Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

PURPOSE: Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, enabling early definitive treatment and potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of PNST in cancer predisposition syndrome NF1. EXPERIMENTAL DESIGN: cfDNA was isolated from plasma samples of a novel cohort of 101 NF1 patients and 21 healthy controls and underwent whole genome sequencing. We investigated diagnosis-specific signatures of copy number alterations (CNA) with in silico size selection as well as well as fragment profiles. Fragmentomics were analyzed using complementary feature types: bin-wise fragment size ratios, end-motifs, and fragment non-negative matrix factorization (NMF) signatures. RESULTS: The novel cohort of NF1 patients validated that our previous cfDNA CNA-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. CONCLUSIONS: Novel cfDNA fragmentomic signatures distinguish atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management. This study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 and provides a blueprint for de-centralizing non-invasive cancer surveillance in hereditary cancer syndromes.

Determination of change of direction deficit thresholds across a spectrum of angles in basketball players.

Change of direction deficit (CODD) offers valuable insights into a player's balance between linear and multidirectional speed. However, there are still no established reference values for CODD. The objectives of this study were to determine CODD thresholds for various change of direction angles in basketball players according to gender and analyse the relationships between CODD and execution time in speed tests. One hundred and thirty basketball players (46% female; age: 23.7 ± 5.29 years; height: 189.1 ± 11.1 cm; body mass: 84.3 ± 15.7 kg) undertook 10-m linear and change of direction speed test at 45º, 90º and 180º. A k-means cluster analysis was conducted to standardise CODD thresholds and a one-way analysis of variance to identify the differences between clusters. The results revealed angulation-specific CODD thresholds, ranging from 3% to 8%, 17% to 25% and 43% to 51% for 45º, 90º and 180º cutting angles, respectively for the pooled sample. Furthermore, differences inter-clusters (p < 0.05) were observed for execution time at all cutting angles for both genders. Therefore, strength and conditioning coaches are encouraged to assess CODD as a highly valid variable for evaluating change of direction performance and to use current CODD thresholds to tailor training programmes according to each athlete's needs.

Differences in Biomechanical Determinants of ACL Injury Risk in Change of Direction Tasks Between Males and Females: A Systematic Review and Meta-Analysis.

BACKGROUND: Change of direction (COD) movements are associated with non-contact anterior cruciate ligament (ACL) injuries in multidirectional sports. Females appear at increased risk compared to males, which could be attributable to whole body kinematic strategies and greater multiplanar knee joint loads (KJLs) during COD which can increase ACL loading. OBJECTIVE: The aim of this systematic review and meta-analysis was to examine and quantitatively synthesise the evidence for differences between males and females regarding KJLs and their biomechanical determinants (whole body kinematic strategies determining KJLs) during COD tasks. METHODS: Databases including SPORTDiscus, Web of Science, and PubMed were systematically searched (July 2021-June 2023) for studies that compared differences in knee joint loads and biomechanical determinants of KJLs during COD between males and females. Inclusion criteria were: (1) females and males with no prior history of ACL injury (18-40 years); (2) examined biomechanical determinants of KJLs and/ or KJLs during COD tasks > 20°; (3) compared ≥ 1 outcome measure between males and females. Studies published between 2000 and 2023 examining a cutting task > 20° with a preceding approach run that compared KJLs or the whole body multiplanar kinematics associated with them, between sexes, using three-dimensional motion analysis. RESULTS: This meta-analysis included 17 studies with a pooled sample size of 451 participants (227 males, 224 females). Meta-analysis revealed females displayed significantly less peak knee flexion during stance (SMD: 0.374, 95% CI 0.098-0.649, p = 0.008, I2: 0%); greater knee abduction at initial contact (IC) (SMD: 0.687, 95% CI 0.299-1.076, p = 0.001, I2: 55%); less hip internal rotation (SMD: 0.437, 95% CI 0.134-0.741, p = 0.005, I2: 34%) and hip abduction at IC (SMD: -0.454, 95% CI 0.151-0.758, p = 0.003, I2: 33%). No significant differences were observed between males and females for any internal or externally applied KJLs. All retrieved studies failed to control for strength, resistance training or skill history status. CONCLUSION: No differences were observed in KJLs between males and females despite females displaying greater knee abduction at IC and less peak knee flexion during the stance phase of CODs, which are visual characteristics of non-contact ACL injury. Further research is required to examine if this translates to a similar injury risk, considering morphological differences in strain characteristics of the ACL between males and females. This observation may in part explain the disproportionate ACL injury incidence in female multidirectional athletes. Further higher quality controlled research is required whereby participants are matched by skill training history, resistance training history and strength status to ensure an appropriate comparison between males and females.

Early detection of malignant and pre-malignant peripheral nerve tumors using cell-free DNA fragmentomics.

Early detection of neurofibromatosis type 1 (NF1) associated peripheral nerve sheath tumors (PNST) informs clinical decision-making, potentially averting deadly outcomes. Here, we describe a cell-free DNA (cfDNA) fragmentomic approach which distinguishes non-malignant, pre-malignant and malignant forms of NF1 PNST. Using plasma samples from a novel cohort of 101 NF1 patients and 21 healthy controls, we validated that our previous cfDNA copy number alteration (CNA)-based approach identifies malignant peripheral nerve sheath tumor (MPNST) but cannot distinguish among benign and premalignant states. We therefore investigated the ability of fragment-based cfDNA features to differentiate NF1-associated tumors including binned genome-wide fragment length ratios, end motif analysis, and non-negative matrix factorization deconvolution of fragment lengths. Fragmentomic methods were able to differentiate pre-malignant states including atypical neurofibromas (AN). Fragmentomics also adjudicated AN cases suspicious for MPNST, correctly diagnosing samples noninvasively, which could have informed clinical management. Overall, this study pioneers the early detection of malignant and premalignant peripheral nerve sheath tumors in NF1 patients using plasma cfDNA fragmentomics. In addition to screening applications, this novel approach distinguishes atypical neurofibromas from benign plexiform neurofibromas and malignant peripheral nerve sheath tumors, enabling more precise clinical diagnosis and management.