The transplant cohort of the German center for infection research (DZIF Tx-Cohort): study design and baseline characteristics.

Infectious complications are the major cause of morbidity and mortality after solid organ and stem cell transplantation. To better understand host and environmental factors associated with an increased risk of infection as well as the effect of infections on function and survival of transplanted organs, we established the DZIF Transplant Cohort, a multicentre prospective cohort study within the organizational structure of the German Center for Infection Research. At time of transplantation, heart-, kidney-, lung-, liver-, pancreas- and hematopoetic stem cell- transplanted patients are enrolled into the study. Follow-up visits are scheduled at 3, 6, 9, 12 months after transplantation, and annually thereafter; extracurricular visits are conducted in case of infectious complications. Comprehensive standard operating procedures, web-based data collection and monitoring tools as well as a state of the art biobanking concept for blood, purified PBMCs, urine, and faeces samples ensure high quality of data and biosample collection. By collecting detailed information on immunosuppressive medication, infectious complications, type of infectious agent and therapy, as well as by providing corresponding biosamples, the cohort will establish the foundation for a broad spectrum of studies in the field of infectious diseases and transplant medicine. By January 2020, baseline data and biosamples of about 1400 patients have been collected. We plan to recruit 3500 patients by 2023, and continue follow-up visits and the documentation of infectious events at least until 2025. Information about the DZIF Transplant Cohort is available at https://www.dzif.de/en/working-group/transplant-cohort .

BarrettNET-a prospective registry for risk estimation of patients with Barrett's esophagus to progress to adenocarcinoma.

Risk stratification in patients with Barrett's esophagus (BE) to prevent the development of esophageal adenocarcinoma (EAC) is an unsolved task. The incidence of EAC and BE is increasing and patients are still at unknown risk. BarrettNET is an ongoing multicenter prospective cohort study initiated to identify and validate molecular and clinical biomarkers that allow a more personalized surveillance strategy for patients with BE. For BarrettNET participants are recruited in 20 study centers throughout Germany, to be followed for progression to dysplasia (low-grade dysplasia or high-grade dysplasia) or EAC for >10 years. The study instruments comprise self-administered epidemiological information (containing data on demographics, lifestyle factors, and health), as well as biological specimens, i.e., blood-based samples, esophageal tissue biopsies, and feces and saliva samples. In follow-up visits according to the individual surveillance plan of the participants, sample collection is repeated. The standardized collection and processing of the specimen guarantee the highest sample quality. Via a mobile accessible database, the documentation of inclusion, epidemiological data, and pathological disease status are recorded subsequently. Currently the BarrettNET registry includes 560 participants (23.1% women and 76.9% men, aged 22-92 years) with a median follow-up of 951 days. Both the design and the size of BarrettNET offer the advantage of answering research questions regarding potential causes of disease progression from BE to EAC. Here all the integrated methods and materials of BarrettNET are presented and reviewed to introduce this valuable German registry.

Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors.

Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the in vitro effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.

Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany.

CONTEXT: Anaplastic thyroid carcinoma (ATC) is an orphan disease and confers a dismal prognosis. Standard treatment is not established. OBJECTIVE: The aim of this study is to describe clinical characteristics, current treatment regimens and outcome of ATC and to identify clinical prognostic markers and treatment factors associated with improved prognosis. DESIGN: Retrospective cohort study at five German tertiary care centers. PATIENTS AND METHODS: Totally 100 ATC patients diagnosed between 2000 and 2015 were included in the analysis. Disease-specific overall survival (OS) was compared with the Kaplan-Meier method and log-rank test; Cox proportional hazard model was used to identify risk factors. RESULTS: The 6-month, 1-year and 5-year disease-specific OS rates were 37, 28 and 5%, respectively. Stage-dependent OS at 6 months was 78, 54 and 18% for stage IVA, B and C, respectively. 29% patients survived >1 year. Multivariate analysis of OS identified age ≥70 years, incomplete local resection status and the presence of distant metastasis as significant risk factors associated with shorter survival. Radical surgery (hazard ratio [HR] 2.20, 95% confidence interval (CI) 1.19-4.09, P = 0.012), external beam radiation therapy (EBRT) ≥40 Gy (HR = 0.34, 0.15-0.76, P = 0.008) and any kind of chemotherapy (CTX) (HR = 11.64, 2.42-60.39, P = 0.003) were associated with longer survival in multivariate analyses adjusted for age and tumor stage. A multimodal treatment regimen was significantly associated with a survival benefit (HR = 1.04, 1.01-1.08, P < 0.0001) only in IVC patients. CONCLUSION: Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

Health-related quality of life after radical prostatectomy depends on patient's age but not on comorbidities.

PURPOSE: Localized prostate cancer affects younger and healthy patients as well as older patients with comorbidities. The purpose of this study was to evaluate the effect of age and comorbidities on the quality-of-life (QoL) course before and after radical retropubic prostatectomy. PATIENTS AND METHODS: Overall, 374 patients with localized prostate cancer scheduled for radical prostatectomy were prospectively included. The QoL questionnaire QLQ-C30 (European Organisation for Research and Treatment of Cancer) was completed 1 day before surgery and 3, 6, 9, and 12 months after radical prostatectomy. Sexual and urinary functions were not assessed in this analysis. Subgroups according to age at diagnosis (≤60,>60 to≤70, and>70y) and comorbidities (Charlson scores≤2 and ≥3) were defined. Subgroups were compared using the Wilcoxon-Mann-Whitney test, whereas changes in a group over time were analyzed with the Wilcoxon signed rank test. RESULTS: In all patient groups, no change was found 12 months after surgery compared with preoperative values in global health as well as functioning (role, physical, cognitive, and social). Emotional functioning improved significantly after surgery compared with preoperative functioning. Older patients (>70y) had better emotional and social functioning compared with younger patients (≤60y). The other scores were comparable between older and younger patients. Global health and physical, role, cognitive, and social functioning were independent of the number of comorbidities, although patients with a Charlson score≥3 did worse regarding fatigue and dyspnoe. CONCLUSION: The QoL of older patients or patients with multiple comorbidities is not negatively influenced by radical prostatectomy. This should be considered when discussing the indication for prostatectomy in older or comorbid patients.

Time to recovery of adrenal function after curative surgery for Cushing's syndrome depends on etiology.

CONTEXT: Successful tumor resection in endogenous Cushing's syndrome (CS) results in tertiary adrenal insufficiency requiring hydrocortisone replacement therapy. OBJECTIVE: The aim was to analyze the postsurgical duration of adrenal insufficiency of patients with Cushing's disease (CD), adrenal CS, and ectopic CS. DESIGN: We performed a retrospective analysis based on the case records of 230 patients with CS in our tertiary referral center treated from 1983-2014. The mean follow-up time was 8 years. PATIENTS: We included 91 patients of the three subtypes of CS undergoing curative intended surgery and documented followup after excluding cases with persistent disease, pituitary radiation, concurrent adrenostatic or somatostatin analog treatment, and malignant adrenal disease. RESULTS: The probability of recovering adrenal function within a 5 years followup differed significantly between subtypes (P = .001). It was 82% in ectopic CS, 58% in CD and 38% in adrenal CS. In the total cohort with restored adrenal function (n = 52) the median time to recovery differed between subtypes: 0.6 years (interquartile range [IQR], 0.03-1.1 y) in ectopic CS, 1.4 years (IQR, 0.9-3.4 y) in CD, and 2.5 years (IQR, 1.6-5.4 y) in adrenal CS (P = .002). In CD the Cox proportional-hazards model showed that the probability of recovery was associated with younger age (hazard ratio, 0.896; 95% confidence interval, 0.822-0.976; P = .012), independently of sex, body mass index, duration of symptoms, and basal ACTH and cortisol levels. There was no correlation with length and extend of hypercortisolism or postoperative glucocorticoid replacement doses. CONCLUSIONS: Time to recovery of adrenal function is dependent on the underlying etiology of CS.

Favorable long-term outcomes of bilateral adrenalectomy in Cushing's disease.

OBJECTIVE: Bilateral adrenalectomy (BADX) is an important treatment option for patients with Cushing's syndrome (CS). Our aim is to analyze the long-term outcomes, surgical, biochemical, and clinical as well as morbidity and mortality, of patients who underwent BADX. DESIGN: A total of 50 patients who underwent BADX since 1990 in two German centers were identified. Of them, 34 patients had Cushing's disease (CD), nine ectopic CS (ECS), and seven ACTH-independent bilateral adrenal hyperplasia (BAH). METHODS: Standardized follow-up examination was performed in 36 patients with a minimum follow-up time of 6 months after BADX and a median follow-up time of 11 years. RESULTS: Surgical morbidity and mortality were 6 and 4% respectively. All patients were found to be in remission after BADX. Almost all Cushing's-specific comorbidities except for psychiatric diseases improved significantly. Health-related quality of life remained impaired in 45.0% of female and 16.7% of male patients compared with a healthy population. The median number of adrenal crises per 100 patient-years was four. Nelson tumor occurred in 24% of CD patients after a median time span of 51 months. Long-term mortality after 10 years was high in ECS (44%) compared with CD (3%) and BAH (14%). CONCLUSIONS: BADX is an effective and relatively safe treatment option especially in patients with CD. The majority of patients experience considerable improvement of Cushing's symptoms.

Towards responsive IT-infrastructures--assessment of a health information system.

Marburg University Medical Center has been introducing a comprehensive health information system since 1999, using a single-vendor application framework with an integrated generator tool for the development of clinical applications. To find out if this architecture and our participative software engineering approach can be considered a step towards a responsive infrastructure, we compared the situation after the first deployment phase (basically a holistic approach) with the situation after the system was further developed and adapted to the users' needs using the generator tool approach. We collected system statistics and conducted user satisfaction surveys in 2001/02 and 2003 using standardized measurements. The survey results showed that user involvement as well as system content were judged significantly higher after the second deployment phase. Insofar, we could demonstrate the feasibility of our approach. However, definite statements concerning the superiority of the generator tool approach to other concepts are not yet possible. We will continue our assessment, and we strongly suggest further studies in other institutions introducing comparable clinical functionality.