The tissue-renin-angiotensin-system of the human intervertebral disc.

Symptomatic intervertebral disc (IVD) degeneration accounts for significant socioeconomic burden. Recently, the expression of the tissue renin-angiotensin system (tRAS) in rat and bovine IVD was demonstrated. The major effector of tRAS is angiotensin II (AngII), which participates in proinflammatory pathways. The present study investigated the expression of tRAS in human IVDs, and the correlation between tRAS, inflammation and IVD degeneration. Human IVD tissue was collected during spine surgery and distributed according to principal diagnosis. Gene expression of tRAS components, proinflammatory and catabolic markers in the IVD tissue was assessed. Hydroxyproline (OHP) and glycosaminoglycan (GAG) content in the IVD tissue were determined. Tissue distribution of tRAS components was investigated by immunohistochemistry. Gene expression of tRAS components such as angiotensin-converting enzyme (ACE), Ang II receptor type 2 (AGTR2), angiotensinogen (AGT) and cathepsin D (CTSD) was confirmed in human IVDs. IVD samples that expressed tRAS components (n = 21) revealed significantly higher expression levels of interleukin 6 (IL-6), tumour necrosis factor α (TNF-α), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 and 5 compared to tRAS-negative samples (n = 37). Within tRAS-positive samples, AGT, matrix-metalloproteinases 13 and 3, IL-1, IL-6 and IL-8 were more highly expressed in traumatic compared to degenerated IVDs. Total GAG/DNA content of non-tRAS expressing IVD tissue was significantly higher compared to tRAS positive tissue. Immunohistochemistry confirmed the presence of AngII in the human IVD. The present study identified the existence of tRAS in the human IVD and suggested a correlation between tRAS expression, inflammation and ultimately IVD degeneration.

Lung Transplantation in Hungary From Cardiac Surgeons' Perspective.

Thoracic organ transplantation made a fresh start in Hungary with the first double lung transplant in December 2015. This major leap in Hungarian transplantation was preceded by almost 10 years of preparation, new infrastructure development, and structural changes not only at the organizational level but in human resources as well. In the following years, until recently, altogether 47 lung transplants were performed on 24 men and 23 women. The underlying pathologies were as follows: chronic obstructive pulmonary disease, 25; cystic fibrosis, 11; idiopathic pulmonary fibrosis, 7; as well as other diseases, including bronchiectasis, eosinophilic granuloma, lymphangioleiomyomatosis, and primary pulmonary hypertension in 4 cases. The youngest recipient was 13 and the oldest was 65 years old. Overall survival rates at 30 days and at 1 year were 96% and 82%, respectively. No patients were lost in the cystic fibrosis and other diseases group, whereas the 1-year survival rates of the chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis groups were 73% and 71%, respectively. The results show the robustness and viability of the program, although there is still opportunity for further improvement. In this short paper, we summarize the fields of possible further cooperation of thoracic and cardiac teams as well as future challenges facing the new Hungarian lung transplant program.

Antibody-Mediated Rejection in a Multiple Lung Transplant Patient: A Case Report.

Lung transplant is an effective way to treat many end-stage lung diseases. However, one of the main barriers of allograft organ transplant is still the immunologic rejection of transplanted tissue, which is a response of the HLA molecules. Rejection is a complex process involving both T-cell-mediated delayed-type hypersensitivity reactions and antibody-mediated hypersensitivity reactions to histocompatibility molecules on foreign grafts. We report the case of a 25-year-old female patient with cystic fibrosis who underwent 2 lung transplants because of her initial diagnosis and appearance of bronchiolitis obliterans syndrome after the first transplant. Only 13 months after the second transplant, despite the therapies applied, a new rejection occurred associated with high mean fluorescent intensity donor-specific antibody levels, which resulted later in the death of the patient. The present case draws attention to the importance of matching HLA molecules between donor and recipient in addition to immunosuppressive therapy.

The impact of genome evolution on the allotetraploid Nicotiana rustica - an intriguing story of enhanced alkaloid production.

BACKGROUND: Nicotiana rustica (Aztec tobacco), like common tobacco (Nicotiana tabacum), is an allotetraploid formed through a recent hybridization event; however, it originated from completely different progenitor species. Here, we report the comparative genome analysis of wild type N. rustica (5 Gb; 2n = 4x = 48) with its three putative diploid progenitors (2.3-3 Gb; 2n = 2x =24), Nicotiana undulata, Nicotiana paniculata and Nicotiana knightiana. RESULTS: In total, 41% of N. rustica genome originated from the paternal donor (N. undulata), while 59% originated from the maternal donor (N. paniculata/N. knightiana). Chloroplast genome and gene analyses indicated that N. knightiana is more closely related to N. rustica than N. paniculata. Gene clustering revealed 14,623 ortholog groups common to other Nicotiana species and 207 unique to N. rustica. Genome sequence analysis indicated that N. knightiana is more closely related to N. rustica than N. paniculata, and that the higher nicotine content of N. rustica leaves is the result of the progenitor genomes combination and of a more active transport of nicotine to the shoot. CONCLUSIONS: The availability of four new Nicotiana genome sequences provide insights into how speciation impacts plant metabolism, and in particular alkaloid transport and accumulation, and will contribute to better understanding the evolution of Nicotiana species.

Breakthrough in the Transplantation of Thoracic Organs in Hungary.

In 2016 the focus was, by all means, on the transplantation on thoracic organs. More than 50 heart transplantations were performed in this year. With this achievement, the Hungarian Heart Transplantation Program became one of the leading programs in the world. In the Thoracic Surgery Unit of the National Institute of Oncology and the Thoracic Surgery Department of Semmelweis University the first successful lung transplantation was carried out on December 12, 2015 when the Hungarian Lung Transplantation Program was launched.

Launching the Hungarian Lung Transplantation Program.

The first successful lung transplantation was done in 1963 by James Hardy in the United States. The Vienna Lung Transplant program was launched in 1989 by Professor Walter Klepetko, and in 1996 lung transplantation became available in this center also for Hungarian patients. By 2013, conditions for full-scale Hungarian lung transplantation program were ripe. The Hungarian government invested 3 million Euros for infrastructural developments that made the operation and the perioperative care available. Besides funding, the professional training of medical personnel was also essential for this program to start. Hungarian specialists have had internship opportunities to study all aspects of lung transplantation at the Thoracic Surgery Department in Vienna. After successful preparations, the first lung transplantation in Hungary was performed on December 12, 2015.

Ki67 index is an independent prognostic factor in epithelioid but not in non-epithelioid malignant pleural mesothelioma: a multicenter study.

BACKGROUND: Estimating the prognosis in malignant pleural mesothelioma (MPM) remains challenging. Thus, the prognostic relevance of Ki67 was studied in MPM. METHODS: Ki67 index was determined in a test cohort of 187 cases from three centres. The percentage of Ki67-positive tumour cells was correlated with clinical variables and overall survival (OS). The prognostic power of Ki67 index was compared with other prognostic factors and re-evaluated in an independent cohort (n=98). RESULTS: Patients with Ki67 higher than median (>15%) had significantly (P<0.001) shorter median OS (7.5 months) than those with low Ki67 (19.1 months). After multivariate survival analyses, Ki67 proved to be-beside histology and treatment-an independent prognostic marker in MPM (hazard ratio (HR): 2.1, P<0.001). Interestingly, Ki67 was prognostic exclusively in epithelioid (P<0.001) but not in non-epithelioid subtype. Furthermore, Ki67 index was significantly lower in post-chemotherapy samples when compared with chemo-naive cases. The prognostic power was comparable to other recently published prognostic factors (CRP, fibrinogen, neutrophil-to-leukocyte ratio (NLR) and nuclear grading score) and was recapitulated in the validation cohort (P=0.048). CONCLUSION: This multicentre study demonstrates that Ki67 is an independent and reproducible prognostic factor in epithelioid but not in non-epithelioid MPM and suggests that induction chemotherapy decreases the proliferative capacity of MPM.

[Basic in vitro studies on VEGF inhibition with aflibercept: similarities and differences to other VEGF-binding therapeutic proteins]. / Grundlegende In-vitro-Untersuchungen zur VEGF-Inhibition mit Aflibercept: Gemeinsamkeiten und Unterschiede zu anderen VEGF-bindenden therapeutischen Proteinen.

Patients suffering from various retinal diseases benefit from therapies directed against the vascular endothelial growth factor (VEGF). Aflibercept (Eylea) is another VEGF-binding protein available for intravitreal injection, in addition to the antibody bevacizumab (Avastin) and the F(ab) fragment ranibizumab (Lucentis). Aflibercept's distinct structure and broader binding specificity may have clinically relevant consequences, which is supported by basic in vitro studies and observations in animal eyes. All pathological processes involving neovascularisation are driven by the dominant action of VEGF, but other factors including placenta growth factor (PlGF), a mitogenic protein for retinal endothelial cells, potentially modulate its effects. Aflibercept is an inhibitor of both VEGF and PlGF and therefore may have superior therapeutic effects in some cases. However, whether or not aflibercept's broader binding specificity or different affinities for the different VEGF-binding proteins to VEGF result in substantially diverse therapeutic efficiencies has not yet been clarified. In vitro studies confirm that aflibercept efficiently prevents or normalises VEGF-stimulation of retinal cells and disturbance of their barrier function. These experiments also show that aflibercept is taken up by important retinal cell types and affects their normal function, i.e., migration of endothelial cells and phagocytosis of pigment epithelial cells. In accordance with a role of the Fc domains of aflibercept and bevacizumab, substantial amounts of both proteins are internalised, whereas only a small portion of ranibizumab enters the cells. Internalisation and storage by ocular cells, also observed in vivo after intravitreal injection into eyes of monkeys, may result in not yet recognised side effects during long-term treatment of patients with certain VEGF-binding proteins.

Pulmonary metastasectomy for soft tissue sarcoma--report from a dual institution experience at the Medical University of Vienna.

BACKGROUND: Pulmonary metastasectomy when possible has become therapeutic standard in soft tissue sarcoma patients. However, published reports frequently describe mixed series of patients with bone or soft tissue sarcoma. We report the outcome of 46 soft tissue sarcoma (STS) patients who underwent pulmonary metastasectomy (PM). METHODS: This current analysis includes retrospective survival data from 46 consecutive STS patients with pulmonary metastases who underwent PM at the Medical University of Vienna between January 2003 and December 2013. RESULTS: In total 72 pulmonary metastasectomies were performed. 322 metastatic nodules were resected with a median number of four nodules per intervention and the R0 resection rate was 97.2%. The postoperative complication rate as documented was low. Median follow-up (mFU) was 31.8 months (range 3.7-127.4). Median overall survival as calculated from first detection of metastatic disease was 47.1 months (95% confidence interval (CI)=36.2-58.1 months) and 45.3 months (95% CI=33.3-57.4 months) when calculated from first PM until death or last follow-up (n=46). Five-year overall survival calculated from primary diagnosis was 62% and 32% when estimated from first PM. Previous disease free interval (DFI) as calculated from date of surgery of the primary tumour until the date of diagnosis of lung metastasis was 12.2 months (range 0-140.1 months). Median relapse-free survival (mRFS) after first PM to the date of recurrence of lung metastasis, death or last follow-up was 13.4 months (95% CI=3-23.8 months). CONCLUSION: Median overall survival in this selected patient cohort is 45.3 months. Despite the lack of prospective randomised controlled trials, PM is a reasonable treatment strategy in selected patients.

Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study.

Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes ≥ A2 within the first year post-TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher-grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies.

[Ophthalmopathology in everyday clinical routine]. / Ophthalmopathologie im klinischen Einsatz.

This article is intended to take up the cudgels on behalf of ophthalmopathology. To achieve this it is required to shed a light on ophthalmopathology in everyday clinical routine and to emphasise its relevance in today's world. Furthermore, it is intended to show how ophthalmopathology (unconsciously in part) has an impact on our actions. An ophthalmopathologist thinks differently, diagnoses differently and operates differently! Therefore ophthalmopathology should be a cornerstone not only in patient care but also in research and education.

[Treatment of diabetic macular oedema with the VEGF inhibitors ranibizumab and bevacizumab: conclusions from basic in vitro studies]. / Therapie des diabetischen Makulaödems mit den VEGF-Inhibitoren Ranibizumab und Bevacizumab: Schlüsse aus grundlegenden In-vitro-Untersuchungen.

Diabetic macular oedema (DMO) which may occur at all stages of diabetic retinopathy (DR) is a severe vision-threatening complication. In most cases, laser treatment does not improve visual acuity. Therefore research in ophthalmology focuses on the improvement of the prognosis of DMO patients with a drug-based DMO therapy. Vascular endothelial growth factor (VEGF) is considered the most important therapeutic target because this growth factor also is the most potent permeability factor affecting the inner retinal barrier formed by endothelial cells (ECs). Compared to its angiogenic stimulation of proliferation and migration of ECs, effects of VEGF on permeability have not been studied in all details. In vitro investigations on the behaviour of primary or immortalised retinal endothelial cells confirmed the key role of VEGF in the regulation of the permeability of the inner retinal barrier. Despite the presence of a variety of other factors found to be elevated in DR, a VEGF-disrupted barrier can be completely restored with the VEGF-inhibiting ranibizumab (Lucentis®) and bevacizumab (Avastin®) when applied at clinically achievable concentrations. The antibody bevacizumab, but not the antibody fragment ranibizumab, accumulates in both retinal EC and pigment epithelial cells during prolonged treatment. This observation might be relevant because patients are often treated for several years and additional long-term side effects may be recognised in the future.

Early diagnosis and management of esophageal and gastric cancer.

Esophageal and gastric cancers have high mortality rates secondary to the late presentation of most patients at advanced stages. Improved survival is achievable when the disease is confined to the more superficial mucosal layers and treated. This review will focus on the detection, screening, staging, endoscopic treatment, and surveillance of early upper gastrointestinal cancer - squamous cell carcinoma of the esophagus, esophageal adenocarcinoma, and gastric adenocarcinoma.