[Linguistic Validation of the "German Lung Fibrosis Health Related Quality of Life Questionnaire"]. / Sprachliche Validierung des Fibrose-Fragebogens zur Erfassung der Lebensqualität bei Patienten mit idiopathischer Lungenfibrose und idiopathischer nichtspezifischer interstitieller Pneumonie.

Health status and quality of life are impaired in patients with idiopathic pulmonary fibrosis (IPF) and idiopathic non-specific interstitial fibrosis (iNSIP). In Germany exists only the K-BILD questionnaire for patients with ILD 1 in a professional translation by Kreuter et al. 2 This questionnaire focuses on the main problems in patients with progressive lung fibrosis in a limited manner. Therefore a new quality of life questionnaire for patients with idiopathic pulmonary fibrosis was developed and linguistically validated. METHODS: The linguistic validation of our questionnaire was carried out in a multistage process in collaboration with the developer of the questionnaire and bilingual, professional translators. Review by the developers and back translations as well as clinical assessment by IPF- and iNSIP-patients ensured that the translated questionnaire reflected the intention of the original English version of our questionnaire.Cross-validation was carried out with the St. Georges Respiratory Questionnaire (SGRQ). RESULTS: The new questionnaire concerning the health status was composed in English and German language. The questions cover five scales (sensitivity, selectivity and symptoms like breathlessness and cough and a visual analog scale on general health status) with 23 items. CONCLUSIONS: The results show that the FFB maps the special needs of the patients with IPF and iNSIP well and can support clinical and scientific questions and can be helpful in monitoring the clinical course.

Addition of decellularized extracellular matrix of porcine nasal cartilage improves cartilage regenerative capacities of PCL-based scaffolds in vitro.

Composite scaffolds can improve regenerative capacities of scaffolds in various tissue-engineering approaches. In order to generate a 3D printable scaffold that is capable of cartilage regeneration, decellularized extracellular matrix (DECM) of porcine nasal cartilage was added to 3D printed polycaprolactone (PCL) scaffolds. Subsequently, scaffolds (PCL, PCL/DECM and DECM) were seeded with human primary nasoseptal chondrocytes and differentiated with cartilage inductive medium for up to 42 days in vitro. Afterwards samples were analyzed with scanning electron microscopy, histology, biochemical assays and gene expression analysis. In short, results showed cell attachment and proliferation on all scaffolds. There was a trend towards ossification on pure PCL scaffolds, whereas we found evidence for cartilage tissue formation on DECM scaffolds as well as on PCL/DECM scaffolds. Moreover, biochemical analysis indicated an enhanced differentiation on novel PCL/DECM scaffolds. In conclusion, the addition of DECM to 3D printable PCL scaffolds may yield a new composite material for regenerative approaches in cartilage for facial reconstructive surgery. Further research will be necessary to evaluate these findings in vivo.

Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, ß- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aß production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aß production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.

[A Young Asylum Seeker with Hemoptysis and Positive Tuberculosis Screening: Not Always Tuberculosis!] / Hämoptysen bei einem jungen Asylbewerber mit positivem Tuberkulose-Screening: Nicht immer Tuberkulose!

This paper reports on the case of a 19 year old asylum seeker from Eritrea who presented with hemoptysis, a positive tuberculosis screening (Enzyme Linked Immuno Spot Assay - EliSpot) and mushy faeces submitted with a suspected diagnosis of tuberculosis. Laboratory testing revealed thrombopenia, leukopenia and eosinophilia, while the chest X-ray was inconspicuous. Acid-proof rod bacteria were neither evident in bronchoscopy samples nor in expectorated sputum samples. However, sonographic findings showed a profound splenomegaly, and laboratory testing revealed a Schistosoma mansoni infection. This case demonstrates that in asylum seekers with suspected tuberculosis endemic diseases of the home country need to be considered as alternative diagnoses.

The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients).

BACKGROUND: Despite our growing knowledge about the pathomechanisms of cancer cachexia, a whole clinical picture of the cachectic patient is still missing. Our objective was to evaluate the clinical characteristics in cancer patients with and without cachexia to get the whole picture of a cachectic patient. METHODS: Cancer patients of the University Clinic "Klinikum rechts der Isar" with gastrointestinal, gynecological, hematopoietic, lung and some other tumors were offered the possibility to take part in the treatment concept including a nutrition intervention and an individual training program according to their capability. We now report on the first 503 patients at the time of inclusion in the program between March 2011 and October 2015. We described clinical characteristics such as physical activity, quality of life, clinical dates and food intake. RESULTS: Of 503 patients with cancer, 131 patients (26.0%) were identified as cachectic, 369 (73.4%) as non-cachectic. The change in cachexia were 23% reduced capacity performance (108 Watt for non-cachectic-patients and 83 Watt for cachectic patients) and 12% reduced relative performance (1.53 Watt/kg for non-cachectic and 1.34 Watt/kg for cachectic patients) in ergometry test. 75.6% of non-cachectic and 54.3% of cachectic patients still received curative treatment. CONCLUSION: Cancer cachectic patients have multiple symptoms such as anemia, impaired kidney function and impaired liver function with elements of mild cholestasis, lower performance and a poorer quality of life in the EORTC questionnaire. Our study reveals biochemical and clinical specific features of cancer cachectic patients.

Motor associations of iron accumulation in deep grey matter nuclei in Parkinson's disease: a cross-sectional study of iron-related magnetic resonance imaging susceptibility.

BACKGROUND AND PURPOSE: To determine whether iron deposition in deep brain nuclei assessed using high-pass filtered phase imaging plays a role in motor disease severity in Parkinson's disease (PD). METHODS: Seventy patients with mild to moderate PD and 20 age- and gender-matched healthy volunteers (HVs) underwent susceptibility-weighted imaging on a 3 T magnetic resonance imaging scanner. Phase shifts (radians) in deep brain nuclei were derived from high-pass filtered phase images and compared between groups. Analysis of clinical laterality and correlations with motor severity (Unified Parkinson's Disease Rating Scale, Part III, UPDRS-III) were performed. Phase shifts (in radians) were compared between HVs and three PD subgroups divided according to UPDRS-III scores using analysis of covariance, adjusting for age and regional area. RESULTS: Parkinson's disease patients had significantly (P < 0.001) higher radians than HVs bilaterally in the putamen, globus pallidus and substantia nigra (SN). The SN contralateral to the most affected side showed higher radians (P < 0.001) compared to the less affected side. SN radians positively correlated with UPDRS-III and bradykinesia-rigidity subscores, but not with tremor subscores. ancova followed by post hoc Bonferroni-adjusted pairwise comparisons revealed that SN radians were significantly greater in the PD subgroup with higher UPDRS-III scores compared to both lowest UPDRS-III PD and HV groups (P < 0.001). CONCLUSIONS: Increased nigral iron accumulation in PD appears to be stratified according to disease motor severity and correlates with symptoms related to dopaminergic neurodegeneration. This semi-quantitative in vivo iron assessment could prove useful for objectively monitoring PD progression, especially in clinical trials concerning iron chelation therapies.

CXCR1 Regulates Pulmonary Anti-Pseudomonas Host Defense.

Pseudomonas aeruginosa is a key opportunistic pathogen causing disease in cystic fibrosis (CF) and other lung diseases such as chronic obstructive pulmonary disease (COPD). However, the pulmonary host defense mechanisms regulating anti-P. aeruginosa immunity remain incompletely understood. Here we demonstrate, by studying an airway P. aeruginosa infection model, in vivo bioluminescence imaging, neutrophil effector responses and human airway samples, that the chemokine receptor CXCR1 regulates pulmonary host defense against P. aeruginosa. Mechanistically, CXCR1 regulates anti-Pseudomonas neutrophil responses through modulation of reactive oxygen species and interference with Toll-like receptor 5 expression. These studies define CXCR1 as a novel, noncanonical chemokine receptor that regulates pulmonary anti-Pseudomonas host defense with broad implications for CF, COPD and other infectious lung diseases.

Electrophysiological validation of STN-SNr boundary depicted by susceptibility-weighted MRI.

BACKGROUND: Direct targeting of subthalamic nucleus (STN) without secondary electrophysiological verification during deep brain stimulation (DBS) is replacing atlas-based indirect targeting techniques. Recent groups have reported increased contrast and better delineation of STN and substantia nigra (SNr) in susceptibility-weighted imaging protocols (SWI). We aim to validate the STN-SNr boundary seen in MRI- SWI by correlating with intraoperative microelectrode recordings (MER) as a part of developing a multi-contrast DBS MRI planning protocol. METHODS: Prospective service evaluation involving electrophysiological verification by correlation of MER trajectory and STN-SNr boundary seen in SWI in seven consecutive patients undergoing DBS surgery were analyzed. The angle of inclination of the STN-SNr boundary and DBS trajectory in the coronal plane were calculated. Considering 4-mm dispersion of a coronal 3 MER array, we predicted, measured, and correlated the depths at which each electrode engaged the boundary. RESULTS: All central microelectrodes identified the STN-SNr boundary within 1 mm of the predicted depth with 100 % accuracy. Ninety percent of the lateral MER identified the STN-SNr boundary as predicted from SWI and angle of the encounter of the MER front. CONCLUSIONS: The study demonstrates that STN morphology can be depicted using SWI MRI and coincides reliably with the electrophysiological MER boundary. Thus, this imaging modality can be used to refine STN direct targeting protocols in DBS surgery for PD.

Immortalised human mesenchymal stem cells undergo chondrogenic differentiation in alginate and PGA/PLLA scaffolds.

Adult mesenchymal stem cells (MSCs) are a promising cell source in tissue engineering due to their availability, ease of isolation and high proliferative activity. This study was undertaken to investigate whether immortalised human MSC are able to undergo chondrogenic differentiation when cultured in alginate or in resorbable scaffolds. We directly compared chondrogenesis MSCs with that of human nasoseptal chondrocytes. Two previously established human stem cell lines L87/4 and V54-2 immortalised using the SV40 large T-antigen were either cultured in alginate or in polyglycolic acid/poly-L-lactic acid (PGA/PLLA) (90/10) copolymer scaffolds. TGF-ß1 was added for induction of chondrogenesis. Human nasoseptal chondrocytes and human fibroblasts were used as controls. Cultures were analysed for sulfated glycosaminoglycans (alcian blue staining) and for the presence of collagen type I, II and X (immunolabelling). SV40 large T-antigen immortalised human MSCs have the potential to undergo chondrogenic differentiation: After 21 days, cartilage-specific type II collagen was present in alginate and PGA/PLLA scaffolds, independent of the addition of TGF-ß1. Collagen type X was present in monolayer cultures as well as in alginate and PGA/PLLA scaffolds. Collagen type I was produced in marginal amounts only. Immortalised human MSCs are a suitable tool to study chondrogenesis in vitro and to screen biomaterials for cartilage tissue engineering applications.

[Physical characterization of decellularized cartilage matrix for reconstructive rhinosurgery]. / Physikalische Charakterisierung dezellularisierter Knorpelmatrix zur Anwendung in der Rhinochirurgie.

BACKGROUND: The use of autologous auricular and rib cartilage for the reconstruction of nasal defects and deformities is associated with a number of disadvantages. The development of alternative materials is therefore the focus of intensive research. Recent studies demonstrated that decellularized cartilage is a promising material for cartilage tissue engineering. Hence, the aim of this study was to characterize the materials surface and cellular reactions to the decellularized cartilage matrix in long term-3D-culture. MATERIAL AND METHODS: Material geometry of decellularized cartilage was examined by microcomputed tomography as well as material characteristics by scanning and transmission electron microscopy. The expression of integrins on the surface of human chondrocytes was determined after seeding and migration into the scaffold. RESULTS: After decellularization an obvious enlargement of the matrix surface and an intensive interaction between the chondrocytes and the collagen matrix was observed. ITGA1 and ITGB1 were upregulated indicating chondrogenic differentiation. CONCLUSION: Therefore, decellularized porcine cartilage provides an optimal microstructure for human chondrocytes with respect to cell integration and matrix production. Thus, it offers promising characteristics for clinical application in reconstructive surgery.

[Non-cirrhotic portal hypertension presented by acute upper gastrointestinal bleeding 7 years after oxaliplatin-chemotherapy]. / Nicht zirrhotische portale Hypertension mit bedrohlicher Blutungskomplikation 7 Jahre nach Oxaliplatin-Chemotherapie.

After having received adjuvant FOLFOX treatment consisting of oxaliplatin, folinic acid and fluoruracil following hemicolectomy in colon cancer 7 years ago, the findings of non-cirrhotic portal hypertension presented by acute upper gastrointestinal bleeding in a 49-year old woman were interpreted as oxaliplatin-associated. Imaging techniques, hepatic venous pressure measurement and liver biopsy supported pre-sinusoidal damage due to NRH (nodular regenerative hyperplasia) as the underlying cause, even though histological findings were moderate. Following primary endoscopic treatment, a stable condition has thus far been achievable with standard drug therapy.

Hippocampus sparing in whole-brain radiotherapy. A review.

Radiation treatment techniques for whole-brain radiation therapy (WBRT) have not changed significantly since development of the procedure. However, the recent development of novel techniques such as intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT) and helical tomotherapy, as well as an increasing body of evidence concerning neural stem cells (NSCs) have altered the conventional WBRT treatment paradigm. In this regard, hippocampus-sparing WBRT is a novel technique that aims to spare critical hippocampus regions without compromising tumour control. Published data on this new technique are limited to planning and feasibility studies; data on patient outcome are still lacking. However, several prospective trials to analyse the feasibility of this technique and to document clinical outcome in terms of reduced neurotoxicity are ongoing.

Radiation treatment parameters for re-irradiation of malignant glioma.

BACKGROUND AND PURPOSE: Most patients with malignant glioma ultimately fail locally or loco-regionally after the first treatment, with re-irradiation being a reasonable treatment option. However, only limited data are presently available allowing for a precise selection of patients suitable for re-treatment with regard to safety and efficacy. MATERIAL AND METHODS: Using the department database, 39 patients with a second course of radiation were identified. Doses to gross tumor volume (GTV), planning target volume (PTV), and relevant organs at risk (OARs; brainstem, optic chiasm, optic nerves, brain) were retrospectively analyzed and correlated to outcome parameters. Relevant treatment parameters including D(max), D(min), D(mean), and volume (ml) were obtained. Equivalent uniform dose (EUD) values were calculated for the tumor and OARs. To address the issue of radiation necrosis/leukoencephalopathy posttherapeutic MRI images were routinely examined every 3 months. RESULTS: Median follow-up was 147 days. The time interval between first and second irradiation was regularly greater than 6 months. Median EUDs to the OARs were 11.9 Gy (range 0.7-27.4 Gy) to the optic chiasm, 17.6 Gy (range 0.7-43.0 Gy) to the brainstem, 4.9/2.1 Gy (range 0.3-24.5 Gy) to the right/left optic nerve, and 29.4 Gy (range 25.2-32.5 Gy) to the brain. No correlation between treated volume and survival was observed. Cold spots and dose did not correlate with survival. Re-irradiated volumes were treated with on average lower doses if they were larger and vice versa. CONCLUSION: In general, re-irradiation is a safe and feasible re-treatment option. No relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. In this regard, this analysis provides baseline data for the selection of putative patients. EUD values are derived and may serve as reference for further studies, including intensity-modulated radiotherapy (IMRT) protocols.

Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer.

BACKGROUND: Activity of the tumour-suppressor gene PTEN is reduced in different types of cancer and implicates non-responsiveness to targeted therapy. This study evaluates the gene and protein status of PTEN in salivary gland carcinomas. METHODS: A total of 287 carcinomas of the major and minor salivary glands were investigated for phosphatase and tensin homologue located on chromosome 10 (PTEN) deletion and loss of PTEN expression using fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), respectively. Results were correlated to clinicopathological parameters, long-term survival, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (IHC and FISH) status of the tumours. RESULTS: Hemizygous deletions of PTEN were found in 35 out of 232 (15.1%) carcinomas, while homozygous deletions were observed in 17 out of 232 (7.3%) tumours. Phosphatase and tensin homologue located on chromosome 10 deletion was common in certain histological subtypes and especially homozygous deletion was associated with high-grade malignancy, lymph node metastases and unfavourable long-term prognosis (P<0.001). Loss of PTEN expression was present in 59 out of 273 (21.6%) carcinomas and was significantly correlated to genomic PTEN deletion, high-grade malignancy (P<0.001), increased tumour size (P=0.036), lymph node metastases (P=0.007) and worse disease-specific survival (P=0.002). Genomic PTEN deletion, in particular homogenous deletion (P<0.001) predominantly occurred in tumours with increased gene copy number of EGFR (60.0%) and/or amplification of HER2 (63.6%). Loss of PTEN expression was frequently found in tumours overexpressing EGFR (28.6%) and/or HER2 (52.6%). CONCLUSION: PTEN function is reduced in different types of salivary gland cancer indicating unfavourable prognosis. Its association with EGFR and HER2 signalling might affect targeted therapy.

Radiotherapy with and without temozolomide in elderly patients with glioblastoma.

BACKGROUND AND PURPOSE: The optimal treatment for elderly patients (age ≥ 70 years) with glioblastoma (GBM) remains controversial. We conducted a retrospective analysis in 43 consecutive elderly patients with glioblastoma who either underwent radiotherapy (RT) or radiotherapy plus concomitant temozolomide (TMZ). PATIENTS AND METHODS: A total of 43 patients (≥ 70 years of age, median age 75.8 years) with newly diagnosed glioblastoma and a Karnofsky performance status (KPS) ≥ 70 were treated with RT alone (median 60 Gy in 2 Gy single fractions) or RT plus TMZ at a dose of 75 mg/m(2) per day. The two groups were well-balanced; univariate (log-rank test) and multivariate Cox proportional hazards analysis were used to identify relevant prognostic factors. RESULTS: The median overall survival (mOS) of the entire patient cohort was 264 days (8.8 months) and the median progression-free survival (PFS) was 192 days (6.4 months). The factors age, sex, previous surgery, KPS, and concomitant use of TMZ had no significant influence on OS/PFS; multivariate analysis was performed to obtain adjusted hazard ratios. TMZ use resulted in a trend toward poorer overall survival when applied concomitantly (314 days compared to 192 days within the TMZ group, p = 0.106). The subgroup analysis revealed that TMZ use resulted in significantly worse survival rates in patients with KPS70 (p = 0.027), but for patients with KPS80 this difference was not detectable. CONCLUSION: TMZ should only be used carefully in elderly patients with unfavorable KPS. In this patient cohort, radiotherapy alone is a reasonable option. Standard RT plus concomitant TMZ may be an advantageous treatment option for elderly patients with newly diagnosed glioblastoma who present with good prognostic factors.

[Prognosis and quality of life after decompressive hemicraniectomy: a nationwide survey in Germany on the attitudes held by doctors and nurses]. / Prognose und Lebensqualität nach Entlastungstrepanation : Eine deutschlandweite Erhebung zu den Einstellungen von Ärzten und Krankenpflegepersonal.

BACKGROUND: Decompressive hemicraniectomy reduces mortality in patients with space-occupying MCA infarction. Quality of life in surviving patients is discussed controversially. We assessed attitudes of neurologists and nurses providing care to this patient group towards decompressive hemicraniectomy. METHODS: A postal questionnaire on attitudes and opinions on prognosis and quality of life after decompressive hemicraniectomy was returned by 280 neurologists and 166 nurses from tertiary care centers throughout Germany. RESULTS: In both groups of professionals, estimates of the probability of survival after decompressive hemicraniectomy and the resulting degree of disability were consistent with results of clinical outcomes studies. Only 9% of the nurses and 33% of the physicians assumed that the majority of survivors achieve an acceptable quality of life; 58% of physicians and 32% of nurses would suggest decompressive hemicraniectomy to their nearest relative. Under the assumption of an uncertain outcome, 61% of physicians and 22% of nurses would agree to decompressive hemicraniectomy. In both professional groups, agreement for surgery increases when scenarios with a more favorable outcome were proposed [modified Rankin Scale (mRS) 2-5)]. If an outcome of 4 on the mRS is proposed, indicating moderately severe disability, only a minority favored decompressive hemicraniectomy (25% of doctors and 8% of nurses). CONCLUSIONS: Despite a realistic assessment of prognosis after decompressive hemicraniectomy, a majority of respondents estimated the quality of life of survivors as unsatisfactory. Nurses had a more pessimistic attitude towards decompressive hemicraniectomy. The majority of respondents consider an outcome of 4 on the mRS as unacceptable.

Prospective assessment of complications associated with ultrasound activated resorbable pin osteosynthesis in pediatric craniofacial surgery: preliminary results.

Ultrasound activated resorbable pin osteosynthesis (UARPO) has recently shown favourable results in operations on children suffering for craniosynostosis. However, data on complications coming with this new technique in children suffering from craniosynostoses are scarce and have only been assessed retrospectively so far. It has been the aim of the present study to prospectively follow up children undergoing craniosynostosis surgery with a focus on complications related to UARPO materials. Ten pediatric patients (3 female/7 male) were operated due to craniosynostosis at an average age of 9.1±3.8 months using UARPO (SonicWeld/Resorb-X, KLS Martin, Tuttlingen, Germany). Clinical followup evaluations were carried out 1, 3, 6, 9, 12 and 18 months after surgery according to signs of local infection, stability of the remodeled cranial vault and the palpability of the osteosynthesis material. If secondary surgery was necessary, the indication was documented and evaluated by histological and wound smear examinations. No intra-operative or postoperative complications during the inpatient period occurred. 3 patients needed secondary operation due to a localized chronic swelling at the former incision site which developed 3, 9 and 12 months after the operation. Histological examinations yielded a giant cell formation surrounding the resorbable materials in all cases. Additionally, the wound smear showed a bacterial infection in one site. The current prospective study is the first in the field. It reveals a high percentage of delayed foreign body reactions with UARPO, bearing the need of secondary surgery. It seems that this high complication rate found in the present prospective study may weigh out the advantages of UARPO.

Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy.

Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER-2 status in the tumor. Trastuzumab in combination with cisplatin/5-fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer.