Publications by authors named "Stefan Hacker"

42 Publications

Differences between Primary and Revision Rhinoplasty: Indications, Techniques, Grafts, and Outcomes.

Plast Reconstr Surg 2021 Sep;148(3):532-541

From the Department of Facial Plastic Surgery, Marienhospital Stuttgart; and the Department of Plastic Surgery, Nottingham University Hospitals.

Background: The nose is at the center of the face and has essential functional and aesthetic properties. Over recent years, rhinoplasty has gained increasing popularity through the influence of "selfies" and social media. As a result, a growing demand for secondary correction has also emerged. Revision rhinoplasty is more complex than primary cases and often requires the use of extranasal grafting material. The authors sought to analyze the indications, techniques, and outcomes after primary and revision rhinoplasty.

Methods: A total of 245 patients (153 primary cases and 92 revisions) undergoing surgery at the authors' specialized clinic for facial plastic surgery were included. All patients were treated by an experienced facial plastic surgeon according to the authors' established clinic standards. A retrospective data analysis was performed to evaluate the differences between the groups regarding the indications, intraoperative techniques, and postoperative outcomes.

Results: Although more patients sought revision surgery for aesthetic reasons alone than isolated functional issues, almost two-thirds of the revision patients had functional and aesthetic problems in combination. Complex reconstructive techniques, extracorporeal septoplasties, and extranasal grafts were more commonly used in revision cases. The occurrence of another revision during the follow-up period was significantly higher after revision surgery compared to primary rhinoplasty cases (primary rhinoplasty, 10.5 percent; revision surgery, 23.9 percent; p = 0.006).

Conclusions: There are differences between primary and revision rhinoplasty that must be appreciated by the treating surgeon. The patient should be informed about the increased complexity of the secondary procedure, the possible need for extranasal grafts, and the increased risk of a further revision.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000008216DOI Listing
September 2021

Tissue distribution of epirubicin after severe extravasation in humans.

Cancer Chemother Pharmacol 2021 08 27;88(2):203-209. Epub 2021 Apr 27.

Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center of the Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Purpose: As critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose-toxicity relation.

Methods: From six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).

Results: After extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.

Conclusion: Surgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.
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http://dx.doi.org/10.1007/s00280-021-04280-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236455PMC
August 2021

Invited Discussion on: "Management of Patients Seeking Surgical Rhinoplasty with Previous Nasal Injections of Hyaluronic Acid".

Aesthetic Plast Surg 2021 08 29;45(4):1683-1684. Epub 2021 Mar 29.

Department of Facial Plastic Surgery, Marienhospital Stuttgart, Boeheimstrasse 37, 70199, Stuttgart, Germany.

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http://dx.doi.org/10.1007/s00266-021-02172-zDOI Listing
August 2021

Letter to the Editor: Controllable Factors to Reduce the Rate of Complications in Primary Breast Augmentation: A Review of the Literature.

Aesthetic Plast Surg 2021 Mar 2. Epub 2021 Mar 2.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1007/s00266-021-02176-9DOI Listing
March 2021

The secretome of stressed peripheral blood mononuclear cells increases tissue survival in a rodent epigastric flap model.

Bioeng Transl Med 2021 Jan 22;6(1):e10186. Epub 2020 Sep 22.

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration Vienna Austria.

Reconstructive surgery transfers viable tissue to cover defects and to restore aesthetic and functional properties. Failure rates after free flap surgery range from 3 to 7%. Co-morbidities such as diabetes mellitus or peripheral vascular disease increase the risk of flap failure up to 4.5-fold. Experimental therapeutic concepts commonly use a monocausal approach by applying single growth factors. The secretome of γ-irradiated, stressed peripheral blood mononuclear cells (PBMCsec) resembles the physiological environment necessary for tissue regeneration. Its application led to improved wound healing rates and a two-fold increase in blood vessel counts in previous animal models. We hypothesized that PBMCsec has beneficial effects on the survival of compromised flap tissue by reducing the necrosis rate and increasing angiogenesis. Surgery was performed on 39 male Sprague-Dawley rats (control, = 13; fibrin sealant, = 14; PBMCsec, = 12). PBMCsec was produced according to good manufacturing practices (GMP) guidelines and 2 ml were administered intraoperatively at a concentration of 2.5 × 10 cells/ml using fibrin sealant as carrier substance. Flap perfusion and necrosis (as percentage of the total flap area) were analyzed using Laser Doppler Imaging and digital image planimetry on postoperative days 3 and 7. Immunohistochemical stainings for von Willebrand factor (vWF) and Vascular Endothelial Growth Factor-receptor-3 (Flt-4) were performed on postoperative day 7 to evaluate formation of blood vessels and lymphatic vessels. Seroma formation was quantified using a syringe and flap adhesion and tissue edema were evaluated clinically through a cranial incision by a blinded observer according to previously described criteria on postoperative day 7. We found a significantly reduced tissue necrosis rate (control: 27.8% ± 8.6; fibrin: 22.0% ± 6.2; 20.9% reduction, = .053 vs. control; PBMCsec: 19.1% ± 7.2; 31.1% reduction, = .012 vs. control; 12.9% reduction, 0.293 vs. fibrin) together with increased vWF+ vessel counts (control: 70.3 ± 16.3 vessels/4 fields at 200× magnification; fibrin: 67.8 ± 12.1; 3.6% reduction, = .651, vs. control; PBMCsec: 85.9 ± 20.4; 22.2% increase, = .045 vs. control; 26.7% increase, = .010 vs. fibrin) on postoperative day 7 after treatment with PBMCsec. Seroma formation was decreased after treatment with fibrin sealant with or without the addition of PBMCsec. (control: 11.9 ± 9.7 ml; fibrin: 1.7 ± 5.3, 86.0% reduction, 0.004 vs. control; PBMCsec: 0.6 ± 2.0; 94.8% reduction, = .001 vs. control; 62.8% reduction, = .523 vs. fibrin). We describe the beneficial effects of a secretome derived from γ-irradiated PBMCs on tissue survival, angiogenesis, and clinical parameters after flap surgery in a rodent epigastric flap model.
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http://dx.doi.org/10.1002/btm2.10186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823127PMC
January 2021

40 Years of Total Extracorporeal Septal Reconstruction: The Past, Present, and Future.

Plast Reconstr Surg 2020 12;146(6):1357-1367

From the Department of Facial Plastic Surgery, Marienhospital Stuttgart.

Background: Even today, severe septal deformities are a challenging problem for any rhinoplasty surgeon. Standard techniques are often not able to achieve satisfactory long-term results regarding function or aesthetic form. In such severe cases, a partial or total extracorporeal septal reconstruction may be used, as these techniques provide reliable and lasting results.

Methods: The aim of this work is to present the authors' experience with the technique of total extracorporeal septal reconstruction and its development to today's standard and to prove its effectiveness in the long-term follow-up.

Results: This article presents 40 years of clinical experience in this field and describes the technical changes that have evolved. Low complication rates, safe techniques, and favorable long-term outcomes of the total extracorporeal septal reconstruction show the benefits of this technique.

Conclusion: The indication for a total extracorporeal septal reconstruction has been limited by the development of less complex surgical procedures, but it still represents the best technique to achieve long-term functional and aesthetic results in patients with very complex septal deformities.

Clinical Question/level Of Evidence: Therapeutic, V.
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http://dx.doi.org/10.1097/PRS.0000000000007399DOI Listing
December 2020

Does obesity impact the outcome of severely burned patients?

Int Wound J 2020 Apr 3;17(2):380-386. Epub 2020 Jan 3.

Division of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria.

Although obesity appears to be an important predictor of mortality and morbidity, little data about the impact of body mass index (BMI) on the outcome of severely burned patients are available. Patients admitted to the General Hospital Vienna between 1994 and 2014, who underwent surgery because of burn injuries, were enrolled in this study. BMI was used to divide patients into five groups: BMI 18.5 to 24.9, 25 to 29.9, 30 to 34.9, 35 to 39.9, and > 40. The groups were compared in terms of difference of mortality and morbidity. Of 460 patients, 34.3% (n = 158) died. Mortality rates were the lowest in patients with obesity class III and the highest in patients with BMI 35 to 39.9 (BMI 18.5-24.9: 30.5%, BMI 25-29.9: 31.5%, BMI 30-34.9: 41.3%, BMI 35-39.9: 55.5%, BMI > 40: 30%; P = .031). BMI was not found to be an independent risk factor when corrected with age, percent total body surface area burned, full-thickness burns, and inhalation injury. No significant differences in length of stay, inhalation trauma, pneumonia, wound infection, sepsis, and invasive ventilation were observed. BMI as an independent risk factor for severely burned patients could not be confirmed via multivariate analysis.
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http://dx.doi.org/10.1111/iwj.13282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064920PMC
April 2020

Sexual dimorphism in the anatomy of the ulnar collateral thumb ligament.

Wien Klin Wochenschr 2019 May 1;131(9-10):216-220. Epub 2019 Apr 1.

, Laudongasse 25, 1080, Vienna, Austria.

Background: Treatment of ruptured ulnar collateral thumb metacarpophalangeal (MCP) joint ligaments (UCL) necessitate a profound anatomic knowledge for optimal surgical repair in order to preserve range of motion and ensure postoperative joint stability. Therefore, knowledge of the angle between the UCL and the longitudinal axis of the first metacarpal bone could be useful.

Methods: In this study 46 ulnar collateral thumb MCP joint ligaments in 15 male and 15 female embalmed anatomic specimens were dissected and the angles between the longitudinal axis of the first metacarpal bone and the proper (PUCL) as well as the accessory ulnar collateral thumb MCP ligament (AUCL) were measured.

Results: In male specimens the angle for the PUCL measured on average 133.5° (±2.35°) and 122.75° (±3.8°) for the AUCL. A significantly different angle was measured for female specimens which showed on average 137.88° (±3.51°) for the PUCL and 128.65° (±4.14°) for the AUCL.

Conclusions: Optimal surgical repair or reconstruction of torn ulnar collateral thumb MCP joint ligaments should aim for an angle of approximately 135° in PUCL and 126° in AUCL in relation to the longitudinal axis of the metacarpal bone. Differences in men and women should be considered if possible.

Level Of Evidence: IV (anatomic study).
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http://dx.doi.org/10.1007/s00508-019-1483-8DOI Listing
May 2019

Bony Fixation of the Nasal Framework.

Facial Plast Surg 2019 Feb 13;35(1):23-30. Epub 2019 Feb 13.

Clinic for Facial Plastic Surgery, Marienhospital Stuttgart, Stuttgart, Germany.

The importance of a straight and stable central framework is beyond dispute. Many authors allude to technical aspects how to achieve the above-mentioned requirements. Far less is said about the contact zones of the framework and how to achieve a long-lasting and solid fixation. In the authors' patient group, they found the need to work on the septum/the central framework in approximately 84% of the cases. In 61% of the patients, the authors had to operate on the fixation point. Of course, there is a great variety of anatomical findings. So the required techniques differ immensely. The surgeon must be prepared for all kinds of different situations. Especially the dorsal fixation and the anchoring on the maxilla without having a standard anterior nasal spine can be a great challenge. In their daily routine, suture techniques (e.g., the transcutaneous transosseous cerclage suture) have become the authors' working horse for these complex fixation situations.
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http://dx.doi.org/10.1055/s-0039-1677767DOI Listing
February 2019

Gender has no influence on mortality after burn injuries: A 20-year single center study with 839 patients.

Burns 2019 02 28;45(1):205-212. Epub 2018 Aug 28.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: According to the ABSI - Abbreviated Burn Severity Index - women exhibit an increased risk of succumbing to burn injuries. In contrast, following non-thermal trauma, increased mortality has been shown for the male gender. Therefore, the purpose of this study was to evaluate gender-specific differences among burn patients with special regard to burn mortality.

Methods: We retrospectively studied 839 patients who were admitted to the Burn Intensive Care Unit (BICU) and underwent surgical treatment between June 1994 and December 2014. In-hospital mortality was the main clinical endpoint. Odds ratios (ORs) were calculated using univariate and multivariate logistic regression models for the association between sex and mortality.

Results: In total, we included 530 male and 309 female burn patients. All patients had at least partial-thickness burns and underwent one or more operative procedures. Women were significantly older than men (mean 60.0 years vs 46.2 years; p<0.001). Despite having smaller injuries (24.6% vs 30.3% total body surface area (TBSA); p<0.001), burn mortality among women significantly differed from that of men (27.8% vs 21.7%; OR 1.39, p=0.045, 95% CI 1.01-1.92). This association, however, did not persist after adjusting for age, %TBSA, inhalation injury and full-thickness burns (OR 1.07, p=0.77, 95% CI 0.68-1.70).

Conclusions: Despite increasing research directed at women's health, the assoziation between gender and burn mortality has yielded conflicting results. This study does not support a gender-specific difference in burn mortality in our study population.
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http://dx.doi.org/10.1016/j.burns.2018.08.012DOI Listing
February 2019

Increased serum concentrations of soluble ST2 predict mortality after burn injury.

Clin Chem Lab Med 2018 11;56(12):2079-2087

Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.

Background: Large burn injuries induce a systemic response in affected patients. Soluble ST2 (sST2) acts as a decoy receptor for interleukin-33 (IL-33) and has immunosuppressive effects. sST2 has been described previously as a prognostic serum marker. Our aim was to evaluate serum concentrations of sST2 and IL-33 after thermal injury and elucidate whether sST2 is associated with mortality in these patients.

Methods: We included 32 burn patients (total body surface area [TBSA] >10%) admitted to our burn intensive care unit and compared them to eight healthy probands. Serum concentrations of sST2 and IL-33 were measured serially using an enzyme-linked immunosorbent assay (ELISA) technique.

Results: The mean TBSA was 32.5%±19.6%. Six patients (18.8%) died during the hospital stay. Serum analyses showed significantly increased concentrations of sST2 and reduced concentrations of IL-33 in burn patients compared to healthy controls. In our study cohort, higher serum concentrations of sST2 were a strong independent predictor of mortality.

Conclusions: Burn injuries cause an increment of sST2 serum concentrations with a concomitant reduction of IL-33. Higher concentrations of sST2 are associated with increased in-hospital mortality in burn patients.
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http://dx.doi.org/10.1515/cclm-2018-0042DOI Listing
November 2018

Neo-glans reconstruction for penile cancer: Description of the primary technique using autologous testicular tunica vaginalis graft.

Arab J Urol 2018 Jun 21;16(2):218-223. Epub 2018 Mar 21.

Department of Urology, Teaching Hospital, Landesklinikum Korneuburg, Austria.

Partial penectomy (glansectomy with/or without distal corporectomy) is an acceptable alternative for smaller distal pT3 penile carcinoma lesions in highly motivated and compliant patients. The authors describe a novel technique of neo-glans reconstruction using a tunica vaginalis (TV) testis allograft. However, due to an unclear resection margin on final histology, the patient underwent re-do surgery with a neo-glans revision using the well-established mesh split-thickness skin graft (STSG) technique. The penile length was preserved and the penile and bulbar part of the urethra was additionally mobilised in order to obtain a natural and aesthetic result for the meatus. Neo-glans reconstruction with TV coverage may be another promising alternative, which certainly requires further evaluation. We believe that the donor-site associated morbidity is minimal when compared to other harvesting sites. However, this is just an assumption, because direct comparison data on grafting techniques and neo-glans reconstruction are not available. Nevertheless, we think that for re-do procedures a standardised approach using a STSG technique should be the treatment method of choice.
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http://dx.doi.org/10.1016/j.aju.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992260PMC
June 2018

Hypermethylation of CDKN2A exon 2 in tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients.

BMC Cancer 2017 Apr 12;17(1):260. Epub 2017 Apr 12.

Department of Analytical Chemistry, University of Vienna, Währinger Str. 38, 1090, Vienna, Austria.

Background: Breast carcinogenesis is a multistep process involving genetic and epigenetic changes. Tumor tissues are frequently characterized by gene-specific hypermethylation and global DNA hypomethylation. Aberrant DNA methylation levels have, however, not only been found in tumors, but also in tumor-surrounding tissue appearing histologically normal. This phenomenon is called field cancerization. Knowledge of the existence of a cancer field and its spread are of clinical relevance. If the tissue showing pre-neoplastic lesions is not removed by surgery, it may develop into invasive carcinoma.

Methods: We investigated the prevalence of gene-specific and global DNA methylation changes in tumor-adjacent and tumor-distant tissues in comparison to tumor tissues from the same breast cancer patients (n = 18) and normal breast tissues from healthy women (n = 4). Methylation-sensitive high resolution melting (MS-HRM) analysis was applied to determine methylation levels in the promoters of APC, BRCA1, CDKN2A (p16), ESR1, HER2/neu and PTEN, in CDKN2A exon 2 and in LINE-1, as indicator for the global DNA methylation extent. The methylation status of the ESR2 promoter was determined by pyrosequencing.

Results: Tumor-adjacent and tumor-distant tissues frequently showed pre-neoplastic gene-specific and global DNA methylation changes. The APC promoter (p = 0.003) and exon 2 of CDKN2A (p < 0.001) were significantly higher methylated in tumors than in normal breast tissues from healthy women. For both regions, significant differences were also found between tumor and tumor-adjacent tissues (p = 0.001 and p < 0.001, respectively) and tumor and tumor-distant tissues (p = 0.001 and p < 0.001, respectively) from breast cancer patients. In addition, tumor-adjacent (p = 0.002) and tumor-distant tissues (p = 0.005) showed significantly higher methylation levels of CDKN2A exon 2 than normal breast tissues serving as control. Significant correlations were found between the proliferative activity and the methylation status of CDKN2A exon 2 in tumor (r = -0.485, p = 0.041) and tumor-distant tissues (r = -0.498, p = 0.036).

Conclusions: From our results we can conclude that methylation changes in CDKN2A exon 2 are associated with breast carcinogenesis. Further investigations are, however, necessary to confirm that hypermethylation of CDKN2A exon 2 is associated with tumor proliferative activity.
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http://dx.doi.org/10.1186/s12885-017-3244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389179PMC
April 2017

Patient satisfaction, body image, and quality of life after lower body lift: a prospective pre- and postoperative long-term survey.

Surg Obes Relat Dis 2017 May 11;13(5):882-887. Epub 2017 Jan 11.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria.

Background: Body contouring surgery after massive weight loss remains a fast growing field due to the rising number of postbariatric surgery patients, and it can improve patients' quality of life substantially. Patient expectations in these procedures are very high, but only little is known as to whether these procedures have a long lasting influence on body image, patient satisfaction, and quality of life.

Setting: University hospital, Austria.

Methods: We evaluated 40 consecutive female patients who underwent a lower body lift between 2009 and 2013. Patients took part in a prospective pre- and postoperative questionnaire survey inquiring about their psychological and physical wellbeing. The mean postoperative follow up interval was 61±14 months. We used 2 validated (Body Image Questionnaire and Body Appraisal Inventory) and one self-designed questionnaires (body lift follow-up questionnaire). The postoperative response rate in January 2016 was 72.5%.

Results: Lower body lift significantly reduced dismissive body ratings and increased long-term feelings of attractiveness and self-esteem, and significantly reduced discomfort associated with excess skin. Patients reported feeling happier, more attractive, and more self-confident. The procedure enhanced their physical wellbeing, even years after surgery.

Conclusion: Lower body lift satisfied patients' expectations and improved long-term quality of life. Therefore, it is an essential component in the treatment of patients who have experienced massive weight loss.
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http://dx.doi.org/10.1016/j.soard.2017.01.010DOI Listing
May 2017

Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients.

Oncotarget 2016 Nov;7(45):73347-73369

Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

Overexpression of ABCB1, ABCC1 and ABCG2 in tumor tissues is considered a major cause of limited efficacy of anticancer drugs. Gene expression of ABC transporters is regulated by multiple mechanisms, including changes in the DNA methylation status. Most of the studies published so far only report promoter methylation levels for either ABCB1 or ABCG2, and data on the methylation status for ABCC1 are scarce. Thus, we determined the promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in 19 human cancer cell lines. In order to contribute to the elucidation of the role of DNA methylation changes in acquisition of a multidrug resistant (MDR) phenotype, we also analyzed the promoter methylation patterns in drug-resistant sublines of the cancer cell lines GLC-4, SW1573, KB-3-1 and HL-60. In addition, we investigated if aberrant promoter methylation levels of ABCB1, ABCC1 and ABCG2 occur in tumor and tumor-surrounding tissues from breast cancer patients.Our data indicates that hypomethylation of the ABCC1 promoter is not cancer type-specific but occurs in cancer cell lines of different origins. Promoter methylation was found to be an important mechanism in gene regulation of ABCB1 in parental cancer cell lines and their drug-resistant sublines. Overexpression of ABCC1 in MDR cell models turned out to be mediated by gene amplification, not by changes in the promoter methylation status of ABCC1. In contrast to the promoters of ABCC1 and ABCG2, the promoter of ABCB1 was significantly higher methylated in tumor tissues than in tumor-adjacent and tumor-distant tissues from breast cancer patients.
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http://dx.doi.org/10.18632/oncotarget.12332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341984PMC
November 2016

Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model.

Sci Rep 2016 04 29;6:25168. Epub 2016 Apr 29.

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Waehringer Guertel 18-20, 1090 Vienna, Austria.

Burn wounds pose a serious threat to patients and often require surgical treatment. Skin grafting aims to achieve wound closure but requires a well-vascularized wound bed. The secretome of peripheral blood mononuclear cells (PBMCs) has been shown to improve wound healing and angiogenesis. We hypothesized that topical application of the PBMC secretome would improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting in a porcine model. Full-thickness burn injuries were created on the back of female pigs. Necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (Sec(PBMC)), apoptotic PBMCs (Apo-Sec(PBMC)), or controls. The wounds treated with Apo-Sec(PBMC) had an increased epidermal thickness, higher number of rete ridges, and more advanced epidermal differentiation than controls. The samples treated with Apo-Sec(PBMC) had a two-fold increase in CD31+ cells, indicating more angiogenesis. These data suggest that the repeated application of Apo-Sec(PBMC) significantly improves epidermal thickness, angiogenesis, and skin quality in a porcine model of burn injury and skin grafting.
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http://dx.doi.org/10.1038/srep25168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850437PMC
April 2016

Applicability of HIN-1, MGMT and RASSF1A promoter methylation as biomarkers for detecting field cancerization in breast cancer.

Breast Cancer Res 2015 Sep 14;17:125. Epub 2015 Sep 14.

Department of Analytical Chemistry, University of Vienna, Währinger Str. 38, 1090, Vienna, Austria.

Introduction: It has been shown in some articles that genetic and epigenetic abnormalities cannot only be found in tumor tissues but also in adjacent regions that appear histologically normal. This phenomenon is metaphorically called field cancerization or field defect. Field cancerization is regarded as clinically significant because it is assumed to be an important factor in local recurrence of cancer. As the field showing these molecular abnormalities may not be removed completely by surgery, these changes might lead to neoplasms and subsequent transformation to a tumor. We aimed to investigate the applicability of the methylation status of six tumor suppressor genes as biomarkers for detecting field cancerization in breast cancer.

Methods: The promoter methylation status of CCND2, DAPK1, GSTP1, HIN-1, MGMT and RASSF1A was determined by methylation-sensitive high-resolution melting (MS-HRM) analysis. MS-HRM methods for CCND2, MGMT and RASSF1A were developed in-house, primer sequences for DAPK1, GSTP1 and HIN-1 have already been published. Biopsy samples were taken from tumor, tumor-adjacent and tumor-distant tissue from 17 breast cancer patients. Normal breast tissues of four healthy women served as controls.

Results: All MS-HRM methods proved to be very sensitive. LODs were in the range from 0.1 to 1.5 %, LOQs ranged from 0.3 to 5.3 %. A total of 94 %, 82 % and 65 % of the tumors showed methylation of RASSF1A, HIN-1 and MGMT promoters, respectively. The methylation status of these promoters was significantly lower in tumor-distant tissues than in tumor tissues. Tumor-adjacent tissues showed higher methylation status of RASSF1A, HIN-1 and MGMT promoters than tumor-distant tissues, indicating field cancerization. The methylation status of the HIN-1 promoter in tumor-adjacent tissues was found to correlate strongly with that in the corresponding tumors (r = 0.785, p < 0.001), but not with that in the corresponding tumor-distant tissues (r = 0.312, p = 0.239).

Conclusions: Among the gene promoters investigated, the methylation status of the HIN-1 promoter can be considered the best suitable biomarker for detecting field cancerization. Further investigation is needed to test whether it can be used for defining surgical margins in order to prevent future recurrence of breast cancer.
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http://dx.doi.org/10.1186/s13058-015-0637-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570691PMC
September 2015

Hypothenar Hammer Syndrome: Long-Term Results After Vascular Reconstruction.

Ann Plast Surg 2016 Jan;76(1):40-5

From the *Medical University of Vienna, Department for Surgery, Division of Plastic and Reconstructive Surgery, Vienna, Austria; and †Clinic for Hand Surgery, Salzburger Leite, Bad Neustadt/Saale, Germany.

Background: Hypothenar hammer syndrome is a rare vascular lesion of the distal ulnar artery in Guyon tunnel caused by acute or repetitive blunt trauma to the hypothenar eminence. Described treatment options vary greatly, from nonoperative management treatments to surgical interventions. The aim of this study was to evaluate the long-term outcomes of patients after surgical reconstruction of the ulnar artery.

Methods: In this retrospective study, the results of 12 patients treated for hypothenar hammer syndrome were evaluated. Preoperative and postoperative examinations of the hand were recorded. Function impairment was assessed with the "Disabilites of the Arm, Shoulder and Hand" questionnaire. Comparisons were also made based on ulnar artery patency versus occlusion. All patients were evaluated for ulnar artery patency as determined by Allen's test and magnetic resonance angiography.

Results: All patients were men with an average age of 42.8 years. In 3 patients, a direct end-to-end anastomosis of the ulnar artery was performed, and 9 patients received a reconstruction with a reverse interpositional vein graft. Nine vascular reconstructions remained patent after a mean follow-up period of 56.9 months. These patients had a complete or at least partial relief of their pain, dysesthesia, and cold intolerance compared with preoperatively. Patients with reoccluded ulnar arteries were statistically significant younger (P = 0.036) than patients with patent ulnar artery. They also had a higher pain level (P = 0.009) and a longer follow-up period (P = 0.036) than those with patent reconstruction. There was a trend for higher functional impairment in patients with reoccluded ulnar artery (P = 0.100). Smoking habits showed no influence on ulnar artery patency.

Conclusions: For patients with symptomatic hypothenar hammer syndrome and failed nonoperative treatment, surgical intervention is a good option. After more than 4.5 years after surgery 9 of 12 vascular reconstructions remained patent (75% patency rate), ensuring an immediate and long-term improvement of symptoms.
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http://dx.doi.org/10.1097/SAP.0000000000000562DOI Listing
January 2016

Latissimus dorsi breast reconstruction: how much nerve resection is necessary to prevent postoperative muscle twitching?

Plast Reconstr Surg 2014 Dec;134(6):1125-1129

Vienna, Austria From the Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University Vienna.

Background: The latissimus dorsi muscle flap represents a valuable option in breast reconstruction but can result in postoperative twitching and retraction, discomfort, arm movement limitations, and breast deformation. These complications can be avoided by denervation of the thoracodorsal nerve; however, the optimal method of nerve management is unknown. This study presents the authors' experience with the outcomes of latissimus dorsi flaps for breast reconstruction in the light of thoracodorsal nerve management strategies.

Methods: The authors retrospectively collected data from 74 patients who underwent partial or total breast reconstruction with a latissimus dorsi flap alone or with an implant between January of 1999 and October of 2011. Follow-up data were collected at 12 and 24 months postoperatively.

Results: In 56 patients (75.7 percent), the latissimus dorsi muscle was denervated at the time of surgery, whereas the thoracodorsal nerve remained intact in 18 patients (24.3 percent). No partial or total flap loss was observed. At 12 and 24 months' follow-up, all patients with an intact thoracodorsal nerve showed twitching of the muscle, and 50 percent and 67.9 percent, respectively, of the denervated patients showed twitching (p < 0.001). No patient had twitching if more than 4 cm of nerve was excised at 12 or 24 months postoperatively, and the length of nerve resection was predictive of the presence of twitching.

Conclusion: Denervation of the latissimus dorsi is a safe and reliable procedure that should be performed at the time of breast reconstruction and should include more than 4 cm to achieve a nontwitching breast with a stable volume and shape.
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http://dx.doi.org/10.1097/PRS.0000000000000739DOI Listing
December 2014

Wound Healing Effect of Conditioned Media Obtained From Adipose Tissue on Human Skin Cells: A Comparative in Vitro Study.

Ann Plast Surg 2016 Aug;77(2):156-63

From the *Division of Plastic and Reconstructive Surgery, Department of Surgery; †Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy at the Clinical Division of Endocrinology and Metabolism, Department of Medicine III; ‡Department of Surgery; and §Division of Thoracic Surgery, Department of Surgery, Medical University of Vienna; and ∥Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria.

Background: Split-thickness skin grafting is the gold standard to cover extensive acute and chronic wounds with a well-vascularized wound bed. Although some headway has been made in developing biological agents to speed up healing, there is still no treatment that sufficiently replaces skin grafts to date. The use of secretory factors of adipose tissue may be a feasible approach to developing topical wound applications for faster wound healing.

Methods: In this study, the effect of conditioned media (CMs) of human adipose-derived stem cells (ASCs), adipocytes, or adipose tissue on human skin cells was evaluated for viability, proliferation, and migration in vitro. Differentiation potential of stem cells treated with CM was monitored by AdipoRed staining and qualitative real-time polymerase chain reaction. Angiogenic potential of human endothelial cells treated with CM was tested via sprouting assay.

Results: The CM of adipose tissue significantly enhanced ASC proliferation (P < 0.01). Treatment with CM showed no inductive effect on ASC differentiation into adipocytes but, at the same time, significantly induced cell sprouting of endothelial cells (P < 0.001). We show for the first time that CM of adipose tissue is a potent inducer of proliferation of ASCs and angiogenesis, with comparable effects with those of stem cell-enriched CM.

Conclusions: We suggest the use of the secretome of adipose tissue to produce CM for topical application on wounds, rather than working with adipose tissue or including the difficult process of enriching the patients' stem cells in vitro.
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http://dx.doi.org/10.1097/SAP.0000000000000358DOI Listing
August 2016

Secretome of peripheral blood mononuclear cells enhances wound healing.

PLoS One 2013 22;8(3):e60103. Epub 2013 Mar 22.

Department of Dermatology, Medical University Vienna, Vienna, Austria.

Non-healing skin ulcers are often resistant to most common therapies. Treatment with growth factors has been demonstrated to improve closure of chronic wounds. Here we investigate whether lyophilized culture supernatant of freshly isolated peripheral blood mononuclear cells (PBMC) is able to enhance wound healing. PBMC from healthy human individuals were prepared and cultured for 24 hours. Supernatants were collected, dialyzed and lyophilized (SEC(PBMC)). Six mm punch biopsy wounds were set on the backs of C57BL/6J-mice and SEC(PBMC) containing emulsion or controls were applied daily for three days. Morphology and neo-angiogenesis were analyzed by H&E-staining and CD31 immuno-staining, respectively. In vitro effects on diverse skin cells were investigated by migration assays, cell cycle analysis, and tube formation assay. Signaling pathways were analyzed by Western blot analysis. Application of SEC(PBMC) on 6 mm punch biopsy wounds significantly enhanced wound closure. H&E staining of the wounds after 6 days revealed that wound healing was more advanced after application of SEC(PBMC) containing emulsion. Furthermore, there was a massive increase in CD31 positive cells, indicating enhanced neo-angiogenesis. In primary human fibroblasts (FB) and keratinocytes (KC) migration but not proliferation was induced. In endothelial cells (EC) SEC(PBMC) induced proliferation and tube-formation in a matrigel-assay. In addition, SEC(PBMC) treatment of skin cells led to the induction of multiple signaling pathways involved in cell migration, proliferation and survival. In summary, we could show that emulsions containing the secretome of PBMC derived from healthy individuals accelerates wound healing in a mouse model and induce wound healing associated mechanisms in human primary skin cells. The formulation and use of such emulsions might therefore represent a possible novel option for the treatment of non-healing skin ulcers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060103PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606336PMC
September 2013

Ecarin modified rotational thrombelastometry: a point-of-care applicable alternative to monitor the direct thrombin inhibitor argatroban.

Wien Klin Wochenschr 2013 Mar 26;125(5-6):156-9. Epub 2013 Feb 26.

Department of Anaesthesiology, General Intensive Care and Pain Control, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Purpose: Adequate monitoring of the effect of the direct thrombin inhibitor argatroban may facilitate individualized dosing and perioperative management of anticoagulation. Ecarin Clotting Time is proposed for this purpose, but has the major disadvantage of limited availability. There is a point-of-care applicable ecarin-activated test modification for rotational thrombelastometry (ROTEM®) which is sensitive to direct thrombin inhibitors. The aim of the study was to evaluate the correlation between argatroban concentration and this ecarin modified thrombelastometry (EMT).

Methods: In this in vitro experiment, blood drawn from healthy volunteers was spiked with argatroban at clinically relevant concentrations and analyzed with ROTEM® using EMT. The main endpoint was the clotting time (CT).

Results: EMT-CT was prolonged with increasing argatroban concentrations (from 83.3 ± 6.7 s without argatroban to 743.5 ± 138.2 s at 2 μg/ml argatroban). The correlation between argatroban concentration and EMT-CT was high (r = 0.94) and statistically significant (p < 0.01).

Conclusion: These promising preclinical results mandate further clinical research to determine an EMT-CT target range regarding the clinical outcomes of thrombosis and bleeding.
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http://dx.doi.org/10.1007/s00508-013-0327-1DOI Listing
March 2013

Mononuclear cell secretome protects from experimental autoimmune myocarditis.

Eur Heart J 2015 Mar 14;36(11):676-85. Epub 2013 Jan 14.

Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Währinger Gürtel 18-20, 1090 Vienna, Austria

Aims: Supernatants of serum-free cultured mononuclear cells (MNC) contain a mix of immunomodulating factors (secretome), which have been shown to attenuate detrimental inflammatory responses following myocardial ischaemia. Inflammatory dilated cardiomyopathy (iDCM) is a common cause of heart failure in young patients. Experimental autoimmune myocarditis (EAM) is a CD4+ T cell-dependent model, which mirrors important pathogenic aspects of iDCM. The aim of this study was to determine the influence of MNC secretome on myocardial inflammation in the EAM model.

Methods And Results: BALB/c mice were immunized twice with an alpha myosin heavy chain peptide together with Complete Freund adjuvant. Supernatants from mouse mononuclear cells were collected, dialysed, and injected i.p. at Day 0, Day 7, or Day 14, respectively. Myocarditis severity, T cell responses, and autoantibody formation were assessed at Day 21. The impact of MNC secretome on CD4+ T cell function and viability was evaluated using in vitro proliferation and cell viability assays. A single high-dose application of MNC secretome, injected at Day 14 after the first immunization, effectively attenuated myocardial inflammation. Mechanistically, MNC secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells.

Conclusion: MNC secretome abrogated myocardial inflammation in a CD4+ T cell-dependent animal model of autoimmune myocarditis. This anti-inflammatory effect of MNC secretome suggests a novel and simple potential treatment concept for inflammatory heart diseases.
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http://dx.doi.org/10.1093/eurheartj/ehs459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359357PMC
March 2015

Thymomas and thymic carcinomas: prognostic factors and multimodal management.

Thorac Cardiovasc Surg 2014 Mar 6;62(2):153-60. Epub 2012 Dec 6.

Medical University of Vienna-Thoracic Surgery Wien, Wien, Austria.

Background: Thymomas and thymic carcinomas are rare malignant tumors. We report the experience with the resection and multimodal treatment at a single department in Central Europe in the years 2001 to 2010.

Objective: We sought to determine prognostic factors in this patient population.

Methods: A 10-year retrospective analysis of 84 resections on 72 patients for thymomas/thymic carcinomas or their recurrences was performed.

Results: Patients admitted to a single thoracic surgery center presented with Masaoka-Koga stage I (29.2%), II (43.1%), III (13.9%), and IV (13.9%). In approximately 88.9% of cases, a complete resection could be reached. Using overall survival as an outcome measure, the 5-year survival rate was 87%. Of all the cases presented, 9.7% cases showed tumor recurrence and 6.9% cases showed tumor progression. There was decreased survival rate with increasing Masaoka-Koga stage (p = 0.017) and incomplete resection (p < 0.001).

Conclusion: Completeness of resection and Masaoka-Koga stage were significant prognostic factors. Multidisciplinary treatments of patients with thymoma or thymic carcinoma result in good patient care, and global efforts with larger number of patients are needed to elucidate more about the biology, diagnosis, and treatment of these tumors.
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http://dx.doi.org/10.1055/s-0032-1322611DOI Listing
March 2014

Age-related changes in expression and function of Toll-like receptors in human skin.

Development 2012 Nov 3;139(22):4210-9. Epub 2012 Oct 3.

Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Laboratory of Cellular and Molecular Immunobiology of the Skin, Medical University of Vienna, Austria.

Toll-like receptors (TLRs) initiate innate immune responses and direct subsequent adaptive immunity. They play a major role in cutaneous host defense against micro-organisms and in the pathophysiology of several inflammatory skin diseases. To understand the role of TLRs in the acquisition of immunological competence, we conducted a comprehensive study to evaluate TLR expression and function in the developing human skin before and after birth and compared it with adults. We found that prenatal skin already expresses the same spectrum of TLRs as adult skin. Strikingly, many TLRs were significantly higher expressed in prenatal (TLRs 1-5) and infant and child (TLRs 1 and 3) skin than in adult skin. Surprisingly, neither dendritic cell precursors in prenatal skin nor epidermal Langerhans cells and dermal dendritic cells in adult skin expressed TLRs 3 and 6, whereas the staining pattern and intensity of both TLRs in fetal basal keratinocytes was almost comparable to those of adults. Stimulation of primary human keratinocytes from fetal, neonatal and adult donors with selected TLR agonists revealed that the synthetic TLR3 ligand poly (I:C) specifically, mimicking viral double-stranded RNA, induced a significantly enhanced secretion of CXCL8/IL8, CXCL10/IP-10 and TNFα in fetal and neonatal keratinocytes compared with adult keratinocytes. This study demonstrates quantitative age-specific modifications in TLR expression and innate skin immune reactivity in response to TLR activation. Thus, antiviral innate immunity already in prenatal skin may contribute to protect the developing human body from viral infections in utero in a scenario where the adaptive immune system is not yet fully functional.
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http://dx.doi.org/10.1242/dev.083477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912866PMC
November 2012

Discrimination of clinical stages in non-small cell lung cancer patients by serum HSP27 and HSP70: a multi-institutional case-control study.

Clin Chim Acta 2012 Jul 23;413(13-14):1115-20. Epub 2012 Mar 23.

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Vienna, Austria.

Introduction: Lung cancer represents a major healthcare problem. Accordingly, there is an urgent need to identify serum biomarkers for early diagnosis of lung pathology. We have recently described that patients with manifest COPD evidence elevated levels of heat shock proteins (HSPs). Based on these data, we speculated whether HSPs are also increased in patients with diagnosed lung cancer.

Methods: Serum levels of HSP27, phospho-HSP27 (pHSP27) and HSP70 in patients with non-small cell lung cancer (NSCLC) diagnosed at an early (stages I-II, n=37) or advanced (stages IIIA-IV, n=72) stage were determined by using ELISA. Healthy smokers (n=24), healthy never-smoker volunteers (n=33) and COPD patients (n=34) according to GOLD classification served as control population.

Results: Serum levels of HSP27 were elevated in patients with NSCLC diagnosed at an early or advanced stage when compared with both healthy control groups (P<0.005 and P<0.0001 respectively). Statistically significant differences were furthermore found between the groups of patients with early vs. advanced stage NSCLC (P=0.0021). Serum levels of HSP70 were also significantly elevated in patients with NSCLC diagnosed at an early or at an advanced stage when compared with either healthy control groups (P=0.0028 and P<0.0001 respectively). In univariate logistic regression models including healthy subjects and patients with NSCLC, HSP70 had an area under the curve (AUC) of 0.779 (P<0.0001) and HSP27 showed an AUC of 0.870 (P<0.0001).

Conclusion: Our data suggest that serum HSP27 levels might serve as a possible tool to discriminate between early and advanced stages NSCLC.
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http://dx.doi.org/10.1016/j.cca.2012.03.008DOI Listing
July 2012

Fibrinogen function after severe burn injury.

Burns 2012 Feb 23;38(1):77-82. Epub 2011 Nov 23.

Dept. of Anesthesiology, General Intensive Care and Pain Control, Medical University Of Vienna, Austria.

Background: Evidence regarding hypercoagulability in the first week after burn trauma is growing. This hypercoagulable state may partly be caused by increased fibrinogen levels. Rotational thrombelastometry offers a test which measures functional fibrinogen (FIBTEM(®)). To test the hypothesis that in patients with severe burn injury fibrinogen function changes over time, we simultaneously measured FIBTEM(®) and fibrinogen concentration early after burn trauma.

Methods: After Ethics Committee approval consecutive patients with severe burn trauma admitted to the burn intensive care unit of the General Hospital of Vienna were included in the study. Blood examinations were done immediately and 12, 24 and 48 h after admission. At each time point fibrinogen level (Clauss) and 4 commercially available ROTEM(®) tests were performed.

Results: 20 consecutive patients were included in the study. Fibrinogen level and FIBTEM(®) MCF were within the reference range until 24 h after burn trauma but increased significantly 48 h after trauma. There was a significant correlation between FIBTEM(®) MCF and fibrinogen level (R=0.714, p<0.001).

Conclusion: The results of this prospective observational clinical study show that fibrinogen function changes early after burn trauma and can be visualized by ROTEM(®) with the fibrinogen-sensitive FIBTEM(®) test.
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http://dx.doi.org/10.1016/j.burns.2010.12.004DOI Listing
February 2012

HSP27 and HSP70 serum and urine levels in patients suffering from chronic kidney disease.

Clin Chim Acta 2012 Jan 18;413(1-2):282-6. Epub 2011 Oct 18.

Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria.

Background: Chronic kidney disease (CKD) is a condition associated with inflammation and high levels of uremic toxins and reactive oxygen species. As a counterregulation to systemic stress heat shock proteins (HSP) are increased expressed to minimize cell death and preserve cell integrity by inhibiting apoptotic pathways. The aim of this study was to determine HSP27 and HSP70 concentrations in sera and urine of patients suffering from CKD.

Methods: Concentrations of HSP27 and HSP70 in urine and serum were determined in 119 patients with CKD stages 1 to 5 and 23 healthy volunteers by using ELISA technique.

Results: HSP27 serum levels were significantly elevated in patients suffering from CKD stages 3 to 5 as well as fractional HSP27 excretion in stages 2-5 versus healthy controls. Absolute HSP70 urinary values were significantly elevated in stages 4 and 5 and fractional HSP70 excretion was increased in stage 5 compared to controls. Moreover, ROC curve analysis showed the potential of urine and especially serum HSP levels to identify various stages of CKD.

Conclusion: We provide evidence for elevated HSP27 concentrations in serum and urine and increased HSP70 excretion levels in patients suffering from CKD. Moreover, our results show that HSP levels might offer potential to examine the stages of CKD as well as the disease course which could further promote individually adjusted treatment planning.
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http://dx.doi.org/10.1016/j.cca.2011.10.010DOI Listing
January 2012

Increased total cytokeratin-18 serum and urine levels in chronic kidney disease.

Clin Chim Acta 2011 Apr 31;412(9-10):713-7. Epub 2010 Dec 31.

Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria.

Background: Increased cell death in chronic kidney disease (CKD) by either necrosis or apoptosis has been confirmed by a variety of studies. Possible sources are an inadequate persistent inflammation and ischemia as a consequence of CKD or caused by the underlying renal disease. Detection of total or caspase cleaved cytokeratin 18 (CK-18) is a novel and elegant method to determine necrosis or apoptosis of epithelial cells in the patients' sera and urine.

Methods: 120 patients with CKD stages 1 to 5 were included in the study. Twenty healthy volunteers served as controls. Total and caspase cleaved CK-18 urine and serum concentrations were determined by ELISA.

Results: The concentration of serum total CK-18 was significantly higher in CKD stages 3-5 as compared to the healthy controls. Urinary total CK-18 excretion was increased in patients with CKD 5 compared to controls. A significant correlation between urine total CK18 and urine protein and albumin levels was found. Moreover, ROC curve analysis showed the potential of serum and especially urine total CK-18 levels to predict various CKD stages.

Conclusions: We provide evidence for increased total CK-18 serum and urine levels in CKD patients, possibly indicating that epithelial cell necrosis is prevalent in CKD.
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http://dx.doi.org/10.1016/j.cca.2010.12.030DOI Listing
April 2011
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