the identity of test substances prior to exposure. Our review is intended primarily for those in toxicology and risk assessment seeking an entry point into the extensive and diverse literature on methodological and reporting quality applicable to their work.

Increased activities of cardiac matrix metalloproteinases matrix metalloproteinase (MMP)-2 and MMP-9 are associated with mortality during the acute phase of experimental Trypanosoma cruzi infection.

The strong inflammatory reaction that occurs in the heart during the acute phase of Trypanosoma cruzi infection is modulated by cytokines and chemokines produced by leukocytes and cardiomyocytes. Matrix metalloproteinases (MMPs) have recently emerged as modulators of cardiovascular inflammation. In the present study we investigated the role of MMP-2 and MMP-9 in T. cruzi-induced myocarditis, by use of immunohistochemical analysis, gelatin zymography, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction to analyze the cardiac tissues of T. cruzi-infected C57BL/6 mice. Increased transcripts levels, immunoreactivity, and enzymatic activity for MMP-2 and MMP-9 were observed by day 14 after infection. Mice treated with an MMP inhibitor showed significantly decreased heart inflammation, delayed peak in parasitemia, and improved survival rates, compared with the control group. Reduced levels of cardiac tumor necrosis factor-alpha, interferon-gamma, serum nitrite, and serum nitrate were also observed in the treated group. These results suggest an important role for MMPs in the induction of T. cruzi-induced acute myocarditis.