Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial
(2022) Journal of Neurology, Neurosurgery and Psychiatry, 93 (8), pp. 871-875. Cited 1 time.
Paganoni, S. , Hendrix, S., […], Miller, T.M., […] , Gilbert, W.af , Yeramian, P.ad , Cudkowicz, M.
Background Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS). Objective Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial. Methods Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation. Results Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO. Conclusions Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS. Trial registration number NCT03127514; NCT03488524. © 2022 BMJ Publishing Group. All rights reserved.
Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle
(2022) Science Translational Medicine, 14 (653), p. eabn4819.
Feng, J., Zhao, Y., Xie, Z., Zang, K., Sviben, S., Hu, X., Fitzpatrick, J.A.J., Wen, L., Liu, Y., Wang, T., Lawson, K., Liu, Q., Yan, Y., Dong, X., Han, L., Wu, G.F., Kim, B.S., Hu, H.
Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3+ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.
Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac086, .
Grabowski, M.M.a , […], Kim, A.H. , Chiang, V.L., Chen, C.C., Leuthardt, E.C., Barnett, G.H., Kirkpatrick, J.P., Mohammadi, A.M.a, Fecci, P.E.
Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by “planned LITT+SRT”versus “LITT alone”versus “repeat SRT alone.”Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P =. 022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P =. 004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Immune deconvolution and temporal mapping identifies stromal targets and developmental intervals for abrogating murine low-grade optic glioma formation
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdab194, .
De Andrade Costa, A., Chatterjee, J., Cobb, O., Cordell, E., Chao, A., Schaeffer, S., Goldstein, A., Dahiya, S., Gutmann, D.H.
Background: Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods: A combination of bulk and single-cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results: We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8+ T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8+, but not CD4+, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions: Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation. © 2021 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Multivariate analysis of associations between clinical sequencing and outcome in glioblastoma
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdac002, .
Yang, P.H., Tao, Y., Luo, J., Paturu, M., Lu, H.-C., Ramkissoon, S., Heusel, J.W., Leuthardt, E.C., Chicoine, M.R., Dowling, J.L., Dunn, G.P., Duncavage, E., Dahiya, S., Chattherjee, A.R.g, Kim, A.H.
Background: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear. Methods: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection. Results: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A, CDKN2B, EGFR, PTEN, TERT promoter, and TP53. All patients possessed at least one of these 6 mutant genes. Conclusions: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival. © 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Children with supratentorial midline pilocytic astrocytomas exhibit multiple progressions and acquisition of neurologic deficits over time
(2022) Neuro-Oncology Advances, 4 (1), art. no. vdab187, .
Brossier, N.M., Strahle, J.M., Cler, S.J., Wallendorf, M., Gutmann, D.H.
Pilocytic astrocytomas (PAs) are the most common brain tumors of childhood1 and can arise anywhere within the neuroaxis, including the posterior fossa (pf-PA), supratentorial midline (sm-PA; including optic pathway, hypothalamus, thalamus), supratentorial cortex (sc-PA), brainstem (bs-PA), and spinal cord (sp-PA). While tumor location (sm, bs) has been proposed as a prognostic factor associated with poor progression-free survival (PFS),2-4 this effect is abrogated when resection status (gross total resection [GTR], subtotal resection [STR]) is included.2,4 To determine whether tumor location has any value in predicting PA clinical outcome, we evaluated clinical outcomes of children with biopsy-proven PA treated at St. Louis Children’s Hospital between 2003 and 2021 (n = 251). Subjects with a diagnosis of neurofibromatosis type 1 (NF1; n = 13) and those with discrepancies in their pathologic diagnosis (n = 11) or missing pertinent clinical data (n = 36) were excluded, leaving 191 total subjects for analysis. Consistent with prior reports,5 children with sc-PA were typically older at diagnosis than those with pf-PA. There were no differences in PA location incidence by sex,1 but individuals with sm-PA and bs-PA had higher rates of STR (Figure 1A) and reduced PFS (Figure 1B).2,3 Importantly, this difference in PFS was related to resection status, such that longer PFS was observed in sm-JPA and bs-JPA cases in which a GTR was achieved (Figure 1C). © The Author(s) 2021.