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Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation. Significance: NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL. This article is highlighted in the In This Issue feature, p. 1

Fishways are an important link for the reestablishment of river continuity, interrupted by transverse structures e.g. weirs, dams and hydropower plants. The meander fishway and vertical slot fishwa...

INTRODUCTION: The purpose of this study was to determine whether alcohol use disorder (AUD) patients undergoing reverse shoulder arthroplasty (RSA) have increased: 1) lengths of stay (LOS); 2) complications; and 3) costs. METHODS: The study identified 19,168 patients in the study (n = 3198) and control (n = 15,970) cohort. In-hospital LOS, 90-day complications, and costs were assessed. RESULTS: AUD patients had significantly longer LOS (3- vs. 2-days, p

BACKGROUND Liver cancer is the fifth most common cancer and the second cause of cancer-related deaths worldwide. Transarterial chemoembolization (TACE) is the best treatment of intermediate hepatocellular carcinoma (HCC). Doxorubicin is the most commonly used drug despite a low level of evidence. AIM To compare the objective response rate of idarubicin-based TACE (Ida-TACE) against doxorubicin-based TACE (Dox-TACE) in intermediate stage HCC. METHODS Between January 2012 and December 2014, all patients treated with TACE at our academic hospital were screened. Inclusion criteria were patients with Child-Pugh score A or B, a performance status below or equal to 1, and no prior TACE. Either lipiodol TACE or drug-eluting beads TACE could be performed with 10 mg of idarubicin or 50 mg of doxorubicin. Each patient treated with idarubicin was matched with two doxorubicin-treated patients. The TACE response was assessed by independent radiologists according to the mRECIST criteria. RESULTS Sixty patients were treated with doxorubicin and thirty with idarubicin. There were 93% and 87% of cirrhotic patients and 87% and 70% of Child-Pugh A in the doxorubicin and idarubicin groups, respectively. The median number of HCC per patient was two in both groups with 31% and 26% of single nodules in doxorubicin and idarubicin groups, respectively. Objective response rate after first TACE was 76.7% and 73.3% (P = 0.797) with 41.7% and 40.0% complete response in doxorubicin and idarubicin groups, respectively. Progression-free survival was 7.7 mo in both groups, and liver transplant-free survival was 24.9 mo and 21.9 mo in doxorubicin and idarubicin groups, respectively. Safety profiles were similar in both groups, with grade 3-4 adverse events in 35% of Dox-TACE and 43% of Ida-TACEs. CONCLUSION Ida-TACE and Dox-TACE showed comparable results in terms of efficacy and safety. Ida-TACE may represent an interesting alternative to Dox-TACE in the management of patients with intermediate stage HCC.

The elbow is formed by the articulations between the distal humerus, proximal ulna, and proximal radius. This complex joint produces motion of a synovial hinge joint and a pivot joint providing humans with a distinct evolutionary advantage: the ability to throw. However, such movement places great mechanical force upon the small joint, necessitating reinforcement by the adjacent ligaments, tendons, muscles, and fascial planes that function in concert to stabilize the elbow. This chapter will review conventional elbow anatomy and common anatomic variations. This is followed by a discussion of MR imaging optimization, with a review of patient positioning, protocols, technical parameters, and study selection.

Laser beam welding plays an important role in automotive industry as it offers a number of advantages. These include contactless joining, localized energy input, thermally and mechanically durable welds and low electrical contact resistance of the bonded connections. The latter is exploited in the laser beam welding of copper contacts as used for electrical connections in e-mobility. However, copper entails a higher susceptibility to seam defects due to the metallurgical properties compared to, for example, car body materials which in many cases are processed by laser beam as well. In order to meet the high standards of the automotive industry an inline validation of the connections is essential. A suitable method is the monitoring of the welding process by means of thermography which has already proven itself for other metals and joining techniques but has not yet been investigated in detail for laser beam welding of copper. Consequently, this paper deals with the possibilities of thermographic process monitoring in laser beam welding of copper components. It examines the extent to which defects can be registered; so far pores have been detected reliably up to a minimal diameter of 0.5 mm.

Background Secondary lymphoedema is a challenging pandemic. This condition may arise after oncologic resection of tumor-draining lymph nodes and/or radiation. Plastic-surgical procedures for lymphoedema comprise transplantation of vascularized lymph node flaps, which are, however, technically challenging and difficult to implement on a global level due to the scarcity of microsurgery facilities in some countries. To improve this situation, comparative research in valid animal models is needed. Methods A total of 33 minipigs were subjected to lymphatic resection in the hind limbs. This large animal model was used in a first phase to compare different lymph node fragmentation methods and assess lymphatic regeneration after avascular transplantation. In a second phase, several stimulants were tested for their effect on lymphatic regeneration after fragment transplantation. In a third phase, animals additionally received irradiation of the groin. In this novel animal model, autologous avascular lymph node fragment transplantation was complemented by peripheral injections of vascular endothelial growth factor-C (VEGF-C). Finally, regeneration rates were quantified in relative numbers (percentage) in the irradiated tissue. Results In the first phase, transversal lymph node fragmentation under preservation of the nodal capsule showed the best percentage of regeneration (62.5%). Peripheral intradermal administration of VEGF-C enhanced lymph node fragment regeneration (70.8%) better than injections of tetanus toxoid (41.6%) or Streptococcus suis (62.5%). Lymph node fragment regeneration also occurred in an irradiated porcine model of lymphadenectomy under VEGF-C administration (66.6%). Conclusions The present findings provide a pre-clinical proof-of-concept for a possible simplification strategy for current operative procedures of autologous lymph node transplantation. Level of evidence : Not gradable

BACKGROUND The Coordinated National Network to Engage Cardiologists in the antithrombotic Treatment of patients with Atrial Fibrillation undergoing Percutaneous Coronary Intervention (CONNECT AF+PCI-I) program provided a snapshot (Nov 2015-Jul 2018) of the antithrombotic management of 467 non-valvular atrial fibrillation (NVAF) patients undergoing PCI in Canada (Bagai et al Can J Cardiol 2018;34:S16). Since then, further randomized clinical trials have supported updated Canadian Cardiovascular Society (CCS) AF and Antiplatelet guideline recommendations for antithrombotic strategies for NVAF and coronary artery disease (CAD) patients undergoing PCI and/or medical management. Thus, an updated quality enhancement assessment in Canadian practice (CONNECT AF+PCI-II) was undertaken. METHODS AND RESULTS By retrospective chart audit (Aug 2018-Dec 2020), 68 cardiologists from 8 provinces identified 626 patients with NVAF. 37% had stable CAD, 56% had an acute coronary syndrome (ACS) and PCI, and 7% had an ACS and were medically managed. Median age was 76 (25th,75th percentiles 69, 83; 87% ≥65 years); 29% female; 38% diabetes; median CHADS2 score 2 (1, 3); median CHA2DS2-VASc score 4 (3, 5); median HAS-BLED score 3 (2, 3). 73% were receiving oral anticoagulation (OAC) before the index ACS/PCI (apixaban 31%, rivaroxaban 24%, dabigatran 6%, edoxaban 2%, warfarin 10%). Initial antithrombotic therapy after the index ACS/PCI was: 53% triple therapy (OAC+dual antiplatelet therapy [DAPT=ASA+P2Y12 receptor inhibitor], 31% OAC+P2Y12 inhibitor, 9% DAPT, 4% OAC+ASA, 2% OAC alone, and CONCLUSION While triple therapy remains the most common initial antithrombotic strategy used in AF patients undergoing PCI and/or admitted with ACS in Canada, treatment duration has shortened over time. Further, more patients are receiving CCS guideline-recommended OAC+ P2Y12 receptor inhibitor post-PCI compared to previously, and OAC monotherapy 1 year post-ACS/PCI.

International audience; Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60, FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%, p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6, p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4, p = 0.7), respectively. Abdominal pain at the baseline (HR = 2.03, p = 0.03), tumors located in the tail of the pancreas (HR = 4.35, p = 0.01), CA19-9 &gt, 200 UI/L (HR = 2.03, p = 0.004) and tumor resection (HR = 0.37, p = 0.007) were independent prognostic factors for PFS, similarly to OS. CA19-9 ≤ 200 UI/L (OR = 2.6, p = 0.047) was predictive of the tumor response. Consolidation chemoradiotherapy, more often used in the FFX group (11.7% vs. 50.6%, p &lt, 0.001), was not predictive. Conclusion: This retrospective study did not show any difference between GN and FFX as the first-line treatment in patients with LAPC.

As a result of the energy transition in Germany, companies can increasingly benefit from adjusting electricity consumption to fluctuating electricity prices. Through energy-oriented production planning, production processes are scheduled depending on price forecasts. The resulting electricity demand is procured with the obligation to consume the electricity within certain tolerances. The procurement entails risks, as faults or other unexpected events can lead to deviations in electricity consumption. These can be associated with high penalty costs, if contractual tolerances or the peak load are violated. To take a holistic view on the additional costs, the effects on production goals must also be considered. This paper shows the assessment of production risks and delivers an approach for suitable preventive or reactive measures by changing the production plan. The approach was applied on a use case of a foundry with exemplary risks, with the result of minimized fault-related additional costs through the selection of a cost-optimal measure.

BACKGROUND: Frequent migraine headaches are disabling and aeromedically disqualifying. Four new monoclonal antibody medications, targeting calcitonin gene-related peptide (CGRP), have been approved by the U.S. Food and Drug Administration (FDA) since 2018, with more expected in the coming years. These medications present new alternatives for the treatment of migraine unresponsive to other therapeutic and prophylactic agents.CASE REPORT: We present a case of a 45-yr-old commercial pilot who presented with migraine headaches increasing in frequency to 1315 per month in spite of the use of propranolol for prophylaxis and sumatriptan for abortive treatment of the headaches. Upon presentation, he was not flying due to his frequent headaches and he was started on monthly subcutaneous injections of fremanezumab. Following his second injection, his headaches stopped entirely, and he has continued on the medication and not experienced another migraine headache. He underwent an aeromedical neurology evaluation and consideration for Authorization of Special Issuance of Medical Certificate, which was granted by the Federal Aviation Administration (FAA).DISCUSSION: This is the first case to our knowledge of the successful use of an anti-CGRP monoclonal antibody medication in an active pilot. The pilot appears to be a super responder to the medication, having achieved complete remission of a nearly life-long condition. Though only a small portion of treated individuals will see this sort of response, these medications represent an effective additional option for migraine prophylaxis in the pilot population.Garber MA, Sirven JI, Roth RS, Hemphill JM. Migraine prophylaxis using novel monoclonal antibody injections in a commercial pilot. Aerosp Med Hum Perform. 2020; 91(10):824825.

Background: There has been renewed interest in ulnar collateral ligament (UCL) repair in throwing athletes because of a greater understanding of UCL injuries, improvement in ligament repair technology, and potentially expedited rehabilitation time and return to play relative to UCL reconstruction. Purpose: To evaluate elbow articular contact and overall joint torque after UCL reconstruction and repair augmented with a collagen-coated fiber tape, InternalBrace. Study Design: Controlled laboratory study. Methods: Ten matched pairs of cadaveric arms (mean age, 41 ± 11 years) were dissected to expose the UCL. Each specimen was secured into a custom test fixture at 90°, and 1 specimen from each pair underwent either a modified Jobe UCL reconstruction or UCL repair with InternalBrace. Each specimen underwent 10 cycles of elbow valgus angular displacement between 0° and 5° at a rate of 1 deg/s in the intact state, after UCL avulsion, and then after UCL reconstruction or repair. Articular contact mechanics and overall joint torque and stiffness were recorded. Results: Contact mechanics of reconstructed and repaired specimens were not significantly different. Both reconstruction and repair procedures returned the overall resistance of the joint to valgus torsion to near-intact levels. UCL repair tended to restore joint torque more closely to the intact state than did reconstruction, given that reconstruction showed a nonsignificant trend toward lower torque than the intact state ( P = .07). Conclusion: Neither UCL reconstruction nor UCL repair with InternalBrace overconstrained the elbow joint, as both groups had similar contact pressures compared with the native joint. Both procedures also restored elbow joint torque and stiffness to levels not statistically different from the intact state. Clinical Relevance: Given the sound biomechanical properties of UCL repair with InternalBrace, it may have a significant role as treatment for UCL injuries.

Background: Graft-tunnel mismatch (GTM) is a condition in which the anterior cruciate ligament (ACL) graft is either too long or too short. GTM is particularly problematic when bone–patellar tendon–bone grafts are used because of a potential compromise in fixation of the bone plug on the tibia. Hypothesis: The Blumensaat line (BL), a radiographic landmark representing the roof of the intercondylar fossa, will accurately approximate the native ACL (nACL) length and may aid in the prevention of GTM. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: A total of 130 patients (66 males, 64 females) underwent direct measurement of the nACL during knee arthroscopy. The lengths of the nACL and patellar ligament (PL) were measured intraoperatively, and BL length was measured on lateral knee radiographs. The nACL length was compared with PL and BL lengths to calculate the absolute difference (AD). Mean AD was calculated and used to determine mean percentage difference (MPD). Pearson correlation coefficients (CC) between BL, PL, and nACL length were calculated, along with inter- and intraobserver reliability coefficients for the measurement of BL. Results: For male patients, the mean length of the nACL was 32.5 mm, BL was 30.4 mm, and PL was 49.2 mm. The AD between the BL and nACL was 2.4 ± 1.3 mm, MPD was 2.6% ± 1.9%, and CC was 0.88. The CC between the PL and nACL was 0.08. For female patients, the mean length of the nACL was 30.2 mm, BL was 27.5 mm, and PL was 44.4 mm. The AD between the BL and nACL was 2.7 ± 1.7 mm, MPD was 4.5% ± 2.4%, and CC was 0.93. The CC between the PL and nACL was 0.1. The inter- and intraobserver reliability coefficients for the measurement of BL were 0.86 and 0.83, respectively. Conclusion: A strong correlation was found between BL and nACL with a high inter- and intraobserver reliability. This correlation provides a simple and reliable method to closely approximate nACL length before reconstruction and may aid in the prevention of graft-tunnel mismatch.

The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action-to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness.

Massive, irreparable rotator cuff tears are challenging to manage. Often, these tears are not amenable to primary repair and necessitate additional treatment options. This is especially true in patients with absent glenohumeral arthritis in the setting of a massive, irreparable rotator cuff tear. Superior capsular reconstruction (SCR), originally described by Mihata using a fascia lata autograft, has grown in popularity for the treatment of irreparable rotator cuff tears as a salvage option with good clinical outcomes. More recently, SCR techniques have been described using dermal allograft. Biomechanical studies and reported clinical series show promising results, with favorable postoperative clinical outcomes. The procedure, however, may be technically challenging, especially when performed using an all-arthroscopic technique. This article describes an all-arthroscopic technique using a predetermined graft size, unique medial fixation to ease graft passage, and knotless single-row lateral fixation to optimize suture management and efficiency.

The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action—to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir’s discovery, mechanism of action, and the current studies exploring its clinical effectiveness., We review clinical development of remdesivir, a prodrug with a demonstrated ability to inhibit SARS-CoV-2 replication, which supports its clinical evaluation for COVID-19 treatment.

An upgrade of the Near Detector of the T2K long baseline neutrino oscillation experiment, ND280, has been proposed. This upgrade will include two new Time Projection Chambers, each equipped with 16 resistive MicroMegas modules for gas amplification. A first prototype of resistive MicroMegas has been designed, built, installed in the HARP field cage, and exposed to a beam of charged particles at CERN. The data have been used to characterize the performances of the resistive MicroMegas module. A spatial resolution of 300 $\mu m$ and a deposited energy resolution of 9% were observed for horizontal electrons crossing the TPCs at 30 cm from the anode. Such performances fully satisfy the requirements for the upgrade of the ND280 TPC., Comment: 31 pages, 26 figures

With rising health care costs in the United States, trainees will be increasingly challenged in discussing testing stewardship with patients. We piloted a high-value care (HVC) communication skills curriculum utilizing the Four Habits Model for communication. We hoped residents would 1) learn to apply the Four Habits communication model to HVC discussions with standardized patients (SP) and 2) improve value-based communication skills through training in a high-intensity curriculum with feedback from trained faculty facilitators and peers. Thirty interns at the University of Minnesota were randomized to a standard HVC communication SP encounter (n = 15) or a high-intensity HVC communication skills curriculum (n = 15). The high-intensity curriculum included video and audio-recorded SP encounters followed by facilitated small group discussions/feedback. Experiences were reported in a post-intervention survey; communication skills were assessed with the CARE empathy scale. 70% (21/30) of interns (57% high intensity, 43% standard) responded to the survey. In total, 88% of high intensity v. 44% of standard interns agreed/strongly agreed that the curriculum was valuable for their communication skills. High-intensity interns were more likely to report that feedback was valuable with subsequent incorporation of feedback into future patient encounters. High-intensity participants also reported higher levels of interest in future HVC curricula (55% vs 22%). There was no difference in overall performance on the CARE empathy scale. Our HVC high-intensity skills curriculum was well received by interns and provided opportunities to practice structured conversations and debrief around testing stewardship.

The implantation of an internal biliary stent (IBS) during liver transplantation has recently been shown to reduce biliary complications. To avoid a potentially morbid ablation procedure, we developed a resorbable and radiopaque internal biliary stent (RIBS). We studied the mechanical and radiological properties of RIBS upon in vivo implantation in rats and we evaluated RIBS implantability in human anatomical specimens. For this purpose, a blend of PLA50-PEG-PLA50 triblock copolymer, used as a polymer matrix, and of X-ray-visible triiodobenzoate-poly(e-caprolactone) copolymer (PCL-TIB), as a radiopaque additive, was used to design X-ray-visible RIBS. Samples were implanted in the peritoneal cavity of rats. The radiological, chemical, and biomechanical properties were evaluated during degradation. Further histological studies were carried out to evaluate the degradation and compatibility of the RIBS. A human cadaver implantability study was also performed. The in vivo results revealed a decline in the RIBS mechanical properties within 3 months, whereas clear and stable X-ray visualization of the RIBS was possible for up to 6 months. Histological analyses confirmed compatibility and resorption of the RIBS, with a limited inflammatory response. The RIBS could be successfully implanted in human anatomic specimens. The results reported in this study will allow the development of trackable and degradable IBS to reduce biliary complications after liver transplantation. STATEMENT OF SIGNIFICANCE: Biliary reconstruction during liver transplantation is an important source of postoperative morbidity and mortality although it is generally considered as an easy step of a difficult surgery. In this frame, internal biliary stent (IBS) implantation is beneficial to reduce biliary anastomosis complications (leakage, stricture). However, current IBS are made of non-degradable silicone elastomeric materials, which leads to an additional ablation procedure involving potential complications and additional costs. The present study provides in vitro and human postmortem implantation data related to the development and evaluation of a resorbable and radiopaque internal biliary stent (RIBS) that could tackle these drawbacks.

STUDY DESIGN Observational study. OBJECTIVE To evaluate how online patient comments will affect website ratings for spine surgeons. SUMMARY OF BACKGROUND DATA With the ever-growing utilization of physician review websites, healthcare consumers are assuming more control over whom they choose for care. We evaluated patient feedback and satisfaction scores of spine surgeons using comments from three leading physician rating websites: Healthgrades.com, Vitals.com, Google.com. This is the largest review of online comments and the largest review of spine surgeon comments. METHODS From the North American Spine Society (NASS) membership directory, 210 spine surgeons practicing in Florida (133 orthopedic trained; 77 neurosurgery trained) with online comments available for review were identified, yielding 4701 patient comments. These were categorized according to subject: (1) surgeon competence, (2) surgeon likeability/character, (3) office staff, ease of scheduling, office environment. Type 1 and 2 comments were surgeon-dependent factors whereas type 3 comments were surgeon-independent factors. Patient comments also reported a score (1-5), 5 being the most favorable and 1 being the least favorable. RESULTS There were 1214 (25.8%) comments from Healthgrades, 2839 (60.4%) from Vitals, and 648 (13.8%) from Google. 89.9% (4225) of comments pertained to surgeon outcomes and likeability (comment type 1 and 2), compared with 10.1% (476) surgeon-independent comments (comment type 3) (P

In this article a brief version of the newly developed S3 guidelines on screening, diagnosis, therapy and follow-up of abdominal aortic aneurysms (AAA), which was developed under the auspices of the German Society of Vascular Surgery and VascularMedicine (DGG) is presented. In addition to the DGG, participating professional societies were the German Radiological Society (DRG), German Society for Angiology/Society for Vascular Medicine (DGA), German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), German Society for Ultrasound in Medicine (DEGUM), German Vascular League e.V., German Society for Interventional Radiology (DEGIR), German Society for Anesthesiology and Intensive Care Medicine (DGAI), German Society for Thoracic and Cardiovascular Surgery (DGTHG) and the German Society of Surgery (DGCH). The guidelines are based on a systematic literature search in Medline (PubMed) for the period from 1 January 2000 to 1 January 2017. Important publications from 2017 were also considered. The selection of evidence was made by a multilevel screening process. In addition to the evidence, other criteria were included in the assessment of the recommendation level, such as the consistency of the study results, the clinical relevance of the endpoints and effect sizes, the benefit–risk balance, the applicability of the study results to the patient target group and the care system, the feasibility of the recommendations in everyday life, patient preferences and ethical and legal considerations. All recommendations/findings were approved with strong consensus (approval of >95% of the participating professional societies/associations). Thus, the present text version of the S3 guidelines on AAA represents the view of all participating societies.

Die unter Federfuhrung der Deutschen Gesellschaft fur Gefaschirurgie und Gefasmedizin (DGG) neu erarbeitete S3-Leitlinie zu Screening, Diagnostik, Therapie und Nachsorge des Bauchaortenaneurysmas (AAA) wird in Kurzfassung vorgestellt. Beteiligte Fachgesellschaften waren neben der DGG die Deutsche Rontgen-Gesellschaft (DRG), Deutsche Gesellschaft fur Angiologie/Gesellschaft fur Gefasmedizin (DGA), Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin (DIVI), Deutsche Gesellschaft fur Ultraschall in der Medizin (DEGUM), Deutsche Gefasliga e. V., Deutsche Gesellschaft fur Interventionelle Radiologie (DEGIR), Deutsche Gesellschaft fur Anasthesiologie und Intensivmedizin (DGAI), Deutsche Gesellschaft fur Thorax‑, Herz- und Gefaschirurgie (DGTHG) und die Deutsche Gesellschaft fur Chirurgie (DGCH). Die Leitlinie beruht auf einer systematischen Literaturrecherche in Medline (PubMed) fur den Zeitraum vom 01.01.2000 bis 01.01.2017. Wichtige Publikationen des Jahres 2017 wurden ebenfalls berucksichtigt. Die Auswahl der Evidenz erfolgte durch einen mehrstufigen Screeningprozess. In die Bewertung des Empfehlungsgrades gingen neben der Evidenz weitere Kriterien ein, wie die Konsistenz der Studienergebnisse, die klinische Relevanz der Endpunkte und Effektstarken, das Nutzen-Risiko-Verhaltnis, die Anwendbarkeit der Studienergebnisse auf die Patientenzielgruppe und das Versorgungssystem, die Umsetzbarkeit der Empfehlungen im Alltag, Patientenpraferenzen und ethische und rechtliche Gesichtspunkte. Alle Empfehlungen/Feststellungen wurden mit „starkem Konsens“ verabschiedet (Zustimmung von >95 % der teilnehmenden Fachgesellschaften/-verbande). Somit reprasentiert die vorliegende Textfassung der S3-Leitlinie Bauchaortenaneurysma die Ansicht aller beteiligten Fachgesellschaften.

Aim of the present study is to compare magnetic resonance imaging (MRI) and positron emission tomography (PET) parameters in the follow up of chronic periaortitis (CP), with a focus on changes in the apparent diffusion coefficient (ADC) and standardized uptake values (SUV). 127 patients with CP were treated in our urology between 2007 and 2017. We identified 14 patients with parallel abdominal MRI and PET-CT examinations before therapy and in the follow up resulting in a total of 56 examinations. Relative contrast uptake and diffusion-weighted MRI parameters were compared to SUV in the corresponding PET-CT examinationsand laboratory infection markers. All examined MRI and PET-CT parameters showed significant changes between basis and follow-up examinations. Median ADC values increased significantly (p

Background and purpose In 2011, fingolimod was approved in Switzerland for the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to assess the effectiveness and retention of fingolimod in a real-life Swiss setting, in which patients can receive fingolimod as both first- and second-line treatment for RRMS. Methods This cross-sectional, observational study with retrospective data collection was performed at 19 sites that comprised both hospitals and office-based physicians across Switzerland. Sites were asked to document eligible patients in consecutive chronological order to avoid selection bias. Demographic and clinical data from 274 consenting adult patients with RRMS who had received treatment with fingolimod were analyzed. Results Mean treatment duration with fingolimod was 32 months. Under fingolimod, 77.7% of patients remained free from relapses and 90.3% did not experience disability progression. The proportion of patients who were free from any clinical disease activity, i.e. without relapses and disability progression, was 72.1%. A total of 28.5% of patients had been RRMS treatment-naive prior to fingolimod therapy. High long-term treatment retention rates ranging between 95.7% at 24 months and 87.8% at 36 months were observed. Conclusion In this Swiss cohort of naive and pre-treated subjects with RRMS, the majority of patients under fingolimod treatment showed freedom from relapses and disability progression. In addition, treatment retention rate over 2 and 3 years was high, irrespective of previous treatment.

In line with other major surgeries including breast cancer surgery (BCS), recent studies suggest a striking rate of chronic postsurgical pain (CPSP) following breast reconstruction. This commentary will critically examine evidence for the degree to which the prevalence of CPSP following breast reconstruction is directly attributable to reconstructive surgery. The discussion will trace similarities and distinctions between breast reconstruction and BCS in considering the risk for CPSP, and describe recent advances in the definition of CPSP, highlighting methodological limitations in the general investigation of CPSP, which also characterize the study of CPSP more specifically for breast reconstruction outcome. A convenience sample of relevant studies examining CPSP following breast reconstruction reveals inadequate evidence to support a serious concern for reconstruction-induced CPSP and further that these studies fail to adhere to recommended methodological standards to effectively isolate surgery as the etiology of persistent pain reported by women following reconstructive surgery. Suggestions for future exploration of problematic chronic pain after breast reconstruction are considered.

Sickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene, which results in red blood cell sickling, hemolysis, vaso-occlusive crises (VOCs), and other complications. Increasing HbF has the potential to prevent or reduce disease-related pathophysiology, including the risk of recurring events such as hemolysis and VOCs. Individuals with SCD who also have hereditary persistence of fetal hemoglobin (HPFH) and exhibit HbF levels of 25 - 30% are often asymptomatic from their SCD, underscoring the protective effect of increased HbF in SCD. Preclinical results with FTX-6058 demonstrate robust target engagement and corresponding increases in HbF levels up to approximately 40% of total hemoglobin, demonstrating the potential to have a significant impact in people living with SCD. FTX-6058 is an investigational, potent, and selective oral small-molecule inhibitor of Embryonic Ectoderm Development (EED) that has been demonstrated to induce robust fetal hemoglobin (HbF) protein expression in cell and murine models of SCD. Here, we report the in vivo effects of EED modulation, and subsequent polycomb repressive complex 2 (PRC2) inhibition in the Townes mouse model of Sickle Cell Disease. Compared with untreated and hydroxyurea treated animals, FTX-6058 (QD, 5mg/kg) exhibits potent target engagement as evidenced by ~70% reduction in H3K27me3 levels, the key epigenetic mark catalyzed by PRC2. Consistent with the robust target engagement observed with FTX-6058, a 2 - 3 fold increase in F cells and HbF protein were observed after 13 and 21 days of FTX-6058 treatment, which was pharmacologically superior to the fetal hemoglobin induction observed with 100 mg/kg hydroxyurea (~25% relative increase in F cells and HbF protein). A linear correlation was also observed between F cells and HbF protein production with FTX-6058 treatment, further supporting the robust HbF induction observed. Consistent with SCD disease presentation, Townes model mice have high reticulocyte counts as a result of premature RBC destruction and hemolysis. Townes model mice treated for 21 days with FTX-6058 ameliorated hemolysis as evidenced by decreases in reticulocytes and increases in red blood cells and total hemoglobin levels. Furthermore, FTX-6058 demonstrated the ability to impact inflammatory drivers of disease as evidenced by decreases in neutrophils and white blood cells. FTX-6058 did not have effects on other hematopoietic lineages. FTX-6058 also impacted pathophysiologic symptoms (e.g., splenomegaly) associated with SCD, as evidenced by ~25% reduction in spleen weight. While some trends were detected, no statistically significant changes were observed in hematological parameters or pathophysiologic symptoms with hydroxyurea, the current standard of care in SCD. These results observed with hydroxyurea underscore the need for new, novel therapies in SCD and other hemoglobinopathies. Taken together, these studies further support the therapeutic rationale of PRC2 modulation in SCD. The fetal hemoglobin induction and effects on hematological parameters and pathophysiologic symptoms observed with FTX-6058 have the potential to translate to meaningful clinical benefits in SCD and other hemoglobinopathies. Disclosures Matson: Fulcrum Therapeutics, Inc.: Current Employment. Xie: Fulcrum Therapeutics, Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Roth: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Stuart: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Bruno: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Efremov: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Thompson: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Silver: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Moxham: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company.

FTX-6058, a selective and potent binder of embryonic ectoderm development protein (EED), is being investigated in Sickle Cell Disease (SCD). In-vitro and pre-clinical Townes mouse studies show FTX-6058 upregulates expression of the gamma globulin gene leading to increased levels of fetal hemoglobin (HbF). In human clinical trials, as an early indicator of FTX-6058 induced gamma globulin expression, a reverse transcriptase droplet digital PCR (RT-ddPCR) assay was developed and validated by Precision for Medicine. Versus RT-qPCR, RT-ddPCR gives absolute copy number, does not require a standard curve, and is more precise and reproducible for low expressed targets 1,2. Precision for Medicine developed and validated RT-ddPCR assays for the target globin genes α, β, and γ and for the housekeeping genes TFRC and OAZ1. RNA isolated from 3 healthy and 3 SCD affected individuals was used for development and validation of the assay. The upper and lower limits of quantification were 120,000 and 10.5 copies/20μL reaction, respectively. For samples with >50 copies/20μL reaction, the CV for technical replicates was 1 Zhao Y, Xia Q, Yin Y, Wang Z (2016), Comparison of Droplet Digital PCR and Quantitative PCR Assays for Quantitative Detection of Xanthomonas citri Subsp. citri. PLoS ONE 11(7): e0159004. doi:10.1371/journal.pone.0159004 2 Taylor SC, Laperriere G, Germain H (2017), Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data. Scientific Reports 7(2409): DOI:10.1038/s41598-017-02217-x Disclosures Roth: Fulcrum Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Fulcrum Therapeutics, Inc.: Consultancy. Tsavachidou: Fulcrum Therapeutics, Inc.: Consultancy. Davis: Fulcrum Therapeutics, Inc.: Consultancy.

At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.

// Avadhut D. Joshi 1,* , Rachel C. Botham 2,* , Lisa J. Schlein 3 , Howard S. Roth 2 , Antonella Mangraviti 1 , Alexandra Borodovsky 1 , Betty Tyler 1 , Steve Joslyn 4 , Jayme S. Looper 5 , Michael Podell 6 , Timothy M. Fan 7 , Paul J. Hergenrother 2 and Gregory J. Riggins 1 1 Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA 2 Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL, USA 3 Department of Pathobiology, University of Illinois Urbana-Champaign, Urbana, IL, USA 4 VetCT Australia, Fremantle WA, Australia 5 Department of Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, LA, USA 6 Department of Neurology, MedVet Chicago, Chicago, IL, USA 7 Department of Veterinary Clinical Medicine, University of Illinois Urbana-Champaign, Urbana, IL, USA * These authors have contributed equally to this work Correspondence to: Gregory J. Riggins, email: // Paul J. Hergenrother, email: // Timothy M. Fan, email: // Keywords : PAC-1, procaspase-3 activator, glioblastoma, small molecule therapy Received : March 29, 2017 Accepted : June 09, 2017 Published : July 07, 2017 Abstract Purpose: Glioblastoma is a deadly brain cancer with a median survival time of ~15 months. Ionizing radiation plus the DNA alkylator temozolomide (TMZ) is the current standard therapy. PAC-1, a procaspase-3 activating small molecule, is blood-brain barrier penetrant and has previously demonstrated ability to synergize with diverse pro-apoptotic chemotherapeutics. We studied if PAC-1 could enhance the activity of TMZ, and whether addition of PAC-1 to standard treatment would be feasible in spontaneous canine malignant gliomas. Experimental Design: Using cell lines and online gene expression data, we identified procaspase-3 as a potential molecular target for most glioblastomas. We investigated PAC-1 as a single agent and in combination with TMZ against glioma cells in culture and in orthotopic rodent models of glioma. Three dogs with spontaneous gliomas were treated with an analogous human glioblastoma treatment protocol, with concurrent PAC-1. Results: Procaspase-3 is expressed in gliomas, with higher gene expression correlating with increased tumor grade and decreased prognosis. PAC-1 is cytotoxic to glioma cells in culture and active in orthotopic rodent glioma models. PAC-1 added to TMZ treatments in cell culture increases apoptotic death, and the combination significantly increases survival in orthotopic glioma models. Addition of PAC-1 to TMZ and radiation was well-tolerated in 3 out of 3 pet dogs with spontaneous glioma, and partial to complete tumor reductions were observed. Conclusions: Procaspase-3 is a clinically relevant target for treatment of glioblastoma. Synergistic activity of PAC-1/TMZ in rodent models and the demonstration of feasibility of the combined regime in canine patients suggest potential for PAC-1 in the treatment of glioblastoma.

Background Fecal incontinence frequently occurs after total mesorectal excision for rectal cancer. This prospective study analyzed predictive factors and the impact of pelvic intraoperative neuromonitoring at different follow-up intervals. Methods Fifty-two patients were included undergoing total mesorectal excision for rectal cancer, and 29 under control of pelvic intraoperative neuromonitoring. Fecal incontinence was assessed using the Wexner Score at 3 and 6 months after stoma closure (follow-ups 1 and 2) as well as 1 and 2 years after surgery (follow-ups 3 and 4). Risk factors were identified by means of logistic regression. Results New onset of fecal incontinence was significantly lower in the neuromonitoring group at each follow-up (follow-up 1: 2 of 29 patients (7%) vs. 8 of 23 (35%), (p = 0.014); follow-up 2: 3 of 29 (10%) vs. 9 of 23 (39%), (p = 0.017); follow-up 3: 5 of 29 (17%) vs. 11 of 23 (48%), p = 0.019; follow-up 4: 6 of 28 (21%) vs. 11 of 22 (50%), p = 0.035). Non-performance of neuromonitoring was found to be an independent predictor for fecal incontinence throughout the survey. Neoadjuvant chemoradiotherapy was an independent predictor in the further course 1 and 2 years after surgery. Conclusions Performance of pelvic intraoperative neuromonitoring is associated with significantly lower rates of fecal incontinence. Neoadjuvant chemoradiotherapy was found to have negative late effects. This became evident 1 year after surgery.

Background Observational studies have demonstrated that african american patients with Systemic Sclerosis (SSc) have a more unfavorable prognosis compared with non-African americans. However, no studies have evaluated racial disparities using data from a randomized controlled trial (RCT) where all patients have equal access to care and standard treatment and follow-up during the trial. Objectives To compare morbidity and mortality in african american and non-African american patients who participated in the Scleroderma Lung Study (SLS) I and II.1,2 Methods SLS I randomized 158 SSc patients with interstitial lung disease (ILD) from 13 US SSc centers to 1 year of oral CYC (cyclophosphamide) versus placebo. SLS II randomized 142 SSc-ILD participants from 14 US SSc centers to 1 year of oral CYC, followed by 1 year of placebo, versus 2 years of mycophenolate (MMF). Up to 12 (SLS I) and 5 (SLS II) years after randomization, we contacted enrolled patients or designated surrogates to assess the following: mortality, cause of mortality, and development of organ failure. We used cox proportional hazard modeling to determine the variables associated with survival. Results Baseline characteristics of the SLS I and II cohorts were similar. In SLS I, african american participants (N=26) were younger than non-African american participants (N=132) (43.1 vs. 49.5 years, P=0.015). In SLS II, african american participants (N=33) had slightly increased baseline forced vital capacity (FVC) (69.2 vs 65.6, P=0.038), compared with non-American american participants (N=109). There were no significant baseline differences in the extent of cutaneous sclerosis (Modified Rodnan Skin Score [MRSS]), presence of diffuse cutaneous disease or serological profiles between racial groups. After adjusting for age, MRSS, FVC, there was no difference in long-term mortality outcomes (due to all causes or due to respiratory failure) in african american versus Non-African american SSc-ILD participants in SLS I or II (Figure 1). There was also no difference in time to the development of respiratory failure in african american versus Non-African american SSc-ILD participants in SLS I or II. Conclusion Data from two of the largest RCTs in SSc-ILD demonstrated that african american patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-African american SSc-ILD patients, even after adjusting for age and baseline disease severity. These findings contrast with the racial disparities described in previous observational studies and warrant further investigation. References [1] Tashkin, et al. NEJM2006;354:2655. [2] Tashkin, et al. Lancet Resp Med2016;4:708. Figure 1a. Time to death in african american participants of SLS I (red line) and non-African american participants of SLS I (blue line). Figure 1b. Time to death in african american participants of SLS II (red line) and non-African american participants of SLS II (blue line). Disclosure of interests Elizabeth Volkmann Shareholder of: Pfizer, inc., Consultant for: Boehringer ingelheim, Speakers bureau: Boehringer ingelheim, Ning Li: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: actelion acceleron, arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, inc, Philip Clements: None declared, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech, Shervin assassi: None declared, Michael Roth Grant/research support from: Genentech/Roche, Robert Elashoff: None declared, Donald Tashkin Consultant for: EMD Serono

Introduction Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. A pooled analysis showed a global prevalence of 11.2%. Few studies looked at the prevalence of IBS in health care providers. The aim of this study was to determine the prevalence of IBS among board-certified physicians and surgeons. Methods Board-certified physicians and surgeons in Saudi Arabia were invited to complete a web-based survey. It included questions regarding participant demographics, specialty, practice type and hours worked per week. The Rome IV-validated questionnaire was used to identify subjects with IBS. The primary outcome of the study was the prevalence of IBS among physicians. Secondary outcomes included exploring the effect on IBS prevalence of age, gender, marital status, work hours, specialty, gastroenterology subspecialty and working in a public versus private hospital. Results The final analysis included 594 subjects, with 419 males and a median age of 41. The vast majority (86%) were married. Nearly 90% worked in a public hospital exclusively, and the median number of hours worked per week was 48. The overall prevalence of IBS was 16.3%. In a binary logistic regression model, age (odds ratio [OR] = 0.931, P < 0.0001), gender (OR = 0.504, P = 0.003) and work hours (OR = 2.397, P < 0.0001) significantly predicted the presence of IBS. Marital status and specialty did not predict IBS prevalence. Discussion This cross-sectional study shows that the prevalence of IBS among physicians in Saudi Arabia to be 16.3%. IBS was more common in females, those who worked longer hours and younger physicians. There was no association between practicing certain specialties and IBS. However, the lack of difference in our cohort may be attributed to the relatively small sample size from each specialty.

e16175 Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.

Background:The forced vital capacity (FVC) is often used as the primary endpoint in treatment trials for systemic sclerosis-interstitial lung disease (SSc-ILD), and while trends in FVC have been found to predict mortality in SSc-ILD,1,2 FVC measurements are also influenced by extra-pulmonary factors, such as cutaneous sclerosis, myopathy, and patient/technician effort. Change in the quantitative extent of ILD (QILD) on HRCT is an emerging endpoint in clinical trials; however, no studies have evaluated whether changes in radiographic extent ILD predict mortality in SSc-ILD.Objectives:To evaluate the relationship between changes QILD in the whole lung (WL) and long-term survival in patients who participated in the Scleroderma Lung Study (SLS) I3 and II.4Methods:SLS I randomized 158 SSc-ILD patients to 12 months of cyclophosphamide (CYC) vs. placebo. SLS II randomized 142 SSc-ILD patients to 12 months of CYC, followed by 12 months of placebo vs. 24 months of mycophenolate (MMF). QILD-WL scores were calculated at baseline and 12 months (SLS I) and 24 months (SLS II). Participants were followed for up to 12 (SLS I) and 8 years (SLS II). Using landmark survival analysis, Kaplan Meier curves were generated to compare survival between participants who had worse QILD-WL scores (≥2% increase) and those who had stable/improved QILD-WL scores (Results:Among all the SLS I and II participants, 82 and 90 had follow up HRCT scans, respectively, and were included in these analyses. SLS I participants with an increase in QILD-WL scores of ≥2% at 12 months had significantly worse long-term survival (P= 0.01; Figure). Similarly, SLS II participants with an increase in QILD-WL scores of ≥2% at 24 months had significantly worse long-term survival (P= 0.019; Figure). After adjusting for baseline FVC, age, and modified Rodnan skin score (mRSS), an increase in QILD-WL scores of ≥2% remained associated with worse long-term survival in SLS I (trend: P=0.089) and SLS II (P=0.014).Conclusion:Progression of the radiographic extent of ILD of ≥2% was associated with worse long-term survival in two independent SSc cohorts with extensive long-term follow up. The findings provide compelling evidence that short-term changes in the radiographic extent of ILD may serve as a surrogate endpoint for mortality in patients with SSc.References:[1]Goh NS, et al. Arthritis Rheum 2017.[2]Volkmann ER, et al. Ann Rheum Dis 2019.[3]Tashkin DP, et al. NEJM 2006.[4]Tashkin DP, et al. Lancet Resp Med 2016.Disclosure of Interests:Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Forbius, Corbus, Donald Tashkin: None declared, Michael Roth Grant/research support from: Genentech/Roche, Jonathan Goldin: None declared, Grace Kim: None declared

Introduction This document is a summary of the French Intergroup guidelines regarding the management of hepatocellular carcinoma (HCC) published in March 2019. Method It is a collaborative work under the auspices of most of the French medical societies involved in the management of HCC. It is based on the previous guidelines published in 2017. Recommendations are graded in 3 categories according to the level of evidence of data found in the literature. Results The diagnosis and staging of HCC is essentially based on clinical, biological and imaging features. A pathological analysis obtained by a biopsy of tumoral and non-tumoral liver is recommended. HCCs can be divided into 2 groups, taking into account not only the tumor stage, but also liver function. HCCs accessible to curative treatments are tumors that are in Milan criteria or with an AFP score ≤ 2, mainly treated by surgical resection, local ablation or liver transplantation. Intermediate and advanced HCCs with no liver insufficiency, accessible only to palliative treatments, benefit from TACE, SIRT or systemic therapy according to the presence or absence of macrovascular invasion or extrahepatic spread. Conclusion Such recommendations are in permanent optimization and each individual case must be discussed in a multidisciplinary expert board.

Simple Summary In this study, efficacy and safety of embolization alone and trans-arterial chemoembolization were compared in 265 patients with intermediate stage hepatocellular carcinoma. Trans-arterial chemoembolization was associated with a significant increase of complete radiological response, but without significant impact on overall response, and survival outcomes after propensity score matching. Both techniques showed similar safety profiles. To this day, embolization alone and trans-arterial chemoembolization are two available options in the treatment of intermediate stage hepatocellular carcinoma. Abstract No definitive conclusion could be reached about the role of chemotherapy in adjunction of embolization in the treatment of hepatocellular carcinoma (HCC). We aim to compare radiological response, toxicity and long-term outcomes of patients with hepatocellular carcinoma (HCC) treated by trans-arterial bland embolization (TAE) versus trans-arterial chemoembolization (TACE). We retrospectively included 265 patients with HCC treated by a first session of TACE or TAE in two centers. Clinical and biological features were recorded before the treatment and radiological response was assessed after the first treatment using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Correlation between the treatment and overall, progression-free and transplantation-free survival was performed after adjustment using a propensity score matching: 86 patients were treated by bland embolization and 179 patients by TACE, including 44 patients with drug-eluting beads and 135 with lipiodol TACE, 89.8% of patients were male with a median age of 65 years old. Cirrhosis was present in 90.9% of patients with a Child Pugh score A in 84% of cases. After adjustment, no difference in the rate of AE, including liver failure, was observed between the two treatments. TACE was associated with a significant increase in complete radiological response (odds ratio (OR) = 8.5 (95% confidence interval (CI): 2.8–25.4)) but not in the overall response rate (OR = 2.2 (95% CI = 0.8–5.8)). No difference in terms of overall survival (p = 0.3905), progression-free survival (p = 0.4478) and transplantation-free survival (p = 0.9020) was observed between TACE and TAE. TACE was associated with a higher rate of complete radiological response but without any impact on overall radiological response, progression-free survival and overall survival compared to TAE.

Purpose: Studies have shown the prevalence of iron deficiency anemia (IDA) increasing worldwide, and currently the literature is limited on the impact of IDA on outcomes following revision total hip arthroplasty (RTHA). Therefore, the purpose of this study was to determine whether IDA patients undergoing RTHA have longer: 1) in-hospital lengths of stay (LOS); 2) medical complications; and 3) costs of care. Materials and Methods: A retrospective query of a nationwide administrative claims database was performed. Using Boolean command operations, the study group consisted of all patients in the database undergoing RTHA with IDA; whereas, patients without IDA served as controls. To reduce the effects of confounding, study group patients were matched to controls in a 1:5 ratio by age, sex, and medical comorbidities yielding 92,948 patients with (n=15,508) and without (n=77,440) IDA undergoing revision THA. A P-value less than 0.001 was considered statistically significant. Results: IDA patients were found to have significantly longer in-hospital LOS (5 days vs. 4 days, P

Background: The purpose of this study was to assess the effect of insurance type (Medicaid, Medicare, and private insurance) on access to foot and ankle surgeons for total ankle arthroplasty. Methods: We called 240 foot and ankle surgeons who performed total ankle arthroplasty in 8 representative states (California, Massachusetts, Ohio, New York, Florida, Georgia, Texas, and North Carolina). The caller requested an appointment for a fictitious patient to be evaluated for a total ankle arthroplasty. Each office was called 3 times to assess the responses for Medicaid, Medicare, and BlueCross. From each call, we recorded appointment success or failure and any barriers to an appointment, such as need for a referral. Results: Patients with Medicaid were less likely to receive an appointment compared to patients with Medicare (19.8% vs 92.0%, P < .0001) or BlueCross (19.8% vs 90.4%, P < .0001) and experienced more requests for referrals compared to patients with Medicare (41.9% vs 1.6%, P < .0001) or BlueCross (41.9% vs 4%, P < .0001). Waiting periods were longer for patients with Medicaid compared to those with Medicare (22.6 days vs 11.7 days, P = .004) or BlueCross (22.6 days vs 10.7 days, P = .001). Reimbursement rates did not correlate with appointment success rate or waiting period. Conclusion: Despite the passage of the PPACA, patients with Medicaid continue to have difficulty finding a surgeon who will provide care, increased need for a primary care referral, and longer waiting periods for appointments. Level of Evidence: Level II, prognostic study.

After spending eight years as a full-time academic administrator at Lafayette College in Easton, PA – one of only a handful of institutions where discipline-specific engineering programs are embedded in an undergraduate-only, liberal arts environment – I returned to full-time teaching in fall 2015. I began teaching civil engineering at Lafayette in 1991 and became department head in 2003, the start of an administrative journey that eventually reduced my teaching load to zero. From 2006 until 2014, I served as an American Council on Education fellow, the interim director of engineering, and then associate provost for academic operations.

Purpose We describe a case of bilateral anterior lenticonus in a patient with Alport syndrome treated with femtosecond laser-assisted cataract surgery (FLACS). Observations FLACS was performed without complication, and a desirable postoperative visual acuity was achieved. Conclusions and importance Femtosecond laser-assisted cataract surgery is an effective approach for managing patients with anterior lenticonus secondary to Alport syndrome.

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.