This systematic review focused on the common conventional physiotherapy interventions used with children with cerebral palsy (CP), aged 4 to 18 years, and critically appraised the recent evidence of each of these interventions using the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The search strategy yielded 34 articles after inclusion and exclusion criteria were applied. The investigated physiotherapy interventions included strength and functional training, weight-supported treadmill training (WBSTT), and neurodevelopmental treatment (NDT). A category of treatment dosage was also included. Strength training was the most studied intervention with significant improvements found in the strength of selected muscle groups using dynamometry, with fewer studies showing significant improvement in function. Functional training showed improvements in gross motor function, endurance, and temperospatial measures, such as gait speed and stride length. Nonsignificant trends of improvement on the Gross Motor Function Measure (GMFM) and gait velocity were found for WBSTT by a few studies with low levels of evidence (case series). Of three studies that evaluated NDT, one high-level evidence study, i.e., randomized controlled trial (RCT) found significant improvements on the GMFM. All studies reviewing treatment dosage had high levels of evidence (RCTs), yet found no significant differences for different intensities of treatment. These results indicate that the levels of evidence for physiotherapy interventions, particularly strengthening and to a lesser extent functional training, in school-aged children with CP has improved; however, further high-level evidence is needed for other interventions.

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The inevitable emergence of acquired resistance is a major limitation to the clinical benefit of precision medicine strategies. Single-lesion tumor biopsies have long been the mainstay of understanding acquired resistance, but recent data suggest tumor biopsies may under-represent the molecular heterogeneity of acquired resistance. Alternatively, studies have suggested that liquid biopsy approaches analyzing cell-free DNA (cfDNA) may offer significant advantages, but extensive prospective comparisons of matched liquid vs. tumor biopsies obtained at the time of acquired resistance are lacking. Here, we assess systematic liquid biopsy upon acquired resistance to targeted therapy in 44 patients across seven molecularly defined subtypes of gastrointestinal cancers. Liquid biopsy at disease progression identified at least one functionally validated molecular mechanism of resistance in 75% of patients, wherein 52% exhibited >1 resistance alteration (range 2-9, median 3 per patient). In 23 patients in whom a matched post-progression tumor biopsy could be obtained, tumor biopsy was less effective than liquid biopsy in identifying resistance mechanisms, with resistance alterations detected in only 48% of patients, and multiple resistance mechanisms detected in only 9% of cases. In matched cases, liquid biopsy detected at least one resistance alteration not detected in tumor biopsy in 78% of cases. Targeted analysis and whole-exome sequencing of serial cfDNA, multiple post-progression biopsies, and rapid autopsy specimens from select cases revealed key insights into the geographic and complex characteristics of heterogeneity captured by liquid biopsy in the setting of acquired resistance. These data illustrate that acquired resistance is characterized by frequent and profound tumor heterogeneity, and suggests that liquid biopsy may more effectively identify heterogeneous clinically relevant resistance alterations compared to standard tumor biopsy. Citation Format: Aparna R. Parikh, Ignaty Leshchiner, Liudmila Elagina, Lipika Goyal, Chaya Levovitz, Giulia Siravegna, Dimitri Livitz, Kahn Rhrissorrakrai, Liz Martin, Emily E. Van Seventer, Megan Hanna, Kara Slowik, Filippo Utro, Christopher J. Pinto, Alicia Wong, Brian P. Danysh, Ferran Fece de la Cruz, Isobel J. Fetter, Brandon Nadres, Heather A. Shahzade, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Bruce Giantonio, Janet E. Murphy, Ryan D. Nipp, Eric Roeland, David P. Ryan, Colin D. Weekes, Eunice L. Kwak, Jason E. Faris, Francois Aguet, Ipsita Guha, Mehlika Hazar-Rethinam, Dora Dias-Santagata, David T. Ting, Andrew X. Zhu, Theodore S. Hong, Todd R. Golub, A J. Iafrate, Viktor Adalsteinsson, Alberto Bardelli, Laxmi Parida, Dejan Juric, Gad Getz, Ryan B. Corcoran. Liquid biopsy versus tissue biopsy to assess acquired resistance and tumor heterogeneity in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-257.

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