Citations

AbstractBackgroundGlioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments.MethodsWe collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV).ResultsWe collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32).ConclusionMRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.

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.

Abstract Resistance is one the main reason for overall decrease in survival of cancer patient treated with cisplatin in different types of cancer. Cisplatin kills cancer cells by various mechanisms, but mainly through formation of inter- and intra stand crosslinks of DNA. Different types of translesion polymerase including Polymerase kappa (POLK) are involved in repair of DNA lesions. We observed high expression levels of POLK in cisplatin resistant bladder and ovarian cancer cells compared to parental cells. Due to its low proof-reading activity POLK can incorporate 8-oxo-dGTP into DNA. The MTH1 protein (Nudix hydrolase- NUDT1) sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Recently we have generated MTH1 inhibitors that damage the DNA and induce cancer specific cell death through incorporation of more oxidized dNTPs. We found cisplatin resistant bladder cancer cells (NTUB1/P) were more sensitive to MTH1 inhibitors in comparison to parental NTUB1 cells. As POLK is involved in incorporation of 8-oxo-dGTP into DNA, we hypothesized that high expression levels of POLK in cisplatin resistant cells make them more sensitive to MTH1 inhibitors as more 8-oxo-dGTP would be incorporated into DNA, resulting in more DNA damage and cell death in comparison to parental cells. Indeed, we observes higher induction of cleaved-PARP, γH2AX, cleaved-Caspase 3 and more annexin v positive cells in cisplatin resistant NTUB1/P cells in comparison to parental NTUB1 cells upon treatment with MTH1 inhibitors. MTH1 inhibitor also significantly delays the NTUB1/P xenograft tumor growth in comparison to vehicle treatment in immunosuppressive mice. Knocking down POLK in cisplatin resistant NTUB1/P cells by siRNA resulted in decreased incorporation of 8-oxo-dGTP and sensitivity to MTH1 inhibitors compared to non target control cells. Overexpression of POLK in NTUB1 and NTUB1/P cells results in further sensitization to MTH1 inhibitors. In conclusion elevated levels of POLK in cisplatin resistance cells determines increased sensitivity towards MTH1 inhibitors. Thus MTH1 inhibitors can be a potential promising therapy for the treatment of cisplatin resistant tumors in patients. Citation Format: Kumar Sanjiv, Helge Gad, Sean Rudd, Rachel Hurley, Patric Herr, José Manuel Calderón Montaño, Oliver Mortusewicz, Tobias Koolmeister, Sylvain Jaques, Estefanía Burgos Morón, Andreas Hoglund, Te-Chang Lee, Martin Scobie, Scott Kaufmann, John Weroha, Ulrika Warpman Berglund, Andrea Wahner Hendrickson, Thomas Helleday. Polymerase kappa determines the sensitivity of MTH1 inhibitors to cisplatin-resistant cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1260.

AbstractDecision aids are evidenced‐based tools designed to increase patient understanding of medical options and possible outcomes, facilitate conversation between patients and clinicians, and improve patient engagement. Decision aids have been used for shared decision making (SDM) interventions outside of the ED setting for more than a decade. Their use in the ED has only recently begun to be studied. This article provides background on this topic and the conclusions of the 2016 Academic Emergency Medicine consensus conference SDM in practice work group regarding “Shared Decision Making in the Emergency Department: Development of a Policy‐Relevant, Patient‐Centered Research Agenda.” The goal was to determine a prioritized research agenda for the development and testing of SDM interventions for use in emergency care that was most important to patients, clinicians, caregivers, and other key stakeholders. Using the nominal group technique, the consensus working group proposed prioritized research questions in six key domains: 1) content (i.e., clinical scenario or decision area), 2) level of evidence available, 3) tool design strategies, 4) risk communication, 5) stakeholders, and 6) outcomes.

Key Points The incidence of mutations within the MAPK pathway, the CRBN pathway, and TP53 is significantly increased in drug-refractory MM. Mutations in CRBN might contribute to IMiD resistance in drug-refractory MM.

Abstract Varus knee malalignment caused by medial compartment arthritis results in progressive asymmetric wear of the tibiofemoral joint. This wear can cause progressively painful gonarthrosis. Surgical methods to address varus knee malalignment include lateral closing‐wedge proximal tibial osteotomy, medial opening‐wedge osteotomy, and arthroplasty. Medial opening‐wedge proximal tibial osteotomy is an effective procedure for restoring proper coronal alignment and reducing knee pain. In this technical note, we present a reproducible technique for proximal tibial osteotomy. Technique Video video See video under supplementary data.

Background: Hip arthroscopy for young patients with femoroacetabular impingement (FAI) has been successful, but the efficacy of hip arthroscopy in older patients is not clearly defined. Purpose: To evaluate the clinical outcomes of patients 55 years and older who are undergoing hip arthroscopy and to compare outcomes with those of patients younger than 55 years. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 201 (63 male, 138 female) patients undergoing primary hip arthroscopy for FAI without radiographic arthritis (Tönnis grade <3) were isolated from a prospective database and stratified by age to <55-year and ≥55-year groups. Patients were evaluated preoperatively and 1 and 2 years postoperatively using the modified Harris Hip Score (mHHS) and Hip Outcome Score (HOS: functional scores, as well as Activities of Daily Living [ADL] and Sport subscales). A Wilcoxon signed rank sum test was used to evaluate the differences in outcome scores between the cohorts at each interval. Results: The <55-year group included 174 patients (mean age, 37 ± 12 years), and the ≥55-year group included 27 patients (mean age, 61 ± 5 years). The minimum follow-up time was 2 years in each group. Preoperative Tönnis grades and mHHS scores (59 vs 59; P = .75) were similar between groups. The ≥55-year cohort underwent labral debridement more frequently (78% vs 36%; P =.02) and were more likely to have full-thickness cartilage defects (22% vs 4%; P = .04). Despite this, the mHHS in both groups improved significantly from baseline, without significant differences at 1 year (86 [≥55 years] vs 81 [<55 years]; P = .53) or 2 years (73.88 [≥55 years] vs 79.54 [<55 years]; P = .06). However, at a minimum 2-year follow-up, patients <55 years had significant improvements over patients ≥55 years in the HOS subscales for ADL score (85.6 vs 75.2; P = .03), ADL rating (80.1 vs 70.0; P = .004), Sport score (70.2 vs 55.6; P = .04), and Sport rating (70.2 vs 58.0; P = .04). Conclusion: Although younger patients had superior HOS outcomes reported at 2 years compared with older patients after hip arthroscopy for FAI, both groups had significant improvement compared with their baseline. These data suggest that carefully selected patients 55 years and older without radiographic arthritis may benefit from hip arthroscopy.

Abstract Coronal limb malalignment is a significant contributor to asymmetric joint wear, gait abnormalities, and the development and progression of degenerative joint disease. Osteotomies about the knee were developed to realign the mechanical axis of the limb to unload the affected compartment. Valgus malalignment is less common than varus malalignment, but can contribute to a variety of clinical conditions, including lateral compartment cartilage defects and arthritis, lateral patellofemoral instability, and medial collateral ligament laxity. In this article, we describe our preferred operative technique for a lateral opening wedge varus‐producing distal femoral osteotomy to correct mild to moderate valgus malalignment. Technique Video video See video under supplementary data.

AbstractWe performed a retrospective review of outcomes after heart transplantation during long‐term follow‐up of a surgical cohort of 1138 Fontan patients who were followed at the Mayo Clinic. Follow‐up information was obtained from medical records and a clinical questionnaire that was mailed to patients not known to be deceased at the initiation of the study. Forty‐four of 1138 Fontan patients with initial or subsequent evaluation at Mayo had cardiac transplantation between 1988 and 2014 (mean age at transplantation was 23.2 ± 12 yr, median was 19.8 yr; mean interval between Fontan and transplantation was 13.0 ± 7.7 yr, median was 13.1 yr). Two patients had combined organ transplantation (one heart–lung, one heart–liver). Twelve of the 44 (27%) patients had PLE prior to transplantation. There was no difference in post‐bypass Fontan pressures or incidence of late reoperations for AVV repair/replacement between transplanted and non‐transplanted patients. There were 16 (36%) deaths in the transplantation cohort; seven occurred within 30 days of transplantation. Overall one, five, 10, and 15 yr post‐transplantation survival was 80%, 72%, 69%, and 55%, respectively. Although this is a challenging group of patients, intermediate‐term results suggest that cardiac transplantation remains a reasonable option for patients with a failed Fontan circulation.