As childhood cancer treatments have improved to include new and innovative agents, the need for more advanced monitoring of their long-term effects and related research has increased. This has resulted in a need for evidence-based research methodologies for the longitudinal care of childhood cancer patients treated with targeted agents and immunotherapies. The rationale for this pilot study was to determine the feasibility and acceptability of a data capture methodology for pediatric, adolescent, and young adult cancer patients treated with targeted agents and immunotherapy as there is little research to inform this delivery of care. Data were collected from thirty-two patients and two providers for descriptive statistics and thematic analyses. Feasibility was characterized by expected participant attrition. Key drivers of acceptability were (1) providers' language and clarity of communication and (2) convenient participation requirements. Long-term follow-up research practices developed with input from key stakeholders, including patients, caregivers, and providers, can lead to acceptable and feasible research protocols that optimize successful participant recruitment. These evidence-based research practices can result in high participant satisfaction and can be implemented as program development initiatives across centers caring for childhood cancer survivors.
Delivery of Health Care , Neoplasms , Adolescent , Young Adult , Humans , Child , Feasibility Studies , Pilot Projects , Neoplasms/drug therapy , Immunotherapy
Background: Spinal cord injuries incite varying degrees of symptoms in patients, ranging from weakness and incoordination to paralysis. Common amongst spinal cord injury (SCI) patients, neuropathic pain (NP) is a debilitating medical condition. Unfortunately, there remain many clinical impediments in treating NP because there is a lack of understanding regarding the mechanisms behind SCI-induced NP (SCINP). Given that more than 450,000 people in the United States alone suffer from SCI, it is unsatisfactory that current treatments yield poor results in alleviating and treating NP. Summary: In this review, we briefly discussed the models of SCINP along with the mechanisms of NP progression. Further, current treatment modalities are herein explored for SCINP involving pharmacological interventions targeting glia cells and astrocytes. Key message: The studies presented in this review provide insight for new directions regarding SCINP alleviation. Given the severity and incapacitating effects of SCINP, it is imperative to study the pathways involved and find new therapeutic targets in coordination with stem cell research, and to develop a new gold-standard in SCINP treatment.
BACKGROUND: Treatment of spinal cord injury (SCI) induced neuropathic pain (NP) proves to be extremely clinically challenging as the mechanism behind SCINP is poorly understood. Matrix metalloproteinase (MMP) is largely responsible for the early disruption of the blood spinal cord barrier. This system initiates macrophage infiltration and degradation of myelin, which plays a pivotal role in how NP occurs. In a recent study, we demonstrated that folic acid (FA) treatment to cSCI rats reduced NP and improved functional recovery by repressing MMP-2 expression. We hypothesize that MMP-2 expression is suppressed because FA actively methylates the DNA sequence that encodes for the MMP-2 protein. However, modulation of MMP-2 expression for alleviation of NP is only pertinent to the mid- to late-phase of injury. Therefore, we need to explore alternate therapeutic methods to target the early- to mid-phase of injury to wholly alleviate NP. PURPOSE: Furthering our previous findings on inhibiting MMP-2 expression by FA in mid- and late- phase following cSCI in rats, we hypothesized that FA will methylate and suppress MMP-9 expression during the early- phase, day 1, 3, 7 post cSCI and mid- phase (day 18 post cSCI), in comparison with MMP-2 expression during mid- and the late-phase of cSCI. METHODS: Adult male Sprague Dawley rats (250-270g) underwent cSCI, using a NYU impactor, with 12.5 gm/cm injury. The spinal cord-injured animals were treated intraperitoneally (i.p.) with a standardized dose of FA (80 µg/kg body weight) on day 1, 2, 3, prior to cSCI, followed by daily injection up to 14 or 17 days post-cSCI in different experiments. Animals were euthanized on day 1, 3, 7 post cSCI (early- phase), day 18 post cSCI (mid- phase), and day 42 post cSCI (late-phase) and the epicenter region of injured spinal cord were harvested for MMP-9 and MMP-2 expression analysis by Western blots technique. RESULTS: i) During early-phase on day 1, 3, and 7, the quantitation displayed no statistical significance in MMP-9 expression, between water- and FA- injected rats. ii) On day 18 post-cSCI, FA significantly modulates the expression of MMP-9 (p = 0.043) iii) Comparing results with MMP-2 expression and inhibition, FA significantly modulates the expression of MMP-2 on day 18 post cSCI (FA- and water-injected rats (p = 0.003). iv) In addition, FA significantly modulates the expression of MMP-2 on day 42 post-cSCI comparing FA- and water- injected rat groups (p = 0.034). CONCLUSION: We report that FA administration results in alleviating cSCI-induced NP by inhibiting MMP-9 in the proposed mid- phase of cSCI. However, FA administration resulted in MMP-2 decline during both mid- through late- phase following cSCI. Our study elucidates a new phase of cSCI, the mid-phase. We conclude that further investigation on discovering and quantifying the nature of the mid- phase of SCI injury is needed.
BACKGROUND/AIMS: Spine and spinal cord pathologies and associated neuropathic pain are among the most complex medical disorders to treat. While rodent models are widely used in spine and spinal cord research and have provided valuable insight into pathophysiological mechanisms, these models offer limited translatability. Thus, studies in rodent models have not led to the development of clinically effective therapies. More recently, swine has become a favored model for spine research because of the high congruency of the species to humans with respect to spine and spinal cord anatomy, vasculature, and immune responses. However, conventional breeds of swine commonly used in these studies present practical and translational hurdles due to their rapid growth toward weights well above those of humans. METHODS: In the current study, we evaluated the suitability of a human-sized breed of swine developed at the University of Wisconsin-Madison, the Wisconsin Miniature SwineTM (WMSTM), in the context of thoracic spine morphometry for use in research to overcome limitations of conventional swine breeds. The morphometry of thoracic vertebrae (T1-T15) of 5-6 months-old WMS was analyzed and compared to published values of human and conventional swine spines. RESULTS: The key finding of this study is that WMS spine more closely models the human spine for many of the measured vertebrae parameters, while being similar to conventional swine in respect to the other parameters. CONCLUSION: WMS provides an improvement over conventional swine for use in translational spinal cord injury studies, particularly long-term ones, because of its slower rate of growth and its maximum growth being limited to human weight and size.
BACKGROUND: The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases (MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. PURPOSE: Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI-induced NP. METHODS: Sprague-Dawley male rats weighing 250-270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 µg/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP-2 expression analysis. RESULT: The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35, indicative of a decrease in NP. However, when tested 25 days after stopping FA administration on day 42 of cSCI, no significant difference in TH was observed between FA-treated and control animals. Western blot analysis of the injured spinal cord from FA-treated animals showed significant decline in MMP2 expression compared to spinal cord samples from water-treated controls. CONCLUSION: Together, these data suggest that FA could alleviate NP and improve functional recovery post-SCI, possibly by reducing the expression of MMP2. Further studies will open up a novel and easy natural therapy, ideal for clinical translation with minimal side effects, for managing SCI-induced NP. Such studies might also throw light on a possible epigenetic mechanism in FA-induced recovery after SCI.
