Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis

Objective.To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking,PTPN22R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA).Methods.Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage.Results.Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28–1.90, p = 8.5 × 10−6), carriage of at least 1 of thePTPN22risk alleles (OR 1.50, 95% CI 1.13–2.00, p = 5.5 × 10−3) and both ever smoking and carriage of at least 1 of thePTPN22risk alleles (OR 2.22, 95% CI 1.69–2.91, p = 8.3 × 10−9). There was no evidence of an association between presence of erosive damage and smoking status or carriage ofPTPN22risk alleles when analyzed overall or separately by ACPA status.Conclusion.This metaanalysis indicates that both smoking and thePTPN22risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction betweenPTPN22and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage.</jats:sec

Personal non-commercial use only. The Journal of Rheumatology erosive damage

ABSTRACT. Objective. To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). Methods. Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. Results. Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10 -6 ), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10 -3 ) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10 -9 ). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. Conclusion. This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated wit

40:7; Personal non-commercial use only

ABSTRACT. Objective. To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). Methods. Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. Results. Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10 -6 ), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10 -3 ) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10 -9 ). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. Conclusion. This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage. (First Release May 1 2013