High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
CM-1 diagnoses have increased in the last decade. Despite the decrease in overall complication rates, fusions are becoming more common and are associated with higher peri-operative complication rates. Commonly associated diagnoses including syringomyelia and hydrocephalus, can dramatically increase complication rates.
Study Design:
Retrospective cohort study.
Objective:
The objective of this study was to examine associations of gabapentin use with inpatient postoperative daily pain scores and opioid use in children undergoing PSF for AIS.
Summary of Background Data:
Gabapentin use in posterior spinal fusion (PSF) postoperative pain management for adolescent idiopathic scoliosis (AIS) is increasingly common in order to decrease opioid use and improve pain control, though there is conflicting data on dosing and effectiveness to support this practice in real world settings.
Methods:
Retrospective cohort study of children aged 10 to 21 years undergoing PSF for AIS between January 2013 and June 2016 at an urban academic tertiary care center. Adjuvant gabapentin exposure was defined as at least 15 mg/kg/d by postoperative day (POD) 1 with an initial loading dose of 10 mg/kg on day of surgery. Primary outcomes were daily postoperative mean pain score and opioid use [morphine milligram equivalents/kg/day(mme/kg/d)]. Secondary outcomes were short and long-term complications.
Results:
Among 129 subjects (mean age, 14.6 y, 74% female, mean coronal cobb, 55.2 degrees), 24 (19%) received gabapentin. Unadjusted GABA exposure was associated with significantly lower opioid use on POD1 and 2 (49% and 31%mme/kg/d, respectively) and lower pain scores (14%) on POD2. Adjusting for preexisting back pain, preoperative coronal Cobb angle, and site, GABA use was associated with significantly lower mean pain scores on POD1 through POD3 (−0.68, P=0.01; −0.86, P=0.002; −0.63, P=0.04). Gabapentin use was also associated with decreased opioid use on POD1 and POD2 (−0.39mme/kg/d, P<0.001; −0.27, P=0.02). There was no difference in complications by gabapentin exposure.
Conclusions:
Addition of gabapentin as adjuvant therapy for adolescent PSF, beginning on day of surgery, is associated with improved pain scores and decreased opioid use in the first 48 to 72 hours postoperatively.
Level of Evidence:
This is a retrospective cohort study, classified as Level III under “Therapeutic Studies Investigating the Results of a Treatment.”
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