Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a disease characterized by increased susceptibility to infections, hypogammaglobulinemia, and immune dysregulation. Although CVID is thought to be a disorder of the peripheral B-cell compartment, in 25% of patients, early B-cell development in the bone marrow is impaired. Because poor B-cell reconstitution after hematopoietic stem cell transplantation has been observed, we hypothesized that in some patients the bone marrow environment is not permissive to B-cell development. Studying the differentiation dynamics of bone marrow-derived CD34+ cells into immature B cells in vitro allowed us to distinguish patients with B-cell intrinsic defects and patients with a nonpermissive bone marrow environment. In the former, immature B cells did not develop and in the latter CD34+ cells differentiated into immature cells in vitro, but less efficiently in vivo. In a further group of patients, the uncommitted precursors were unable to support the constant development of B cells in vitro, indicating a possible low frequency or exhaustion of the precursor population. Hematopoietic stem cell transplantation would result in normal B-cell repopulation in case of intrinsic B-cell defect, but in defective B-cell repopulation in a nonpermissive environment. Our study points to the importance of the bone marrow niche in the pathogenesis of CVID.

[Tumor-like bony lesions of the skeleton]. / Tumorähnliche Knochenläsionen des Skeletts.

Tumor-like bony lesions are, by definition bony lesions, which can be clinically, radiologically and histologically mistaken for real bone tumors. This article presents the aneurysmal bone cyst (ABC), solitary bone cyst (SBC), fibrous dysplasia, osteofibrous dysplasia Campanacci and non-ossifying fibroma (NOF). Many tumor-like bony lesions are often incidental findings. The combination of X­ray imaging specifically supplemented by magnetic resonance imaging (MRI) or computed tomography (CT) enables a diagnostic classification in the majority of cases.

[Tumor-like bony lesions of the skeleton]. / Tumorähnliche Knochenläsionen des Skeletts.

Tumor-like bony lesions are, by definition bony lesions, which can be clinically, radiologically and histologically mistaken for real bone tumors. This article presents the aneurysmal bone cyst (ABC), solitary bone cyst (SBC), fibrous dysplasia, osteofibrous dysplasia Campanacci and non-ossifying fibroma (NOF). Many tumor-like bony lesions are often incidental findings. The combination of X­ray imaging specifically supplemented by magnetic resonance imaging (MRI) or computed tomography (CT) enables a diagnostic classification in the majority of cases.

Genotyping of circulating cell-free DNA enables noninvasive tumor detection in myxoid liposarcomas.

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin. About 50% of patients with STS experience relapse and more than 30% will die within 10 years after diagnosis. In this study we investigated circulating free DNA (cfDNA) and tumor-specific genetic alterations therein (circulating tumor DNA, ctDNA) as diagnostic biomarkers. Plasma concentrations and fragmentation of cfDNA was analyzed with quantitative PCR. Patients with STS (n = 64) had significantly higher plasma concentrations and increased fragmentation of cfDNA when compared to patients in complete remission (n = 19) and healthy controls (n = 41) (p < 0.01 and p < 0.001). Due to overlapping values between patients with STS and controls, the sensitivity and specificity of these assays is limited. Sensitive assays to detect genomic alterations in cfDNA of synovial sarcomas (t(X;18)), myxoid liposarcomas (t(12;16) and TERT C228T promoter mutation) and well-differentiated/de-differentiated liposarcomas (MDM2 amplifications) were established. ctDNA was quantified in nine liposarcoma patients during the course of their treatment. Levels of breakpoint t(12;16) and TERT C228T ctDNA correlated with the clinical course and tumor burden in patients with myxoid liposarcomas (n = 4). ctDNA could detect minimal residual disease and tumor recurrence. In contrast, detection of MDM2 amplifications was not sensitive enough to detect tumors in patients with well-differentiated/de-differentiated liposarcomas (n = 5). Genotyping of cfDNA for tumor specific genetic alterations is a feasible and promising approach for monitoring tumor activity in patients with myxoid liposarcomas. Detection of ctDNA during follow-up examinations despite negative standard imaging studies might warrant more sensitive imaging (e.g. PET-CT) or closer follow-up intervals to timely localize and treat recurrences.

Neuromuscular adaptations and sensorimotor integration following a unilateral transfemoral amputation.

BACKGROUND: Following an amputation, the human postural control system develops neuromuscular adaptations to regain an effective postural control. We investigated the compensatory mechanisms behind these adaptations and how sensorimotor integration is affected after a lower-limb transfemoral amputation. METHODS: Center of pressure (CoP) data of 12 unilateral transfemoral amputees and 12 age-matched able-bodied subjects were recorded during quiet standing with eyes open (EO) and closed (EC). CoP adjustments under each leg were recorded to study their contribution to posture control. The spatial structure of the CoP displacements was characterized by measuring the mean distance, the mean velocity of the CoP adjustments, and the sway area. The Entropic Half-Life (EnHL) quantifies the temporal structure of the CoP adjustments and was used to infer disrupted sensory feedback loops in amputees. We expanded the analysis with measures of weight-bearing imbalance and asymmetry, and with two standardized balance assessments, the Berg Balance Scale (BBS) and Timed Up-and-Go (TUG). RESULTS: There was no difference in the EnHL values of amputees and controls when combining the contributions of both limbs (p = 0.754). However, amputees presented significant differences between the EnHL values of the intact and prosthetic limb (p <  0.001). Suppressing vision reduced the EnHL values of the intact (p = 0.001) and both legs (p = 0.028), but not in controls. Vision feedback in amputees also had a significant effect (increase) on the mean CoP distance (p <  0.001), CoP velocity (p <  0.001) and sway area (p = 0.007). Amputees presented an asymmetrical stance. The EnHL values of the intact limb in amputees were positively correlated to the BBS scores (EO: ρ = 0.43, EC: ρ = 0.44) and negatively correlated to the TUG times (EO: ρ = - 0.59, EC: ρ = - 0.69). CONCLUSION: These results suggest that besides the asymmetry in load distribution, there exist neuromuscular adaptations after an amputation, possibly related to the loss of sensory feedback and an altered sensorimotor integration. The EnHL values suggest that the somatosensory system predominates in the control of the intact leg. Further, suppressing the visual system caused instability in amputees, but had a minimal impact on the CoP dynamics of controls. These findings points toward the importance of providing somatosensory feedback in lower-limb prosthesis to reestablish a normal postural control. TRIAL REGISTRATION: DRKS00015254 , registered on September 20th, 2018.

Non-ossifying fibroma: natural history with an emphasis on a stage-related growth, fracture risk and the need for follow-up.

BACKGROUND: The aim of this study was to assess and present the radiological morphology of the non-ossifying fibroma (NOF), to describe the life span according to the Ritschl-stages in an effort to determine critical stages with regard to pathological fractures and discuss the need for a follow-up. METHODS: Reports of a consecutive series of 87 patients with 103 NOFs and a mean follow-up of 27 months were analysed according to the Ritschl-stages with regard to age at time of diagnosis, localisation, duration of stage and symptoms. RESULTS: Mean patient age in our series was 20 years and lesions most frequently affected the long bones of the lower extremity. Nineteen lesions were categorized in stage A, 53 in stage B, 17 in stage C and 14 in stage D. Most lesions were detected incidentally. In six of ten clinically symptomatic patients with an average age of ten years a pathological fracture occurred, and four of them were located in the tibia. All of these were in stage B with a mean length of 44 mm, an average expansion in relation to the bone-diameter of 75 % in transversal and 87 % in sagittal plane. Duration of the stages was variable. In the critical stage B the mean was 21 months. CONCLUSION: The non-ossifying fibroma follows a characteristic radiomorphological course with variable duration of each stage. Stage B lesions were found to be at an increased risk of fracture, and the age range over which fractures occur was wide. No fractures were detected in the other three stages. Follow-up, including clinical survey and imaging, at six to twelve month intervals may therefore be considered in the case of larger stage B lesions until stage C is reached.

Identification of a blood-borne miRNA signature of synovial sarcoma.

BACKGROUND: Synovial sarcoma account for approximately 10 % of all soft-tissue tumors and occur most frequently in young adults. A specific translocation in this sarcoma induces fusion of the SYT gene on chromosome 18 to the SSX genes on chromosome X, leading to proliferation of the tumor cells. The need for non-invasive biomarkers indicating recurrence and activity of this disease has sparked research into short non-coding RNA known as microRNA (miRNA). METHODS: Blood samples of patients with active synovial sarcoma and of synovial sarcoma patients in complete remission as well as of healthy donors and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma were collected. Whole blood RNA was extracted and samples of patients with active synovial sarcoma and of healthy donors were analyzed using an Affymetrix GeneChip miRNA Array v. 4.0. qRT-PCR was carried out to confirm a panel of miRNAs which where differentially expressed in the miRNA array. This miRNA-panel was further evaluated in patients with synovial sarcoma in complete remission and patients with active leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma as well as in an independent cohort of synovial sarcoma patients. RESULTS: Unsupervised hierarchical clustering of the miRNA arrays separated patients with active synovial sarcoma from healthy controls. A panel of seven miRNAs (miR-99a-5p, miR-146b-5p, miR-148b-3p, miR-195-5p, miR-223-3p, miR-500b-3p and miR-505-3p) was further validated by qRT-PCR to be significantly upregulated in synovial sarcoma patients. Moreover, most of the analyzed miRNAs were shown to be significantly upregulated in synovial sarcoma patients compared to leiomyosarcoma, MPNST, Ewing sarcoma and liposarcoma patients. Validation of the miRNA panel in an independent cohort of synovial sarcoma patients confirmed higher expression levels compared to healthy controls and patients in complete remission. CONCLUSION: Our results have identified a specific whole blood miRNA signature that may serve as an independent biomarker for the diagnosis of local recurrence or distant metastasis of synovial sarcoma. It even distinguishes synovial sarcoma from other sarcoma subtypes, thus potentially serving as a specific biomarker for synovial sarcoma.

Novel endoscopic sacroiliac screw removal technique: reduction of intraoperative radiation exposure.

OBJECTIVE: We report in the following on our technique of endoscopic sacroiliacal screw removal as a new extra-articular endoscopic method in soft tissue surgery, aimed at the reduction of radiation exposure for both the patient and the surgical teams. Patients who underwent endoscopic implant removal from the dorsal pelvic ring (Group A) were retrospectively compared with a control group, in which the screws were removed via the conventional approach (Group B). The parameters of interest were the extent of x-ray exposure in seconds and surgical duration in minutes as well as approach related peri- and postoperative complications. RESULTS: 34 screws were removed endoscopically from 28 patients in group A and 35 screws from 29 patients in group B. The mean skin-to-skin time in group A was 36.1 (15-111) min and 32.7 (12-114) min in group B. The difference was not statistically significant (p > 0.05). The average radiation time in group A was 5.7 ± 3.2 s (range, 0-101 s), while in group B the radiation time was significantly longer (52.6 ± 23 s (range, 0-239 s); p = 0.005). CONCLUSIONS: Endoscopic screw removal from the posterior pelvic ring reduces the intraoperative radiation time whereas the skin-to-skin times do not differ from the conventional procedure. LEVEL OF EVIDENCE: Case-control study, Level III.

[Bone-RADS: Diagnostic algorithm for management of incidental solitary bone lesions]. / Bone-RADS: Diagnostischer Algorithmus zum Management von inzidentellen solitären Knochenläsionen.

The bone reporting and data system (Bone-RADS) is a guideline of the Society of Skeletal Radiology for the standardized assessment of incidentally found solitary bone lesions. It consists of basic definitions and continuative algorithms for the radiological diagnosis of bone lesions in computed tomography (CT) and magnetic resonance imaging (MRI). This Continuing Medical Education (CME) article gives a compact summary of the Bone-RADS classification for users. After reading this article Bone-RADS can be used by anyone. The authors have compiled the critical comments and obstacles at the end of the article.

Does the Pathologic Fracture Predict Severe Paralysis in Patients with Metastatic Epidural Spinal Cord Compression (MESCC)?-A Retrospective, Single-Center Cohort Analysis.

Currently, there is uncertainty about the predictive factors for metastatic epidural spinal cord compression (MESCC) and consecutive symptomatology in tumor patients. Prognostic algorithms for identifying patients at risk for paralysis are missing. The influence of the pathologic fracture on the patient's symptoms is widely discussed in the literature and we hypothesize that pathologic fractures contribute to spinal cord compression and are therefore predictive of severe paralysis. We tested this hypothesis in 136 patients who underwent surgery for spinal metastases. The most common primary cancers were prostate (24.3%, n = 33), breast (11.0%, n = 15), lung (10.3%, n = 14), and cancer of unknown primary (10.3%, n = 14). MESCC primarily affected the thoracic (77.2%, n = 105), followed by the lumbar (13.2%, n = 18) and cervical (9.6%, n = 13) spine. Pathologic fractures occurred in 63.2% (n = 86) of patients, mainly in osteolytic metastases. On the American spinal injury association (ASIA) impairment scale (AIS), 63.2% (n = 86) of patients exhibited AIS grade D and 36.8% (n = 50) AIS grade C-A preoperatively. The presence of a pathologic fracture alone did not predict severe paralysis (AIS C-A, p = 0.583). However, the duration of sensorimotor impairments, patient age, spinal instability neoplastic score (SINS), and the epidural spinal cord compression (ESCC) grade together predicted severe paralysis (p = 0.006) as did the ESCC grade 3 alone (p = 0.028). This is in contrast to previous studies that stated no correlation between the degree of spinal cord compression and the severity of neurologic impairments. Furthermore, the high percentage of pathologic fractures found in this study is above previously reported incidences. The risk factors identified can help to predict the development of paralysis and assist in the improvement of follow-up algorithms and the timing of therapeutic interventions.

The effect of intramedullary bone endoscopy on the endosteal blood supply in long bones. An experimental study in sheep.

This study investigated whether the Intramedullary Bone Endoscopy (IBE) procedure within the cavity of an intact long bone will interfere with the local endosteal blood supply. In a sheep model, 10 animals underwent the IBE procedure with complete perioperative anaesthesiology monitoring. After the femora were harvested, histological analysis was performed to examine destruction of the endosteum and consecutive reduction in perfusion. Only one animal showed evidence of detachment of the endosteum with destruction of several microns of the endosteum, although this did not interfere with the cortical perfusion. None of the vessels were occluded by fat or other causes of occlusion, e.g. blood coagulation. Our findings indicate that with the IBE procedure under visual control there is a potential risk to damage the endosteum. However, the interference was limited to a small part of the endosteum and did not lead to a reduction in the cortical perfusion. Clinical use could be in localized intramedullary lesions such as osteomyelitis or benign bone tumours.

Chondrogenic Bone Tumors: The Importance of Imaging Characteristics. / Chondrogene Knochentumoren: Bildgebung als Wegweiser?

BACKGROUND: Chondrogenic tumors are the most frequent primary bone tumors. Malignant chondrogenic tumors represent about one quarter of malignant bone tumors. Benign chondrogenic bone tumors are frequent incidental findings at imaging. Radiological parameters may be helpful for identification, characterization, and differential diagnosis. METHODS: Systematic PubMed literature research. Identification and review of studies analyzing and describing imaging characteristics of chondrogenic bone tumors. RESULTS AND CONCLUSIONS: The 2020 World Health Organization (WHO) classification system differentiates between benign, intermediate (locally aggressive or rarely metastasizing), and malignant chondrogenic tumors. On imaging, typical findings of differentiated chondrogenic tumors are lobulated patterns with a high signal on T2-weighted magnetic resonance imaging (MRI) and ring- and arc-like calcifications on conventional radiography and computed tomography (CT). Depending on the entity, the prevalence of this chondrogenic pattern differs. While high grade tumors may be identified due to aggressive imaging patterns, the differentiation between benign and intermediate grade chondrogenic tumors is challenging, even in an interdisciplinary approach. KEY POINTS: · The WHO defines benign, intermediate, and malignant chondrogenic bone tumors. · Frequent benign tumors: osteochondroma and enchondroma; Frequent malignant tumor: conventional chondrosarcoma. · Differentiation between enchondroma versus low-grade chondrosarcoma is challenging for radiologists and pathologists. · Pain, deep scalloping, cortical destruction, bone expansion, soft tissue component: favor chondrosarcoma. · Potential malignant transformation of osteochondroma: progression after skeletal maturity, cartilage cap thickness (> 2 cm adult; > 3 cm child). · Potentially helpful advanced imaging methods: Dynamic MRI, texture analysis, FDG-PET/CT. CITATION FORMAT: · Engel H, Herget GW, Füllgraf H et al. Chondrogenic Bone Tumors: The Importance of Imaging Characteristics. Fortschr Röntgenstr 2021; 193: 262 - 274.

Influence of Augmented Visual Feedback on Balance Control in Unilateral Transfemoral Amputees.

Patients with a lower limb amputation rely more on visual feedback to maintain balance than able-bodied individuals. Altering this sensory modality in amputees thus results in a disrupted postural control. However, little is known about how lower limb amputees cope with augmented visual information during balance tasks. In this study, we investigated how unilateral transfemoral amputees incorporate visual feedback of their center of pressure (CoP) position during quiet standing. Ten transfemoral amputees and ten age-matched able-bodied participants were provided with real-time visual feedback of the position of their CoP while standing on a pressure platform. Their task was to keep their CoP within a small circle in the center of a computer screen placed at eye level, which could be achieved by minimizing their postural sway. The visual feedback was then delayed by 250 and 500 ms and was combined with a two- and five-fold amplification of the CoP displacements. Trials with eyes open without augmented visual feedback as well as with eyes closed were further performed. The overall performance was measured by computing the sway area. We further quantified the dynamics of the CoP adjustments using the entropic half-life (EnHL) to study possible physiological mechanisms behind postural control. Amputees showed an increased sway area compared to the control group. The EnHL values of the amputated leg were significantly higher than those of the intact leg and the dominant and non-dominant leg of controls. This indicates lower dynamics in the CoP adjustments of the amputated leg, which was compensated by increasing the dynamics of the CoP adjustments of the intact leg. Receiving real-time visual feedback of the CoP position did not significantly reduce the sway area neither in amputees nor in controls when comparing with the eyes open condition without visual feedback of the CoP position. Further, with increasing delay and amplification, both groups were able to compensate for small visual perturbations, yet their dynamics were significantly lower when additional information was not received in a physiologically relevant time frame. These findings may be used for future design of neurorehabilitation programs to restore sensory feedback in lower limb amputees.

Interdisciplinary approach to multiple myeloma - time to diagnosis and warning signs.

Delayed diagnosis is a common challenge in the management of multiple myeloma (MM). This prospective interdisciplinary study evaluated symptoms and time to diagnosis (TTD) in 81/295 screened patients at our tertiary center, who were examined by an orthopedist prior to the MM diagnosis. The most frequent complaint was back pain (81%), mainly localized thoracic and/or lumbar. Pain was independent of movement in 85%, occurred at night in 69%, and at multiple localizations in 30% of patients. Notably, 63% patients with an orthopedic disease noticed substantial symptom change before the MM diagnosis was made. The median TTD was 7 months and did not differ significantly between patients with or without a preexisting skeletal disease. To avoid delayed diagnosis, physicians should consider MM as a differential diagnosis, whenever warning signs such as skeletal pain independent from movement, at night, at various localizations, and change in pain characteristics accompanied by fatigue, are reported.

Time from first symptom onset to the final diagnosis of multiple myeloma (MM) - possible risks and future solutions: retrospective and prospective 'Deutsche Studiengruppe MM' (DSMM) and 'European Myeloma Network' (EMN) analysis.

Multiple myeloma (MM) often presents with unspecific symptoms and is challenging to diagnose. We performed this DSMM/EMN-analysis via test-(retro-) and validation (prospective) study to determine the time interval from the onset of first symptoms to the diagnosis of MM. The retrospective and prospective analyses were performed in 101 and 176 patients, respectively. The median time from first symptoms to the MM diagnosis in both cohorts was 4 and 6 months, respectively. Frequencies of MM-related pathologic bone fractures, renal, and infectious complications at diagnosis occurred in 41%, 35%, and 16% of patients, respectively. Our MM-questionnaire determined that 39% of patients were dissatisfied with the diagnostic process. PFS and OS proved insignificantly different with shorter (≤6) and longer (>6 months) latency periods. In conclusion, our in depth studies demonstrate that delays in diagnosis do not decrease PFS or OS, but induce MM-related complications and influence patients' satisfaction with their medical care.

Anatomical Reconstruction of the Acromion Using an Autologous Iliac Crest Graft for Treatment of Recurrent Chondroblastoma: A Case Report.

CASE: A 38-year-old man presented with recurrent chondroblastoma of the acromion after primary curettage and bone grafting. The patient underwent revision surgery with resection of the acromion and reconstruction using an autologous iliac crest graft. He had regained normal shoulder function without recurrence at a follow-up of 17 months. CONCLUSIONS: This case demonstrates a rare location of chondroblastoma and successful anatomical and functional reconstruction. The described surgical procedure could be considered for large tumorous lesions of the acromion, for which curettage would be insufficient, and to preserve and reconstruct a functionally intact shoulder girdle.

Efficacy and Safety of Microsurgery in Interdisciplinary Treatment of Sarcoma Affecting the Bone.

Background: Sarcomas are tumors of mesenchymal origin with high variation in anatomical localization. Sarcomas affecting the bone often require an interdisciplinary resection and reconstruction approach. However, it is critical that microsurgical reconstruction strategies do not negatively impact tumor safety and overall survival, as limb salvage is only the secondary goal of tumor surgery. Here, we analyzed the efficacy and safety of microsurgery in interdisciplinary treatment of sarcoma affecting the bone. Patients and Methods: We performed a retrospective chart review of all patients treated for soft-tissue and bone sarcoma at the senior author's institution with a focus on bone affection and microsurgical reconstruction between 2000 and 2019. This particular subgroup was further investigated for tumor resection status, 5-year survival rate, length of hospital stay, as well as overall complication and amputation rates. Results: Between 2000 and 2019, 803 patients were operated for sarcoma resection and reconstruction by the Department of Plastic and Hand Surgery. Of these, 212 patients presented with sarcoma of the extremity affecting the bone. Within this subgroup, 40 patients required microsurgical reconstruction for limb salvage, which was possible in 38 cases. R0 resection was achieved in 93.8%. The 5-year survival was 96.7%, and the overall complication rate was 25%, of which 40% were microsurgery associated complications. Conclusion: Safe and function-preserving treatment of soft-tissue and bone sarcoma is challenging. Primary reconstruction with microsurgical techniques of sarcoma-related defects enables limb-sparing and adequate oncosurgical cancer treatment without increasing the risk for local recurrence or prolonged hospital stay. The treatment of sarcoma patients should be reserved to high-volume centers with experienced plastic surgeon embedded in a comprehensive treatment concept.