ASXL1 mutations are associated with a response to alvocidib and 5-azacytidine combination in myelodysplastic neoplasms.

Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.

Cervical vertebral body replacement using a modern in situ expandable and angulable corpectomy cage system: early clinical and radiological outcome.

PURPOSE: Vertebral body replacement (VBR) cages are commonly implanted to reconstruct the cervical vertebrae in cases of tumour, trauma, spondylodiscitis, and degeneration. Expandable cages have been widely used for this purpose; however, the lacking congruence at the implant-bone interface and consequent implant displacement were considered as a serious drawback of such systems. Aim of this study is to evaluate the early clinical and radiological outcome of a modern in situ not only expandable but also angulable cervical corpectomy cage system. METHODS: A total of 42 patients who underwent a single or multilevel cervical VBR procedure were included and retrospectively evaluated in this single-centre case series. The neurological status was assessed using American Spinal Injury Association (ASIA) score. Complications were categorized into surgical (including implant-associated) and general medical. Radiographic parameters included regional angulation, segmental height, and coronal alignment. RESULTS: Mean age was 59.5 ± 20.6 years. The recorded ASIA score improved postoperatively by 10 points (p  0.0001). Surgical including implant-associated complication rates were 19.05%. Radiographic evaluation showed a height gain of 11.2 mm (p < 0.0001), lordotic correction of 7° (p < 0.0001), and coronal alignment of 3° (p < 0.0001). At the last follow-up, loss of angulation correction of 1.9° (p  0.0002), subsidence of 1.92 mm (p  0.0006), and fusion rates of 68.42% were observed. CONCLUSIONS: The use of an in situ angulable and expandable cage system in cervical VBR seems to offer better results compared to conventional static or expandable cages regarding segmental height gain, lordotic correction, and clinical improvement as well as low complication and revision rates. Significant height gain in multilevel surgeries is associated with higher rates of implant-associated complications.

Anthropometric three-dimensional computed tomography reconstruction measurements of the acetabulum in children/adolescents.

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.

Singleton-Merten syndrome: A rare cause of femoral head necrosis.

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.

Incidence of concomitant chondral/osteochondral lesions in acute ankle fractures and their effect on clinical outcome: a systematic review and meta-analysis.

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.

Anthropometry of the proximal femur and femoral head in children/adolescents using three-dimensional computed tomography-based measurements.

PURPOSE: Defining 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. METHODS: Morphology of the proximal femur was retrospectively assessed in 170 hips (85 children, < 15 years). Measurements included covered femoral head volume (CFHV), femoral head diameter (FHD), femoral head extrusion index (FHEI), coronal alpha angle (CAA), lateral centre-edge angle (LCEA), anterior (AOS) and posterior head-neck offset (POS) and femoral neck-shaft angle (FNSA). Correlation analyses as well as inter- and intra-rater reliability were performed. RESULTS: CFHV, 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). CONCLUSION: This 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.

[Solitary locoregional metastasis of an undifferentiated pleomorphic sarcoma in the M. quadratus femoris]. / Solitäre lokoregionäre Metastase eines undifferenzierten pleomorphen Sarkoms im M. quadratus femoris.

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.

[Risk factors affecting mortality in patients with hip fractures at a regional trauma center]. / Einflussfaktoren auf die Mortalität bei Patienten mit hüftgelenknahen Frakturen an einem regionalen Traumazentrum.

BACKGROUND: Primary care hospitals and regional trauma centers play an essential role in the treatment of hip fractures. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

One- vs. Two-Stage Revision for Periprosthetic Shoulder Infections: A Systematic Review and Meta-Analysis.

Periprosthetic shoulder infection (PSI) remains a challenging complication after shoulder arthroplasty. Therapeutic options include one- or two-stage revision, irrigation and debridement, and resection arthroplasty. With our systematic review and meta-analysis, we aimed to compare one- and two-stage revisions for periprosthetic shoulder joint infections and determine the most appropriate therapeutic procedure. We performed an extensive literature search in PubMed, Ovid Medline, Cochrane Library, Web of Science, and CINAHL and filtered out all relevant studies. The meta-analysis was performed using the random-effects model, heterogeneity was analyzed using I2, and publication bias was assessed using the Egger's test. A total of 8 studies with one-stage revisions, 36 studies with two-stage revisions, and 12 studies with both one-stage and two-stage revisions were included. According to the random-effects model, the reinfection rate for the entirety of the studies was 12.3% (95% Cl: 9.6-15.3), with a low-to-moderate heterogeneity of I2 = 47.72%. The reinfection rate of the one-stage revisions was 10.9%, which was significantly lower than the reinfection rate of the two-stage revisions, which was 12.93% (p = 0.0062). The one-stage revision rate was significantly lower with 1.16 vs. 2.25 revisions in the two-stage revision group (p < 0.0001). The postoperative functional outcome in one-stage-revised patients was comparable but not statistically significant (p = 0.1523). In one- and two-stage revisions, most infections were caused by Cutibacterium acnes. In summary, our systematic review and meta-analysis show the superiority of single-stage revision regarding reinfection and revision rates in periprosthetic shoulder joint infection.

Vitamin D level and low-energy fracture risk in children and adolescents: a population-based case-control study of 45 cases.

The objective is to document the rate of vitamin D deficiency and insufficiency among children with low-energy fractures and compare it to fracture-free control group. We included all children under 15 years presenting to the emergency department with low-energy fractures; controls were children without history of fractures from the outpatient department. Conventional X-ray and laboratory blood tests were performed. Vitamin D deficiency was defined as serum level ≤20 ng/ml, and the mean values were compared through two-sample t-tests. The influence of vitamin D on the fractures was defined using Chi-square test, significance with P-value < 0.05. The relationships between variables and odds of fracture occurrence were examined using logistic regression models. The final sample included 37 cases (30 males, 7 females, 7.4 ± 3.7 years) and 70 control individuals (42 males, 28 females, 7.8 ± 4.6 years) without significant differences regarding age, sex, and month of inclusion. Children with fractures had lower levels of vitamin D (21.87 ± 8.40 ng/ml vs. 25.89 ± 7.62 ng/ml) (P = 0.01). Vitamin D played a protective role against low-energy fractures (OR, 1.08; 95% CI, 1.01-1.14; P = 0.02), boys showed three times greater fracture risk than girls (OR, 3.00; 95% CI, 1.12-8.07; P = 0.03). Finally, vitamin D deficiency correlated with almost five times increased risk of pediatric low-energy fractures (OR, 4.63; 95% CI, 1.92-11.18; P = 0.001). This is the first MENA study establishing a relation between vitamin D deficiency and low-energy fractures among children and adolescents. The findings show the protective role of vitamin D on the pediatric bone and may help physicians preventing morbidity on children and costs on their families and the socioeconomic health system.

A Multi-Disciplinary MRI Assessment May Optimize the Evaluation of Chondral Lesions in Acute Ankle Fractures: A Prospective Study.

Chondral lesions (CL) in the ankle following acute fractures are frequently overlooked immediately after the injury or diagnosed at a later stage, leading to persistent symptoms despite successful surgery. The literature presents a wide range of discrepancies in the reported incidence of CLs in acute ankle fractures. The objective of this prospective study is to provide a precise assessment of the occurrence of chondral lesions (CLs) in acute ankle fractures through MRI scans conducted immediately after the trauma and prior to scheduled surgery. Furthermore, the study aims to highlight the disparities in the interpretation of these MRI scans, particularly concerning the size and extent of chondral damage, between radiologists and orthopedic surgeons. Over the period of three years, all patients presenting with an unstable ankle fracture that underwent operative treatment were consecutively included in this single-center prospective study. Preoperative MRIs were obtained for all included patients within 10 days of the trauma and were evaluated by a trauma surgeon and a radiologist specialized in musculoskeletal MRI blinded to each other's results. The location of the lesions was documented, as well as their size and ICRS classification. Correlations and kappa coefficients as well as the p-values were calculated. A total of 65 patients were included, with a mean age of 41 years. The evaluation of the orthopedic surgeon showed CLs in 52.3% of patients. CLs occurred mainly on the tibial articular surface (70.6%). Most talar lesions were located laterally (11.2%). The observed CLs were mainly ICRS grade 4. According to the radiologist, 69.2% of the patients presented with CLs. The most common location was the talar dome (48.9%), especially laterally. Most detected CLs were graded ICRS 3a. The correlation between the two observers was weak/fair regarding the detection and classification of CLs and moderate regarding the size of the detected CLs. To enhance the planning of surgical treatment for ankle chondral lesions (CLs), it may be beneficial to conduct an interdisciplinary preoperative assessment of the performed scans. This collaborative approach can optimize the evaluation of ankle CLs and improve overall treatment strategies.

Cemented versus Cementless Stem Fixation in Revision Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

The number of revision knee arthroplasties (rTKA) is growing significantly as is the use of intramedullary stems for optimized stability. The choice of the most appropriate stem fixation method is still controversial. The purpose of this meta-analysis is to compare cemented versus cementless stem fixation in rTKA. Publications with patients undergoing rTKA with a follow-up > 24 months were systemically reviewed. Extracted parameters included total revision and failure rates for any reason, incidence of aseptic loosening, periprosthetic infection, and radiolucent lines, as well as the clinical outcome. A statistical regression analysis was then performed on all extracted clinical and radiological outcome data. A total of 35 publications met the inclusion criteria and were included and analyzed. Overall, 14/35 publications compared cementless versus cemented stem fixation, whereas 21/35 publications investigated only one stem fixation method. There were no significant differences in revision (p = 0.2613) or failure rates (p = 0.3559) and no differences in the incidence of aseptic loosening (p = 0.3999) or periprosthetic infection (p = 0.1010). The incidence of radiolucent lines was significantly higher in patients with cemented stems (26.2% versus 18.6%, p < 0.0001). However, no differences in clinical outcomes were observed. No superiority of a specific stem fixation method in rTKA was found. Rates of revision or failure for any reason as well as incidence of aseptic loosening and periprosthetic infection in cemented versus cementless stem fixation showed no significant difference. A higher incidence of radiolucent lines was observed in cemented stem fixation; however, no effect was observed on the clinical outcome.

Significant improvement of bone marrow-derived MSC expansion from MDS patients by defined xeno-free medium.

BACKGROUND: Robust and reliable in vitro and in vivo models of primary cells are necessary to study the pathomechanisms of Myelodysplastic Neoplasms (MDS) and identify novel therapeutic strategies. MDS-derived hematopoietic stem and progenitor cells (HSPCs) are reliant on the support of bone marrow (BM) derived mesenchymal stroma cells (MSCs). Therefore, isolation and expansion of MCSs are essential for successfully modeling this disease. For the clinical use of healthy MSCs isolated from human BM, umbilical cord blood or adipose tissue, several studies showed that xeno-free (XF) culture conditions resulted in superior growth kinetics compared to MSCs cultured in the presence of fetal bovine serum (FBS). In this present study, we investigate, whether the replacement of a commercially available MSC expansion medium containing FBS with a XF medium is beneficial for the expansion of MSCs derived from BM of MDS patients which are often difficult to cultivate. METHODS: MSCs isolated from BM of MDS patients were cultured and expanded in MSC expansion medium with FBS or XF supplement. Subsequently, the impact of culture media on growth kinetics, morphology, immunophenotype, clonogenic potential, differentiation capacity, gene expression profiles and ability to engraft in immunodeficient mouse models was evaluated. RESULTS: Significant higher cell numbers with an increase in clonogenic potential were observed during culture of MDS MSCs with XF medium compared to medium containing FBS. Differential gene expression showed an increase in transcripts associated with MSC stemness after expansion with XF. Furthermore, immunophenotypes of the MSCs and their ability to differentiate into osteoblasts, adipocytes or chondroblasts remained stable. MSCs expanded with XF media were similarly supportive for creating MDS xenografts in vivo as MSCs expanded with FBS. CONCLUSION: Our data indicate that with XF media, higher cell numbers of MDS MSCs can be obtained with overall improved characteristics in in vitro and in vivo experimental models.

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

Anthropometric measurements of the pediatric hip using CT-based simulated anteroposterior radiographs of the pelvis.

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.

5-Year Clinical and Radiographic Results of the Direct Anterior Approach for Total Hip Arthroplasty Using a Collared Cementless Femoral Short-Stem Prosthesis.

The aim of this study was to investigate the radiological and clinical outcome of the direct anterior approach (DAA) in total hip arthroplasty (THA) using a collared cementless femoral short-stem. This retrospective study included 124 patients with 135 THAs operated from 2014 to 2016 using a collared cementless triple tapered hydroxyapatite-coated femoral short-stem (AMIStem H Collared®, Medacta International, Castel San Pietro, Switzerland) implanted with a DAA. Follow-up was performed at three months, 12 months, and five years. Clinical outcome was assessed using the hip osteoarthritis outcome score (HOOS) and radiological analysis was done using conventional radiographs, which included evaluation of the femur morphology based on Dorr classification, of radiolucencies based on the Gruen zone classification and of stem subsidence. The mean age was 67.7 ± 11.3 years and the mean body mass index (BMI) was 27.4 ± 4.4 kg/m2. The stem survival rate at five years was 99.1% with one revision due to recurrent dislocations. Mean HOOS score improved from 40.9 ± 18.3 preoperatively to 81.5 ± 19.7 at three months, 89.3 ± 10.9 at 12 months, and 89.0 ± 14.0 at five years (all with p < 0.001). No significant correlations were found between age, femoral bone morphology, BMI and HOOS, and the appearance of relevant radiolucencies.

Wide Variability in Return-to-Sport Criteria used by Team Physicians After Anterior Cruciate Ligament Reconstruction in Elite Athletes-A Qualitative Study.

Purpose: The purpose of this study is to explore currently used readiness to return to sport (RTS) criteria after anterior cruciate ligament reconstruction (ACLR) used in elite athletes to gain novel insights into the RTS decision-making process of professional team physicians. Methods: Eighteen qualitative semistructured interviews with professional team physicians were conducted by a single trained interviewer. The interviews were used to identify team physician concepts and themes regarding the criteria used to determine RTS after ACLR. General inductive analysis and a coding process were used to identify themes and subthemes arising from the data. A hierarchical approach in coding helped to link themes. Results: The most important RTS criteria included muscle strength, followed by satisfactory functional testing including hop tests, a satisfactory clinical examination, joint stability, psychological readiness, time since the ACLR surgery, absence of joint effusion, subjective feeling of knee stability, pain-free return to sporting movements, completion of a sport-specific rehabilitation, and at last allied team support. Conclusions: This study identified 4 main themes, including (1) objective findings, (2) informative feedback of the team members, (3) subjective findings, and (4) type of sport and time to surgery as having the most influence on RTS decision after ACLR. However, interviews showed that even among professional team physicians, the main criteria to RTS in these categories were inconsistent. A definitive set of conclusive guidelines could not be established and would be a fruitful and useful area for future research through further quantitative studies and international consensus meetings along the foundation of the presenting study. Level of Evidence: V, evidence-based practices, qualitative study.

Evidence for Recombinant GRP78, CALR, PDIA3 and GPI as Mediators of Genetic Instability in Human CD34+ Cells.

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.

Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes.

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.