Citations

Targeting three defects with one strategy The neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia are most commonly caused by a mutation in the C9orf72 gene. The mutation is an expanded hexanucleotide repeat in a noncoding region. The expanded repeat produces sense and antisense RNA transcripts, which accumulate in patient cells and appear to sequester RNA-binding proteins. The sense and antisense transcripts are also translated into dipeptide repeat proteins, which are aggregation-prone and accumulate in the brain and spinal cord. Last, loss of function from reduced expression of C9orf72 in neurons and glia could contribute to the disease. Kramer et al. targeted both sense and antisense repeats by blocking a single gene called SPT4 , which mitigated degeneration in human cells by reducing all three types of pathologies. Science , this issue p. 708

Abstract BACKGROUND Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a “resectability index” for each lesion by pooling responses from all 13 surgeons. RESULTS Neurosurgeons’ individual surgical goals varied significantly ( P = .015), but the resectability index calculated from the surgeons’ pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor ( R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes ( P < .01) and nonresectable residual ( P < .01), but not resectable residual. CONCLUSION In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials.

Objective Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. Design We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. Results We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10−5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. Conclusions This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.

Purpose To compare microfracture (MFX) and osteochondral autograft transfer (OAT) surgical techniques to determine (1) postoperative activity level, (2) subjective patient outcomes, (3) failure rates, and (4) assess if any lesion characteristics favored one technique over the other. Methods A comprehensive review of literature was performed of all studies comparing MFX and OAT. Studies included were all prospective studies that reported on activity‐based outcome measures such as Tegner activity scores and subjective outcomes such as the International Knee Documentation Committee score. Failure rates, as determined by the publishing authors, were recorded for each study. Meta‐analyses were conducted using a random‐effects model. Paired standardized mean differences (Hedges's g to account for small sample bias) were used for continuous outcome measures, and risk ratios (Mantel‐Haenszel method for small sample bias) for dichotomous outcome measures. Results Six prospective studies satisfied the eligibility criteria and included 249 patients (186 male, 120 female) with an average age of 26.4 years and follow‐up of 67.2 months. Tegner scores were superior in patients treated with OAT compared with MFX (ΔOAT‐MFX for pre‐post scores = 0.94 Tegner points, standardized mean difference [SMD] = 0.469, P = .005). Failure rates of MFX were higher than OAT (OAT = 11%, MFX = 32%, risk ratio = 2.42, P < .036). OAT was superior to MFX at 3 years in relation to subjective outcome scores (SMD = 0.404, P = .008). When assessing OAT lesions larger than 3 cm 2 , OAT was superior to MFX with respect to activity level (SMD = 0.506, P = .001). Conclusions OAT may achieve higher activity levels and lower risk of failure when compared with MFX for cartilage lesions greater than 3 cm 2 in the knee, although there was no significant difference for lesions less than 3 cm 2 at midterm. However, because of variability in patient‐specific factors such as age, preinjury activity level, lesion location and size, the superiority of OAT over MFX cannot be generalized to all patient populations and therefore requires individualized patient care. Level of Evidence Level II, meta‐analysis of Level I and II studies.

Objectives: Medial meniscus posterior root tears (MMPRTs) present a unique challenge for both patients and surgeons as these tears have shown to be biomechanically equivalent to complete meniscectomy. However, little is known about the natural history of these lesions. Therefore, the purpose of this study is to describe the clinical course of MMPRTs with respect to subsequent operative and non-operative treatments, and associated comorbidities. Methods: Over 2600 MRIs were identified by searching radiologist reads for the terms “root” or “root tear” from 2005-2013. Presence or absence of MMPRTs and other associated boney, meniscal, or ligamentous injuries were identified and recorded. Of these MRIs, 102 MRIs from 102 patients who had unrepaired MMPRTs with minimum 2-year follow-up and no prior ligamentous surgery were followed. These MRIs were evaluated to confirm the presence of a meniscal root tear and the presence or absence of associated meniscal or ligamentous injuries, as well as meniscal extrusion, subchondral edema, or insufficiency fractures. Chart review was performed to obtain the treatment summary after diagnosis. Radiographs from before and after the diagnosis of MMPRT were reviewed and Kellgren-Lawrence scores were determined. Finally, the association between concomitant boney, ligamentous, or meniscal injuries, patient factors, and rate of arthroplasty, as well as final Kellgren-Lawrence scores were evaluated. Chi-square analysis was used for categorical variables, and Wilcoxon Rank-Sums was used for continuous variables. Kaplan-Meier analysis was used to evaluate the effect of meniscal extrusion on the time-dependant rate of arthroplasty. Results: 104 patients (43 M:61F) were diagnosed with MMPRTs at a mean age of 54±13. These patients were followed for a mean of 66±26 months. 75 (74%) patients had associated meniscal extrusion, 64 (62%) had associated subchondral edema, and 14 (13%) had associated insufficiency fractures at the time of diagnosis. After initial diagnosis, 59 (58%) underwent subsequent surgical treatment. This included 52 (51%) patients undergoing arthroscopic partial meniscectomy, and 29 (28%) patients undergoing total knee arthroplasty at a mean 38±32 (range 3-107) months after MRI. Kellgren-Lawrence grades worsened from 1.3±0.7 before diagnosis to 2.2±1.0 after (p<0.001), with a mean 44±32 months between radiographs. There was a higher rate of radiographic arthritis (K-L grade 2+) after diagnosis (73%) than before diagnosis (36%) (p<0.001). The presence of meniscal extrusion on MRI was associated with the presence of arthritis on post-diagnosis radiographs (p=0.03). Meniscal extrusion, subchondral edema, and insufficiency fractures were not associated with increased rates of surgical treatment, or time to arthroplasty. Conclusion: Little information is available to guide patients and physicians on the clinical outcomes for MMPRTs. These injuries are associated with a relatively high rate of arthroplasty and worsening arthritis, especially with concomitant meniscal extrusion. More information is needed to determine the efficacy of meniscal root repair in preventing these unfavorable outcomes.

Objectives: Distal femoral varus osteotomy is an effective treatment for unloading valgus knee malalignment; however, there is limited evidence on the ability for patients to return to athletics following this procedure. The purpose of this study is to report the functional outcomes and return to sport for athletic patients that underwent distal femoral varus osteotomy. Methods: A consecutive series of athletic patients that had undergone distal femoral varus osteotomy for symptomatic lateral compartment overload and valgus knee malalignment were prospectively reviewed. All patients had a minimum of 2-year follow-up. Radiographs were assessed to determine pre-operative and post-operative alignment. Details regarding sport of interest, ability to return to sport, and timing of return were obtained from the patients. Prospective institutional registries were utilized to collect pre-operative and post-operative Marx Activity Scale and International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC) scores; these values were compared using paired t-tests with p < 0.05 as the threshold for significance. Results: A total of 13 patients with a mean age of 24 years (range: 17-35) and a mean follow-up of 43 months (range: 24-74) were included in the study. Six patients underwent medial closing wedge osteotomy, and seven patients underwent lateral opening wedge osteotomy. The mean alignment correction was 8 degrees (range: 5-13). Nine patients underwent one or more concomitant procedures at the time of the osteotomy: 6 lateral femoral condyle osteochondral allografts, 2 partial lateral meniscectomies, 1 lateral meniscus allograft transplantation, and 1 revision anterior cruciate ligament reconstruction. All patients were able to successfully return to their sport of choice (4 soccer, 2 softball, 2 running, 1 football, 1 basketball, 1 ice hockey, 1 volleyball, 1 rowing) at a mean of 11 months (range: 9-13). Furthermore, all 13 patients demonstrated an improvement in both Marx Activity Scale and IKDC scores after surgery. The mean improvement in Marx Activity Scale was 7 (mean pre-op: 4, mean post-op: 11, p < 0.01), and the mean improvement in IKDC score was 36 (mean pre-op: 53, mean post-op: 89, p < 0.01). Conclusion: Valgus knee malalignment results in overload of the lateral compartment and can severely limit one’s ability to participate in athletic activities. Correction of valgus knee malalignment through distal femoral varus osteotomy - either medial closing wedge or lateral opening wedge - can reliably result in improvement in function and return to sport, provided that concomitant chondral, meniscal, and ligamentous pathology is addressed. Therefore, distal femoral varus osteotomy should be considered in the athletic population for correction of symptomatic valgus knee malalignment.

Abstract Understanding of meniscal function through basic science, natural history, and biomechanics has highlighted the importance of preserving the meniscus to maintain normal knee biomechanics. Tears that may alter these biomechanics can contribute to the progressive nature of degenerative joint disease in the knee. Radial tears result in the disruption of the circumferential fibers causing inability of the native meniscus to resist normal hoop stresses, thereby leading to increased focal areas of pressure that cause complications such as early onset arthrosis. In this technical note, we describe our preferred operative technique to repair radial meniscal tears using an arthroscopic inside‐out approach with satisfactory clinical outcomes and healing response. Technique Video video See video under supplementary data.