Intrazelluläre Wirksamkeit von Gentamicin und Rifampicin im humanen Osteoblasten-Infektionsmodell

Ziel dieser Arbeit war es, ein Osteoblasteninfektionsmodell zu etablieren und die intrazelluläre Wirksamkeit von Gentamicin und Rifampicin auf die Referenzstämme der aktuellen Literatur im Osteoblasteninfektionsmodell zu untersuchen. Die Internallisierungsfähigkeit von ATCC 49230 wurde im Vergleich zu den Referenzstämmen im Osteoblasteninfektionsmodell, unter zu Hilfenahme des Transmissionselektronenmikroskopes als auch Toxinanalysen evaluiert. ATCC 49230 weist eine 2,5 fache Internalisierungsrate als Cowan I auf und besitzt zusätzlich die Fähigkeit zur Externalisierung, extrazellulären Replikation als auch zur Reinternalisierung in noch nicht befallene Osteoblasten. Beim Einsatz von Antibiotika sollte somit immer bedacht werden in wie weit eine intrazelluläre Wirksamkeit vorliegt, des Weiteren belegen die Daten eindeutig die Notwendigkeit von Antibiotikakombinations-Therapien in lokal hohen Konzentrationen, um eine suffiziente Therapie von Knocheninfektionen zu gewährleisten

Comparative study of the corrosion behavior of peripheral stents in an accelerated corrosion model: experimental in vitro study of 28 metallic vascular endoprostheses

PURPOSEClinical cases of stent-fractures show that corrosion behavior might play a role in these fractures. Implanted in vivo, especially in combination with other implanted foreign materials, these metallic products are exposed to special conditions, which can cause a process of corrosion. Here, we aimed to test the corrosion potential of stents made of different materials in an in vitro setting.METHODSA total of 28 peripheral stents of different materials (nitinol, cobalt-chromium-nickel, tantalum, V4A) and surface treatments (electropolish, mechanical polish, no polish) were tested in vitro. Corrosion was accelerated by applying a constant voltage of 3.5 V and amperage of 1.16 mA in 0.9% NaCl.RESULTSNitinol stents showed the lowest susceptibility to corrosion and the longest period without damage. The Memotherm II® (BARD Angiomed®) was the only stent that showed neither macroscopic nor microscopic damages. The worst performing material was cobalt-chromium-nickel, which showed corrosion damages about ten times earlier compared to nitinol. Considering the reasons for termination of the test, nitinol stents primarily showed length deficits, while V4A and tantalum stents showed fractures. Cobalt-chromium-nickel stents had multiple fractures or a complete lysis in equal proportions. When placed in direct contact, nitinol stents showed best corrosion resistance, regardless of what material they were combined with. In terms of polishing treatments, electropolished stents performed the best, mechanical-polished stents and those without polishing treatment followed.CONCLUSIONThe analysis of corrosion behavior may be useful to select the right stent fulfilling the individual needs of the patient within a large number of different stents

Reducing tumor growth and angiogenesis using a triple therapy measured with Contrast-enhanced ultrasound (CEUS)

Background To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the “flash-replenishment” (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS). Methods Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3). Results Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p≤0.05) and 32.2%(p≤0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p≤0.01), while the control-group was associated with a significant (p≤0.01) increase of the rBV in the wt area and a non-significant increase (p≤0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p≤0.01) in the follow-up measurements in the therapy group. Conclusion The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the “flash replenishment”(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy

Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: Efficacy, safety and prognostic factors

OBJECTIVE To analyze the clinical efficacy of (90)Y radioembolization in liver metastases from pancreatic cancer, to describe treatment toxicities and to identify biomarkers as predictors of outcome. METHODS Data from 19 pancreatic cancer patients (9 females/10 males) who had received (90)Y radioembolization for metastatic liver disease between 06/2004 and 01/2011 were analyzed retrospectively. RESULTS The median age at (90)Y radioembolization was 63 years (range 43-77). In 16 patients, previous palliative gemcitabine-based chemotherapy was given for metastatic disease. Objective response in the liver after (90)Y radioembolization was 47%. Median local progression-free survival in the liver was 3.4 months (range 0.9-45.0). Median overall survival (OS) was 9.0 months (range 0.9-53.0) and 1-year survival was 24%. Cox regression models for baseline biomarkers at (90)Y radioembolization revealed correlations of increased carbohydrate antigen 19-9 (p = 0.02) and C-reactive protein (p = 0.03) with shorter OS. Short-term adverse events (nausea, vomiting, fatigue, fever and abdominal pain) did not exceed grade 3. As long-term adverse events, liver abscesses, gastroduodenal ulceration, cholestasis and cholangitis, ascites and spleen infarction were observed. CONCLUSION (90)Y radioembolization is able to induce an encouraging local response rate of liver metastases of pancreatic cancer patients. Most short-term toxicities are manageable; however, patients should be followed up carefully for severe long-term toxicities

Stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma and oligometastatic liver disease

Background: To report our experience with SBRT in primary and secondary liver tumors. Methods: We retrospectively analysed 55 patients (70 lesions) with a median follow-up of 10 months (range 1-57) treated from 2011 to 2016. All patients had not been eligible for other local treatment options. Median age was 64 years and 64% were male. 27 patients (36 lesions) suffered from hepatocellular carcinoma (HCC, Child A: 78%, Child B:18%, Child C:4%), 28 patients (34 lesions) had oligometastatic liver disease (MD). Treatment planning was based on 4D-CT usually after placement of fiducials. Dose and fractionation varied depending on localization and size, most commonly 3 x 12.5 Gy (prescribed to the surrounding 65%-isodose) in 56% and 5x8Gy (80% isodose) in 20% of the treated lesions. Results: Local recurrence was observed in 7 patients (13%) and 8 lesions (11%), resulting in estimated 1- and 2-year local control rates (LC) of 91 and 74%. Estimated 1- and 2-year rates of Freedom from hepatic failure (FFHF) were 42 and 28%. Number of lesions was predictive for LC and FFHF in the entire cohort. Estimated 1- and 2-year overall survival (OS) was 76 and 57%. OS was significantly affected by number of treated lesions and performance status. In the HCC subgroup, pretreatment liver function and gender were also predictive for OS. Maximum acute non-hepatic toxicity was grade 1 in 16% and grade 2 in 10% of the patients. Three HCC patients (11%) developed marked deterioration of liver function (grade 3/4). Conclusions: SBRT resulted in high local control and acceptable survival rates in patients with HCC or MD not amendable to other locally-ablative treatment options with limited toxicity. Care should be taken in HCC patients with Child B cirrhosis

Percutaneous CT fluoroscopy-guided core biopsy of pancreatic lesions: technical and clinical outcome of 104 procedures during a 10-year period

Background: In unclear pancreatic lesions, a tissue sample can confirm or exclude the suspected diagnosis and help to provide an optimal treatment strategy to each patient. To date only one small study reported on the outcome of computed tomography (CT) fluoroscopy-guided biopsies of the pancreas. Purpose: To evaluate technical success and diagnostic rate of all CT fluoroscopy-guided core biopsies of the pancreas performed in a single university center during a 10-year period. Material and Methods: In this retrospective study we included all patients who underwent a CT fluoroscopy-guided biopsy of a pancreatic mass at our comprehensive cancer center between 2005 and 2014. All interventions were performed under local anesthesia on a 16-row or 128-row CT scanner. Technical success and diagnostic rates as well as complications and effective patient radiation dose were analyzed. Results: One hundred and one patients (54 women;mean age, 63.912.6 years) underwent a total of 104 CT fluoroscopy-guided biopsies of the pancreas. Ninety-eight of 104 interventions (94.2%) could be performed with technical success and at least one tissue sample could be obtained. In 88 of these 98 samples, a definitive pathological diagnosis, consistent with clinical success could be achieved (89.8%). Overall 19 minor and three major complications occurred during the intra- or 30-day post-interventional period and all other interventions could be performed without complications;there was no death attributable to the intervention. Conclusion: CT fluoroscopy-guided biopsy of pancreatic lesions is an effective procedure characterized by a low major complication and a high diagnostic rate

CT fluoroscopy-guided percutaneous osteoplasty with or without radiofrequency ablation in the treatment of painful extraspinal and spinal bone metastases: technical outcome and complications in 29 patients

PURPOSE:We aimed to assess the safety and technical outcome of computed tomography (CT) fluoroscopy-guided osteoplasty with or without prior percutaneous radiofrequency ablation (RFA) in patients with painful osteolyses.METHODS:We performed a retrospective analysis of 29 patients with painful extraspinal and spinal osteo- lyses (16 women, 13 men; 63.1±14.4 years) who underwent CT fluoroscopy-guided osteoplasty (10-20 mAs tube current) with or without RFA (26 and 14 lesions, respectively), in 33 consecutive procedures from 2002 to 2016. Technical success was defined as at least one complete RFA cycle and subsequent polymethyl metacrylate (PMMA) bone cement injection covering ≥75% of longest diameter of extraspinal osteolysis on axial plane or of distance between vertebral endplates. Procedure-related complications within 30 days and dose-length-product (DLP) were also evaluated.RESULTS:Osteolyses were located in the pelvis (acetabulum, n=10; iliac bone, n=4), spine (thoracic, n=6; lumbar, n=5; sacral, n=8), long bones (femur, n=3; tibia, n=1), sternum (n=2) and glenoid (n=1). Mean size of the treated osteolysis was 4.0±1.2 cm (range, 1.9–6.9 cm). Of 40 osteolyses, 31 (77.5%) abutted neighboring risk structures (spinal canal or neuroforamen, n=18; neighboring joint, n=11; other, n=8). Mean number of RFA electrode positions and complete ablation cycles was 1.5±0.9 and 2.1±1.7, respectively. Mean PMMA filling volume was 7.7±5.7 mL (range, 2–30 mL). Small asymptomatic PMMA leakages were observed in 15 lesions (37.5%). Mean total DLP was 850±653 mGy*cm. Six minor complications were observed, without any major complications.CONCLUSION:CT fluoroscopy-guided percutaneous osteoplasty with or without concomitant RFA for the treatment of painful extraspinal and spinal osteolyses can be performed with a low complication rate and high technical success

Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study

OBJECTIVE Hepatocellular carcinoma (HCC) is a major cause of death worldwide and its incidence is expected to increase globally. Aim of this study was to assess whether the implementation of screening policies and the improvement of treatment options translated into a real-world survival benefit in HCC patients. DESIGN 4078 patients diagnosed with HCC between 1998 and 2016 from the Munich Cancer Registry were analysed. Tumour characteristics and outcome were analysed by time period and according to age and presence of metastases at diagnosis. Overall survival (OS) was analysed using Kaplan-Meier method and relative survival (RS) was computed for cancer-specific survival. Cox proportional hazard models were conducted to control for prognostic variables. RESULTS While incidence of HCC remained substantially stable, tumours were diagnosed at increasingly earlier stages, although the median age at diagnosis increased. The 3 years RS in HCC improved from 19.8% in 1998-2002, 22.4% in 2003-2007, 30.6% in 2008-2012 up to 31.0% in 2013-2016. Median OS increased from 6 months in 1998-2002 to 12 months in 2008-2016. However, analysis according to the metastatic status showed that survival improved only in patients without metastases at diagnosis whereas the prognosis of patients with metastatic disease remained unchanged. CONCLUSION These real-world data show that, in contrast to the current assumptions, the incidence of HCC did not increase in a representative German region. Earlier diagnosis, likely related to the implementation of screening programmes, translated into an increasing employment of effective therapeutic options and a clear survival benefit in patients without metastases at diagnosis, irrespective of age

Addition of local hepatic therapy to sorafenib in patients with advanced hepatocellular carcinoma (stage BCLC C)

BACKGROUND/AIMS For most patients with hepatocellular carcinoma (HCC), diagnosis is invariably done only in the advanced stages of the disease. For advanced, non-metastatic stage, standard therapy is transarterial chemoembolization (TACE). For metastatic disease, the recommended therapy is systemic treatment with sorafenib. In this study, we evaluated the benefit of an additional local hepatic treatment for patients with advanced metastatic disease. METHODS In a retrospective study, we assessed the overall survival (OS), time to progression (TTP), and disease control rate (DCR) in 37 patients with metastasized HCC treated with sorafenib. Sixteen patients received additional local therapy, while 21 patients received only sorafenib. RESULTS Median OS of patients with combined therapy was significantly higher with 25 months (95% CI: 13.7-36.3 months) as compared to 11 months (95% CI: 6.2-15.8 months) in patients treated with sorafenib alone. TTP was 7 months (95% CI: 5.3-8.7 months) compared to 5 months (95% CI: 3-7 months) and DCR was 87 versus 72% after 3 months and 31 versus 22% after 9 months. CONCLUSION These data suggest that control of the liver tumor burden by local therapy in combination with sorafenib might prove beneficial for metastasized HCC. Randomised studies are needed to confirm this exploratory finding

Reducing tumor growth and angiogenesis using a triple therapy measured with Contrast-enhanced ultrasound (CEUS)

Background To evaluate the in vivo response by detecting the anti-angiogenic and invasion-inhibiting effects of a triple-combination-therapy in an experimental-small-animal-squamous-cell-carcinoma-model using the “flash-replenishment” (FR) method to assess tissue hemodynamics via contrast-enhanced-ultrasound (CEUS). Methods Human hypopharynx-carcinoma-cells were subcutaneously injected into the left flank of 22-female-athymic-nude-rats. After seven days of subcutaneous tumor growth, FR-measurements were performed on each rat. Treatment-group and control-group were treated every day for a period of one week, with the treatment-group receiving solvents containing a triple therapy of Upamostat®, Celecoxib® and Ilomastat® and the control-group solvents only. On day seven, follow-up measurements were performed using the same measurement protocol to assess the effects of the triple therapy. VueBox® was used to quantify the kinetic parameters and additional immunohistochemistry analyses were performed for comparison with and validation of the CEUS results against established methods (Proliferation/Ki-67, vascularization/CD31, apoptosis/caspase3). Results Compared to the control-group, the treatment-group that received the triple-therapy resulted in a reduction of tumor growth by 48.6% in size. Likewise, the immunohistochemistry results showed significant decreases in tumor proliferation and vascularization in the treatment-group in comparison to the control-group of 26%(p≤0.05) and 32.2%(p≤0.05) respectively. Correspondingly, between the baseline and follow-up measurements, the therapy-group was associated with a significant(p ≤ 0.01) decrease in the relative-Blood-Volume(rBV) in both the whole tumor(wt) and hypervascular tumor(ht) areas (p≤0.01), while the control-group was associated with a significant (p≤0.01) increase of the rBV in the wt area and a non-significant increase (p≤0.16) in the ht area. The mean-transit-time (mTT) of the wt and the ht areas showed a significant increase (p≤0.01) in the follow-up measurements in the therapy group. Conclusion The triple-therapy is feasible and effective in reducing both tumor growth and vascularization. In particular, compared with the placebo-group, the triple-therapy-group resulted in a reduction in tumor growth of 48.6% in size when assessed by CEUS and a significant reduction in the number of vessels in the tumor of 32% as assessed by immunohistochemistry. As the immunohistochemistry supports the CEUS findings, CEUS using the “flash replenishment”(FR) method appears to provide a useful assessment of the anti-angiogenic and invasion-inhibiting effects of a triple combination therapy