Risa Shorr

Cell-Based Therapy Using Umbilical Cord Blood for Novel Indications in Regenerative Therapy and Immune Modulation: An Updated Systematic Scoping Review of the Literature

Cell-based therapy using umbilical cord blood (UCB) is being used increasingly in novel applications. To balance heightened public expectations and ensure appropriateness of emerging cell-based treatment choices, regular evidence-based assessment of novel UCB-derived therapies is needed. We performed a systematic search of the literature and identified 57 studies (814 patients) for analysis. Sixteen of these studies (353 patients) included a control group for comparison. The most commonly reported novel indication for therapy was neurologic diseases (25 studies, 476 patients), including studies of cerebral palsy (12 studies, 276 patients). Other indications included diabetes mellitus (9 studies, 149 patients), cardiac and vascular diseases (7 studies, 24 patients), and hepatic diseases (4 studies, 106 patients). Most studies administered total nucleated cells, mononuclear cells, or CD34-selected cells (31 studies, 513 patients), whereas 20 studies described the use of UCB-derived mesenchymal stromal cells. The majority of reports (46 studies, 627 patients) described cellular products obtained from allogeneic sources, whereas 11 studies (187 patients) used autologous products. We identified 3 indications where multiple prospective controlled studies have been published: 4 of 4 studies reported clinical benefit in cerebral palsy, 1 of 3 studies reported benefit for cirrhosis, and 1 of 3 studies reported biochemical response in type 1 diabetes), although heterogeneity among the studies precluded meaningful pooled analysis of results. We anticipate a more clear understanding of the clinical benefit for specific indications once more controlled studies are reported. Patients should continue to be enrolled on registered clinical trials for novel therapies. Blood establishments, transplantation centers, and regulatory bodies need to prepare for greater clinical demand.

Clinical Studies of Ex Vivo Expansion to Accelerate Engraftment After Umbilical Cord Blood Transplantation: A Systematic Review

Cell dose limits greater use of umbilical cord blood (UCB) in hematopoietic cell transplantation. The clinical benefits of ex vivo expansion need clarity to understand its potential impact. A systematic search of studies addressing UCB ex vivo expansion was conducted. Fifteen clinical studies (349 transplanted patients) and 13 registered trials were identified. The co-infusion of an expanded unit and a second unmanipulated unit (8 studies), the fractional expansion of 12% to 60% of a single unit (5 studies), and the infusion of a single expanded unit (2 studies) were reported. More recently, published studies and 12 of 13 ongoing trials involve the use of novel small molecules in addition to traditional cytokine cocktails. Higher total cell number was closely associated with faster neutrophil engraftment. Compared with historical controls, neutrophil engraftment was significantly accelerated in more recent studies using small molecules or mesenchymal stromal cells (MSC) co-culture, and in some cases, platelet recovery was also statistically improved. Recent studies using nicotinamide and StemRegenin-1 reported long-term chimerism of the expanded unit. No significant improvement in survival or other transplant-related outcomes was demonstrated for any of the strategies. Ex vivo expansion of UCB can accelerate initial neutrophil engraftment after transplant. More recent studies suggest that long-term engraftment of ex vivo expanded cord blood units is achievable. Results of larger randomized controlled trials are needed to understand the impact on patient outcomes and health care costs.

Knowledge translation to fitness trainers: A systematic review

BackgroundThis study investigates approaches for translating evidence-based knowledge for use by fitness trainers. Specific questions were: Where do fitness trainers get their evidence-based information? What types of interventions are effective for translating evidence-based knowledge for use by fitness trainers? What are the barriers and facilitators to the use of evidence-based information by fitness trainers in their practice?MethodsWe describe a systematic review of studies about knowledge translation interventions targeting fitness trainers. Fitness trainers were defined as individuals who provide exercise program design and supervision services to the public. Nurses, physicians, physiotherapists, school teachers, athletic trainers, and sport team strength coaches were excluded.ResultsOf 634 citations, two studies were eligible for inclusion: a survey of 325 registered health fitness professionals (66% response rate) and a qualitative study of 10 fitness instructors. Both studies identified that fitness trainers obtain information from textbooks, networking with colleagues, scientific journals, seminars, and mass media. Fitness trainers holding higher levels of education are reported to use evidence-based information sources such as scientific journals compared to those with lower education levels, who were reported to use mass media sources. The studies identified did not evaluate interventions to translate evidence-based knowledge for fitness trainers and did not explore factors influencing uptake of evidence in their practice.ConclusionLittle is known about how fitness trainers obtain and incorporate new evidence-based knowledge into their practice. Further exploration and specific research is needed to better understand how emerging health-fitness evidence can be translated to maximize its use by fitness trainers providing services to the general public.

The impact of perioperative red blood cell transfusions in patients undergoing liver resection: A systematic review

BACKGROUND Liver resection is associated with a high proportion of red blood cell transfusions. There is a proposed association between perioperative transfusions and increased risk of complications and tumor recurrence. This study reviews the evidence of this association in the literature. METHODS The Medline, EMBASE, and Cochrane databases were searched for clinical trials or observational studies of patients undergoing liver resection that compared patients who did and did not receive a perioperative red blood cell transfusion. Outcomes were mortality, complications, and cancer survival. RESULTS Twenty-two studies involving 6832 patients were included. All studies were retrospective, with no clinical trials. No studies were scored as low risk of bias. The overall proportion of patients transfused was 38.3%. After multivariate analysis, 1 of 5 studies demonstrated an association between transfusion and increased mortality; 5 of 6 demonstrated an association between transfusion and increased complications; and 10 of 18 demonstrated an association between transfusion and decreased cancer survival. CONCLUSION This review supports the evidence linking perioperative blood transfusions to negative outcomes. The most convincing association was with post-operative complications, some association with long-term cancer outcomes, and no convincing association with mortality. These findings support the initiation, and further study, of restrictive transfusion protocols.

Optimal Management of Leptomeningeal Carcinomatosis in Breast Cancer Patients—A Systematic Review

The incidence of leptomeningeal carcinomatosis in breast cancer patients (LC-BC) is increasing. Despite significantly affecting patient quality of life (QoL) and overall survival (OS), little is known about its optimal management. A systematic review of treatment strategies for LC-BC was performed. EMBASE, Ovid Medline, Pubmed, and the Cochrane Central Register of Controlled Trials were searched from 1946 to 2015 for trials reporting on treatments for LC-BC. All treatment modalities and study types were considered. The outcome measures of interest included OS, time to neurologic progression (TTNP), QoL, and treatment toxicity. Of 718 unique citations, 173 studies met the prespecified eligibility criteria. Most were not specific to LC-BC patients. Of 4 identified randomized controlled trials (RCTs), 1 was specific to LC-BC patients and compared systemic therapy and involved-field radiotherapy with or without intrathecal (IT) methotrexate (35 patients), and the remaining 3 had compared different IT chemotherapy regimens (58 of 157 with LC-BC). Of the remaining studies, 19 were nonrandomized interventional studies (225 LC-BC patients), 148 were observational studies (3230 LC-BC patients), and 2 systematic reviews. Minimal prospective data were available on OS, TTNP, QoL, and toxicity. Owing to study heterogeneity, meta-analyses of the endpoint data could not be performed. Limited high-quality evidence exists regarding optimal treatment of LC-BC. The identified studies were heterogeneous and often methodologically poor. The only RCT that specifically assessed the role of IT chemotherapy showed no benefit, and, if anything, harm. Further prospective, tumor-specific trials with improved interstudy methodologic consistency and transparently reported data on OS, TTNP, QoL, and toxicity are urgently needed.

Bone-targeted therapy use in patients with bone metastases from lung cancer: A systematic review of randomized controlled trials

BACKGROUND Patients with advanced lung cancer commonly have bone metastases. Compared with other malignancies, the use of bone-targeted agents (e.g. bisphosphonates and denosumab) is less common in lung cancer patients. This may be due to the perception that bone-targeted agents are less effective in this population. OBJECTIVE To perform a systematic review to evaluate data from randomized trials of bone-targeted agents in lung cancer patients with bone metastases. METHODS A systematic search of Medline, Embase and the Cochrane Register of Controlled Trials through May 2015 was performed. Randomized trials of bone-targeted therapies in lung cancer patients with bone metastases were sought. Outcomes studied included skeletal related events (SREs), pain, quality of life, progression-free survival and overall survival. Random effects meta-analyses were planned if studies were judged homogeneous. RESULTS Of 632 abstracts, 17 publications describing 13 studies were included. Sample sizes ranged between 50 and 1776. Of 3379 patients, 1903 had lung cancer, with subgroup data available for 8 of 13 studies. Patient demographics were comparable, but enrollment criteria and endpoints were heterogeneous across studies, precluding meta-analysis. Study-specific results suggested that bone-modifying agents reduce the incidence of SREs and bone pain in lung cancer patients. Three studies suggested a survival benefit. CONCLUSION Data from included trials suggests benefit of bone-targeted agents in lung cancer for the prevention of SREs and bone pain. There is a trend toward improvement in overall survival and progression-free survival, although further research is needed. Impact on quality of life and key subgroups for benefit both require future research.

Optimal transfusion practices after allogeneic hematopoietic cell transplantation: a systematic scoping review of evidence from randomized controlled trials

Integrating evidence from randomized controlled trials (RCTs) into patient care is needed to optimize patient outcomes. Transfusion support during allogeneic hematopoietic cell transplantation (alloHCT) is a cornerstone of essential supportive care, yet optimal transfusion practices remain unclear.

A Systematic Review of the Incidence and Risk Factors for Taxane Acute Pain Syndrome in Patients Receiving Taxane-Based Chemotherapy for Prostate Cancer

&NA; Taxane acute pain syndrome (TAPS) is characterized by myalgia and arthralgia starting 24 to 48 hours after taxane‐based chemotherapy and lasting ≤ 7 days. Little is known about its incidence and predisposing factors in patients with prostate cancer. A systematic review was performed to identify studies reporting the incidence and risk factors for TAPS in patients receiving taxane‐based chemotherapy for prostate cancer. Embase, Ovid Medline, and other nonindexed citations were searched from 1947 to July 7, 2015. Randomized trials and prospective observational studies reporting the outcomes for prostate cancer patients who had received taxane‐based chemotherapy were assessed. Four reviewers independently screened the citations and full text reports for data collection. Of 980 citations, 5 studies (2710 patients) met the eligibility criteria. The incidence of myalgia and arthralgia was reported in 4 trials (14%, [29% and 38%], 44.2%, and 46%). TAPS was not reported with cabazitaxel chemotherapy. Clinical risk factors were identified in 4 studies, suggesting that TAPS was numerically more common in the castrate‐resistant setting and when concurrent medications (eg, corticosteroids) were not used. Although the TAPS incidence has been poorly reported in clinical practice, the results of the present study suggest that arthralgia and myalgia are a common toxicity in patients with prostate cancer. An improved and universal definition of TAPS, patient‐directed reporting of TAPS, and improved standardized assessments are needed to better identify patients at the greatest risk of experiencing TAPS and improving patient care.

De-escalation of bone-targeted agents for metastatic prostate cancer

The Editor Current Oncology 10 September 2015 Despite advances in therapy, bone remains the most common site of prostate cancer recurrence. Once cancer has spread to bone, it is incurable and can be associated with pain, decreased quality of life, reduced mobility, and skeletal related events (sres). Given that more than half of all prostate cancer patients with bone metastases experience sres (for example, radiotherapy or surgery to bone, pathologic fractures, or spinal cord compression), reducing the occurrence of those events is an important therapeutic goal1. Currently, based on the results of several randomized trials, patients with bone metastases from castrate-resistant prostate cancer (mcrpc) are often treated with bone-targeted agents such as bisphosphonates or denosumab every 3–4 weeks. Historically, the dosing frequency for bone-targeted agents was adopted from data for the management of hypercalcemia of malignancy and for convenience (3- to 4-weekly dosing allowed clinicians to deliver the drugs at the same time that patients were receiving chemotherapy)1. However, that rationale ignores studies of biomarkers of bone turnover (a surrogate marker of sre risk), which have consistently shown, for both zoledronate and denosumab, rapid and sustained falls in turnover at significantly lower doses and for significantly longer than 3–4 weeks2. The question about the optimal dosing interval is particularly important given that the toxicity of bone-targeted agents is related to both the potency of the agent and the cumulative dose. A meta-analysis of de-escalated bone-targeted therapy (that is, treatment every 12 weeks instead of every 4 weeks) in patients with metastatic breast cancer was recently published. The results show no difference in sres or pain with de-escalated therapy3. Interest in similar de-escalated therapy for patients with mcrpc is now increasing. If de-escalated treatment is as efficacious as 3–4-weekly dosing, then not only would costs to both patients and the health care system be significantly reduced, but drug side effects could also potentially be reduced. In view of the findings in the breast cancer population, we conducted a systematic review to answer the question “Does 12-weekly bone-targeted agent use in mcrpc patients with bone metastases provide a benefit similar to that with 4-weekly treatment?” We were interested in randomized trials that had evaluated de-escalation of any established bone-targeted agent (for example, zoledronate and denosumab) against the standard 4-weekly treatment. Our systematic review was conducted as outlined in the Cochrane handbook, and only two studies met our inclusion criteria4,5. The study by Fizazi et al.4 was a phase ii open-label randomized trial in which 33 patients with mcrpc were randomized to either subcutaneous denosumab 180 mg every 4 weeks (n = 17) or every 12 weeks (n = 16). All patients randomized to denosumab had received treatment with zoledronic acid before randomization. Twenty-seven patients receiving denosumab completed the study. Bio-markers (urinary N-telopeptide) were assessed at week 13 and week 25. There was no significant difference between the 12-weekly and 4-weekly denosumab arms in terms of on-study biomarker changes, pain, or occurrence of sres. Those results are clearly interesting and similar to the findings in a similar population of breast cancer patients4; however, they are limited by the small sample size. The ongoing phase iii open-label randomized noninferiority reduse trial5 is comparing 4-weekly denosumab 120 mg with 12-weekly denosumab 120 mg in patients with bone metastases from breast cancer and mcrpc. The primary endpoint is time to first on-study symptomatic sre. The secondary endpoints include safety, time to subsequent on-study sre, quality of life, health economics, and bone turnover markers. Target accrual is 1380 patients; no data from the study are yet available. We have identified a knowledge gap in the existing literature that compares de-escalated with standard schedules of bone-targeted therapies in patients with bone metastases from crpc. More randomized trials are needed to compare the benefits and safety of de-escalated treatment. The study endpoints should include symptomatic sre rates, pain control, health-related quality of life, and safety, as well as health care costs. While waiting for the results of the reduse trial, researchers have a unique opportunity to perform additional practice-changing trials to identify the optimal schedule of denosumab dosing.

The prevalence of patient engagement in published trials: a systematic review

Plain English summaryWith the growing movement to engage patients in research, questions are being asked about who is engaging patients and how they are being engaged. Internationally, research groups are supporting and funding patient-oriented research studies that engage patients in the identification of research priorities and the design, conduct and uptake of research. As we move forward, we need to know what meaningful patient engagement looks like, how it benefits research and clinical practice, and what are the barriers to patient engagement?We conducted a review of the published literature looking for trials that report engaging patients in the research. We included both randomized controlled trials and non-randomized comparative trials. We looked at these trials for important study characteristics, including how patients were engaged, to better understand the practices used in trials. Importantly, we also discuss the number of trials reporting patient engagement practices relative to all published trials. We found that very few trials report any patient engagement activities even though it is widely supported by many major funding organizations. The findings of our work will advance patient-oriented research by showing how patients can be engaged and by stressing that patient engagement practices need to be better reported.AbstractBackgroundPatient-Oriented Research (POR) is research informed by patients and is centred on what is of importance to them. A fundamental component of POR is that patients are included as an integral part of the research process from conception to dissemination and implementation, and by extension, across the research continuum from basic research to pragmatic trials [J Comp Eff Res 2012, 1:181–94, JAMA 2012, 307:1587–8]. Since POR’s inception, questions have been raised as to how best to achieve this goal.We conducted a systematic review of randomized controlled trials and non-randomized comparative trials that report engaging patients in their research. Our main goal was to describe the characteristics of published trials engaging patients in research, and to identify the extent of patient engagement activities reported in these trials.MethodsThe MEDLINE®, EMBASE®, Cinahl, PsycINFO, Cochrane Methodology Registry, and Pubmed were searched from May 2011 to June 16th, 2016. Title, abstract and full text screening of all reports were conducted independently by two reviewers. Data were extracted from included trials by one reviewer and verified by a second. All trials that report patient engagement for the purposes of research were included.ResultsOf the 9490 citations retrieved, 2777 were reviewed at full text, of which 23 trials were included. Out of the 23 trials, 17 were randomized control trials, and six were non-randomized comparative trials. The majority of these trials (83%, 19/23) originated in the United States and United Kingdom. The trials engaged a range of 2-24 patients/ community representatives per study. Engagement of children and minorities occurred in 13% (3/23) and 26% (6/23) of trials; respectively. Engagement was identified in the development of the research question, the selection of study outcomes, and the dissemination and implementation of results.ConclusionsThe prevalence of patient engagement in patient-oriented interventional research is very poor with 23 trials reporting activities engaging patients. Research dedicated to determining the best practice for meaningful engagement is still needed, but adequate reporting measures also need to be defined.