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Background:Both the superficial medial collateral ligament (sMCL) and the deep MCL (dMCL) contribute to the restraint of anteromedial (AM) rotatory instability (AMRI). Previous studies have not investigated how MCL reconstructions control AMRI.Purpose/Hypothesis:The purpose was to establish the optimal medial reconstruction for restoring normal knee kinematics in an sMCL- and dMCL-deficient knee. It was hypothesized that AMRI would be better controlled with the addition of an anatomically shaped (flat) sMCL reconstruction and with the addition of an AM reconstruction replicating the function of the dMCL.Study Design:Controlled laboratory study.Methods:A 6 degrees of freedom robotic system equipped with a force-torque sensor was used to test 8 unpaired knees in the intact, sMCL/dMCL sectioned, and reconstructed states. Four different reconstructions were assessed. The sMCL was reconstructed with either a single-bundle (SB) or a flattened hamstring graft aimed at better replicating the appearance of the native ligament. These reconstructions were tested with and without an additional AM reconstruction. Simulated laxity tests were performed at 0°, 30°, 60°, and 90° of flexion: 10 N·m valgus rotation, 5 N·m internal and external rotation (ER), and an AM drawer test (combined 134-N anterior tibial drawer in 5 N·m ER). The primary outcome measures of this force-controlled setup were anterior tibial translation (ATT; in mm) and axial tibial rotation (in degrees).Results:Sectioning the sMCL/dMCL increased valgus rotation, ER, and ATT with the simulated AM draw test at all flexion angles. SB sMCL reconstruction was unable to restore ATT, valgus rotation, and ER at 30°, 60°, and 90° of flexion to the intact state ( P < .05). Flat MCL reconstruction restored valgus rotation at all flexion angles to the intact state ( P > .05). ER was restored at all angles except at 90°, but ATT laxity in response to the AM drawer persisted. Addition of an AM reconstruction improved control of ATT relative to the intact state at all flexion angles ( P > .05). Combined flat MCL and AM reconstruction restored knee kinematics closest to the intact state.Conclusion:In a cadaveric model, AMRI resulting from an injured sMCL and dMCL complex could not be restored by an isolated SB sMCL reconstruction. A flat MCL reconstruction or an additional AM procedure, however, better restored medial knee stability.Clinical Relevance:In patients evaluated with a combined valgus and AM rotatory instability, a flat sMCL and an additional AM reconstruction may be superior to an isolated SB sMCL reconstruction.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0–163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (

Purpose Ultrasound (US) examination of the medial joint space of the knee has played a subordinate diagnostic role up till now. The purpose of the present study was to describe mean values of medial joint width and to investigate the impact of gender, age, and body mass index (BMI) on medial joint laxity in healthy knees using modern, dynamic US in a standardized fashion in unloaded and standardized loaded conditions. Methods A total of 65 subjects with 79 healthy knees were enrolled in this study. All volunteers underwent clinical examination of the knee. The medial knee joint width was determined using US in a supine position at 0° and 30° of knee flexion in unloaded and standardized loaded (= 15 Dekanewton, daN) conditions using a specific device. Mean values were described and correlations between medial knee joint width and gender, age, and BMI were assessed. Results Thirty-two females and 33 males were enrolled in this study. The mean medial joint width in 0° unloaded was 5.7 ± 1.2 mm and 7.4 ± 1.4 mm loaded. In 30° of knee flexion, the mean medial joint width was 6.1 ± 1.1 mm unloaded and 7.8 ± 1.2 mm loaded. The average change between unloaded and loaded conditions in 0° was 1.7 ± 1.0 mm and in 30° 1.7 ± 0.9 mm. A significant difference between genders was evident for medial joint width in 0° and 30° of flexion in unloaded and loaded conditions (p p = 0.032). No significant correlation between BMI and medial joint width in US could be found. Conclusion Mean values of medial joint width in unloaded and standardized loaded conditions using a fixation device could be demonstrated. Based on the results of this study, medial knee joint width in US is gender- and age-related in healthy knees. These present data may be useful for evaluating patients with acute or chronic pathologies to the medial side of the knee. Level of evidence III.

An expert panel convened by the European Alliance for Personalized Medicine (EAPM) reflected on achievements and outstanding challenges in Europe in mantle cell lymphoma (MCL). Through the prism of member state experience, the panel noted advances in outcomes over the last decade, but highlighted issues constituting barriers to better care. The list notably included availability of newer treatments, infrastructure and funding for related testing, and shortages of relevant skills and of research support. The prospect of improvements was held to reside in closer coordination and cooperation within and between individual countries, and in changes in policy and scale of investment at both national and EU levels.

Introduction: Regimens involving intensive immuno-chemotherapy, followed by high-dose therapy and autologous stem cell transplant represent the standard treatment for younger fit patients with mantle cell lymphoma (MCL). Targeted approaches (i.e. ibrutinib, bortezomib, and lenalidomide) represent the backbone of therapy for relapsed cases. Areas covered: Acalabrutinib is a novel small molecule with a butynamide moiety specifically designed to irreversibly inhibit Bruton tyrosine kinase (BTK), which is more potent and selective than ibrutinib. Relevant publications have been identified through literature searches using the terms 'mantle cell lymphoma' and 'acalabrutinib'. Expert opinion: Acalabrutinib has been approved for the treatment of relapsed/refractory (RR) MCL patients. To date, clinical trials have reported some adverse effects such as cardiac toxicity or atrial fibrillation. Acalabrutinib in combination with other drugs, either in chemo-containing or chemo-free schedules, represent a valid option for MCL. However, none of the treatment schedules containing BTK inhibitors have been shown to be curative in MCL. Acalabrutinib may ultimately represent an option for patients who are 'fit' and exhibit well-controlled disease, which often characterizes only a limited 'niche' among MCL patients.

Purpose: The aim of this study was to compare outcome data after isolated and combined (MCL) plus anterior cruciate ligament (ACL) reconstruction based on objective and subjective measures using data from the (DKRR). There are only a few small-sized case studies on outcomes after MCL reconstruction. MCL reconstruction was hypothesised to improve both objective and subjective outcomes. Methods: All patients who were registered in the DKRR between 2005 and 2016 (N = 25,281) and who underwent isolated ACL (n = 24,683), isolated MCL (n = 103) or combined MCL plus ACL (n = 495) reconstructions were retrospectively identified. Objective (valgus knee stability and sagittal knee laxity) and subjective (Knee Injury and Osteoarthritis Outcome Score (KOOS) and Tegner activity scale score) outcomes in these three cohorts were evaluated at the 1-year follow-up by comparing pre- and post-operative values. Results: Medial stability improved significantly pre- to post-operatively after both isolated MCL and combined MCL plus ACL reconstruction, with 26 (53%) and 195 (69%) of the patients, respectively, having normal valgus stability (0–2 mm laxity). Sagittal stability was similar after MCL plus ACL reconstruction and isolated ACL reconstruction (1.7 and 1.5 mm, respectively). At the 1-year follow-up, although the KOOS of the patients in the isolated MCL and combined MCL plus ACL reconstruction cohorts improved significantly, they were lower than those of the patients in the isolated ACL reconstruction cohort. Conclusion: Both isolated MCL reconstruction and combined MCL plus ACL reconstruction resulted in significant and clinically relevant improvements in the subjective outcomes from pre-operative conditions to the 1-year follow-up. Valgus stability also improved significantly, with two-thirds of patients obtaining normal valgus stability after MCL reconstruction. Subjective outcomes were similar between isolated MCL reconstruction and combined MCL plus ACL reconstructions, but were poorer than isolated ACL reconstructions. Level of evidence: Level III.

BACKGROUND: Multi-ligament knee injury is the state of having two or more of the major knee ligaments, namely: the anterior cruciate ligament (ACL), the posterior cruciate ligament (PCL), the medial collateral ligament (MCL), the lateral collateral ligament (LCL), the posteromedial corner (PMC), and the posterolateral corner (PLC). The knee is a hinge joint; this dictates two direction movements on the y-axis plane. The knee joints carry the weight load of the body uniquely. The role of the knee ligaments is not conserved only to maintain knee in a rigid position while standing, but also orchestrates the biomechanics of knee motion in harmony. Multi-ligament knee injury is very rare (incidence < 10:10,000 of trauma cases). Patients with multiple ligaments injuries of the knee become disabled for a long period. This disability rises from the pain and stiffness of the knee joint. A disability that might be associated with increased frequencies of sick leave from work, or much more dire consequences, such as quitting a job or being relieved of duty. AIM: To assess the functional outcome of the knee of patients with a multi-ligament knee injury after treatment using a standard scoring system and to determine the recovery rates of each treatment option to a multi-ligament knee injury. METHODS: it is a cross-sectional study conducted from January 2018 to January 2019. All patients with multi-ligament knee injuries that were diagnosed by MRI, and underwent reconstruction surgeries or on the waiting list, at Ribat University Hospital and Alyaa Specialized Hospital, Alkuwiti specialised hospital, and Haj Alsafi Hospital for the past 2 years were included. Lyshlome knee scoring scale was used to assess the functional outcome of each patient. RESULTS: 24 patients were enrolled in this study (16 had reconstruction surgery, 8 did not). 3 had excellent outcome (LKSS = 95 – 100), 8 of them had good score (LKSS = 84-94), 5 had fair outcome (LKSS = 65-83). All those who did not have reconstruction had a poor score (LKSS < 64). CONCLUSION: Reconstruction of multi-ligament knee injury shows a good outcome than it was left alone. Post-operative physiotherapy increases the potential of reconstruction. While our data is limited because of the rare condition, we plan to expand our study area to include a larger sample size. We also recommend extending the post-operative physiotherapy to improve the outcome of a multi-ligament knee injury.

Background Daratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL). Patients and Methods This was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489). Results The trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4). Conclusion In NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.

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Simple Summary High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (Auto-HSCT) is a standard frontline treatment for fit mantle cell lymphoma (MCL) patients. As there is a need for predictive factors to identify patients unlikely to benefit from this therapy, we investigated the prognostic impact of lymphoma cell contamination of autologous stem cell grafts. Analyzing a cohort of 36 MCL patients, we show that lymphoma cell contamination of stem cell grafts is associated with poor outcomes after Auto-HSCT. Its analysis might thus improve risk assessment and enable risk-stratified treatment strategies for MCL patients. Abstract Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL.

Background To investigate the effect of complete rupture of the posterior cruciate ligament (PCL) on the biomechanics and histology of the medial collateral ligament (MCL). Materials and methods Seventy-two male rabbits were randomly divided into two groups: the ruptured group was treated with complete PCL amputation, while the intact group was only subjected to PCL exposure without amputation. Eighteen rabbits were randomly sacrificed at 8, 16, 24, and 40 weeks after the operation, and their specimens were processed for mechanical tensile testing, nano-indentation experiments, hematoxylin-eosin (HE) staining, and picrosirius-polarization staining. Results There was no significant difference in the length and maximum displacement of the MCL between the ruptured group and the intact group at each time point. The maximum load of the ruptured group was significantly smaller than that of the intact group at 40 W. The elastic modulus and micro-hardness of the ruptured group increased significantly at 24 W and decreased significantly at 40 W. At 16 W and 24 W after PCL rupture, the number of type I collagen fibers and type III collagen fibers in the MCL of the ruptured group was significantly increased compared with that of the intact group. While the type I collagen fibers of the ruptured group were significantly decreased compared with the intact group at 40 W, there was no significant difference in type III collagen fibers between the ruptured group and the intact group. Conclusion PCL rupture has no significant effect on the mechanical and histological properties of MCL in a short period of time under physiological loading, but the histological and mechanical properties of MCL decrease with time.

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin’s lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1–4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma.

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia.

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2Δ550−738 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity (p < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of cdkn2b gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the cdkn2b promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of cdkn2b in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.

Tears of the medial collateral ligament (MCL) are the most common knee ligament injury. Incomplete tears (grade I, II) and isolated tears (grade III) of the MCL without valgus instability can be treated without surgery, with early functional rehabilitation. Failure of non-surgical treatment can result in debilitating, persistent medial instability, secondary dysfunction of the anterior cruciate ligament, weakness, and osteoarthritis. Reconstruction or repair of the MCL is a relatively uncommon procedure, as non-surgical treatment is often successful at returning patients to their prior level of function. Acute repair is indicated in isolated grade III tears with severe valgus alignment, MCL entrapment over pes anserinus, or intra-articular or bony avulsion. The indication for primary repair is based on the resulting quality of the native ligament and the time since the injury. Primary repair of the MCL is usually performed within 7 to 10 days after the injury. Augmentation repair for the superficial MCL (sMCL) is a surgical technique that can be used when the resulting quality of the native ligament makes primary repair impossible. Reconstruction is indicated when MCL injuries fail to heal in neutral or varus alignment. Reconstruction might be advisable to correct chronic instability. Chronic, medial-sided knee injuries with valgus misalignment should be treated with a two-stage approach. A distal femoral osteotomy should be performed first, followed by reconstruction of the medial knee structures.Cite this article: EFORT Open Rev 2018;3:398-407. DOI: 10.1302/2058-5241.3.170035

// Guangzhen Hu 1 , Shiv K. Gupta 2 , Tammy P. Troska 1 , Asha Nair 3 and Mamta Gupta 4 1 Division of Hematology, Mayo Clinic Rochester, Rochester, MN, USA 2 Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, MN, USA 3 Division of Biomedical Statistics and Informatics, Mayo Clinic Rochester, Rochester, MN, USA 4 Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, GW Cancer Center, Washington, DC, USA Correspondence to: Mamta Gupta, email: // Keywords : lncRNA ROR1-AS1, MCL, PRC2, EZH2 Received : May 05, 2017 Accepted : May 07, 2017 Published : May 17, 2017 Abstract Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. The needs for new therapeutic strategies for MCL patients call for further understanding on the molecular mechanisms of pathogenesis of MCL. Recently, long noncoding RNAs (lncRNAs) have been recognized as key regulators of gene expression and disease development, however, the role of lncRNAs in non-Hodgkin lymphoma and specifically in MCL is still unknown. Next generation RNA-sequencing was carried out on MCL patient samples along with normal controls and data was analyzed. As a result, several novel lncRNAs were found significantly overexpressed in the MCL samples with lncRNA ROR1-AS1 the most significant one. We cloned the ROR1-AS1 lncRNA in expression vector and ectopically transfected in MCL cell lines. Results showed that overexpression of ROR1-AS1 lncRNA promoted growth of MCL cells while decreased sensitivity to the treatment with drugs ibrutinib and dexamethasone. ROR-AS1 overexpression also decreased the mRNA expression of P16 ( P = 0.21), and SOX11 ( p = 0.017), without much effect on P53, ATM and P14 mRNA. RNA-immunoprecipitation assays demonstrated high affinity binding of lncRNA ROR1-AS1 with EZH2 and SUZ12 proteins of the polycomb repressive complex-2 (PRC2). Suppressing EZH2 activity with pharmacological inhibitor GSK343 abolished binding of ROR1-AS1 with EZH2. Taken together, this study identified a functional lncRNA ROR-AS1 involved with regulation of gene transcription via associating with PRC2 complex, and may serve as a novel biomarker in MCL patients.

On 18 September 2017, a marketing authorisation valid through the European Union (EU) was issued for midostaurin in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are Fms-like tyrosine kinase 3 mutation positive and as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL). The recommended dose of midostaurin is 50 mg orally twice daily for AML and 100 mg orally twice daily for ASM, SM-AHN and MCL. Midostaurin was evaluated in two pivotal studies. Study A2301 (RATIFY) included 717 patients with AML. Overall survival (OS) was statistically significantly different between the two groups, and the median OS was 74.7 months in the midostaurin+daunorubicin+cytarabine group and 25.6 months in the placebo+daunorubicin+cytarabine group (HR 0.774; 95% CI 0.629 to 0.953; p=0.0078). Study D2201 included 116 patients with ASM, SM-AHN or MCL. An overall response rate, by IWG-MRT/ECNM (international working group – myelofibrosis research and treatment/European competence network on mastocytosis) criteria of 28.3% was observed in all patients and 60.0%, 20.8% and 33.3% in patients with ASM, SM-AHN and MCL respectively. The most common adverse drug reactions (ADRs) with midostaurin treatment in AML were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and fever. In ASM, SM-AHN, MCL the most common ADRs were nausea, vomiting, diarrhoea, peripheral oedema and fatigue. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU.

This study aimed to quantify the elongation patterns of the collateral ligaments following TKA during functional activities of daily living. Using mobile video-fluoroscopy to capture radiographic images of the knee in a group of six patients, each with an ultra-congruent knee implant, tibiofemoral kinematics were reconstructed throughout complete cycles of level gait, downhill walking, stair descent, and squat activities. Kinematic data were then used to drive subject-specific multibody knee models to estimate length-change patterns of the LCL as well as three bundles of the MCL. In addition, a sensitivity analysis examined the role of the attachment site in the elongation patterns. Our data indicate a slackening of the LCL but non-uniform length-change patterns across the MCL bundles (ranging from lengthening of the anterior fibers to shortening of the posterior fibers) with increasing knee flexion angle. Near-isometric behavior of the intermediate fibers was observed throughout the entire cycle of the studied activities. These length-change patterns were found to be largely consistent across different activities. Importantly, length-change patterns were critically sensitive to the location of the femoral attachment points relative to the femoral component. Thus, in TKA with ultra-congruent implants, implantation of the femoral component may critically govern post-operative ligament function., Annals of Biomedical Engineering, 48 (4), ISSN:1573-9686, ISSN:0191-5649, ISSN:0090-6964

OBJECTIVES: Programming the cochlear implant’s speech processor with subjective methods in young, uncooperative children is difficult. Since young children cannot provide adequate feedback to the clinician, objective methods which do not require patient’s response were often used. Electrical Stapedius Reflex Test is one of the most common procedures used. The goal of this study was to investigate the relationship between electricalstapedius reflex thresholds and behaviorally most comfortable levels in experienced cochlear implant users. MATERIALS AND METHODS: The patients implanted with two brands of cochlear implants were compared in terms of electrical stapedius reflex thresholds versus most comfortable levels. Speech tests results were also compared between the two groups. 46 cochlear implanted patients who had at least 1 year of cochlear implant experience were included in the study. 28 patients were implanted with Nucleus, 18 patients with Med-El devices. RESULTS: Moderate correlations were obtained between Electrical Stapedius Reflex (ESR) thresholds and the comfort (C) levels in Nucleus users; higher correlations were obtained for Med-El patients. ESR thresholds were present at higher levels than the most comfortable and the comfort (MCL/C) levels in both Nucleus and Med-El users. No significant difference was obtained between the two groups in terms of speech tests. CONCLUSION: ESR test can be very informative for programming young and uncooperative patients.

Background: Although anterior cruciate ligament (ACL) tears have received the most attention, the medial collateral ligament (MCL) is thought to be the most commonly injured knee ligament overall. The lateral collateral ligament (LCL) and posterior collateral ligament (PCL) are less frequently compromised but can be involved in severe multiligament injuries. The paucity of information on the native properties of these ligaments in the pediatric population hinders the overall optimization of treatment for these injuries. Purpose: To characterize the mechanical and microstructural properties of pediatric MCLs, LCLs, and PCLs using a rare cadaveric cohort (mean age, 9.2 years). Study Design: Descriptive laboratory study. Methods: MCLs, LCLs, and PCLs were harvested from 5 fresh-frozen pediatric knee specimens (3 male, 2 female) and were subjected to a tensile loading protocol. A subset of contralateral tissues from a single donor was analyzed using bright-field, polarized light, and transmission electron microscopy to measure collagen fiber morphology. Results: The pediatric MCL exhibited values for ultimate stress (11.7 ± 6.7 MPa), ultimate strain (18.2% ± 6.8%), and the Young modulus (93.7 ± 56.5 MPa) that were similar to values for the LCL (11.4 ± 11.5 MPa, 27.7% ± 12.9%, and 64.4 ± 76.6 MPa, respectively). The PCL demonstrated decreased ultimate stress (4.2 ± 1.8 MPa), increased ultimate strain (28.8% ± 11.9%), and a decreased Young modulus (19.8 ± 10.4 MPa) when compared with the MCL and LCL. All 3 ligaments had similar mean crimp wavelengths (MCL, 32.8 ± 3.6 µm; LCL, 27.2 ± 3.5 µm; PCL, 25.8 ± 3.5 µm) and collagen fibril diameters (MCL, 88.0 ± 26.0 nm; LCL, 93.3 ± 34.6 nm; PCL, 90.9 ± 34.0 nm); however, the fibril distribution profiles exhibited different modalities. Conclusion: The pediatric MCL and LCL possessed similar mechanical properties, while the pediatric PCL was weaker but capable of withstanding higher amounts of strain. All 3 of these pediatric structures were weaker than what has been reported in studies with adult cohorts. Clinical Relevance: Results from this study can be considered preliminary mechanical and microstructural data for healthy pediatric collateral and posterior cruciate ligaments that can be used to guide further laboratory and clinical research.

Relapsed mantle cell lymphoma (MCL) usually represents a hard challenge, especially after the failure of high-dose therapy or in elderly patients, and although new agents have been investigated, responses are often short and a significant proportion of patients finally die from progressive disease. Here, we report a case of a relapsed MCL patient that achieved durable response with bortezomib and rituximab. Treatment regimen consisted of bortezomib 1.6 mg/m(2) and rituximab 375 mg/m(2) intravenously on days 1-8-15-22 for the 1st course, followed by 2 courses of bortezomib with the same schedule. After the third course, patients in CR, PR or SD received other 3 courses. The patient achieved a CR, but because of the high risk of relapse we started a 4-week maintenance therapy with rituximab and bortezomib for 4 courses administered at six month interval. After a follow-up of 62 months, the patient maintained CR. We suggest rituximab plus bortezomib could play an important role in the treatment of patients with relapsed/refractory MCL. Maintenance therapy could be an interesting option, especially for patients with a high relapse risk rate.

Background Mantle cell lymphoma (MCL) is an aggressive lymphoma with a dismal prognosis because of numerous relapses. Because the most promising results have been obtained with immunochemotherapy followed by autologous cell stem transplantation (ASCT), we evaluated the efficacy of yttrium-90 ibritumomab ( 90 Y-IT) consolidation after such an intensive treatment. Patients and Methods We retrospectively assessed 57 patients affected by intermediate or high-risk MCL in complete remission (CR) or partial remission (PR) after 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisolone) plus 3 cycles of R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [platinum]) followed by ASCT and additional consolidation treatment with 90 Y-IT in 28 cases. All patients underwent 2 years of rituximab maintenance. Results After ASCT, 94% achieved CR and 4% achieved PR. The median follow-up was 6.2 years (range, 1.8-9.7 years). Treatment intensification was well tolerated and led to a significantly longer response duration in comparison to standard treatment. In contrast to the historical cohort, the addition of 90 Y-IT seems to overcome important risk factors such as Mantle Cell Lymphoma International Prognostic Index (MIPI) score and bone marrow infiltration. Conclusion In the present retrospective analysis, immunochemotherapy followed by ASCT resulted in a very high response rate, and subsequent 90 Y-IT consolidation significantly reduced the number of relapses and increased survival, suggesting that 90 Y-IT consolidation might be a valid option in first-line treatment. However, a prospective confirmatory trial is warranted.

Background: The chop block, a football maneuver in which an offensive player blocks an opponent around the thigh while another offensive player engages the same opponent above the waist, was declared illegal by the National Football League (NFL) before the 2016-2017 season. Chop blocks have been hypothesized to be associated with medial collateral ligament and anterior cruciate ligament injury, especially in offensive/defensive linemen. Purpose: To quantify the impact that the chop-block rule change had on the incidence of knee injuries to defensive players in the NFL over 4 seasons (2014-2018). Study Design: Cohort study; Level of evidence, 3. Methods: NFL injury data for all defensive players from regular-season games played from 2014 through 2018 were collected. For this study, all knee injuries were attributed to competitive game play. Injury rates were reported as the number of injuries per 1000 athletic exposures (with 95% CIs). Results: A total of 256 games were played during the 2014-2015, 2015-2016, 2016-2017, and 2017-2018 NFL regular seasons, and all were included in this study. Among defensive players, the relative risk for a knee injury per 1000 athletic exposures was 0.84 (95% CI, 0.75-0.96) for the 2 seasons after the chop-block rule change (2016-2017 and 2017-2018) versus the 2 seasons before (2014-2015 and 2015-2016) ( P = .009). Thus, the relative risk reduction was 16%. The relative risk for a defensive player to be placed on injured reserve per season was 0.90 (95% CI, 0.72-1.13) for the 2 seasons after the rule change versus the 2 seasons before ( P = .39). Conclusion: The NFL’s recent ruling against in-game chop blocks may have reduced the incidence of knee injuries among defensive players.

Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we found that the plasma of patients with MCL had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We also found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. Addition of exogenous Wnt5a in vitro significantly enhanced the numbers of MCL cell divisions and the proportion of dividing MCL cells entering S/G2 in MCL cells over time in the presence of CD154 and IL-4/10. Treatment of the MCL cells with cirmtuzumab, but not ibrutinib, blocked Wnt5a-enhanced proliferation of MCL cells. This study indicates that cirmtuzumab and ibrutinib may have complementary activity in the treatment of patients with MCL.

The anterior bundle of the medial collateral ligament (AMCL) of the elbow is commonly injured in patients with elbow dislocations and in throwing athletes. Thisin-vitrostudy quantified tension in the native AMCL throughout elbow flexion for different arm positions. We conducted passive and simulated active elbow flexion in seven fresh-frozen cadaveric upper extremities using an established motion simulator. Motions were performed in the valgus and vertical positions from 20–120° while measuring AMCL tension using a custom transducer. Average AMCL tension was higher in the valgus compared to vertical position for both active (p = 0.03) and passive (p = 0.01) motion. Peak AMCL tension was higher in the valgus position for active (p = 0.02) and passive (p = 0.01) motion. There was no significant difference in AMCL tension between active and passive motion in the valgus (p = 0.15) or vertical (p = 0.39) positions. In the valgus position, tension increased with elbow flexion from 20–70° for both active (p = 0.04) and passive (p = 0.02) motion, but not from 70–120°. Thisin-vitrostudy demonstrated that AMCL tension increases with elbow flexion, and is greater in the valgus position relative to the vertical position. This information has important implications to the desired target strength of repair and reconstruction techniques.

Background Mantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin’s lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood. Methods We quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes. Results We found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1. Conclusions Our findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-1100-9) contains supplementary material, which is available to authorized users.

The C‐type lectin receptor (CTLR), Clec4d (MCL, CLECSF8), is a member of the Dectin‐2 cluster of CTLRs, which also includes the related receptors Mincle and Dectin‐2. Like Mincle, Clec4d recognizes mycobacterial cord factor, trehalose dimycolate, and we recently demonstrated its key role in anti‐mycobacterial immunity in mouse and man. Here, we characterized receptor expression in naïve mice, under inflammatory conditions, and during Mycobacterium bovis BCG infection using newly generated monoclonal antibodies. In naïve mice, Clec4d was predominantly expressed on myeloid cells within the peritoneal cavity, blood, and bone marrow. Unexpectedly, basal expression of Clec4d was very low on leukocytes in the lung. However, receptor expression was significantly upregulated on pulmonary myeloid cells during M. bovis BCG infection. Moreover, Clec4d expression could be strongly induced in vitro and in vivo by various microbial stimuli, including TLR agonists, but not exogenous cytokines. Notably, we show that Clec4d requires association with the signaling adaptor FcRγ and Mincle, but not Dectin‐2, for surface expression. In addition, we provide evidence that Clec4d and Mincle, but not Dectin‐2, are interdependently coregulated during inflammation and infection. These data show that Clec4d is an inducible myeloid‐expressed CTLR in mice, whose expression is tightly linked to that of Mincle.

B-cell lymphoma (BCL) heterogeneity represents a key issue, often making the classification and clinical management of these patients challenging. In this pilot study, we outlined the first resolved view of BCL disease heterogeneity on the protein level by deciphering disease-associated plasma biomarkers, specific for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, using recombinant antibody microarrays targeting mainly immunoregulatory proteins. The results showed the BCLs to be heterogeneous, and revealed potential novel subgroups of each BCL. In the case of diffuse large B-cell lymphoma, we also indicated a link between the novel subgroups and survival.

Mantle cell lymphoma is a relatively rare B-cell lymphoma with a specific genetic lesion and a typical immunophenotypic profile. The median age is 65 years. There is no curative treatment, except allogeneic stem cell transplantation for a selected group of patients. For the majority of patients, especially the elderly, the aim of therapy should therefore be a long progression-free survival. Age and comorbidity may hamper the use of the most active treatment regimen, such as high dose cytarabine and autologous stem cell transplantation. Therefore, it is a challenge to select the most appropriate therapy for an elderly patient. Studies specifically designed for elderly patients are rare. A recently performed large randomized study for elderly patients, however, has shown that R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by maintenance rituximab can result in a long progression-free survival. For patients too frail for R-CHOP chemotherapy, a treatment should be offered that benefits the patient in reducing the symptoms of the disease without causing too many side effects. Progression or relapse will occur in all patients sooner or later. Second-line treatment should again be carefully selected. Several options are mentioned. New drugs are being developed, and new combinations are investigated. Further improvement in the outcome of patients with mantle cell lymphoma is expected. Participation in well-designed clinical trials, also by elderly patients, is important to find the real benefit that can be achieved, and to get information on the tolerability of these treatments in this age group.

Background: When surgical intervention is required for a grade 3 superficial medial collateral ligament (sMCL) tear, there is no consensus on the optimal surgical treatment. Anatomic augmented repairs and anatomic reconstructions for treatment of grade 3 sMCL tears have not been biomechanically validated or compared. Hypothesis: Anatomic sMCL augmented repairs and anatomic sMCL reconstruction techniques will reproduce equivalent knee kinematics when compared with the intact state, while creating significant improvements in translational and rotational laxity compared with the sMCL sectioned state. Study Design: Controlled laboratory study. Methods: Eighteen match-paired, fresh-frozen cadaveric knees (average age, 52.6 years; range, 40-59 years) were each used to test laxity of an intact sMCL, a deficient sMCL, and either an anatomic augmented repair or an anatomic reconstruction. Knees were biomechanically tested in a 6 degrees of freedom robotic system, which included valgus rotation, internal and external rotation, simulated pivot shift, and coupled anterior drawer with external rotation. Results: Anatomic augmented repairs and anatomic reconstructions had significantly less medial joint gapping than the sectioned state at all tested flexion angles and showed significant reductions in valgus rotation compared with the sectioned state at all flexion angles. No significant differences between the anatomic augmented repair and anatomic reconstruction were found for any test performed. Despite the similar behavior between the 2 reconstruction groups, neither technique was able to reproduce the intact state. Conclusion: Anatomic sMCL augmented repairs and anatomic sMCL reconstructions were not significantly different when tested at time zero. Both the anatomic augmented repair and the anatomic reconstruction were able to improve knee stability and provide less than 2 mm of medial joint gapping at 0° and 20° of flexion. Clinical Significance: These results suggest that both an anatomic sMCL augmented repair and an anatomic sMCL reconstruction improve knee kinematics compared with a deficient sMCL and provide equivalent joint stability.

The field of Artificial Intelligence has seen steady advances in cognitive systems. However, many of these systems perform poorly when faced with situations outside of their training. Since the real world is dynamic, this brittleness is a major problem in the field today. Adding metacognition to such systems can improve their operation in the face of perturbations found in dynamic environments. I developed a six-level taxonomy that divided metacognitive systems according to their capabilities. This ranged from Level 0: Bereft that offered no metacognitive assistance, to Level 5: Anticipating that would make suggestions before the agent needed assistance. Using this taxonomy, I deconstructed an existing metacognitive system (MCL) so that it could operate at any of the four lower levels of the taxonomy. I added, to the Level 3: Temporal version of MCL, a number of comparison functions designed to determine if the problem the agent is currently facing is similar to any previous problem. I created functions to both establish baseline operation performance and to try to optimize the agent's performance in a perturbed environment. I extended an existing Mars Rover domain simulation to add more problem and recovery options. In this environment, I tested the temporal comparison functions to determine how well they were able to distinguish on type of perturbation from another and how much they helped (or hindered) the agents subjected to those perturbations. Several comparison functions were able to aid the Rover in completing its tasks, although none were perfect.

We have investigated the binding Stoichiometry of the chromosomal MCl protein on DNA using the gel retardation technique. Analysis of the distribution of the complex containing 0, 1, 2, 3...... bound proteins shows that the protein MCl interacts with the DNA as a monomer. Binding experiments with short DNA fragments of various lengths shows that the site size is 11 bp in length. These results are compared to those obtained with other chromosomal proteins including HU protein.

Protein interactions are crucial components of all cellular processes. Recently, high-throughput methods have been developed to obtain a global description of the interactome (the whole network of protein interactions for a given organism). In 2002, the yeast interactome was estimated to contain up to 80,000 potential interactions. This estimate is based on the integration of data sets obtained by various methods (mass spectrometry, two-hybrid methods, genetic studies). High-throughput methods are known, however, to yield a non-negligible rate of false positives, and to miss a fraction of existing interactions. The interactome can be represented as a graph where nodes correspond with proteins and edges with pairwise interactions. In recent years clustering methods have been developed and applied in order to extract relevant modules from such graphs. These algorithms require the specification of parameters that may drastically affect the results. In this paper we present a comparative assessment of four algorithms: Markov Clustering (MCL), Restricted Neighborhood Search Clustering (RNSC), Super Paramagnetic Clustering (SPC), and Molecular Complex Detection (MCODE)., Comparative Study, Evaluation Studies, Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Nousheen Samad1, Anas Younes21Division of Pharmacy, Pharmacy Clinical Programs, 2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of lymphoma associated with a poor prognosis. Chemotherapy is the mainstay of frontline treatment for patients with this disease. Despite high response rates to combination chemotherapy regimens, the majority of patients relapse within a few years of treatment. Therefore, finding efficacious treatments for relapsed or refractory disease has become a growing area of clinical research. The mammalian target of rapamycin (mTOR) is responsible for integrating cell signals from growth factors, hormones, and nutrients and communicating energy status. Scientific research on aberrant molecular pathways in cancer has revealed that several proteins along the mTOR pathway may be upregulated in this and other types of lymphoma. Temsirolimus is the first mTOR inhibitor that has shown clinical efficacy in treating MCL that has relapsed after frontline treatments.Keywords: rapamycin, CCI-779, MCL, mTOR, PI3K, Akt

The aim of this study is to describe the results of a consecutive set of patients treated in acute for the surgical repair of medial collateral ligament (MCL) tears with a mean follow up of 63.78±43.25 months (4- 136). This is a retrospective observational study. From January 2011 to December 2016, 56 patients within the average of 31.75±13.27 (13-55) years old at the time of injury underwent medial compartment repair in an acute setting. The sample size of our study is therefore made up of 26 patients. Patients have been evaluated with functional scores: IKDC (international knee documentation committee evaluation form), the KOOS (Knee injury and osteoarthritis outcome score) and clinical assessment. The Tegner Activity Score was evaluated retrospectively at the 12 months follow-up. The mean KOOS value at the final follow-up were 91.25±9.65 (72-100) for pain, 85.68 ± 12.34 (57-100) for the symptoms category, 94.5±8,07 (75-100) for the activity of daily life, 71.87±22.86 (35-100) for the sport category and 76.37±18.55 (38-100) for the quality of life. At the last follow up the mean IKCD value was 77.68±15.95 (55-98). The mean difference in the Tegner Activity Score between the preoperative time and the postoperative time was 1.06±1.12 with a 95% Confidence Interval 0.46-1.66. The functional outcomes underline how the surgical approach to the medial capsule-ligament compartment of the knee is a reliable treatment to restore excellent joint function. Level of evidence III retrospective observational study.