Identification of Novel High-Frequency DNA Methylation Changes in Breast Cancer

Recent data have revealed that epigenetic alterations, including DNA methylation and chromatin structure changes, are among the earliest molecular abnormalities to occur during tumorigenesis. The inherent thermodynamic stability of cytosine methylation and the apparent high specificity of the alterations for disease may accelerate the development of powerful molecular diagnostics for cancer. We report a genome-wide analysis of DNA methylation alterations in breast cancer. The approach efficiently identified a large collection of novel differentially DNA methylated loci (∼200), a subset of which was independently validated across a panel of over 230 clinical samples. The differential cytosine methylation events were independent of patient age, tumor stage, estrogen receptor status or family history of breast cancer. The power of the global approach for discovery is underscored by the identification of a single differentially methylated locus, associated with the GHSR gene, capable of distinguishing infiltrating ductal breast carcinoma from normal and benign breast tissues with a sensitivity and specificity of 90% and 96%, respectively. Notably, the frequency of these molecular abnormalities in breast tumors substantially exceeds the frequency of any other single genetic or epigenetic change reported to date. The discovery of over 50 novel DNA methylation-based biomarkers of breast cancer may provide new routes for development of DNA methylation-based diagnostics and prognostics, as well as reveal epigenetically regulated mechanism involved in breast tumorigenesis

Osteochondral Allografts in Knee Surgery: Narrative Review of Evidence to Date.

Knee articular cartilage defects can result in significant pain and loss of function in active patients. Osteochondral allograft (OCA) transplantation offers a single-stage solution to address large chondral and osteochondral defects by resurfacing focal cartilage defects with mature hyaline cartilage. To date, OCA transplantation of the knee has demonstrated excellent clinical outcomes and long-term survivorship. However, significant variability still exists among clinicians with regard to parameters for graft acceptance, surgical technique, and rehabilitation. Technologies to optimize graft viability during storage, improve osseous integration of the allograft, and shorten recovery timelines after surgery continue to evolve. The purpose of this review is to examine the latest evidence on treatment indications, graft storage and surgical technique, patient outcomes and survivorship, and rehabilitation after surgery

Statistical Fragility of Single-Row Versus Double-Row Anchoring for Rotator Cuff Repair: A Systematic Review of Comparative Studies.

BackgroundComparative studies and randomized controlled trials (RCTs) often use the P (probability) value to convey the statistical significance of their findings. P values are an imperfect measure, however, and are vulnerable to a small number of outcome reversals to alter statistical significance. The inclusion of a fragility index (FI) and fragility quotient (FQ) may aid in the interpretation of a study's statistical strength.Purpose/hypothesisThe purpose of this study was to examine the statistical stability of studies comparing single-row to double-row rotator cuff repair. It was hypothesized that the findings of these studies would be vulnerable to a small number of outcome event reversals, often fewer than the number of patients lost to follow-up.Study designSystematic review; Level of evidence, 3.MethodsWe analyzed comparative studies and RCTs on primary single-row versus double-row rotator cuff repair that were published between 2000 and 2021 in 10 leading orthopaedic journals. Statistical significance was defined as a P < .05. The FI for each outcome was determined by the number of event reversals necessary to alter significance. The FQ was calculated by dividing the FI by the respective sample size.ResultsOf 4896 studies screened, 22 comparative studies, 10 of which were RCTs, were ultimately included for analysis. A total of 74 outcomes were examined. Overall, the median FI was 2 (interquartile range [IQR], 1-3), and the median FQ was 0.035 (IQR, 0.020-0.057). The mean FI was 2.55 ± 1.29, and the mean FQ was 0.043 ± 0.027. In 64% of outcomes, the FI was less than the number of patients lost to follow-up.) Additionally, 81% of significant outcomes needed just a single outcome reversal to lose their significance.ConclusionOver half of the studies currently used to guide clinical practice have a number of patients lost to follow-up greater than their FI. The results of these studies should be interpreted within the context of these limitations. Future analyses may benefit from the inclusion of the FI and the FQ in their statistical analyses

The Statistical Fragility of Operative vs Nonoperative Management for Achilles Tendon Rupture: A Systematic Review of Comparative Studies.

BackgroundThe statistical significance of randomized controlled trials (RCTs) and comparative studies is often conveyed utilizing the P value. However, P values are an imperfect measure and may be vulnerable to a small number of outcome reversals to alter statistical significance. The interpretation of the statistical strength of these studies may be aided by the inclusion of a Fragility Index (FI) and Fragility Quotient (FQ). This study examines the statistical stability of studies comparing operative vs nonoperative management for Achilles tendon rupture.MethodsA systematic search was performed of 10 orthopaedic journals between 2000 and 2021 for comparative studies focusing on management of Achilles tendon rupture reporting dichotomous outcome measures. FI for each outcome was determined by the number of event reversals necessary to alter significance (P < .05). FQ was calculated by dividing the FI by the respective sample size. Additional subgroup analyses were performed.ResultsOf 8020 studies screened, 1062 met initial search criteria with 17 comparative studies ultimately included for analysis, 10 of which were RCTs. A total of 40 outcomes were examined. Overall, the median FI was 2.5 (interquartile range [IQR] 2-4), the mean FI was 2.90 (±1.58), the median FQ was 0.032 (IQR 0.012-0.069), and the mean FQ was 0.049 (±0.062). The FI was less than the number of patients lost to follow-up for 78% of outcomes.ConclusionStudies examining the efficacy of operative vs nonoperative management of Achilles tendon rupture may not be as statistically stable as previously thought. The average number of outcome reversals needed to alter the significance of a given study was 2.90. Future analyses may benefit from the inclusion of a fragility index and a fragility quotient in their statistical analyses