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Abstract BACKGROUND Low-grade intracranial dural arteriovenous fistulas (dAVF) have a benign natural history in the majority of cases. The benefit from treatment of these lesions is controversial. OBJECTIVE To compare the outcomes of observation versus intervention for low-grade dAVFs. METHODS We retrospectively reviewed dAVF patients from institutions participating in the CONsortium for Dural arteriovenous fistula Outcomes Research (CONDOR). Patients with low-grade (Borden type I) dAVFs were included and categorized into intervention or observation cohorts. The intervention and observation cohorts were matched in a 1:1 ratio using propensity scores. Primary outcome was modified Rankin Scale (mRS) at final follow-up. Secondary outcomes were excellent (mRS 0-1) and good (mRS 0-2) outcomes, symptomatic improvement, mortality, and obliteration at final follow-up. RESULTS The intervention and observation cohorts comprised 230 and 125 patients, respectively. We found no differences in primary or secondary outcomes between the 2 unmatched cohorts at last follow-up (mean duration 36 mo), except obliteration rate was higher in the intervention cohort (78.5% vs 24.1%, P < .001). The matched intervention and observation cohorts each comprised 78 patients. We also found no differences in primary or secondary outcomes between the matched cohorts except obliteration was also more likely in the matched intervention cohort ( P < .001). Procedural complication rates in the unmatched and matched intervention cohorts were 15.4% and 19.2%, respectively. CONCLUSION Intervention for low-grade intracranial dAVFs achieves superior obliteration rates compared to conservative management, but it fails to improve neurological or functional outcomes. Our findings do not support the routine treatment of low-grade dAVFs.

AbstractBackgroundThe pathological features of AD are neurofibrillary tangles (NFTs) composed of highly phosphorylated tau and senile plaques (SPs) composed of amyloid β protein (Aβ). It was suggested that Cu2 + induced hyperphosphorylation of tau and Zn2 + deposits on SPs. Clioquinol (CQ) has a mild chelating effect on Zn2 + and Cu2 +. In addition, CQ has been shown to reduce Aβ aggregation by removing Zn2+ from SPs. However, the effect of CQ on tau aggregation is not fully understood. The purpose of our study is to examine the effect of CQ on tau metabolism by using a cell culture model of tauopathy.MethodsHuman neuroblastoma cell line M1C cells that express wild‐type tau protein (4R0N) via tetracycline (Tet) off induction was used. M1C cells were exposed to 0.1‐10 μM CQ on day 4 of Tet‐Off induction, and harvested at the end of Day 5. Total tau detected by Tau5, and phosphorylated tau detected by PS199/202, AT180, AT270, CP13, and PHF‐1 antibodies, were examined using Western blot analysis. Immunocytochemical studies, fractional analysis and immunoprecipitation of ubiquitinated tau were also performed. Tau kinases including c‐Jun N‐terminal kinase (JNK), and P38 MAPK and tau phosphatase, protein phosphatase 2A (PP2A) were also examined. C‐terminal truncated pathological tau was detected by using the antibody TauC3. In addition, autophagy and proteasome activity were also examined.ResultPhosphorylated tau levels were reduced by 1‐10 μM CQ treatment. Tau kinases, JNK and p38 MAPK were inactivated by CQ treatment. Interestingly, activation of the tau phosphatase PP2A was also observed with CQ treatment. Fractionation studies showed that CQ treatment reduced AT180 and AT270 positive high molecular weight tau in the Tris‐insoluble, sarkosyl‐soluble fraction. CQ also reduced tau oligomer specific antibody TOC1‐positive oligomeric tau. CQ reduced caspase‐cleaved tau detected by antibody TauC3. P62 levels were reduced by CQ treatment, suggesting that CQ activates autophagy. In addition, CQ slightly reduced high molecular weight ubiquitinated tau. This implies activation of the ubiquitin‐proteasome by CQ.ConclusionCQ could provide beneficial effects against pathogenic forms of tau via multiple mechanisms and may represent a viable therapeutic approach for AD and other tauopathies.

AbstractBackgroundNeurofibrillary tangle (NFT), composed of highly phosphorylated tau is one of the pathological hallmarks of Alzheimer’s disease (AD). Spleen tyrosine kinase (Syk) is non receptor type tyrosine kinase, and has various physiological functions, including histamine release in mast cells, phagocytosis in macrophage, and B cell differentiation. The possibility of Syk inhibitor for clinical application was proposed in allergic rhinitis, rheumatoid arthritis, and immunologic thrombocytopenia. The possible relationship between Syk and AD has been reported recently. We have examined the effects of Syk specific inhibitor BAY61‐3606 on phosphorylation levels of tau protein and oligomeric tau by using cell culture model of tauopathy, M1C cells.MethodsWe utilized human neuroblastoma cell line M1C cells, which expresses wild type tau protein (4R0N) via tetracycline off induction (Tet Off induction). Reduction of phosphorylated tau protein and oligomeric tau protein by Syk inhibitor was examined by using various phospho‐tau antibodies, and tau oligomer specific antibody. Influences of activity of autophagy by Syk inhibitor was also examined by western blot analysis.ResultsIn this cell line, 72kDa of Syk protein was identified by Western blot analysis. Phosphorylated tau detected by various phospho‐tau antibodies, including PHF‐1, CP13, and AT270 was decreased by 1, 10 μM of Syk inhibitor. One of the patholoigical form of tau, caspase cleaved tau detected by TauC3 was also decreased by Syk inhibitor. Oligomeric tau, which detected by tau oligomer specific antibody, TOC1 was also decreased by Syk inhibitor. Syk inhibitor also inactivated glycogen synthase kinase 3β (GSK3β). Syk inhibitor upregulated autophagy detected by increase of LC3‐II, and reduction of P62. In summary, Syk inhibitor decreased phosphorylated tau as well as total tau by upregulating autophagy, and inactivating tau kinases, including GSK3β. Finally, oligomeric tau was reduced by Syk inhibitor.ConclusionSyk inhibitor may have promising for the treatment of tauopathy, including AD.

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

TPS592 Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.

AbstractNerve growth factor (NGF ) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen–activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF ), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.