Search

The key element for differentiation between normal anatomical variants and pathological deformities is the prior definition of normal ranges for anthropometric parameters of acetabulum according to each age group. Aim of the present study is to analyze the development of the acetabulum in children/adolescents by accurate anthropometric measurements using 3D-CT scans and determine the variations occurring depending on age, gender and/or side. This retrospective observational study included 85 patients (170 hips) under 15 years of age (0-15) undergoing 1.5mm CT scanning for non-hip related reasons. The measurements were performed by 2 board-certified orthopaedic surgeons. Each year of life represented an age group forming a total of 16 groups. Median number of patients per age group was 12 (range 4-16). The anthropometric parameters included acetabular volume, inclination, version, depth (coronal and axial), width (coronal and axial), Tönnis angle as well as anterior and posterior acetabular sector angles. Mean values, range, standard deviation, p-values, intra- and interrater reliability were calculated. All measurement values correlated significantly with age. Statistically, there was no side or gender related difference. Rapid growth phases were observed at the age of 11-12. The inter- and intrarater reliability was high (range ICC 0.8-0.99, Cronbach alpha 0.86-0.99, Bland-Altman good agreement). The present data provides age- and gender-related normative values as well as growth phases describing acetabular morphology. It should help paediatricians as well as paediatric and orthopaedic surgeons as a tool for early diagnosis of deformity and guidance for possible procedures.

Normal anatomical variants and pathological deformities of the pediatric hip can only be differentiated after a prior definition of normal ranges for anthropometric parameters with increasing age. Aim of the present study was to provide reliable reference values of the pediatric hip morphometry, using computed tomography (CT)-based rotation-corrected summation images of the pelvis that simulate the widely available plain radiograph-based measurements, but offer the higher precision of the CT technique. This retrospective study included 85 patients (170 hips) under 15 years of age (0-15). The measured anthropometric parameters included femur head extrusion index, lateral center-edge angle, acetabular inclination, Tönnis angle, and femoral neck-shaft angle. Mean values, range, SD, P values, intra-rater, and inter-rater reliability were calculated. All measurements correlated with age. None of the measurements correlated with gender or side. Rapid growth phases were noted in all measurements at the age of 12 (14 in males and 11 in females). The inter-rater and intra-rater reliability was high (range inter/intraclass correlation coefficient 0.926-0.998 Cronbach's alpha 0.986-0.998). The present work provides age- and gender-related normative values of the classically used hip measurements as well as growth phases describing pediatric hip morphology in a broad age range. A discrepancy was noted between the values measured in the current study and the classical X-ray-based reference values in the literature especially for the Tönnis angle and LCEA values. This suggests that the rotation and inclination correction in the CT-based techniques might have the advantage of compensating for a possible overestimation in the conventional X-ray-based methods.

PurposeDefining normal anthropometric ranges of proximal femur and femoral head for each age group in children/adolescents is a necessity when differentiating normal anatomical variants from pathological deformities. Aim of this study is to define a set of normal anthropometric parameters based on 3D-CT measurements in normal asymptomatic children/adolescents and analyse the variations arising depending on age, side, and/or gender.MethodsMorphology of the proximal femur was retrospectively assessed in 170 hips (85 children, ResultsCFHV, LCEA, FHD and AOS/POS increased with age and FHEI, CAA, and FNSA decreased with age. None of the measurements correlated with the side. AOS showed a poor correlation with gender. Rapid growth phases were observed at the age of 1, 7 and 11. The inter- and intra-rater reliability was high (range ICC 0.8–0.99 Cronbach alpha 0.86–0.99).ConclusionThis data delivers a description of growth phases as well as gender and age-correlated reference values of the proximal femoral morphology that could be used by paediatricians and orthopaedic/paediatric surgeons to early diagnose proximal femur deformities and provide guidance in the planning of possible operations.

Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.

Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials.

Soluble factors released from irradiated human mesenchymal stromal cells (MSC) may induce genetic instability in human CD34+ cells, potentially mediating hematologic disorders. Recently, we identified four key proteins in the secretome of X-ray-irradiated MSC, among them three endoplasmic reticulum proteins, the 78 kDa glucose-related protein (GRP78), calreticulin (CALR), and protein disulfide-isomerase A3 (PDIA3), as well as the glycolytic enzyme glucose-6-phosphate isomerase (GPI). Here, we demonstrate that exposition of CD34+ cells to recombinant GRP78, CALR, PDIA3 and GPI induces substantial genetic instability. Increased numbers of γH2AX foci (p < 0.0001), centrosome anomalies (p = 0.1000) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells upon incubation with these factors. Specifically, γH2AX foci were found to be induced 4–5-fold in response to any individual of the four factors, and centrosome anomalies by 3–4 fold compared to control medium, which contained none of the recombinant proteins. Aberrant metaphases, not seen in the context of control medium, were detected to a similar extent than centrosome anomalies across the four factors. Notably, the strongest effects were observed when all four factors were collectively provided. In summary, our data suggest that specific components of the secretome from irradiated MSC act as mediators of genetic instability in CD34+ cells, thereby possibly contributing to the pathogenesis of radiation-induced hematologic disorders beyond direct radiation-evoked DNA strand breaks.

Primary care hospitals and regional trauma centers play an essential role in the treatment of hip fractures.This study investigated the relationship between patient-related parameters and in-hospital mortality as well as complications of hip fractures at a regional trauma center.In a retrospective study, data were collected from all patients 60 years admitted over 2 years to a regional trauma center with a hip fracture. Patient-related parameters included age, sex, fracture location, method of surgical treatment, time of surgery, duration of surgery, length of inpatient stay, blood transfusion, complications, comorbidities, use of anticoagulant medication and need for postoperative intensive care treatment. The relationship between these parameters and hospital mortality as well as complications was investigated.Data were collected from 360 patients undergoing 335 surgeries (f:m 225:110) with a mean age of 83 ± 8 years. The total in-hospital mortality rate was 7.76% (n = 26). Factors increasing in-hospital mortality included: age 85 years (odds ratio [OR] 5.126; 95% confidence interval [CI] 0.665-39.498; p = 0.1167); male sex (OR 1.85 95%-CI [0.82-4.14]; p = 0.0555); time of surgery 24 h (OR 1.896 95%-CI [0.661-5.441]; p = 0.2341); ≥ 3 comorbidities (OR 10.61 95%-CI [3.681-27.501]; p 0.0001); intake of anticoagulants (OR 6.19 95%-CI [2.69-14.24]; p 0.0001) and postoperative intensive care (OR 5.9 95%-CI [2.56-13.76]; p 0.0001).In the present study a statistically significant influence of the number of comorbidities or Charlson comorbidity index, the intake of anticoagulant drugs and need for postoperative intensive care treatment on the in-hospital mortality of patients with proximal femoral fractures in a regional trauma center was found.HINTERGRUND: Krankenhäuser der Grund- und Regelversorgung bzw. regionale Traumazentren spielen eine essenzielle Rolle in der Versorgung hüftgelenknaher Frakturen. ZIEL: Die vorliegende Arbeit untersucht den Zusammenhang zwischen patientenbezogenen Parametern und der Klinikmortalität sowie dem Auftreten von Komplikationen bei solchen Frakturen an einem regionalen Traumazentrum.Im Rahmen einer retrospektiven Studie wurden die Daten von allen Patienten, die über 2 Jahre an einem regionalen Traumazentrum mit einer hüftgelenknahen Fraktur aufgenommen wurden, erfasst. Eingeschlossen wurden nur Patienten älter als 60 Jahre. Die patientenbezogenen Parameter umfassten Alter, Geschlecht, Frakturlokalisation, Methode der operativen Versorgung, Operationszeitpunkt, Dauer der Operation und des stationären Aufenthalts, Bluttransfusion, Komplikationen, Komorbiditäten, Einnahme von Antikoagulanzien und Notwendigkeit einer postoperativen intensivmedizinischen Behandlung. Der Zusammenhang zwischen diesen Parametern und der Klinikmortalität sowie dem Auftreten von Komplikationen wurde untersucht.Daten von 360 Patienten mit 335 Operationen (w:m 225:110) mit einem Alter von 83 ±8 Jahren wurden erfasst. Die Klinikmortalität lag bei 7,76 % (n = 26) und erhöhte sich bei Alter 85 Jahren (Odds Ratio [OR] 5,126; 95%-Konfidenzintervall [95 %-KI] 0,665–39,498; p = 0,1167), männlichem Geschlecht (OR 1,85 95%-KI [0,82–4,14]; p = 0,0555), Zeitpunkt der Operation 24 h (OR 1,896 95%-KI [0,661–5,441]; p = 0,2341), ≥ 3 Vorerkrankungen (OR 10,61 95%-KI [3,681–27,501]; p 0,0001), Einnahme von Antikoagulanzien (OR 6,19 95%-KI [2,69–14,24]; p 0,0001) und notwendiger postoperativer intensivmedizinischer Behandlung (OR 5,9 95%-KI [2,56–13,76]; p 0,0001).In der vorliegenden Studie fanden sich statistisch signifikante Einflüsse der Anzahl der Komorbiditäten, der Einnahme von Antikoagulanzien sowie der intensivmedizinischen Behandlung auf die Klinikmortalität bei Patienten mit hüftgelenknahen Frakturen an einem regionalen Traumazentrum.

ZusammenfassungDas undifferenzierte pleomorphe Sarkom („undifferentiated pleomorphic sarcoma“ [UPS]) gehört zur Gruppe der Weichteilsarkome und macht fast 10 % aller Weichteilsarkome aus. Der Fall eines 49-jährigen Patienten wird vorgestellt, bei dem die kompartmentorientierte Resektion eines primären UPS im linken Musculus gluteus maximus mit adjuvanter Radiotherapie (60 Gy) durchgeführt wurde. Im Rahmen der Tumornachsorge (3 Jahre später) wurde eine lokoregionäre Metastase an einer ungewöhnlichen Lokalisation im M. quadratus femoris festgestellt, welche mittels einer In-toto-Resektion mit intraoperativer Radiotherapie (10 Gy) behandelt wurde. Der intra- und postoperative Verlauf gestalten sich komplikationslos ohne neurologische Defizite. Im Rahmen der Nachtuntersuchung 6 Monate postoperativ war der Patient tumor- und beschwerdefrei.

Introduction Despite successful osteosynthesis, some patients report residual symptoms after ankle fractures. One of the reasons behind the postoperative complaints might be traumatic concomitant chondral lesions (CL) and/or osteochondral lesions (OCL) within the ankle joint. The study aims to systematically review the incidence of CL and/or OCL in ankle fractures and to assess their effect on the clinical outcome. Materials and methods This work was conducted according to PRISMA checklists. A systematic literature search was performed using following keywords: “Ankle Fractures” OR “Trimalleolar Fracture” OR “Bimalleolar Fracture” OR “Maisonneuve fracture” OR “Malleolus Fracture” AND “Cartilage” OR “Cartilage Diseases” OR “Cartilage, Articular” OR “chondral” up to March 2020. The identified articles were analysed to determine the incidence of CL and/or OCL. Included studies in the meta-analysis assessed possible cartilage damage through arthroscopy or MRI immediately after traumatic ankle fractures and described the postoperative clinical outcome. Results The search identified a total of 111 publications; 19 described the incidence of CL and/or OCL after ankle fractures; six met the criteria to be included in the meta-analysis: five (n = 293) diagnosed CL and/or OCL through arthroscopy during ORIF and one study (n = 153) used preoperative MRI. The clinical outcome was evaluated in four studies (n = 177) using AOFAS score and in two (n = 269) using FAOS score. The mean incidence of arthroscopically detected CL and/or OCL was 65 ± 21% [95% CI 53.9 to 76.72]. The cumulative meta-analysis sample size comprised a total of 400 Patients (170 with and 230 without CL and/or OCL) available for a mean follow-up of 23.9 ± 11.5 months [95% CI 11.79 to 36.07]. The average age was 44.3 ± 5.5 years [95% CI 38.57 to 50.13]. The meta-analysis revealed a mean AOFAS score of 91.2 ± 4.8 [95% CI 83.53 to 98.93] with versus 94.4 ± 4.7 [95% CI 86.81 to 102.07] without CL and/or OCL (p = 0.15) and a mean FAOS score of 73.2 ± 11.31 [95% CI − 28.44 to 174.85] with versus 79.0 ± 18.4 [95% CI − 86.77 to 244.87] without CL and/or OCL (p = 0.18). Conclusions CL and/or OCL appear very frequently after ankle fractures. A tendency towards a favourable short- to mid-term clinical outcome was noticed in ankle fractures without CL and/or OCL, however without reaching statistical significance. Level of evidence Level I.

Background Periprosthetic acetabular fractures are an increasing severe complication in revision arthroplasty. A differentiation is made between periprosthetic acetabular fractures (acute/traumatic fractures) and insufficiency fractures (chronic fractures). Objective This article introduces a novel treatment algorithm that provides assistance in therapeutic decision making for implant selection and the anchoring philosophy based on diagnostic decision criteria and the relevant load-bearing osseous structures, taking the defect situation into account. Material and methods The article provides an overview of original and review articles. Results The essential criteria for decisions in treatment planning are based on the stability of the primary cup, the load-bearing ability of the main anatomical structures and the resulting defect situation. For insufficiency fractures the reason for the revision and therefore the exclusion of periprosthetic joint infections (PJI) must additionally be considered. In the case of proven PJI a two-stage or multistage prosthesis exchange must be carried out. Based on the extent of apparent bony defects and pelvic discontinuity, the spectrum of treatment options ranges up to implantation of individual patient custom-made acetabular components. Discussion/conclusion This overview introduces a new treatment algorithm that provides assistance in decision making for traumatic periprosthetic acetabular fractures and insufficiency fractures. It also provides decision criteria for selection of implants and the surgical approach. Due to the complexity of revision arthroplasty often requiring specialized expertise in trauma and orthopedic surgery and experienced revision surgeons, the operative treatment of periprosthetic acetabular fractures should only be carried out in specialized orthopedic and trauma surgery centers with appropriate experience.

The bone marrow (BM) stroma in myeloid neoplasms is altered and it is hypothesized that this cell compartment may also harbor clonal somatically acquired mutations. By exome sequencing of in vitro expanded mesenchymal stromal cells (MSCs) from n = 98 patients with myelodysplastic syndrome (MDS) and n = 28 healthy controls we show that these cells accumulate recurrent mutations in genes such as ZFX (n = 8/98), RANK (n = 5/98), and others. MDS derived MSCs display higher mutational burdens, increased replicative stress, senescence, inflammatory gene expression, and distinct mutational signatures as compared to healthy MSCs. However, validation experiments in serial culture passages, chronological BM aspirations and backtracking of high confidence mutations by re-sequencing primary sorted MDS MSCs indicate that the discovered mutations are secondary to in vitro expansion but not present in primary BM. Thus, we here report that there is no evidence for clonal mutations in the BM stroma of MDS patients., Bone marrow-derived mesenchymal stroma cells (MSCs) in myeloid neoplasia have been hypothesized to carry somatic mutations and contribute to pathogenesis. Here the authors analyse ex-vivo cultures and primary MSCs derived from patients with myelodysplastic syndromes, finding functional alterations but no evidence of clonal mutations.

Rifampin is one of the most important biofilm-active antibiotics in the treatment of periprosthetic joint infection (PJI), and antibiotic regimens not involving rifampin were shown to have higher failure rates. Therefore, an emerging rifampin resistance can have a devastating effect on the outcome of PJI. The aim of this study was to compare the incidence of rifampin resistance between two groups of patients with a PJI treated with antibiotic regimens involving either immediate or delayed additional rifampin administration and to evaluate the effect of this resistance on the outcome. In this retrospective analysis of routinely collected data, all patients who presented with an acute/chronic PJI between 2018 and 2020 were recorded in the context of a single-center comparative cohort study. Two groups were formed: Group 1 included 25 patients with a PJI presenting in 2018–2019. These patients received additional rifampin only after pathogen detection in the intraoperative specimens. Group 2 included 37 patients presenting in 2019–2020. These patients were treated directly postoperatively with an empiric antibiotic therapy including rifampin. In all, 62 patients (32 females) with a mean age of 68 years and 322 operations were included. We found a rifampin-resistant organism in 16% of cases. Rifampin resistance increased significantly from 12% in Group 1 to 19% in Group 2 (p &lt, 0.05). The treatment failure rate was 16% in Group 1 and 16.2% in Group 2 (p = 0.83). The most commonly isolated rifampin-resistant pathogen was Staphylococcus epidermidis (86%) (p &lt, 0.05). The present study shows a significant association between the immediate start of rifampin after surgical revision in the treatment of PJI and the emergence of rifampin resistance, however with no significant effect on outcome.

Periprosthetic joint infection (PJI) is a serious complication after total joint arthroplasty. In the course of a PJI, superinfections with pathogens that do not match the primary infecting micro-organism may occur. To our knowledge, there are no published data on the outcome of such infections in the literature. The aim of this study was to assess the outcome of PJI with superinfections with a difficult-to-treat (DTT) pathogen. Data of 169 consecutive patients with PJI were retrospectively analyzed in this single-center study. Cases were categorized into: Group 1 including non-DTT-PJI without superinfection, Group 2 DTT-PJI without superinfection, Group 3 non-DTT-PJI with DTT superinfection, and Group 4 non-DTT-PJI with non-DTT superinfection. Group 3 comprised 24 patients and showed, after a mean follow-up of 13.5 ± 10.8 months, the worst outcome with infection resolution in 17.4% of cases (p = 0.0001), PJI-related mortality of 8.7% (p = 0.0001), mean revision rate of 6 ± 3.6 (p &lt, 0.0001), and duration of antibiotic treatment of 71.2 ± 45.2 days (p = 0.0023). PJI caused initially by a non-DTT pathogen with a superinfection with a DTT pathogen is significantly associated with the worst outcome in comparison to non-DTT-PJI, PJI caused initially by a DTT pathogen, and to non-DTT-PJI with a non-DTT superinfection.

In orthopaedics and trauma surgery scores are frequently used to assess treatment outcomes. The purpose of the review is to create an overview analysing the content of validity studies of frequently utilized scores for upper and lower extremity.Commonly used outcome measures to assess clinical outcome of upper (n = 19) and lower (n = 22) extremity were included. For each of the scores a comprehensive search in several databases (Medline, PubMed, google scholar) were performed to identify validation studies. The COSMIN-Checklist (COSMIN: Consensus-based Standards for the selection of health Measurement Instruments) introduced by Mokkink et al. were used to analyse systematically the methodological quality of the validation studies.Validity, objectivity and reliability were not routinely considered and addressed in validation studies. The score related validation studies did not include all defined criteria of the COSMIN-Checklist. Six scores of the upper extremity and four scores of the lower extremity are not adequately validated. The best validated scores of the upper extremity is Oxford Shoulder Score (OSS) and for the lower extremity Hip Disabilities and Osteoarthritis Outcome Score (HOOS) as well as Western Ontario and McMaster Universities Score (WOMAC).There is no gold standard for the content-comprehension of validation studies due to the structure of the original study. The more criteria were tested the more informative and significant the outcome measure is. However some scores, such as Neer and Castaing Score, that lack validation are still being successfully used in research and clinical practice. The present review provides an overview of frequently used score in orthopaedics and trauma surgery and their grade of validity.ZIEL: Im Fachbereich Orthopädie und Unfallchirurgie finden zahlreiche Scores Anwendung. Ziel der Studie ist die Erstellung einer Übersichtsarbeit zur Prüfung des Ausmaßes der Validität von häufig eingesetzten klinischen Scores in der Orthopädie und Unfallchirurgie.Die Auswahl fiel basierend auf der Häufigkeit ihres Einsatzes auf 19 bzw. 22 der am meisten genutzten Scores für die obere bzw. untere Extremität. Für die jeweiligen Scores wurden in den Datenbanken Medline, PubMed und Google Scholar Validierungsstudien identifiziert. Zur Beurteilung der methodologischen Qualität der Validierungsstudien wurde die sog. COSMIN-Checkliste (COSMIN: Consensus-based Standards for the selection of health Measurement Instruments) von Mokkink et al. genutzt.Die gemeinsame Betrachtung von Validität, Objektivität und Reliabilität scheint kein Standardvorgehen von Validierungsstudien zu sein. Die in der COSMIN-Checkliste aufgeführten Kriterien der Validität wurden von den meisten Validierungsstudien der Scores nicht vollständig erfüllt. Sechs Scores der oberen Extremität und 4 Scores der unteren Extremität sind nach der COSMIN-Checkliste nicht ausreichend validiert. Die Scores mit der umfangreichsten Validität sind für die obere Extremität der Oxford Shoulder Score und für die untere Extremität der Hip Disabilities and Osteoarthritis Outcome Score (HOOS) sowie der Western Ontario and McMaster Universities Score (WOMAC).Es gibt keinen Goldstandard für den Inhaltsumfang von Validierungsstudien. Die COSMIN-Checkliste gibt eine zuverlässige Übersicht über den Umfang der Validität. Je mehr Kriterien der COSMIN-Checkliste in Validierungsstudien getestet werden, desto umsichtiger sind die Überlegungen des validierenden Studienleiters. In klinischen Studien finden ebenso nicht validierte Scores, z. B. der Score nach Neer und Castaing, regelmäßig ihre Anwendung. Die vorliegende Übersichtsarbeit gibt einen Überblick über den Validitätsumfang der häufig genutzten Scores in der Orthopädie und Unfallchirurgie.

The hypomethylating agent 5-azacytidine (5-Aza) is a standard-of-care for patients with higher-risk myelodysplastic syndromes (MDS). Although an initial response is induced in approximately 50% of 5-Aza treated patients, subsequent relapse is almost certain. Recently, inhibitors of anti-apoptotic BCL-2 protein family members have shown therapeutic potential in acute myeloid leukemia (AML) and higher-risk MDS. Alvocidib (Alv), a CDK9 inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has shown anti-leukemic effects in a phase 1 study of patients with AML (Lee DJ et al, Expert Opin Investig Drugs 2019; Zeidner JF et al, Leuk Res 2015). A phase 1b/2 study with Alv and 5-Aza or decitabine in higher-risk patients with MDS was recently completed (NCT03593915); however, biomarkers for response to the Alv and 5-Aza combination are not well characterized. To identify potential biomarkers of response, we performed a comprehensive in vitro assessment of Alv and 5-Aza combination using a clinically well-characterized cohort of n=45 higher-risk patients with MDS and n=11 healthy controls (HC). CD34+ cells were purified from bone marrow (BM) aspirates using positive selection with MACS beads. CD34+ cells of HC were obtained from femur head replacement surgery bone specimens. After 4 days of expansion in SFEM II medium containing StemSpan Myeloid Expansion Supplement, cells were treated with 5-Aza for 48h, Alv for 24h or their combination (5-Aza for 48h followed by Alv for 24h). Cell viability was determined using CellTiter-Glo (CTG) and Annexin-V apoptosis assays. MCL-1 dependency of MDS samples was assessed using MS1 peptide-based assay. Recurrent myeloid neoplasia mutations in 67 genes were assessed in BM mononuclear cells using NGS panel deep sequencing. The combination of 5-Aza+Alv had an additive cytotoxic effect on CD34+ MDS cells in CTG assay (median cell viability = 74%, 73.8% and 55% for 5-Aza, Alv and combination respectively, p Citation Format: Vladimir Ryabov, Nanni Schmitt, Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Alina Wein, Eva Altrock, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Ahmed Jawhar, Ali Darwich, Patrick Wuchter, Christel Weiss, Georgia Metzgeroth, Jason M. Foulks, Laurenz Steiner, Mohamad Jawhar, Wolf-Karsten Hofmann, Daniel Nowak. Mutations in the ASXL1 and ZRSR2 genes are associated with the response to the combination of alvocidib and 5-azacytidine in higher-risk myelodysplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6257.

The undifferentiated pleomorphic sarcoma (UPS) is a part of the soft tissue sarcoma group and represents almost 10% of all soft tissue sarcomas. The case of a 49-year-old patient is presented who was diagnosed with a primary UPS in the left gluteus maximus muscle, which was treated with compartmental resection with adjuvant radiotherapy (60 Gy). During tumor follow-up (3 years later) a locoregional metastasis at an unusual location in the quadratus femoris muscle was detected, which was treated by in toto resection with intraoperative radiotherapy (10 Gy). The intra and postoperative outcome was without complications and without neurological deficits. In the last follow-up, 6 months postoperatively, the patient was free of tumors and symptoms.Das undifferenzierte pleomorphe Sarkom („undifferentiated pleomorphic sarcoma“ [UPS]) gehört zur Gruppe der Weichteilsarkome und macht fast 10 % aller Weichteilsarkome aus. Der Fall eines 49-jährigen Patienten wird vorgestellt, bei dem die kompartmentorientierte Resektion eines primären UPS im linken Musculus gluteus maximus mit adjuvanter Radiotherapie (60 Gy) durchgeführt wurde. Im Rahmen der Tumornachsorge (3 Jahre später) wurde eine lokoregionäre Metastase an einer ungewöhnlichen Lokalisation im M. quadratus femoris festgestellt, welche mittels einer In-toto-Resektion mit intraoperativer Radiotherapie (10 Gy) behandelt wurde. Der intra- und postoperative Verlauf gestalten sich komplikationslos ohne neurologische Defizite. Im Rahmen der Nachtuntersuchung 6 Monate postoperativ war der Patient tumor- und beschwerdefrei.

Despite successful osteosynthesis, some patients report residual symptoms after ankle fractures. One of the reasons behind the postoperative complaints might be traumatic concomitant chondral lesions (CL) and/or osteochondral lesions (OCL) within the ankle joint. The study aims to systematically review the incidence of CL and/or OCL in ankle fractures and to assess their effect on the clinical outcome. This work was conducted according to PRISMA checklists. A systematic literature search was performed using following keywords: “Ankle Fractures” OR “Trimalleolar Fracture” OR “Bimalleolar Fracture” OR “Maisonneuve fracture” OR “Malleolus Fracture” AND “Cartilage” OR “Cartilage Diseases” OR “Cartilage, Articular” OR “chondral” up to March 2020. The identified articles were analysed to determine the incidence of CL and/or OCL. Included studies in the meta-analysis assessed possible cartilage damage through arthroscopy or MRI immediately after traumatic ankle fractures and described the postoperative clinical outcome. The search identified a total of 111 publications; 19 described the incidence of CL and/or OCL after ankle fractures; six met the criteria to be included in the meta-analysis: five (n = 293) diagnosed CL and/or OCL through arthroscopy during ORIF and one study (n = 153) used preoperative MRI. The clinical outcome was evaluated in four studies (n = 177) using AOFAS score and in two (n = 269) using FAOS score. The mean incidence of arthroscopically detected CL and/or OCL was 65 ± 21% [95% CI 53.9 to 76.72]. The cumulative meta-analysis sample size comprised a total of 400 Patients (170 with and 230 without CL and/or OCL) available for a mean follow-up of 23.9 ± 11.5 months [95% CI 11.79 to 36.07]. The average age was 44.3 ± 5.5 years [95% CI 38.57 to 50.13]. The meta-analysis revealed a mean AOFAS score of 91.2 ± 4.8 [95% CI 83.53 to 98.93] with versus 94.4 ± 4.7 [95% CI 86.81 to 102.07] without CL and/or OCL (p = 0.15) and a mean FAOS score of 73.2 ± 11.31 [95% CI − 28.44 to 174.85] with versus 79.0 ± 18.4 [95% CI − 86.77 to 244.87] without CL and/or OCL (p = 0.18). CL and/or OCL appear very frequently after ankle fractures. A tendency towards a favourable short- to mid-term clinical outcome was noticed in ankle fractures without CL and/or OCL, however without reaching statistical significance. Level I.

Introduction There is increasing evidence for an active role of the bone marrow (BM) microenvironment in the pathogenesis of Myelodysplastic Syndromes (MDS). Genetically engineered murine models have shown that isolated mutations in the BM niche can disrupt the non-mutated hematopoietic compartment and induce MDS-like phenotypes. However, it is still unclear whether primary MDS in humans may possibly be associated with acquired mutations non-hematopoietic BM stroma cells. Although chromosomal aberrations and mutations have been described in in ex vivo expanded MSC cultures from MDS and AML patients, little validation has been performed to address whether such molecular lesions were not clonal outgrowths resulting from the strenuous and massively expansive cell culture procedures. Materials and Methods We performed whole exome sequencing on paired ex vivo expanded MSCs and native BM samples of n=98 MDS and associated myeloid neoplasia cases treated at the Department of Hematology and Oncology of the Medical Faculty Mannheim, Heidelberg University, Germany (median age 73 years, range 44-86). As controls, we included a cohort of n=28 samples from healthy subjects (median age 75 years, range 36-84). MSCs were expanded adherently on plastic dishes by seeding 5x10e6 mononuclear cells in StemMACS MSC Expansion Medium XF (Miltenyi Biotec) for a median of 34 days, (95% confidence interval 22-50d). Whole exome sequencing was carried out using Nextera DNA Flex Tagmentation kit (Illumina) with IDT xGene Research probe v1 at a median coverage at 88x with BM MNC as germline control accounting for possible LOH in the BM sample. Validation experiments were performed by deep re-sequencing of single CFU-F colonies (n=4 patients), sequencing of serial cultures (n=7 patients) and re-sequencing of primary sorted native bone marrow MSCs from n=9 patients. Results In the exome sequencing analyses of ex vivo expanded MSCs we discovered multiple recurrent mutations in MSCs of MDS patients including but not limited to genes such as ZFX (n=8/98) and RANK (n=5/98). MSCs from MDS patients displayed an overall higher mutational burden and increased replicative stress as determined by gH2AX and RPA staining, which correlated with the mutational burden and shorter telomeres as compared to healthy controls. The analysis of mutational signatures revealed that MDS MSCs were distinct compared to healthy MSCs. Furthermore, we found that MDS MSCs displayed increased senescence assessed by flow bGAL staining and associated inflammatory gene expression determined by IL6 qPCR/ELISA for n=32 cases. To investigate whether acquired mutations in MSCs were driven by the ex vivo expansion we performed individualized amplicon based deep re-sequencing of serial culture passages and different BM aspirations for n=7 patients as well as single colony re-sequencing in n=4 patient cases. Furthermore, we re-sequenced primary sorted CD45-,CD235a-,CD31+/-,CD271+/- BM cells of n=9 cases. All of these validation experiments indicated that the discovered mutations were associated with expansion in culture and but not present in clonally relevant cell populations in the primary BM in vivo. Discussion Together with previously published data of the BM niche of myeloid neoplasms, our results add to the notion that MSCs in MDS are molecularly and functionally altered. Nevertheless, our current comprehensive sequencing analyses leave little doubt that if acquired mutations in the stroma of MDS patients play a role in MDS disease initiation at all, then at such a low clonal and possibly locally confined level, that they are not detectable with currently feasible sample acquisition and methodology. In our current study, we discovered no evidence for acquired mutations in BM derived MSCs in MDS. Disclosures Schmitt: Affimed GmbH: Research Funding. Flach: Gilead: Current Employment. Hofmann: BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Nowak: Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; Celgene: Honoraria; AbbVie: Other: Investigator on funded clinical trial; Tolero Pharma, Pharmaxis, Apogenix: Research Funding; Affimed: Research Funding; Takeda: Honoraria.

Periprosthetic shoulder infection (PSI) remains a devastating complication after total shoulder arthroplasty (TSA). Furthermore, there is a paucity in the literature regarding its diagnostic and therapeutic management, especially the absence of therapy concepts devised exclusively for PSI. The aim of the presenting study is to examine the characteristics and outcome of patients with PSI who were treated according to well-established algorithms developed originally for periprosthetic joint infection (PJI) of the hip and knee and determine if these algorithms can be applied to PSI. This single-center case series included all patients with a PSI presenting between 2010 and 2020. Recorded parameters included age, sex, affected side, BMI, ASA score, Charlson comorbidity index, preoperative anticoagulation, indication for TSA (fracture, osteoarthritis or cuff-arthropathy), and type of infection (acute or chronic PSI). The outcome was divided into treatment failure or infect resolution. Staphylococcus epidermidis and aureus were the commonest infecting pathogens. Acute PSI was mainly treated with debridement, irrigation, and retention of the prosthesis (DAIR) and chronic cases with two/multiple-stage exchange. The treatment failure rate was 10.5%. C-reactive protein was preoperatively elevated in 68.4% of cases. The mean number of operative revisions was 3.6 ± 2.6, and the mean total duration of antibiotic treatment was 72.4 ± 41.4 days. The most administered antibiotic was a combination of clindamycin and fluoroquinolone. In summary, the data of the current study suggest that therapeutical algorithms and recommendations developed for the treatment of PJI of the hip and knee are also applicable to PSI.

Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these signals is challenging. Here, RIBEs were analyzed in human CD34+ cells cultured in distinct molecular size fractions of medium, conditioned by 2 Gy irradiated human MSC. Specifically, γH2AX foci (as a marker of DNA double-strand breaks) and chromosomal instability were evaluated in CD34+ cells grown in approximate (I) &lt, 10 kDa, (II) 10–100 kDa and (III) &gt, 100 kDa fractions of MSC conditioned medium and un-/fractionated control medium, respectively. Hitherto, significantly increased numbers of γH2AX foci (p = 0.0286) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells grown in the (II) 10–100 kDa fraction (0.67 ± 0.10 γH2AX foci per CD34+ cell ∨ 3.8 ± 0.3 aberrant metaphases per CD34+ cell sample, mean ± SEM) when compared to (I) &lt, 10 kDa (0.19 ± 0.01 ∨ 0.3 ± 0.2) or (III) &gt, 100 kDa fractions (0.23 ± 0.04 ∨ 0.4 ± 0.4) or un-/fractionated control medium (0.12 ± 0.01 ∨ 0.1 ± 0.1). Furthermore, RIBEs disappeared after heat inactivation of medium at 75 °C. Taken together, our data suggest that RIBEs are mainly mediated by the heat-sensitive (II) 10–100 kDa fraction of MSC conditioned medium. We postulate proteins as RIBE mediators and in-depth proteome analyses to identify key bystander signals, which define targets for the development of next-generation anti-leukemic drugs.

Moving foreground detection is a very important step for many applications such as human behavior analysis for visual surveillance, model-based action recognition, road traffic monitoring, etc. Background subtraction is a very popular approach, but it is difficult to apply given that it must overcome many obstacles, such as dynamic background changes, lighting variations, occlusions, and so on. In the presented work, we focus on this problem (foreground/background segmentation), using a type-2 fuzzy modeling to manage the uncertainty of the video process and of the data. The proposed method models the state of each pixel using an imprecise and adjustable Gaussian mixture model, which is exploited by several fuzzy classifiers to ultimately estimate the pixel class for each frame. More precisely, this decision not only takes into account the history of its evolution, but also its spatial neighborhood and its possible displacements in the previous frames. Then we compare the proposed method with other close methods, including methods based on a Gaussian mixture model or on fuzzy sets. This comparison will allow us to assess our method&rsquo, s performance, and to propose some perspectives to this work.