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.

Evidence for clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications among adults with peripheral artery disease: protocol for a systematic review and meta-analysis.

INTRODUCTION: International guidelines recommend that adults with peripheral artery disease (PAD) be prescribed antiplatelet, statin and antihypertensive medications. However, it is unclear how often people with PAD are underprescribed these drugs, which characteristics predict clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications, and whether underprescription and non-adherence are associated with adverse health and health system outcomes. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE and Evidence-Based Medicine Reviews from 2006 onwards. Two investigators will independently review abstracts and full-text studies. We will include studies that enrolled adults and reported the incidence and/or prevalence of clinician underprescription of or patient non-adherence to guideline-recommended cardiovascular medications among people with PAD; adjusted risk factors for underprescription of/non-adherence to these medications; and adjusted associations between underprescription/non-adherence to these medications and outcomes. Outcomes will include mortality, major adverse cardiac and limb events (including revascularisation procedures and amputations), other reported morbidities, healthcare resource use and costs. Two investigators will independently extract data and evaluate study risk of bias. We will calculate summary estimates of the incidence and prevalence of clinician underprescription/patient non-adherence across studies. We will also conduct subgroup meta-analyses and meta-regression to determine if estimates vary by country, characteristics of the patients and treating clinicians, population-based versus non-population-based design, and study risks of bias. Finally, we will calculate pooled adjusted risk factors for underprescription/non-adherence and adjusted associations between underprescription/non-adherence and outcomes. We will use Grading of Recommendations, Assessment, Development and Evaluation to determine estimate certainty. ETHICS AND DISSEMINATION: Ethics approval is not required as we are studying published data. This systematic review will synthesise existing evidence regarding clinician underprescription of and patient non-adherence to guideline-recommended cardiovascular medications in adults with PAD. Results will be used to identify evidence-care gaps and inform where interventions may be required to improve clinician prescribing and patient adherence to prescribed medications. PROSPERO REGISTRATION NUMBER: CRD42022362801.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Emergent radiotherapy for pelvic malignancies: a narrative review.

BACKGROUND AND OBJECTIVE: Patients with primary genitourinary (GU), gynecologic (GYN) and gastrointestinal (GI) cancers can develop life-threatening or critical function-threatening symptoms that necessitate emergent intervention with palliative radiotherapy (RT). Unfortunately, research describing the use of RT in this critical setting is lacking. We aimed to review literature describing emergent palliative RT for primary pelvic malignancies and provide a narrative synthesis of relevant studies. METHODS: A medical librarian searched Ovid MEDLINE, Embase Classic, and Embase databases for relevant English language references from 1946-2022. No restrictions were placed on study type, publication type or date. References for GU, GYN and GI cancers were grouped and synthesized separately. KEY CONTENT AND FINDINGS: The treatment of bleeding from primary pelvic tumors was the only indication for emergent RT identified, however, no references reported dedicated cohorts of patients treated for bleeding in the emergent setting. Most references were retrospective single institution studies describing various dose fractionation schemes for non-emergent palliative RT. Outcome measures and response assessment times varied. The latency to hemostasis after RT commencement was not well described; most studies reported outcomes captured weeks or months following treatment. In general, high rates of hemostasis for GU, GYN and GI tumors have been reported following RT schedules ranging from a single fraction to many weeks of fractionated treatments. Bleeding seems to respond more favorably than other symptoms including pain and obstruction. CONCLUSIONS: Managing bleeding was the only indication for emergent RT identified in our search. Scant data exist that describe the latency to a hemostatic response following RT. This is an important knowledge gap in the literature given how commonly patients are affected by this complication of primary pelvic malignancies.

Risk Factors for Surgical Site Infection after Lower Limb Revascularisation Surgery: a Systematic Review and Meta-Analysis of Prognostic Studies.

OBJECTIVE: To systematically review and meta-analyse adjusted risk factors for surgical site infection (SSI) after lower limb revascularisation surgery. DATA SOURCES: MEDLINE, Embase, Evidence Based Medicine Reviews, and the Cochrane Central Register of Controlled Trials (inception to 28 April 2022). REVIEW METHODS: Systematic review and meta-analysis conducted according to PRISMA guidelines. After protocol registration, databases were searched. Studies reporting adjusted risk factors for SSI in adults who underwent lower limb revascularisation surgery for peripheral artery disease were included. Adjusted odds ratios (ORs) were pooled using random effects models. GRADE was used to assess certainty. RESULTS: Among 6 377 citations identified, 50 studies (n = 271 125 patients) were included. The cumulative incidence of SSI was 12 (95% confidence interval [CI] 10 - 13) per 100 patients. Studies reported 139 potential SSI risk factors adjusted for a median of 12 (range 1 - 69) potential confounding factors. Risk factors that increased the pooled adjusted odds of SSI included: female sex (pooled OR 1.41, 95% CI 1.20 - 1.64; high certainty); dependent functional status (pooled OR 1.18, 95% CI 1.03 - 1.35; low certainty); being overweight (pooled OR 1.82, 95% CI 1.29 - 2.56; moderate certainty), obese (pooled OR 2.20, 95% CI 1.44 - 3.36; high certainty), or morbidly obese (pooled OR 1.65, 95% CI 1.08 - 2.52; moderate certainty); chronic obstructive pulmonary disease (pooled OR 1.42, 95% CI 1.17 - 1.71; high certainty); chronic limb threatening ischaemia (pooled OR 1.67, 95% CI 1.22 - 2.29; moderate certainty); chronic kidney disease (pooled OR 2.13, 95% CI 1.18 - 3.83; moderate certainty); intra-operative (pooled OR 1.23, 95% CI 1.02 - 1.49), peri-operative (pooled OR 1.92, 95% CI 1.27 - 2.90), or post-operative (pooled OR 2.21, 95% CI 1.44 - 3.39) blood transfusion (moderate certainty for all); urgent or emergency surgery (pooled OR 2.12, 95% CI 1.22 - 3.70; moderate certainty); vein bypass and or patch instead of endarterectomy alone (pooled OR 1.86, 95% CI 1.33 - 2.59; moderate certainty); an operation lasting ≥ 3 hours (pooled OR 1.86, 95% CI 1.33 - 2.59; moderate certainty) or ≥ 5 hours (pooled OR 1.60, 95% CI 1.18 - 2.17; moderate certainty); and early or unplanned re-operation (pooled OR 4.50, 95% CI 2.18 - 9.32; low certainty). CONCLUSION: This systematic review identified evidence informed SSI risk factors following lower limb revascularisation surgery. These may be used to develop improved SSI risk prediction tools and to identify patients who may benefit from evidence informed SSI prevention strategies.

Influence of pulmonary rehabilitation on symptoms of anxiety and depression in interstitial lung disease: A systematic review of randomized controlled trials.

BACKGROUND: Interstitial lung diseases (ILDs) cause fibrosis of lung parenchyma, leading to impaired quality of life, dyspnea, and functional decline. Individuals with ILD experience a high prevalence of anxiety and depression. Recent research has demonstrated pulmonary rehabilitation (PR) alleviates symptoms of anxiety and depression in those with COPD. RESEARCH QUESTION: What is the influence of PR on symptoms of anxiety and depression in individuals with ILD? STUDY DESIGN: We conducted a PRISMA-2020-compliant systematic review of randomized controlled trials (RCTs) investigating PR's effect on anxiety and depression in patients with ILD. We searched MEDLINE, EMBASE, Cochrane, and PsycINFO from inception until April 3, 2023. A narrative synthesis was conducted where a quantitative approach was not feasible. RESULTS: Five RCTs (n = 281) were included. Idiopathic pulmonary fibrosis (IPF) was the most common type of ILD (k = 3). One study reported clinically-significant improvements in symptoms of anxiety among patients with IPF, and two studies for symptoms of depression among patients with sarcoidosis. Dropout rates were similar between intervention and control groups. All studies were at a high risk of bias. INTERPRETATION: Pulmonary rehabilitation is not detrimental to anxiety or depression for patients with ILD, and may improve symptoms of anxiety in IPF and depression in sarcoidosis. However, no conclusion can be drawn from available evidence, which is limited by heterogeneous populations/interventions, sample sizes and unexpectedly low prevalences of clinically-significant anxiety or depression. Further adequately powered RCTs that focus on anxiety and depressive symptoms as primary outcomes are needed.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review protocol.

INTRODUCTION: For close to a century opioid administration has been a standard of care to complement anaesthesia during surgery. Considering the worldwide opioid epidemic, this practice is now being challenged and there is a growing use of systemic pharmacological opioid minimising strategies. Our aim is to conduct a scoping review that will examine clinical trials that have evaluated the impact of intraoperative opioid minimisation strategies on patient-centred outcomes and identify promising strategies. METHODS AND ANALYSIS: Our scoping review will follow the framework developed by Arksey and O'Malley. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL from their inception approximately in March 2023. We will include randomised controlled trials, assessing the impact of systemic intraoperative pharmacologic opioid minimisation strategies on patient-centred outcomes. We define an opioid minimisation strategy as any non-opioid drug with antinociceptive properties administered during the intraoperative period. Patient-centred outcomes will be defined and classified based on the consensus definitions established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC group) and informed by knowledge users and patient partners. We will use a coproduction approach involving interested parties. Our multidisciplinary team includes knowledge users, patient partners, methodologists and knowledge user organisations. Knowledge users will provide input on methods, outcomes, clinical significance of findings, implementation and feasibility. Patient partners will participate in assessing the relevance of our design, methods and outcomes and help to facilitate evidence translation. We will provide a thorough description of available clinical trials, compare their reported patient-centred outcome measures with established recommendations and identify promising strategies. ETHICS AND DISSEMINATION: Ethics approval is not required for the review. Our scoping review will inform future research including clinical trials and systematic reviews through identification of important intraoperative interventions. Results will be disseminated through a peer-reviewed publication, presentation at conferences and through our network of knowledge user collaborators. REGISTRATION: Open Science Foundation (currently embargoed).

The impact of time to hemostatic intervention and delayed care for patients with traumatic hemorrhage: A systematic review.

BACKGROUND: Uncontrolled bleeding is a common cause of preventable mortality in trauma. While it is intuitive that delays to hemostasis may lead to worse outcomes, the impacts of these delays remain incompletely explored. This systematic review aimed to characterize the extant definitions of delayed hemostatic intervention and to quantify the impacts of delays on clinical outcomes. METHODS: We searched EMBASE, MEDLINE, and Web of Science from inception to August 2022. Studies defining "delayed intervention" and those comparing times to intervention among adults presenting to hospital with blunt or penetrating injuries who required major hemostatic intervention were eligible. The coprimary outcomes were mortality and the definition of delay to hemostasis used. Secondary outcomes included units of packed red blood cells received, length of stay in hospital, and length of stay in intensive care. RESULTS: We identified 2,050 studies, with 24 studies including 10,168 patients meeting the inclusion criteria. The majority of studies were retrospective observational cohort studies, and most were at high risk of bias. A variety of injury patterns and hemostatic interventions were considered, with 69.6% of studies reporting a statistically significant impact of increased time to intervention on mortality. Definitions of delayed intervention ranged from 10 minutes to 4 hours. Conflicting data were reported for impact of time on receipt of blood products, while one study found a significant impact on intensive care length of stay. No studies assessed length of stay in hospital. CONCLUSION: The extant literature is heterogeneous with respect to injuries included, methods of hemostasis employed, and durations of delay examined. While the majority of the included studies demonstrated a statistically significant relationship between time to intervention and mortality, an evidence-informed definition of delayed intervention for bleeding trauma patients at large has not been solidified. In addition, standardized research is needed to establish targets, which could reduce morbidity and mortality. LEVEL OF EVIDENCE: Systematic Review; Level IV.

Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01-1.63) and disease-free survival (HR 1.33, 95% CI 1.05-1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors.Registration: PROSPERO CRD42019140187.

Management of genitourinary symptoms in patients with breast cancer: an updated systematic review of available evidence from randomized trials.

PURPOSE: The purpose of this systematic review update is to synthesize available data on management of genitourinary symptoms (GUS) in breast cancer patients, a common and challenging clinical scenario. METHODS: EMBASE, Ovid Medline, and the Cochrane Library were searched from September 2014 to December 2021 for randomized controlled trials which examined various interventions for GUS in breast cancer patients. Outcomes of interest included improvements in vaginal symptoms (e.g., dryness, pain, dyspareunia, itching), vaginal hormone response measured by validated scales (e.g., Vaginal Health Index, and Vaginal Maturation Index), and Female Sexual Function Index (FSFI). A team of reviewers participated in the processes of study selection, data collection, and risk of bias appraisal. A descriptive approach to synthesis was used. RESULTS: Of 842 unique citations identified (412 from this update, 430 from previous review), eight studies (n = 539) met inclusion criteria. Interventions included 0.005% estriol gel (EG; n = 50), intravaginal testosterone (IVT; n = 21), intravaginal prebiotic (n = 13), hyaluronic acid (HA; n = 12), polyacrylic acid (PA; n = 25), pH-balanced gel (n = 118), Replens® (n = 24), and Lidocaine (n = 22). These were compared to placebo/saline/lubricants/usual care (n = 228). FSFI total score was significantly improved by all interventions except IVT and lidocaine, and not measured for Replens®. Significant improvements in vaginal hormone responses were reported for EG and pH-balanced gel; however, no significant effects were found for IVT, HA, or prebiotics. Vaginal symptoms were significantly improved by EG, IVT, PA, and PH-balanced gel. CONCLUSION: Treatment of GUS remains a challenging issue. It is evident that more prospective trials are needed.

Should Cell Salvage Be Used in Liver Resection and Transplantation? A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effect of intraoperative blood cell salvage and autotransfusion (IBSA) use on red blood cell (RBC) transfusion and postoperative outcomes in liver surgery. BACKGROUND: Intraoperative RBC transfusions are common in liver surgery and associated with increased morbidity. IBSA can be utilized to minimize allogeneic transfusion. A theoretical risk of cancer dissemination has limited IBSA adoption in oncologic surgery. METHODS: Electronic databases were searched from inception until May 2021. All studies comparing IBSA use with control in liver surgery were included. Screening, data extraction, and risk of bias assessment were conducted independently, in duplicate. The primary outcome was intraoperative allogeneic RBC transfusion (proportion of patients and volume of blood transfused). Core secondary outcomes included: overall survival and disease-free survival, transfusion-related complications, length of hospital stay, and hospitalization costs. Data from transplant and resection studies were analyzed separately. Random effects models were used for meta-analysis. RESULTS: Twenty-one observational studies were included (16 transplant, 5 resection, n=3433 patients). Seventeen studies incorporated oncologic indications. In transplant, IBSA was associated with decreased allogeneic RBC transfusion [mean difference -1.81, 95% confidence interval (-3.22, -0.40), P =0.01, I 2 =86%, very-low certainty]. Few resection studies reported on transfusion for meta-analysis. No significant difference existed in overall survival or disease-free survival in liver transplant [hazard ratio (HR)=1.12 (0.75, 1.68), P =0.59, I 2 =0%; HR=0.93 (0.57, 1.48), P =0.75, I 2 =0%] and liver resection [HR=0.69 (0.45, 1.05), P =0.08, I 2 =0%; HR=0.93 (0.59, 1.45), P =0.74, I 2 =0%]. CONCLUSION: IBSA may reduce intraoperative allogeneic RBC transfusion without compromising oncologic outcomes. The current evidence base is limited in size and quality, and high-quality randomized controlled trials are needed.

Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies.

Greater use of umbilical cord blood (UCB) for hematopoietic cell transplantation (HCT) is limited by the number of cells in banked units. Ex vivo culture strategies have been increasingly evaluated in controlled studies, but their impact on transplantation-related outcomes remains uncertain owing to the small patient numbers in these studies, necessitating an updated systematic review and meta-analysis. A systematic literature search was conducted using the MEDLINE, Embase, and Cochrane databases to March 18, 2022. Nine cohort-controlled phase I to III trials were identified, and data of 1146 patients undergoing umbilical cord blood transplantation (UCBT) were analyzed (308 ex vivo expanded and 838 unmanipulated controls). Expansion strategies involved cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and coculture with mesenchymal stromal cells in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 unmanipulated unit (4 studies). The included trials reported a median ex vivo expansion of CD34+ cells from 28-fold to 330-fold. Eight of the 9 studies demonstrated a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT demonstrated long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35% to 78% of double-unit recipients. Our meta-analysis revealed a lower risk of death at the study endpoint in patients who received ex vivo expanded grafts (odds ratio [OR], .66; 95% confidence interval [CI], .47 to .95; P = .02), while the risk of grade II-IV acute graft-versus-host disease was unchanged (OR, .79; 95% CI, .58 to 1.08; P = .14). This review indicates that UCBT following ex vivo expansion can accelerate initial engraftment. Durable donor chimerism can be achieved after transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long term outcomes remain unclear. Larger studies with longer-term outcomes are needed to better understand the merits of specific expansion strategies on survival.

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

BACKGROUND AIMS: Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. METHODS: A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. RESULTS: Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42-0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. CONCLUSIONS: MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.

Incidence of stroke in the first year after diagnosis of cancer-A systematic review and meta-analysis.

Background: Patients newly diagnosed with cancer represent a population at highest risk for stroke. The objective of this systematic review and meta-analysis was to estimate the incidence of stroke in the first year following a new diagnosis of cancer. Methods: We searched MEDLINE and EMBASE from January 1980 to June 2021 for observational studies that enrolled adults with a new diagnosis of all cancers excluding non-melanoma skin cancer, and that reported the incidence of stroke at 1 year. PRISMA guidelines for meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. We used the Dersimonian and Laird random effects method to pool cumulative incidences after logit transformation, and reported pooled proportions as percentages. Statistical heterogeneity was assessed using the I 2 statistic. Results: A total of 12,083 studies were screened; 41 studies were included for analysis. Data from 2,552,121 subjects with cancer were analyzed. The cumulative incidence of total stroke at 1 year was 1.4% (95% CI 0.9-2.2%), while the pooled incidence of ischemic stroke was 1.3% (95% CI 1.0-1.8%) and 0.3% (95% CI 0.1-0.9%) for spontaneous intracerebral hemorrhage (ICH), with consistently high statistical heterogeneity (>99% I 2). Conclusion: The estimated incidence of stroke during the first year after a new diagnosis of cancer is 1.4%, with a higher risk for ischemic stroke than ICH. Cancer patients should be educated on the risk of stroke at the time of diagnosis. Future studies should evaluate optimal primary prevention strategies in this high-risk group of patients. Systematic review registration: https://osf.io/ucwy9/.

Can GCSF-stimulated donor lymphocyte infusions improve outcomes for relapsed disease following allogeneic hematopoietic cell transplantation? A systematic review and meta-analysis.

Donor lymphocyte infusions (DLI) can produce graft-versus tumor effects to treat relapse after allogeneic hematopoietic cell transplantation, however, durable responses remain uncommon. A systematic review and meta-analysis are needed to clarify whether DLI collected after stimulation with granulocyte colony-stimulating factor (GCSF; G-DLI) can improve clinical outcomes. Sixteen studies (4 controlled) involving 585 patients were identified in a systematic search up to 17 September 2020. A meta-analysis demonstrated no significant difference in the risk of all-cause mortality (RR: 0.94, 95% CI 0.52-1.68, p = 0.82; n = 3 studies) or relapse-related mortality (RR: 0.72, 0.44-1.18, p = 0.19; n = 3 studies) between G-DLI and conventional DLI (C-DLI) groups. G-DLI products had similar mean CD3+ cells compared to C-DLI products, but median CD34+ cells/kg were increased. No improvement in disease progression, complete response rates, or risk of developing GVHD was observed with G-DLI, however, greater non-relapse mortality was observed compared to C-DLI. Alternative approaches to enhancing graft-versus-tumor effects are needed.

Updated Living Systematic Review and Meta-analysis of Controlled Trials of Mesenchymal Stromal Cells to Treat COVID-19: A Framework for Accelerated Synthesis of Trial Evidence for Rapid Approval-FASTER Approval.

BACKGROUND: Mesenchymal stromal cells (MSCs) may reduce mortality in patients with COVID-19; however, early evidence is based on few studies with marked interstudy heterogeneity. The second iteration of our living systematic review and meta-analysis evaluates a framework needed for synthesizing evidence from high-quality studies to accelerate consideration for approval. METHODS: A systematic search of the literature was conducted on November 15, 2021, to identify all English-language, full-text, and controlled clinical studies examining MSCs to treat COVID-19 (PROSPERO: CRD42021225431). FINDINGS: Eleven studies were identified (403 patients with severe and/or critical COVID-19, including 207 given MSCs and 196 controls). All 11 studies reported mortality and were pooled through random-effects meta-analysis. MSCs decreased relative risk of death at study endpoint (RR: 0.50 [95% CI, 0.34-0.75]) and RR of death at 28 days after treatment (0.19 [95% CI], 0.05-0.78) compared to controls. MSCs also decreased length of hospital stay (mean difference (MD: -3.97 days [95% CI, -6.09 to -1.85], n = 5 studies) and increased oxygenation levels at study endpoint compared to controls (MD: 105.62 mmHg O2 [95% CI, 73.9-137.3,], n = 3 studies). Only 2 of 11 studies reported on all International Society for Cellular Therapy (ISCT) criteria for MSC characterization. Included randomized controlled trials were found to have some concerns (n = 2) to low (n = 4) risk of bias (RoB), while all non-randomized studies were found to have moderate (n = 5) RoB. INTERPRETATION: Our updated living systematic review concludes that MSCs can likely reduce mortality in patients with severe or critical COVID-19. A master protocol based on our Faster Approval framework appears necessary to facilitate the more accelerated accumulation of high-quality evidence that would reduce RoB, improve consistency in product characterization, and standardize outcome reporting.

Definition and Characteristics of Mesenchymal Stromal Cells in Preclinical and Clinical Studies: A Scoping Review.

Mesenchymal stromal cells (MSCs) are widely used in preclinical and clinical research. Despite minimal criteria to define MSCs provided by the International Society for Cell and Gene Therapy (ISCT), concerns have been raised about inconsistent descriptions of cell products used. To address the question "How are MSCs currently defined and characterized?" we conducted a scoping review on original MSC preclinical and clinical studies published over a 3-month period. Selected studies identified from a systematic search of MEDLINE and Embase were categorized as follows: Clinical, Animal, Biology, or Biomaterial studies. Data were extracted from a randomly selected subsample of studies. We extracted information, including epidemiological characteristics of studies, study design, ISCT criteria, and MSC characterization and culture condition. A total of 1053 articles were included and among them, 318 articles were analyzed. Overall, 18% of the articles explicitly referred to the ISCT minimal criteria for MSC. MSC characteristics and culture conditions were inconstantly reported (eg, viability assay reported in only 18% of the articles). Only 20% of documents reported at least 1 functional assay. Clinical studies showed inconsistent completeness in reporting relevant information on the MSC characterization and cell manufacturing processes. These results suggest that further development and implementation of a consensus definition of MSCs and reporting guidelines are needed to enhance rigor, reproducibility, and transparency in MSC research.

Personalised multicomponent interventions for tobacco dependence management in low socioeconomic populations: a systematic review and meta-analysis.

BACKGROUND: There remains a disproportionally high tobacco smoking rate in low-income populations. Multicomponent tobacco dependence interventions in theory are effective. However, which intervention components are necessary to include for low socioeconomic status (SES) populations is still unknown. OBJECTIVE: To assess the effectiveness of multicomponent tobacco dependence interventions for low SES and create a checklist tool examining multicomponent interventions. METHODS: EMBASE and MEDLINE databases were searched to identify randomised controlled trials (RCTs) published with the primary outcome of tobacco smoking cessation measured at 6 months or post intervention. RCTs that evaluated tobacco dependence management interventions (for reduction or cessation) in low SES (experience of housing insecurity, poverty, low income, unemployment, mental health challenges, illicit substance use and/or food insecurity) were included. Two authors independently abstracted data. Random effects meta-analysis and post hoc sensitivity analysis were performed. RESULTS: Of the 33 included studies, the number of intervention components ranged from 1 to 6, with smoking quit rates varying between 1% and 36.6%. Meta-analysis revealed that both the 6-month and 12-month outcome timepoints, multicomponent interventions were successful in achieving higher smoking quit rates than the control (OR 1.64, 95% Cl 1.41 to 1.91; OR 1.74, 95% Cl 1.30 to 2.33). Evidence of low heterogeneity in the effect size was observed at 6-month (I2=26%) and moderate heterogeneity at 12-month (I2=56%) outcomes. CONCLUSION: Multicomponent tobacco dependence interventions should focus on inclusion of social support, frequency and duration of components. Employing community-based participatory-action research approach is essential to addressing underlying psychosocioeconomic-structural factors, in addition to the proven combination pharmacotherapies. PROSPERO REGISTRATION NUMBER: CRD42017076650.

Timing of pharmacologic venous thromboembolism prophylaxis initiation for trauma patients with nonoperatively managed blunt abdominal solid organ injury: a systematic review and meta-analysis.

BACKGROUND: Blunt abdominal solid organ injury is common and is often managed nonoperatively. Clinicians must balance risk of both hemorrhage and thrombosis. The optimal timing of pharmacologic venous thromboembolism prophylaxis (VTEp) initiation in this population is unclear. The objective was to evaluate early (< 48 h) compared to late initiation of VTEp in adult trauma patients with blunt abdominal solid organ injury managed nonoperatively. METHODS: Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched from inception to March 2021. Studies comparing timeframes of VTEp initiation were considered. The primary outcome was failure of nonoperative management (NOM) after VTEp initiation. Secondary outcomes included risk of transfusion, other bleeding complications, risk of deep vein thrombosis (DVT) and pulmonary embolism, and mortality. RESULTS: Ten cohort studies met inclusion criteria, with a total of 4642 patients. Meta-analysis revealed a statistically significant increase in the risk of failure of NOM among patients receiving early VTEp (OR 1.76, 95% CI 1.01-3.05, p = 0.05). There was no significant difference in risk of transfusion. Odds of DVT were significantly lower in the early group (OR 0.36, 95% CI 0.22-0.59, p < 0.0001). There was no difference in mortality (OR 1.50, 95% CI 0.82-2.75, p = 0.19). All studies were at serious risk of bias due to confounding. CONCLUSIONS: Initiation of VTEp earlier than 48 h following hospitalization is associated with an increased risk of failure of NOM but a decreased risk of DVT. Absolute failure rates of NOM are low. Initiation of VTEp at 48 h may balance the risks of bleeding and VTE.

Systematic Scoping Review of Studies Reporting Unexpected Donor-Derived Abnormalities from Recipients of Allogeneic Hematopoietic Cell Transplantation: A Proposed Framework for Donor Disclosure.

Allogeneic hematopoietic cell transplantation (HCT) is used increasingly to treat blood and immune-based disorders. Post-transplantation testing of HCT recipients can lead to unexpected molecular, cytogenetic, and other information in donor-derived cells, raising questions regarding the potential impact on donor health. This study was conducted to identify the breadth of donor-derived abnormalities identified by testing HCT recipients and to determine the extent to which disclosure and donor follow-up are described. A systematic search and scoping review were conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for scoping review guidelines in OVID MEDLINE and Embase (1947 to May 24, 2021). We identified 38 studies (63 donor-recipient pairs) addressing nonleukemic abnormalities to complement existing literature describing donor cell leukemia and donor-derived myelodysplasia. Donors were unrelated adults (n = 20), related family members (n = 28), cord blood donors (n = 6), or not reported (n = 9). Acquired cytogenetic, molecular, and morphologic abnormalities were reported. Donor origin was confirmed by cytogenetic analysis via karyotyping, fluorescence in situ hybridization, single tandem repeat PCR, and other techniques. A disease in donor-derived cells was described in 35 recipients (56.5%). Despite the relevance for testing and disclosure to donors, only 22 cases (32%) mentioned donor follow-up, and in 5 cases the donor developed a disease associated with the identified abnormality. Unrelated donor disclosure was mentioned in 3 of 26 cases (12%), with the findings reported back to the registry. Incidental abnormalities identified in transplanted donor cells may contribute to the post-transplantation risk of illness in the recipient and may be relevant to donor health. A framework for donor disclosure is proposed that incorporates consideration of analytic validity of the testing, potential significance of the finding, and the extent to which the abnormality is actionable. Adoption of effective processes to safeguard both donor and recipient health outcomes related to this issue is needed.