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Purpose. Copal\(^®\) spacem is a new PMMA bone cement for fabricating spacers. This study compares elution of gentamicin, elution of vancomycin, and compressive strength of Copal\(^®\) spacem and of Palacos\(^®\) R+G at different vancomycin loadings in the powder of the cements. We hypothesized that antibiotic elution of Copal\(^®\) spacem is superior at comparable compressive strength. Methods. Compression test specimens were fabricated using Copal\(^®\) spacem manually loaded with 0.5 g gentamicin and additionally 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (COP specimens) and using 0.5 g gentamicin premixed Palacos\(^®\) R+G manually loaded with 2 g, 4 g, and 6 g of vancomycin per 40 g of cement powder (PAL specimens). These specimens were used for determination of gentamicin and vancomycin elution (in fetal calf serum, at 22°C) and for determination of compressive strength both prior and following the elution tests. Results. Cumulative gentamicin concentrations (p < 0.005) and gentamicin concentration after 28 days (p ≤ 0.043) were significantly lower for COP specimens compared to PAL specimens. Cumulative vancomycin concentrations were significantly higher (p ≤ 0.043) for COP specimens after the second day. Vancomycin concentrations after 28 days were not significantly higher for the Copal specimens loaded with 2 g and 4 g of vancomycin. Compressive strength was not significantly different between COP specimens and PAL specimens before elution tests. Compressive strength after the elution tests was significantly lower (p = 0.005) for COP specimens loaded with 2 g of vancomycin. Conclusion. We could not demonstrate consistent superior antibiotic elution from Copal\(^®\) spacem compared to Palacos\(^®\) R+G for fabricating gentamicin and vancomycin loaded spacers. The results do not favor Copal\(^®\) spacem over Palacos\(^®\) R+G for the use as a gentamicin and vancomycin biantibiotic-loaded spacer.
Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.
Background
Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention.
Methods
Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles.
Results
We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD.
Conclusions
Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5%), TNF deficient (12.5%), and TNFR2 deficient mice (22.2%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.
Purpose
Glioma patients face a limited life expectancy and at the same time, they suffer from afflicting symptoms and undesired effects of tumor treatment. Apart from bone marrow suppression, standard chemotherapy with temozolomide causes nausea, emesis and loss of appetite. In this pilot study, we investigated how chemotherapy-induced nausea and vomiting (CINV) affects the patients' levels of depression and their quality of life.
Methods
In this prospective observational multicentre study (n = 87), nausea, emesis and loss of appetite were evaluated with an expanded MASCC questionnaire, covering 10 days during the first and the second cycle of chemotherapy. Quality of life was assessed with the EORTC QLQ-C30 and BN 20 questionnaire and levels of depression with the PHQ-9 inventory before and after the first and second cycle of chemotherapy.
Results
CINV affected a minor part of patients. If present, it reached its maximum at day 3 and decreased to baseline level not before day 8. Levels of depression increased significantly after the first cycle of chemotherapy, but decreased during the further course of treatment. Patients with higher levels of depression were more severely affected by CINV and showed a lower quality of life through all time-points.
Conclusion
We conclude that symptoms of depression should be perceived in advance and treated in order to avoid more severe side effects of tumor treatment. Additionally, in affected patients, delayed nausea was most prominent, pointing toward an activation of the NK1 receptor. We conclude that long acting antiemetics are necessary totreat temozolomide-induced nausea.
Hintergrund
Intensiv- und Beatmungskapazitäten sind für die Behandlung COVID-19-erkrankter Patienten essenziell. Unabhängig davon beanspruchen auch schwer verletzte Patienten häufig Intensiv- und Beatmungskapazitäten. Daraus ergibt sich folgende Fragestellung: Führt eine Ausgangsbeschränkung zu einer Reduktion schwer verletzter Patienten, und kann hierdurch mit frei werdenden Intensivkapazitäten gerechnet werden?
Material und Methoden
Es erfolgte eine retrospektive Auswertung schwer verletzter Patienten mit einem Injury Severity Score (ISS) ≥16 zwischen dem 17.03.2020 und 30.04.2020 (landesweiter Shutdown) an einem überregionalen Traumazentrum. Erfasst wurden der Unfallmechanismus, ISS, Versicherungsträger (BG vs. GKV/PKV), ob es sich um einen dokumentierten Suizidversuch handelte, und ob eine operative Intervention innerhalb der ersten 24 h erforderlich war. Als Kontrollgruppe wurden die Daten des gleichen Zeitraums der Jahre 2018 und 2019 ausgewertet.
Ergebnisse
Es konnte keine wesentliche Veränderung bezüglich der Anzahl an schwer verletzten Patienten festgestellt werden (2018 n = 30, 2019 n = 23, 2020 n = 27). Es zeigten sich insgesamt keine deutlichen Veränderungen der absoluten Zahlen bezüglich der Intensivpflichtigkeit in den ersten 24 h und der Beatmungspflichtigkeit beim Verlassen des Schockraums. Die Anzahl an Patienten, die eine Operation innerhalb der ersten 24 h nach Eintreffen im Schockraum benötigten, war 2020 sogar leicht erhöht, jedoch nicht statistisch signifikant. Der durchschnittliche ISS blieb konstant. Bezüglich der Unfallursache zeigte sich 2020 kein Motorradfahrer, der einen nicht berufsgenossenschaftlich versicherten Unfall erlitt (2018 n = 5, 2019 n = 4, 2020 n = 0). Es wurde 2020 ein erhöhter Anteil an Arbeitsunfällen mit einem ISS ≥16 festgestellt (2018: 10 %, 2019: 26,1 %, 2020: 44,4 %).
Diskussion
Eine Ausgangsbeschränkung führte zu keiner Reduktion verletzter- und intensivpflichtiger Patienten am untersuchten Zentrum. Auch unter einer landesweiten Ausgangsbeschränkung muss für dieses Patientenkollektiv eine ausreichende Menge an Intensiv- und OP-Kapazitäten vorgehalten werden. Die Bestätigung dieser Ergebnisse durch Auswertung nationaler Register steht noch aus.
Hintergrund
Intensiv- und Beatmungskapazitäten sind für die Behandlung COVID-19-erkrankter Patienten essenziell. Unabhängig davon beanspruchen auch schwer verletzte Patienten häufig Intensiv- und Beatmungskapazitäten. Daraus ergibt sich folgende Fragestellung: Führt eine Ausgangsbeschränkung zu einer Reduktion schwer verletzter Patienten, und kann hierdurch mit frei werdenden Intensivkapazitäten gerechnet werden?
Material und Methoden
Es erfolgte eine retrospektive Auswertung schwer verletzter Patienten mit einem Injury Severity Score (ISS) ≥16 zwischen dem 17.03.2020 und 30.04.2020 (landesweiter Shutdown) an einem überregionalen Traumazentrum. Erfasst wurden der Unfallmechanismus, ISS, Versicherungsträger (BG vs. GKV/PKV), ob es sich um einen dokumentierten Suizidversuch handelte, und ob eine operative Intervention innerhalb der ersten 24 h erforderlich war. Als Kontrollgruppe wurden die Daten des gleichen Zeitraums der Jahre 2018 und 2019 ausgewertet.
Ergebnisse
Es konnte keine wesentliche Veränderung bezüglich der Anzahl an schwer verletzten Patienten festgestellt werden (2018 n = 30, 2019 n = 23, 2020 n = 27). Es zeigten sich insgesamt keine deutlichen Veränderungen der absoluten Zahlen bezüglich der Intensivpflichtigkeit in den ersten 24 h und der Beatmungspflichtigkeit beim Verlassen des Schockraums. Die Anzahl an Patienten, die eine Operation innerhalb der ersten 24 h nach Eintreffen im Schockraum benötigten, war 2020 sogar leicht erhöht, jedoch nicht statistisch signifikant. Der durchschnittliche ISS blieb konstant. Bezüglich der Unfallursache zeigte sich 2020 kein Motorradfahrer, der einen nicht berufsgenossenschaftlich versicherten Unfall erlitt (2018 n = 5, 2019 n = 4, 2020 n = 0). Es wurde 2020 ein erhöhter Anteil an Arbeitsunfällen mit einem ISS ≥16 festgestellt (2018: 10 %, 2019: 26,1 %, 2020: 44,4 %).
Diskussion
Eine Ausgangsbeschränkung führte zu keiner Reduktion verletzter- und intensivpflichtiger Patienten am untersuchten Zentrum. Auch unter einer landesweiten Ausgangsbeschränkung muss für dieses Patientenkollektiv eine ausreichende Menge an Intensiv- und OP-Kapazitäten vorgehalten werden. Die Bestätigung dieser Ergebnisse durch Auswertung nationaler Register steht noch aus.
Background
The role of cement-augmented screw fixation for calcaneal fracture treatment remains unclear. Therefore, this study was performed to biomechanically analyze screw osteosynthesis by reinforcement with either a calcium phosphate (CP)-based or polymethylmethacrylate (PMMA)-based injectable bone cement.
Methods
A calcaneal fracture (Sanders type IIA) including a central cancellous bone defect was generated in 27 synthetic bones, and the specimens were assigned to 3 groups. The first group was fixed with four screws (3.5 mm and 6.5 mm), the second group with screws and CP-based cement (Graftys (R) QuickSet; Graftys, Aix-en-Provence, France), and the third group with screws and PMMA-based cement (Traumacem (TM) V+; DePuy Synthes, Warsaw, IN, USA). Biomechanical testing was conducted to analyze peak-to-peak displacement, total displacement, and stiffness in following a standardized protocol.
Results
The peak-to-peak displacement under a 200-N load was not significantly different among the groups; however, peak-to-peak displacement under a 600- and 1000-N load as well as total displacement exhibited better stability in PMMA-augmented screw osteosynthesis compared to screw fixation without augmentation. The stiffness of the construct was increased by both CP- and PMMA-based cements.
Conclusion
Addition of an injectable bone cement to screw osteosynthesis is able to increase fixation strength in a biomechanical calcaneal fracture model with synthetic bones. In such cases, PMMA-based cements are more effective than CP-based cements because of their inherently higher compressive strength. However, whether this high strength is required in the clinical setting for early weight-bearing remains controversial, and the non-degradable properties of PMMA might cause difficulties during subsequent interventions in younger patients.
Background
Dislocations of the elbow are the second most common dislocations of humeral joints following the shoulder. Besides numerous possible concomitant injuries of the collateral ligaments or the extensor or flexor apparatus, an accompanying disruption of the brachial artery is a rare occurrence. In the following, such a case is presented and discussed.
Method
A 70-year-old woman sustained a closed posterior elbow dislocation with accompanying disruption of the brachial artery due to a fall in a domestic environment. Pulselessness of the radial artery led to a computed tomography angiography being performed, which confirmed the diagnosis. Direct operative vascular reconstruction with a vein insert was carried out. Due to strong swelling of the soft tissue, other examinations of the elbow could not be performed initially. A redislocation a few days later led to an operative stabilization of the elbow joint.
Results
The final consultation 4 months postoperatively showed a stable, centered elbow joint and a normal perfusion of the affected arm. The elbow function was good with a range of motion of 0/0/110° of extension/flexion.
Conclusion
An elbow dislocation is a complex injury. An accurate clinical examination of possible concomitant injuries is important and should be repeated in the first few days after the occurrence. Vascular reconstruction should be performed immediately. In the case of persistent joint instability, an operative stabilization is indicated and may be supported by a hinged external fixator.