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Ceritinib-induced regression of an insulin-like growth factor-driven neuroepithelial brain tumor
(2019)
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood–brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
Introduction: Epoxyeicosatrienoic acids (EETs) are able to enhance angiogenesis and regulate inflammation that is especially important in wound healing under ischemic conditions. Thus, we evaluated the effect of local EET application on ischemic wounds in mice.
Methods: Ischemia was induced by cautherization of two of the three supplying vessels to the mouse ear. Wounding was performed on the ear three days later. Wounds were treated either with 11,12 or 14,15 EET and compared to untreated control and normal wounds. Epithelialization was measured every second day. VEGF, TNF-α, TGF-β, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), Ki67, and SDF-1α were evaluated immunohistochemically in wounds on day 3, 6, and 9.
Results: Ischemia delayed wound closure (12.8 days ± 1.9 standard deviation (SD) for ischemia and 8.0 days ± 0.94 SD for control). 11,12 and14,15 EET application ameliorated deteriorated wound healing on ischemic ears (7.6 ± 1.3 SD for 11,12 EET and 9.2 ± 1.4 SD for 14,15 EET). Ischemia did not change VEGF, TNF-α, TGF-β, SDF-1α, TIMP, MMP7 or MMP9 level significantly compared to control. Local application of 11,12 as well as 14,15 EET induced a significant elevation of VEGF, TGF-β, and SDF-1α expression as well as proliferation during the whole phase of wound healing compared to control and ischemia alone.
Conclusion: In summary, EET improve impaired wound healing caused by ischemia as they enhance neovascularization and alter inflammatory response in wounds. Thus elevating lipid mediator level as 11,12 and 14,15 EET in wounds might be a successful strategy for amelioration of deranged wound healing under ischemia.
Delayed wound repair in sepsis is associated with reduced local pro-inflammatory cytokine expression
(2013)
Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.
Introduction: In an emergency department, the majority of pediatric trauma patients present because of minor injuries. The aim of this study was to evaluate temporal changes in age-related injury pattern, trauma mechanism, and surgeries in pediatric patients. Methods: This retrospective study included patients < 18 years of age following trauma from 01/2009 to 12/2018 at a level I trauma center. They were divided into two groups: group A (A: 01/2009 to 12/2013) and group B (B: 01/2014 to 12/2018). Injury mechanism, injury pattern, and surgeries were analyzed. As major injuries fractures, dislocations, and organ injuries and as minor injuries contusions and superficial wounds were defined. Results: 23,582 patients were included (58% male, median age 8.2 years). There was a slight increase in patients comparing A (n = 11,557) and B (n = 12,025) with no difference concerning demographic characteristics. Significant more patients (A: 1.9%; B: 2.4%) were admitted to resuscitation room, though the number of multiple injured patients was not significantly different. In A (25.5%), major injuries occurred significantly less frequently than in B (27.0%), minor injuries occurred equally. Extremity fractures were significantly more frequent in B (21.5%) than in A (20.2%), peaking at 8–12 years. Most trauma mechanisms of both groups were constant, with a rising of sport injuries at 8–12 years. Conclusion: Although number of patients increases only slightly over a decade, there was a clear increase in major injuries, particularly extremity fractures, peaking at 8–12 years. At this age also sport accidents significantly increased. At least, admittance to resuscitation room rose but without an increase of multiple injured patients.
Epoxyeicosatrienoic acids (EET) facilitate regeneration in different tissues, and their benefit in dermal wound healing has been proven under normal conditions. In this study, we investigated the effect of 11,12 EET on dermal wound healing in diabetes. We induced diabetes by i.p. injection of streptozotocin 2 weeks prior to wound creation on the dorsal side of the mouse ear. 11,12 EET was applied every second day on the wound, whereas the control groups received only solvent. Epithelialization was monitored every second day intravitally up to wound closure. Wounds were stained for VEGF, CD31, TGF-β, TNF-α, SDF-1α, NF-κB, and Ki-67, and fibroblasts were counted after hematoxylin-eosin stain on days 3, 6, 9, and 16 after wounding. After induction of diabetes, wounds closed on day 13.00 ± 2.20 standard deviation (SD). Local 11,12 ETT application improved wound closure significantly to day 8.40 ± 1.39 SD. EET treatment enhanced VEGF and CD31 expression in wounds on day 3. It also seemed to raise TNF-α level on all days investigated as well as TGF-β level on days 3 and 6. A decrease in NF-κB could be observed on days 9 and 16 after EET application. The latter findings were not significant. SDF-1α expression was not influenced by EET application, and Ki-67 was significantly less in the EET group on day 9 after EET application. The number of fibroblasts was significantly increased on day 9 after the 11,12 EET application. 11,12 EET improve deteriorated wound healing in diabetes by enhancing neoangiogenesis, especially in the early phase of wound healing. Furthermore, they contribute to the dissolution of the initial inflammatory reaction, allowing the crucial transition from the inflammatory to proliferative phase in wound healing.
Background: Reports of head and neck ultrasound examinations are frequently written by hand as free texts. Naturally, quality and structure of free text reports is variable, depending on the examiner’s individual level of experience. Aim of the present study was to compare the quality of free text reports (FTR) and structured reports (SR) of head and neck ultrasound examinations.
Methods: Both standard FTRs and SRs of head and neck ultrasound examinations of 43 patients were acquired by nine independent examiners with comparable levels of experience. A template for structured reporting of head and neck ultrasound examinations was created using a web-based approach. FTRs and SRs were evaluated with regard to overall quality, completeness, required time to completion, and readability by four independent raters with different specializations (Paired Wilcoxon test, 95% CI) and inter-rater reliability was assessed (Fleiss’ kappa). A questionnaire was used to compare FTRs vs. SRs with respect to user satisfaction (Mann-Whitney U test, 95% CI).
Results: By comparison, completeness scores of SRs were significantly higher than FTRs’ completeness scores (94.4% vs. 45.6%, p < 0.001), and pathologies were described in more detail (91.1% vs. 54.5%, p < 0.001). Readability was significantly higher in all SRs when compared to FTRs (100% vs. 47.1%, p < 0.001). The mean time to complete a report, however, was significantly higher in SRs (176.5 vs. 107.3 s, p < 0.001). SRs achieved significantly higher user satisfaction ratings (VAS 8.87 vs. 1.41, p < 0.001) and a very high inter-rater reliability (Fleiss’ kappa 0.92).
Conclusions: As compared to FTRs, SRs of head and neck ultrasound examinations are more comprehensive and easier to understand. On the balance, the additional time needed for completing a SR is negligible. Also, SRs yield high inter-rater reliability and may be used for high-quality scientific data analyses.
Purpose: The primary treatment goals for advanced-stage thumb carpometacarpal (CMC) joint osteoarthritis are complete pain relief and restoration of thumb strength. The purpose of the present study was to introduce a variation of the abductor pollicis longus (APL) suspension arthroplasty using a single looping of a radial slip from the APL tendon around the flexor carpi radialis (FCR) tendon combined with RegJoint™ interposition and to determine its efficacy in the treatment of thumb CMC joint osteoarthritis.
Methods: Between 2015 and 2017, 21 patients were included. The average age was 60.8 years (range 48–79). The mean follow-up was 27.7 months (range 8–50). Evaluation included pain, radial and palmar abduction, tip pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.
Results: Pain averaged 0.3 (range 0–4) at rest and 1.4 (range 0–4) on exertion. The radial and palmar abduction were 97% and 99% compared to the contralateral side. The tip pinch and grip strength were 4.1 kg (range 3–6.5) and 22 kg (range 13.3–40), respectively. The DASH score accounted for 18.5 (range 0.8–41.7).
Conclusion: The modified APL suspension interposition arthroplasty was an efficient and simplified option for the treatment of thumb CMC joint osteoarthritis, with results comparable or better than other published procedures. The APL suspension technique was easy to perform avoiding difficult bone tunneling and incision of the FCR tendon. The RegJoint™ interposition as spacer prevented impingement of the first metacarpal base on the second metacarpal base or the trapezoid bone.
Introduction: Stem cell transplantation is one of the most promising strategies to improve healing in chronic wounds as systemic administration of endothelial progenitor cells (EPC) enhances healing by promoting neovascularization and homing though a high amount of cells is needed. In the following study, we analysed whether local application can reduce the number of EPC needed achieving the same beneficial effect on wound healing.
Material and Methods: Wound healing after local or systemic treatment with EPC was monitored in vivo by creating standardized wounds on the dorsum of hairless mice measuring wound closure every second day. Systemic group received 2 × 106 EPC i.v. and locally treated group 2 × 105 EPC, locally injected. As control PBS injection was performed the same way. Expression of CD31, VEGF, CD90 and, SDF-1α was analysed immunohistochemically for evaluation of neovascularisation and amelioration of homing.
Results: Local (7.1 ± 0.45 SD) as well as systemic (6.1 ± 0.23 SD) EPC transplantation led to a significant acceleration of wound closure compared to controls (PBS local: 9.7 ± 0.5 SD, PBS systemic 10.9 ± 0.38 SD). Systemic application enhanced CD31 expression on day 6 after wounding and local EPC on 6 and 9 in comparison to control. VEGF expression was not significantly affected. Systemic and local EPC treatment resulted in a significantly enhanced SDF-1α and CD90 expression on all days investigated.
Conclusion: Local as well as systemic EPC treatment enhances wound healing. Moreover, beneficial effects are obtained with a tenfold decrease number of EPC when applied locally. Thus, local EPC treatment might be more convenient way to enhance wound healing as number of progenitor cells is limited.
For acute and chronic soft tissue infections, radical surgical debridement is required and is considered the gold standard, along with its immediate systemic antibiotic therapy. Treatment with local antibiotics and/or antibiotic-containing materials is commonly used as an additional tool in clinical practice. Spraying with fibrin and antibiotics is a newer technique that has been studied for some antibiotics. However, for gentamicin, data are not yet available on absorption, optimal application, antibiotic fate at the site and transfer of antibiotic into the blood. In an animal study involving 29 Sprague Dawley rats, 116 back wounds were sprayed with gentamicin using either gentamicin alone or one of two possible spray combinations of gentamicin and fibrin. Simultaneous application of gentamicin and fibrin via a spray system to soft tissue wounds resulted in significant antibiotic concentration over a long period of time. The technique is easy and cost-effective. The systemic crossover was significantly minimized in our study, which may have led to fewer side effects in patients. These results could lead to an improvement in local antibiotic therapy.