Antegrade Instillation of UGN-101 (Mitomycin for Pyelocalyceal Solution) for Low-Grade Upper Tract Urothelial Carcinoma: Initial Clinical Experience.

PURPOSE: UGN-101 (mitomycin for pyelocalyceal solution) is a recently approved chemoablative treatment for low-grade (LG) upper tract urothelial carcinoma (UTUC). While approved for retrograde or antegrade administration, previous reports discuss only patients treated by retrograde approach. We report our techniques for antegrade administration along with early outcomes from our cohort of patients who have undergone UGN-101 administration via nephrostomy. MATERIALS AND METHODS: UGN-101 is administered as 6 weekly instillations in patients who have undergone endoscopic ablation of LG UTUC. We outline our approach in patients thought to have LG UTUC from initial ureteroscopy to nephrostomy placement, UGN-101 administration and eventual nephrostomy removal. We discuss early durability of response along with adverse events with special attention to ureteral strictures. RESULTS: Eight patients underwent antegrade UGN-101 administration during the study period, all of whom underwent followup ureteroscopy with complete response in 4 patients. Three patients reported 5 adverse events-3 grade 1, 1 grade 2 requiring 1 week delay of treatment and 1 asymptomatic ureteral stricture. Median followup was 7 months. CONCLUSIONS: We outline our approach for antegrade administration of UGN-101 and discuss early results along with adverse events. Future studies should evaluate our method's potential to increase patient comfort, improve logistics and decrease risk of adverse events.

Thymosin beta 4 up-regulates miR-200a expression and induces differentiation and survival of rat brain progenitor cells.

Thymosin beta 4 (Tß4), a secreted 43 amino acid peptide, promotes oligodendrogenesis, and improves neurological outcome in rat models of neurologic injury. We demonstrated that exogenous Tß4 treatment up-regulated the expression of the miR-200a in vitro in rat brain progenitor cells and in vivo in the peri-infarct area of rats subjected to middle cerebral artery occlusion (MCAO). The up-regulation of miR-200a down-regulated the expression of the following targets in vitro and in vivo models: (i) growth factor receptor-bound protein 2 (Grb2), an adaptor protein involved in epidermal growth factor receptor (EGFR)/Grb2/Ras/MEK/ERK1/c-Jun signaling pathway, which negatively regulates the expression of myelin basic protein (MBP), a marker of mature oligodendrocyte; (ii) ERRFI-1/Mig-6, an endogenous potent kinase inhibitor of EGFR, which resulted in activation/phosphorylation of EGFR; (iii) friend of GATA 2, and phosphatase and tensin homolog deleted in chromosome 10 (PTEN), which are potent inhibitors of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway, and resulted in marked activation of AKT; and (iv) transcription factor, p53, which induces pro-apoptotic genes, and possibly reduced apoptosis of the progenitor cells subjected to oxygen glucose deprivation (OGD). Anti-miR-200a transfection reversed all the effects of Tß4 treatment in vitro. Thus, Tß4 up-regulated MBP synthesis, and inhibited OGD-induced apoptosis in a novel miR-200a dependent EGFR signaling pathway. Our findings of miR-200a-mediated protection of progenitor cells may provide a new therapeutic importance for the treatment of neurologic injury. Tß4-induced micro-RNA-200a (miR-200a) regulates EGFR signaling pathways for MBP synthesis and apoptosis: up-regulation of miR-200a after Tß4 treatment, increases MBP synthesis after targeting Grb2 and thereby inactivating c-Jun from inhibition of MBP synthesis; and also inhibits OGD-mediated apoptosis after targeting EGFR inhibitor (Mig-6), PI3K inhibitors (FOG2 and Pten) and an inducer (p53) of pro-apoptotic genes, for AKT activation and down-regulation of p53. These findings may contribute the therapeutic benefits for stroke and other neuronal diseases associated with demyelination disorders.

Effect of doublecortin on self-renewal and differentiation in brain tumor stem cells.

Analysis of microarray probe data from glioma patient samples, in conjunction with patient Kaplan-Meier survival plots, indicates that expression of a glioma suppressor gene doublecortin (DCX) favors glioma patient survival. From neurosphere formation in culture, time-lapse microscopic video recording, and tumor xenograft, we show that DCX synthesis significantly reduces self-renewal of brain tumor stem cells (BTSC) in human primary glioma (YU-PG, HF66) cells from surgically removed human glioma specimens and U87 cells in vitro and in vivo. Time-lapse microscopic video recording revealed that double transfection of YU-PG, HF66, and U87 cells with DCX and neurabin II caused incomplete cell cycle with failure of cytokinesis, that is, endomitosis by dividing into three daughter cells from one mother BTSC. Activation of c-jun NH2-terminal kinase 1 (JNK1) after simvastatin (10 nM) treatment of DCX(+) neurabin II(+) BTSC from YU-PG, HF66, and U87 cells induced terminal differentiation into neuron-like cells. dUTP nick end labeling data indicated that JNK1 activation also induced apoptosis only in double transfected BTSC with DCX and neurabin II, but not in single transfected BTSC from YU-PG, HF66, and U87 cells. Western blot analysis showed that procaspase-3 was induced after DCX transfection and activated after simvastatin treatment in YU-PG, HF66, and U87 BTSC. Sequential immunoprecipitation and Western blot data revealed that DCX synthesis blocked protein phosphatase-1 (PP1)/caspase-3 protein-protein interaction and increased PP1-DCX interaction. These data show that DCX synthesis induces apoptosis in BTSC through a novel JNK1/neurabin II/DCX/PP1/caspase-3 pathway.

Correlates of Google Search Rankings for Spine Surgeons: An Analysis of Academic Pedigree, Social Media Presence, and Patient Ratings.

STUDY DESIGN: Prospective observational study. OBJECTIVE: The objective of this study is to identify correlates of search ranking among academic pedigree, online ratings, and social media following. SUMMARY OF BACKGROUND DATA: Patients increasingly rely on online search in selecting healthcare providers. When choosing a spine surgeon, patients typically value surgical skill and experience as well as demeanor/bedside manner. It is unclear whether current search engine ranking algorithms reflect these preferences. METHODS: A Google.com search for the top 25 spine surgeon websites by search ranking was conducted for each of the largest 25 American cities. Resulting websites were then perused for academic pedigree, experience, and practice characteristics. Surgeons' research output and impact were then quantified via number of publications and H-index. Online ratings and followers in various social media outlets were also noted. These variables were assessed as possible correlates of search ranking via linear regression and multivariate analyses of variance. RESULTS: A total of 625 surgeons were included. Three categorical variables were identified as significant correlates of higher mean Google search ranking-orthopedics (vs. neurosurgery) as a surgical specialty (P = 0.023), board certification (P = 0.024), and graduation from a top 40 residency program (P = 0.046). Although the majority of the identified surgeons received an allopathic medical education, there was no significant difference in the mean rank of surgeons who had an MD versus DO medical degree (P = 0.530). Additionally, none of the continuous variables collected, including years in practice (P = 0.947), publications (P = 0.527), H-index (P = 0.278), social media following such as on Facebook (P = 0.105), or online ratings such as on Healthgrades (P = 0.080), were significant correlates of Google search ranking. CONCLUSIONS: Google search rankings do not always align with patient preferences, currently promoting orthopedic over neurosurgical specialists, graduation from top residency programs, and board certification, while largely ignoring academic pedigree, research, social media presence, and online ratings. LEVEL OF EVIDENCE: 3.

Effect of Magnetic Resonance Imaging on Surgical Approach and Outcomes in the Management of Subaxial Cervical Fractures.

BACKGROUND: In the initial evaluation of suspected cervical fracture, computed tomography (CT) is the gold standard for assessing bony anatomy and fracture morphology with high sensitivity and specificity. However, CT is relatively insensitive to ligamentous, discogenic, and myelopathic injury, leading to supplementary use of MRI, which is more sensitive and specific to these diseases. Here, we assess whether preoperative cervical spine magnetic resonance imaging (MRI) affects surgical management of subaxial cervical fractures. METHODS: The National (Nationwide) Inpatient Sample (NIS) was queried for MRI use, surgical approach, rate of operative intervention, all-cause mortality, days from admission to surgery, discharge disposition, length of hospital stay, and total hospital charges among those with closed subaxial cervical spine fractures from 2012 to 2015. The effect of MRI on these End points was evaluated, controlling for significant baseline differences in demographics, comorbidities, and presentation. RESULTS: A total of 820 patients met inclusion and exclusion criteria; 255 (31.1%) were assessed with MRI and CT, 565 (68.9%) were evaluated with CT alone. After 1:1 propensity score matching based on severity of presentation, preoperative MRI was not significantly associated with surgical approach, in-hospital mortality, discharge disposition, length of stay, or total hospital charges. Segregating patients by functional status group shows MRI use among patients presenting with moderate loss of function associated with a shorter length of time between admission and surgery (1.50 vs. 2.59 days; P = 0.027). CONCLUSIONS: The addition of MRI to CT in the evaluation of subaxial cervical spine fractures does not seem to affect surgical management.