[Regulation of bone metabolism by the Wnt signaling pathway]. / Regulation des Knochenstoffwechsels durch den Wnt-Signalweg.

The development and homeostasis of multicellular organisms depends on a complex cellular interaction between proliferation, migration, differentiation, adhesion, and cell death. Wnt signaling pathways coordinate these different cellular responses. Wnt signaling plays a role as a regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. The Wnt signaling pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for the regeneration of skeletal tissue. Recent studies indicate that Wnt ligands are capable of promoting bone growth, suggesting that Wnt factors could be used to stimulate bone healing in osteogenic disorders.

[Soft tissue sarcomas: limb salvage using reconstructive plastic surgery techniques]. / Weichgewebssarkome: Extremitätenerhalt durch plastisch-rekonstruktive Verfahren.

The treatment of choice for soft tissue sarcomas with local involvement is still the complete surgical removal into healthy tissue. The aim of surgery is to achieve tumor-free resection margins in the sense of a R0 resection. No other treatment option can equally replace this important oncological condition. The enormous development in the field of reconstructive plastic surgery and in particular the advances in flap techniques and microsurgery enable limb salvage and the functional reconstruction even in the case of extensive tumors.

Improvement of local microcirculation through intermittent Negative Pressure Wound Therapy (NPWT).

BACKGROUND: Negative Pressure Wound Therapy (NPWT) is widely used across different kinds of surgical disciplines. A controversial debate was raised by diverging results from studies that were conducted to examine the impact of NPWT on local perfusion. Thus, there is a lack of evidence for one important underlying factors that influences the physiology of wound healing under an applied NPWT-dressing. OBJECTIVE: To investigate the immediate local perfusion changes due to an applied intermittent NPWT protocol. MATERIAL AND METHODS: A NPWT dressing was applied to the antero-lateral thigh of seven healthy volunteers with two probes of both pressure and microcirculatory measuring devices. One of each probe was placed under the NPWT dressing, the other one in close proximity next to it. A protocol consisting of two cycles of 10 min of -125 mmHg pressure, followed by 10 min of 0 mmHg pressure was applied. Measurements of local pressure to the underlying tissue, as well as microcirculatory changes were performed continuously. RESULTS: Applied vacuum caused compressional forces (27.33 mmHg, p < 0.05) towards the underlying tissue. Blood Flow was increased after both suction periods (+52.5%, +108.7%; p < 0.05) and continued increasing until the end of measurements (+145.3%). This was accompanied by significant increase in Oxygen Saturation (+21.6%; p < 0.05) and Relative Hemoglobin Content (+16.7%). Red Blood Cell Velocity was found to be increased without statistical significance. Next to the dressing, changes were also significant but less pronounced. CONCLUSION: Intermittent NPWT improves local microcirculation with consecutive enhancement of oxygen supply.

Sternal Reconstruction with the Omental Flap-Acute and Late Complications, Predictors of Mortality, and Quality of Life.

BACKGROUND: The omental flap is a reliable flap for the coverage of sternal defects. However, little is known about the predictors of mortality and the long-term outcome in such patients. METHODS: We, therefore, performed a retrospective study from 2002 to 2013, including all patients who underwent sternal reconstruction with the omental flap. RESULTS: A total of 50 patients were identified and mean follow-up was 3.8 years. Patient data was collected from the charts and 14 patients were available for telephone interviews. The majority of patients suffered from deep sternal wound infections. There was no complete flap loss and an overall success rate was 96%. In-hospital mortality was 14% and overall survival over follow-up was 50%. Significant predictors of mortality were age > 65, American Society of Anesthesiologists' status, defect size, prolonged ventilation, and the need for tracheotomy. Postoperative quality of life was reduced compared with other cohorts, especially with regard to bodily function. Pain was also a major problem for most patients along with herniation. CONCLUSION: The omental flap is a safe option even in patients with severe comorbidities. However, based on the data in this study, we would recommend the omental flap as a reserve option rather than first-line treatment for sternal defects.

[Remote Ischemic Conditioning - Endogenous Tissue Protection and its Possible Applications in Surgery]. / Remote ischemic Conditioning ­ endogene Gewebeprotektion und ihre Einsatzmöglichkeiten in der Chirurgie.

Tissue perfusion is pivotal to wound healing and tissue regeneration after surgery. Ischemia and reperfusion lead to inflammatory reactions with consecutive tissue damage and necrosis. Multiple conditioning techniques have been described to protect tissue from those damaging mechanisms in the perioperative period. However, most of these fail to meet the requirements of a good therapeutic effect, time and cost efficiency, non-invasiveness and applicability without the need for additional devices or drugs. Remote ischemic conditioning (RIC) is a technique to provide endogenous tissue protection, which fully meets those requirements. Repeated, short cycles of ischemia/reperfusion applied to a circumscribed vascular territory lead to the activation of endogenous signal pathways resulting in increased tolerance to hypoperfusion and limiting the damage caused by reperfusion, even in tissues located far away from the conditioned area. The non-invasive application of the conditioning stimulus requires no more than a pressure cuff, which is placed on the upper arm and is repeatedly inflated to suprasystolic pressures. Different concepts of remote ischemic pre-, peri- and postconditioning enable the usage in both elective and emergency surgical interventions. Based on encouraging experimental studies, the application of RIC has increased in the clinical setting. In addition to studies addressing cardio-, nephro- or neuroprotection there are some initial findings supporting a potential beneficial application in reconstructive microsurgery. This article aims to give an overview of the development, concepts and mechanisms of RIC with a focus on its clinical application in the field of surgery.

Ten minutes of ischemia is superior to shorter intervals for the remote ischemic conditioning of human microcirculation.

BACKGROUND: Surgical flaps have become reliable tools in the microsurgical armamentarium, but are still faced with tissue loss due to impaired perfusion which can lead to complete flap failure. Remote Ischemic Conditioning (RIC) has been demonstrated to be an effective way to improve microcirculation in surgical flaps in humans. However, little is known about the optimal amount and length of RIC cycles. OBJECTIVE: Determination of a superior protocol for RIC of cutaneous microcirculation in humans. METHODS: 60 healthy volunteers were randomized into different groups and received a RIC protocol, consisting of three cycles of either 1 second, 1, 5, or 10 minutes of ischemia followed by ten minutes of reperfusion. RIC was applied with a inflatable tourniquet placed on the upper arm. Changes in microcirculation were assessed via combined laser doppler/spectroscopy (O2C device) at the anterior lateral thigh. Relative increase at the end of conditioning vs. baseline measurements was calculated and compared between groups. RESULTS: RIC caused significant changes in cutaneous microcirculation (p < 0.05) which were more pronounced in groups with longer ischemia intervals. The ten minutes group was significantly superior. CONCLUSION: A conditioning protocol containing three cycles of ten minutes of ischemia is superior to protocols with shorter ischemia intervals for RIC of cutaneous microcirculation.

Albumin reduces the antibacterial efficacy of wound antiseptics against Staphylococcus aureus.

OBJECTIVE: The influence of proteins on the efficacy of antiseptic solutions has been rarely investigated even though exudate can contain high levels of protien. The aim of this study was to analyse the antibacterial efficacy of commonly used solutions in the presence of albumin protein. METHOD: Using Staphylococcus aureus in a standardised quantitative suspension assay, the antibacterial effects of poly (1-(2-oxo-1-pyrrolidinyl) ethylene)-iodine (PVP-I) and octenidin-dihydrochloride/phenoxyethanol (OCT/PE) were analysed in the presence of 0-3% bovine serum albumin (BSA). These were compared with previous results obtained with polyhexamethylene biguanide hydrochloride (PHMB). RESULTS: Presence of albumin caused a significant (p<0.001) decrease in antibacterial effect in the analysed solutions. The concentrations of albumin that provoked highly significant decreases in the bacterial reduction factors of the study agents were: 0.01875 % for PVP-I, followed by 0.75 % for OCT/PE. After addition of 3 % albumin, adequate antimicrobial effects were ensured for titrations to 5 % PVP-I and 8 % OCT/PE. As we could show before, it is not possible to titrate PHMB in order to assure adequate potency. CONCLUSION: This study demonstrates that albumin induces a significant decrease of the antibacterial potency of the analysed solutions.

Curcumin and Viscum album Extract Decrease Proliferation and Cell Viability of Soft-Tissue Sarcoma Cells: An In Vitro Analysis of Eight Cell Lines Using Real-Time Monitoring and Colorimetric Assays.

BACKGROUND: The cytostatic effects of the polyphenol curcumin and Viscum album extract (VAE) were assessed in soft-tissue sarcoma (STS) cells. METHODS: Eight human STS cell lines were used: fibrosarcoma (HT1080), liposarcoma (SW872, T778, MLS-402), synovial sarcoma (SW982, SYO1, 1273), and malignant fibrous histiocytoma (U2197). Primary human fibroblasts served as control cells. Cell proliferation, viability, and cell index (CI) were analyzed by BrdU assay, MTT assay, and real-time cell analysis (RTCA). RESULTS: As indicated by BrdU and MTT, curcumin significantly decreased the cell proliferation of five cell lines (HT1080, SW872, SYO1, 1273, and U2197) and the viability of two cell lines (SW872 and SW982). VAE led to significant decreases of proliferation in eight cell lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, 1293, and U2197) and reduced viability in seven STS lines (HT1080, SW872, T778, MLS-402, SW982, SYO1, and 1273). As indicated by RTCA for 160 h, curcumin decreased the CI of all synovial sarcoma cell lines as well as T778 and HT1080. VAE diminished the CI in most of the synovial sarcoma (SW982, SYO1) and liposarcoma (SW872, T778) cell lines as well as HT1080. Primary fibroblasts were not affected adversely by the two compounds in RTCA. CONCLUSION: Curcumin and VAE can inhibit the proliferation and viability of STS cells.

[Management of Complex Tympanojugular Paragangliomas]. / Interdisziplinäres Management von komplexen tympanojugulären Paragangliomen Fisch Typ C und D.

Background: Tympanojugular paraganglioma (TJP) are benign, high vascularized, local destructive tumors. Despite many studies in the literature, the management of particularly complex TJP (e. g., posterior fossa and/or carotid artery invasion) remains controversial. In the current study we present our treatment strategies for complex TJP and long-term results. Patients and methods: Between 2003 and 2013, 17 patients with TJP Fisch types C and D were treated in our institution. Primary symptoms were hearing loss, followed by facial nerve palsy and lower cranial nerve impairments. 2 patients presented with recurrent tumors. Surgical treatment after endovascular tumor embolization was performed in 14 patients. 2 patients were treated by radiation therapy. Results: Gross tumor resection was achieved in 10 patients. A temporary postoperative facial nerve palsy occurred in 2 patients and permanent postoperative vocal cord palsy in 3 patients. During long term follow-up, one patient experienced regrowth of the residual tumor. No tumor progress was observed in both patients treated with radiation therapy. Outcome assessed by Karnofsky scale showed 100% functionality in 12 patients and 90% in 5 patients. Discussion: Surgical treatment of TJP after endovascular embolization is the treatment of choice in young and healthy patients. In older patients with premorbid conditions, radiation therapy is the main treatment option and is associated with high tumor control rates. Precise preoperative staging together with individualize risk-benefit assessment and interdisciplinary treatment strategy are essential for a favorable outcome.

[Prognostic factors and surgical tactics in patients with locally recurrent soft tissue sarcomas]. / Prognostische Faktoren und chirurgische Taktik bei lokal rezidivierten Weichteilsarkomen.

BACKGROUND: The aim of this study was to identify prognostic indicators of survival in patients with locally recurrent soft tissue sarcoma through a long-term follow-up. METHODS: We retrospectively assessed the relationship between post-recurrence survival (PRS) and potential predictive factors in 135 patients who had experienced local recurrence after surgical treatment. The median follow-up time after initial recurrence was 12.3 years (95% confidence interval [CI]: 10.4-14.2 years). RESULTS: The 5-year estimate of the PRS rate was 53.1% (95% CI: 44.3-61.2%) for the entire series. Synovial sarcoma and fibrosarcoma were associated with a significantly worse post-recurrence outcome compared with other STS histotypes. Patients with negative margins after the final surgery experienced improved survival compared with patients with positive margins (5-year survival: 46.7% [35.2-57.5%] vs. 35.5% [23.4-47.8%]; P=0.01). In a multivariate analysis, the significant prognostic indicators for PRS were histologic grade, tumour site, time to initial recurrence, the number of recurrences and the surgical margin status attained at the last resection. CONCLUSIONS: Complete surgical resection with microscopically clear margins is desirable in patients with locally recurrent STS. However, when achieving clear surgical margins will require major functional impairment of the extremity, a radical surgical approach should be carefully weighed out for the patient in each case.

Upper extremity ischemia is superior to lower extremity ischemia for remote ischemic conditioning of antero-lateral thigh cutaneous blood flow.

Remote ischemic conditioning (RIC) is known to improve microcirculation in various settings, but little is known about the impact of the amount of ischemic tissue mass or the limb itself. Since ischemia and subsequent necrosis of flaps is one of the most dreaded complications in reconstructive surgery, adjuvant methods to improve microcirculation are desirable. We therefore performed a randomized trial to compare the effect of arm versus leg ischemia for RIC of the cutaneous microcirculation of the antero-lateral thigh. Forty healthy volunteers were randomized to undergo 5 min of ischemia of either the upper or lower extremity, followed by 10 min of reperfusion.Ischemia was induced by a surgical tourniquet applied to the proximal limb, which was inflated to 250 mmHg for the upper and 300 mgHg for the lower extremity. This cycle was repeated a total of three times. Cutaneous microcirculation was assessed by combined laser doppler spectrophotometry on the antero-lateral aspect of the thigh to measure cutaneous blood flow (BF), relative hemoglobin content (rHb), and oxygen saturation (StO2). Baseline measurements were performed for 10 min, after which the ischemia/reperfusion cycles were begun. Measurements were performed continuously and were afterwards pooled to obtain a mean value per minute. Both groups showed significant increases in all three measured parameters of cutaneous microcirculation after three cycles of ischemia/reperfusion when compared to baseline (BF: 95.1% (P < 0.001) and 27.9% (P = 0.002); rHb: 9.4% (P < 0.001) and 5.9% (P < 0.001), StO2: 8.4% (P = 0.045) and 9.4% (P < 0.001). When comparing both groups, BF was significantly higher in the arm group (P = 0.019 after 11 min., P = 0.009 after 45 min). In conclusions, both ischemic conditioning of the upper and lower extremity is able to improve cutaneous BF on the ALT donor site. However, RIC of the upper extremity seems to be a superior trigger for improvement of cutaneous BF.

Thoracic Wall Reconstruction in Advanced Breast Tumours.

In advanced mammary tumours, extensive resections, sometimes involving sections of the thoracic wall, are often necessary. Plastic surgery reconstruction procedures offer sufficient opportunities to cover even large thoracic wall defects. Pedicled flaps from the torso but also free flap-plasties enable, through secure defect closure, the removal of large, ulcerated, painful or bleeding tumours with moderate donor site morbidity. The impact of thoracic wall resection on the respiratory mechanism can be easily compensated for and patients' quality of life in the palliative stage of disease can often be improved.

Long-term outcome after local recurrence of soft tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma.

BACKGROUND: The aim of this study was to identify prognostic indicators of survival in patients with locally recurrent soft tissue sarcoma (STS) through a long-term follow-up. METHODS: We retrospectively assessed the relationship between post-recurrence survival (PRS) and potential prognostic factors in 135 patients who had experienced local recurrence, which was suitable for further surgical treatment. The median follow-up time after initial recurrence was 12.3 years (95% confidence interval (CI): 10.4-14.2 years). RESULTS: The 5-year estimate of the PRS rate was 53.1% (95% CI: 44.3-61.2%) for the entire series. Patients with negative margins after the final surgery experienced improved survival compared with patients with positive margins (5-year survival: 46.7% (35.2-57.5%) vs 35.5% (23.4-47.8%); P=0.01). In a multivariate analysis, the significant prognostic indicators for PRS were histologic grade, tumour site, time to initial recurrence, the number of recurrences and the surgical margin status attained at the last resection. CONCLUSIONS: Complete surgical resection with microscopically clear margins is desirable in patients with locally recurrent STS. However, when achieving clear surgical margins will require major functional impairment of the extremity, a radical surgical approach should be weighed for the patient in each case.

Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma.

Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.

TRAIL and taurolidine enhance the anticancer activity of doxorubicin, trabectedin and mafosfamide in HT1080 human fibrosarcoma cells.

BACKGROUND: Disseminated fibrosarcoma still represents a therapeutic dilemma because of lack of effective cytostatics. Therefore we tested tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and taurolidine, in combination with established and new chemotherapeutic agents on human fibrosarcoma (HT1080). MATERIALS AND METHODS: Human fibrosarcoma cells (HT1080) were incubated with doxorubicin, mafosfamide and trabectedin both alone and in combination with taurolidine and TRAIL. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Cell proliferation was analysed using a bromodeoxyuridine (BrdU) ELISA assay. RESULTS: Single application of doxorubicin and trabectedin induced apoptotic cell death and significantly reduced the proliferation of HT1080 cells. In combination treatment, the addition of taurolidine and TRAIL resulted in a stronger reduction in the degree of cell viability when compared to single treatment. Trabectedin and taurolidine displayed a greater potential for inhibiting proliferation than did doxorubicin alone. CONCLUSION: When combined with TRAIL and taurolidine, treatment with doxorubicin and trabectedin demonstrated stronger apoptosis-inducing and antiproliferative effects.

[Proximal radial nerve palsy resulting from acute Epstein-Barr virus infection]. / Epstein-Barr-Virus-assoziierte proximale Radialisparese.

Irreparable peripheral nerve palsies rarely present as neurological complications in infectious mononucleosis. A case of isolated proximal radial nerve palsy resulting from an acute infection with Epstein-Barr virus is reported. The hand function was restored by multiple tendon transfer surgery.