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Background: Polytraumatized patients undergo a strong immunological stress upon insult. Phagocytes (granulocytes and monocytes) play a substantial role in immunological defense against bacteria, fungi and yeast, and in the clearance of cellular debris after tissue injury. We have reported a reduced monocytes phagocytic activity early after porcine polytrauma before. However, it is unknown if both phagocyte types undergo those functional alterations, and if there is a pathogen-specific phagocytic behavior. We characterized the phagocytic activity and capacity of granulocytes and monocytes after polytrauma.
Methods: Eight pigs (Sus scrofa) underwent polytrauma consisting of lung contusion, liver laceration, tibial fracture and hemorrhagic shock with fluid resuscitation and fracture fixation with external fixator. Intensive care treatment including mechanical ventilation for 72 h followed. Phagocytic activity and capacity were investigated using an in vitro ex vivo whole blood stimulation phagocytosis assays before trauma, after surgery, 24, 48, and 72 h after trauma. Blood samples were stimulated with Phorbol-12-myristate-13-acetate and incubated with FITC-labeled E. coli, S. aureus or S. cerevisiae for phagocytosis assessment by flow cytometry.
Results: Early polytrauma-induced significant increase of granulocytes and monocytes declined to baseline values within 24 h. Percentage of E. coli-phagocytizing granulocytes significantly decreased after polytrauma and during further intensive care treatment, while their capacity significantly increased. Interestingly, both granulocytic phagocytic activity and capacity of S. aureus significantly decreased after trauma, although a recovery was observed after 24 h and yet was followed by another decrease. The percentage of S. cerevisiae-phagocytizing granulocytes significantly increased after 24 h, while their impaired capacity after surgery and 72 h later was detected. Monocytic E. coli-phagocytizing percentage did not change, while their capacity increased after 24–72 h. After a significant decrease in S. aureus-phagocytizing monocytes after surgery, a significant increase after 24 and 48 h was observed without capacity alterations. No significant changes in S. cerevisiae-phagocytizing monocytes occurred, but their capacity dropped 48 and 72 h.
Conclusion: Phagocytic activity and capacity of granulocytes and monocytes follow a different pattern and significantly change within 72 h after polytrauma. Both phagocytic activity and capacity show significantly different alterations depending on the pathogen strain, thus potentially indicating at certain and possibly more relevant infection causes after polytrauma.
Purpose: Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes.
Methods: Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles.
Results: Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head–neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3–5 cm in 28, 5–10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size.
Conclusion: Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter.
Background: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.
Methods: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.
Results: Median age of 185 patients was 13.9 years (0.1–56)—with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3–5 cm in 59 (32%), 5–10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.
Discussion: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
Background: To evaluate optimal therapy and potential risk factors.
Methods: Data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed.
Results: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high‐dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three‐year event‐free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra‐abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.
Conclusion: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
Background: We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P.
Methods: Patients were treated in CWS-91 with four- (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five-drug (+etoposide [EVAIA]) cycles, in CWS-96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS-2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT).
Results: Two hundred forty-three patients fulfilled the eligibility criteria. The 5-year event-free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57–69) and 73% (95% CI 67–79), respectively. The 5-year EFS by study was 64% (95% CI 54–74) in CWS-91, 57% (95% CI 48–66) in CWS-96, and 79% (95% CI 67–91) in CWS-2002P (n.s.). The 5-year OS was 72% (95% CI 62–82) in CWS-91, 70% (95% CI 61–79) in CWS-96, and 86% (95% CI 76–96) in CWS-2002P (n.s.). In CWS-96, 5-year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52–81) versus 55% (95% CI 39–76) log-rank p = .13, and 85% (95% CI 75–96) versus 61% (95% CI 45–82), log-rank p = .09.
Conclusion: Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET–ETS fusion positive tumors.
Im Rahmen der Versorgung von polytraumatisierten (schwerstverletzten) Patienten ist insbesondere die systemische Inflammation zu beachten. Durch das initiale Trauma (“first hit“) kommt es zu einer systemischen Dysregulation der inflammatorischen Kaskaden, wobei sowohl eine überschießende (SIRS/Sepsis) wie auch unterschießende Reaktion (CARS) zu schweren Komplikationen wie Multiorganversagen bis hin zum Tod führen kann. Die notfallmässige chirurgische Versorgung fügt durch multiple Faktoren wie Weichteilverletzung, Blutverlust und Intubation dem Patienten einen “second hit“ zu, welcher sich auf den “first hit“ aufsummieren und besagte Komplikationen induzieren kann. Aufgrund dessen wurden verschiedene Therapiekonzepte entwickelt wie beispielsweise die “Damage control surgery“, welche durch minimalinvasive Techniken die notfallmässig versorgungsbedürftigen Verletzungen temporär stabilisiert/versorgt, bis der Patient sich physiologisch stabilisiert und definitiv versorgt werden kann. Eine weitere Strategie stellt die „Safe Definitive Surgery“ dar, welche eine Synopsis bildet aus zu einen frühzeitiger definitiver Versorgung gepaart mit minimalinvasiven Techniken, um während der Operation multipler Frakturen intraoperativ anhand der Physiologie des Patienten regelmäßig zu reevaluieren und daran zu adjustieren.
Bei der definitiven Versorgung von langen Röhrenknochen im Schaftbereich werden klinisch standardmässig Marknägel verwendet. Hierbei eröffnet man den langen Röhrenkochen am proximalen Eintrittspunkt, bohrt den Knochen intramedullär mittels “Reamer“ auf und führt den Nagel ein, welchen man mittels Schrauben multidimensional in der Corticalis verriegelt. Hierbei stellt die intramedulläre Aufbohrung den kritischsten Schritt dar, da hierbei zum einen Knochenmark austritt und durch den Bohrer Thermonekrosen im Knochen auftreten können sowie auch Knochenpartikel austreten. Um diese Nachteile zu beheben, wurde der “Reamer-Irrigator-Aspirator“ (RIA) entwickelt, welcher nebst der klassischen Bohrfunktion noch eine Spül-Saugfunktion innehat und somit parallel intramedullär eine Kühlung herbeiführt, wie auch das Knochenmark nebst Knochenpartikeln absaugt. Hiervon gibt es eine ältere (RIA 1) und eine neuere (RIA 2) Version, wobei sich diese geringfügig in Grösse des Bohrkopfes und der Saugfunktion wie auch im Handling unterscheiden. Wenig ist jedoch zum aktuellen Zeitpunkt bekannt, welche Auswirkungen diese unterschiedlichen Versionen verglichen mit dem konventionellen “Reamer haben“. Um dies näher zu evaluieren, wurde ein standardisiertes Polytrauma-Modell an 30 Schweinen (Sus scrofa) durchgeführt. Unter konstanter Analgesie wurde nach Erreichen einer standardisierten Baseline an 24 der Tiere ein Polytrauma, bestehend aus unilateraler Femurfraktur, stumpfem Thoraxtrauma inklusive Leberlazeration und hämorrhagischem Schock ausgeübt. Sechs Tiere fungierten als Kontrollgruppe (sham), welche kein Trauma sowie Therapie erhielten, aber sonst gleich behandelt wurden. Die polytraumatisierten Tiere erhielten Therapie nach Schockraum- und ATLS Versorgung nach dem Trauma. Bestehend aus “Abdominal Packing“, Kreislaufstabilisierung und Versorgung der Femurfraktur mittels intramedullärer Nagelung. Die 24 polytraumtisierten Versuchstiere wurden bezüglich der Versorgung der Femurfraktur in drei Gruppen aufgeteilt: 1) Konventionelles Reaming, 2) RIA 1 und 3) RIA 2. An sechs Zeitpunkte (t1 (-1.5h) - t6 (6h)) über 7.5 Stunden erfolgten regelmäßige Blut- wie Urinentnahmen und eine bronchoalveoläre Lavage vor fachgerechtem Exitus am letzen Zeitpunkt. Anschließend wurde mittels ELISA in besagten Proben das Interleukin-6, Interleukin-8, Interleukin-10 und Tumornekrosefaktor-alpha bestimmt und statistische Unterschiede zwischen den Gruppen ermittelt.
Die Ergebnisse legen nahe, dass die Verwendung des Reamer-Irrigator-Aspirator Typ 2 aufgrund spezifischer Modifikationen verglichen mit seinem Vorgänger (RIA Typ 1) eine geringere inflammatorische Immunantwort aufweist. Verglichen mit dem konventionellen Reaming konnte in unserer Versuchsreihe in Hinblick auf entzündliche Mediatoren systemisch wie lokal kein Unterschied zu der Versorgung mittels RIA aufgezeigt werden. Jedoch präsentierte sich bei der Benutzung des konventionellen Reamers auch in unserer Versuchsreihe das Auftreten einer Fett/Lungenembolie, was bereits in der Literatur als eine gängige Komplikation dieses Instrumentariums beschrieben wird. Zusammenfassend ist der Reaming-Irrigator-Aspirator eine modernisierte Version des konventionellem Reamers, welcher multiple Vorteile aufweist, jedoch im Rahmen der Kostensenkung wahrscheinlich erst im weiteren zeitlichen Verlauf regelmäßige Anwendung in der Klinik finden wird.