Citations

Abstract Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Purpose To evaluate clinical outcomes, demographics, and radiographic findings for patients whose hip arthroscopies involved amorphous calcification (AC) excision and to compare them with a control group with no AC and with the general population regarding diabetes mellitus and hypothyroidism. Methods Patients who underwent primary hip arthroscopy involving surgical excision of AC deposit in the anterosuperior labralcapsular recess between October 2008 and July 2014 were reviewed. Demographics, radiographic findings, intraoperative findings, and procedures were reviewed. Minimum follow‐up was 2 years and included visual analog scale for pain, patient satisfaction, and the following patient‐reported outcome scores: modified Harris hip score, hip outcomes score sport‐specific subscale, and nonarthritic hip score. These patients were matched (1:2 ratio) to patients who underwent hip arthroscopy with no AC using the following matching criteria: age at surgery ± 5 years, body mass index ± 5, gender, type of labral treatment, and type of capsular treatment. Results We reviewed 12 cases in 11 female patients. Mean latest follow‐up scores improved from 64.0 to 83.4 ( P = .003) for modified Harris hip score, from 57.6 to 80.6 ( P < .001) for nonarthritic hip score, from 35.4 to 62.7 ( P = .021) for hip outcomes score sport‐specific subscale, and from 6.4 to 2.8 ( P = .016) for visual analog scale. The survivorship rate was 91.7%, with one hip converting to total hip arthroplasty. Mean patient satisfaction was 8.4 ± 2.3. Six hips of the 12 (50%) had clock face localization of the AC. They were all between 11 and 12 with a mean of 12:30. Postoperative radiographic findings showed no subsequent AC in all 12 hips. No complications or revisions were reported. There were no significant differences between the AC group and the control group. Conclusions The treatment of AC as part of hip arthroscopy for labral tear and femoro‐acetabular impingement is safe and has favorable and similar outcomes compared with a control group at minimum 2‐year follow‐up. Female gender may be a risk factor for the development of AC. There is no strong evidence that AC should be debrided. Level of Evidence Level III, case control study.

Introduction Mycobacterial spindle cell pseudotumour (MSP) is a rare disease characterised by tumour-like local proliferation of spindle-shaped histiocytes containing acid-fast positive mycobacteria. The aim of this literature review is to describe the clinical parameters and treatment outcomes of patients with MSP. Methods A literature search was conducted using the search terms related to mycobacteria and spindle cell tumours. A previously unreported stem cell transplant recipient from our institution diagnosed with MSP was also included. Demographics, comorbidities, site of infection, treatment and clinical outcomes were analysed. Results Fifty-one patients were analysed. Twenty-six (51%) had HIV infection. Mycobacterium avium complex was the most frequent organism isolated in 24 (47.1%) followed by Mycobacterium tuberculosis complex in eight (16%) cases. Lymph nodes were the most common site of infection (45.1%). Twenty (39.2%) patients received antimycobacterial agents, 12 (23.5%) underwent surgical resection and six (11.8%) received antimycobacterial agents plus surgery. Treatment was successful in 24 (47.1%) patients and failed in 15 (29.4%); 13 of these 15 patients died. Antimycobacterial therapy was significantly associated with successful outcome compared with surgical resection or no treatment (P<0.001). Conclusion MSP is a rare condition associated primarily with immunodeficiencies. Antimycobacterial therapy is significantly associated with successful outcome.

Purpose To report the minimum 2‐year outcomes of transtendinous repair of partial‐thickness undersurface tears of the abductor tendon using patient‐reported outcomes (PROs), visual analog scale (VAS) scores, and patient satisfaction scores. Methods All patients who underwent endoscopic transtendinous gluteus medius repair between October 2009 and May 2013 at 1 institution were prospectively evaluated. The exclusion criteria consisted of less than 2 years' follow‐up, previous hip surgery, inflammatory arthritis, open surgery, full‐thickness abductor tear, and Workers' Compensation patients. All patients underwent a documented preoperative physical examination with strength testing (scale of 0‐5) and observation of their gait. Patient satisfaction and PRO scores were recorded preoperatively; at 3 months postoperatively; and at 1, 2, 5, and 10 years after surgery. The PRO scores collected were the modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living Subscale, Hip Outcome Score–Sports‐Specific Subscale, Non‐arthritis Hip Score, and VAS score. Preoperative strength and gait were compared with latest follow‐up. Results There were 25 patients who fit our criteria. Significant improvement in PRO scores were shown for the modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living Subscale, Hip Outcome Score–Sports‐Specific Subscale, Non‐arthritis Hip Score, and VAS score from 54.9 to 76.2, from 50.2 to 80.6, from 30.1 to 67.3, from 51.9 to 82.4, and from 7.1 to 2.7, respectively ( P < .001). Before surgery, 11 patients had objective weakness; 7 of these patients moved up at least 1 strength grade by final follow‐up. Preoperatively, 14 patients had a Trendelenburg gait; 12 of them had a normal gait at latest follow‐up ( P < .001). The average patient satisfaction rating was 7.5. There were no revision surgical procedures, and no complications were noted. Conclusions Partial‐thickness undersurface tears of the abductor can be treated successfully with endoscopic transtendinous repair preserving the intact attachment of the superficial fibers of the gluteus medius. We recommend this treatment for partial undersurface tears recalcitrant to nonoperative treatment because patients showed clinical benefit at greater than 2 years' follow‐up that exceeded substantial clinical benefit and the minimal clinically important difference. Level of Evidence Level IV, case series.

AbstractObjectivesParamedics and emergency medical technicians (EMTs) perform triage at disaster sites. There is a need for disaster triage training. Live simulation training is costly and difficult to deliver. Screen‐based simulations may overcome these training barriers. We hypothesized that a screen‐based simulation, 60 Seconds to Survival (60S), would be associated with in‐game improvements in triage accuracy.MethodsThis was a prospective cohort study of a screen‐based simulation intervention, 60S. Participants included emergency medical services (EMS) personnel from 21 EMS agencies across 12 states. Participants performed assessments (e.g., check for pulse) and actions (e.g., reposition the airway) for 12 patients in each scenario and assigned color‐coded triage levels (red, yellow, green, or black) to each patient. Participants received on‐screen feedback about triage performance immediately after each scenario. A scoring system was designed to encourage accurate and timely triage decisions. Participants who played 60S included practicing EMTs, paramedics, and nurses as well as students studying to assume these roles. Participants played the game at least three times over 13 weeks.ResultsIn total, 2,234 participants began game play and 739 completed the study and were included in the analysis. Overall, the median number of plays of the game was just above the threshold inclusion criteria (three or more plays) with a median of four plays during the study period (interquartile range [IQR] = 3–7). There was a significant difference in triage accuracy from the first play of the game to the last play of the game. Median baseline triage accuracy in the game was 89.7% (IQR = 82.1%–94.9%), which then increased to a median of 100% at the last game play (IQR = 87.5%–100.0%; p < 0.001). There was some variability in median triage accuracy on fourth through 11th game plays, ranging from 95% to 100%, and on the 12th to 16th plays, the median accuracy was sustained at 100%. There was a significant decrease in the rate of undertriage: from 10.3% (IQR = 5.1%–18.0%) to 0 (IQR = 0%–12.5%; p < 0.001).Conclusion60 Seconds to Survival is associated with improved in‐game triage accuracy. Further study of the correlation between in‐game triage accuracy and improvements in live simulation or real‐world triage decisions is warranted.

ABSTRACT Background and objective This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema. Methods Two consecutive IPF populations having undergone transthoracic echocardiography were examined ( n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk. Results The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema. Conclusion Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema.