Citations

Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES).Methods. The records of 102 ES patients with localized disease ≥18 years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed.Results.The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977–1992 versus 1993–2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993–2007 era (P=0.02). The 5-year OS and EFS for the 1993–2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993–2007 era (P<0.01). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993–2007 era (P=0.17).Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients.

OBJECTIVES: Estimate the causes and risk of death, specifically seizure related, in children followed from onset of epilepsy and to contrast the risk of seizure-related death with other common causes of death in the population. METHODS: Mortality experiences from 4 pediatric cohorts of newly diagnosed patients were combined. Causes of death were classified as seizure related (including sudden unexpected death [SUDEP]), natural causes, nonnatural causes, and unknown. RESULTS: Of 2239 subjects followed up for &gt;30 000 person-years, 79 died. Ten subjects with lethal neurometabolic conditions were ultimately excluded. The overall death rate (per 100 000 person-years) was 228; 743 in complicated epilepsy (with associated neurodisability or underlying brain condition) and 36 in uncomplicated epilepsy. Thirteen deaths were seizure-related (10 SUDEP, 3 other), accounting for 19% of all deaths. Seizure-related death rates were 43 overall, 122 for complicated epilepsy, and 14 for uncomplicated epilepsy. Death rates from other natural causes were 159, 561, and 9, respectively. Of 48 deaths from other natural causes, 37 were due to pneumonia or other respiratory complications. CONCLUSIONS: Most excess death in young people with epilepsy is not seizure-related. Mortality is significantly higher compared with the general population in children with complicated epilepsy but not uncomplicated epilepsy. The SUDEP rate was similar to or higher than sudden infant death syndrome rates. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to or higher than rates for other common causes of death in young people (eg, accidents, suicides, homicides). Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with patients and families.

ObjectiveTo evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA).MethodsThe Rituximab in AAV trial was a randomized, double‐blind, placebo‐controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other).ResultsAlthough remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty‐four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety‐one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)–ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3‐ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare.ConclusionCurrent treatment regimens are largely successful in controlling AAV, but in approximately one‐fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3‐ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

ABSTRACTWe compared the mechanical force of tendon‐to‐bone repair techniques for flexor tendon reconstruction. Thirty‐six flexor digitorum profundus (FDP) tendons were divided into three groups based upon the repair technique: (1) suture/button repair using FDP tendon (Pullout button group), (2) suture bony anchor using FDP tendon (Suture anchor group), and (3) suture/button repair using FDP tendon with its bony attachment preserved (Bony attachment group). The repair failure force and stiffness were measured. The mean load to failure and stiffness in the bony attachment group were significantly higher than that in the pullout button and suture anchor groups. No significant difference was found in failure force and stiffness between the pullout button and suture anchor groups. An intrasynovial flexor tendon graft with its bony attachment has significantly improved tensile properties at the distal repair site when compared with a typical tendon‐to‐bone attachment with a button or suture anchor. The improvement in the tensile properties at the repair site may facilitate postoperative rehabilitation and reduce the risk of graft rupture. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1720–1724, 2013

Consensus abstract Background The management of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority. Methods Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web-based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus. Results The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC-bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management. Conclusion The consensus process has provided guidance for the management of patients with PRC-bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority.

BACKGROUNDIncreased soluble human epidermal growth factor receptor 2 (sHER2) is an indicator of a poor prognosis in HER2‐positive metastatic breast cancer. In this study, the authors evaluated levels of sHER2 during treatment and at the time of disease recurrence in the adjuvant North Central Cancer Treatment Group N9831 clinical trial.METHODSThe objectives were to describe sHER2 levels during treatment and at the time of recurrence in patients who were randomized to treatment arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab), and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available from 2318 patients, serial samples were available from 105 patients, and recurrence samples were available from 124 patients. The cutoff sHER2 value for the assay was 15 ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank‐sum tests, and Cox regression models.RESULTSThere were differences between groups in terms of age, menopausal status, and hormone receptor status. Within treatment arms A, B, and C, patients who had baseline sHER2 levels ≥15 ng/mL had worse disease‐free survival than patients who had baseline sHER2 levels <15 ng/mL (arm A: hazard ratio, 1.81; P = .0014; arm B: hazard ratio, 2.08; P = .0015; arm C: hazard ratio, 1.96; P = .01). Among the 124 patients who experienced disease recurrence, sHER2 levels increased from baseline to the time of recurrence in arms A and B but remained unchanged in arm C. Patients who had recurrence sHER2 levels ≥15 ng/mL had a shorter survival after recurrence with a 3‐year overall survival rate of 51% compared with 77% for those who had recurrence sHER2 levels <15 ng/mL (hazard ratio, 2.36; 95% confidence interval, 1.19‐4.70; P = .01).CONCLUSIONSIn patients with early stage, HER2‐positive breast cancer, a high baseline sHER2 level was identified as a prognostic marker associated with shorter disease‐free survival, and a high sHER2 level at recurrence was predictive of shorter survival. Cancer 2013;119:2675–2682. © 2013 American Cancer Society.

AbstractSeveral lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG‐mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil‐deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well‐being of mammals. Observations that monoclonal antibodies to interleukin‐5 (IL‐5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti‐IL‐5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti‐IL‐5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL‐5 receptor α‐chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil‐associated diseases.

ObjectiveTo identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA).MethodsWe carried out a genome‐wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.ResultsGenome‐wide significant associations were identified in 32 single‐nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome‐wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8).ConclusionWe identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.