Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

BACKGROUND: Omeprazole has recently been described as a modulator of tumour chemoresistance, although its underlying molecular mechanisms remain controversial. Since pancreatic tumours are highly chemoresistant, a logical step would be to investigate the pharmacodynamic, morphological and biochemical effects of omeprazole on pancreatic cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Dose-effect curves of omeprazole, pantoprazole, gemcitabine, 5-fluorouracil and the combinations of omeprazole and 5-fluorouracil or gemcitabine were generated for the pancreatic cancer cell lines MiaPaCa-2, ASPC-1, Colo357, PancTu-1, Panc1 and Panc89. They revealed that omeprazole inhibited proliferation at probably non-toxic concentrations and reversed the hormesis phenomena of 5-fluorouracil. Electron microscopy showed that omeprazole led to accumulation of phagophores and early autophagosomes in ASPC-1 and MiaPaCa-2 cells. Signal changes indicating inhibited proliferation and programmed cell death were found by proton NMR spectroscopy of both cell lines when treated with omeprazole which was identified intracellularly. Omeprazole modulates the lysosomal transport pathway as shown by Western blot analysis of the expression of LAMP-1, Cathepsin-D and β-COP in lysosome- and Golgi complex containing cell fractions. Acridine orange staining revealed that the pump function of the vATPase was not specifically inhibited by omeprazole. Gene expression of the autophagy-related LC3 gene as well as of Bad, Mdr-1, Atg12 and the vATPase was analysed after treatment of cells with 5-fluorouracil and omeprazole and confirmed the above mentioned results. CONCLUSIONS: We hypothesise that omeprazole interacts with the regulatory functions of the vATPase without inhibiting its pump function. A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death. This may circumvent common resistance mechanisms of pancreatic cancer. Since omeprazole use has already been established in clinical practice these results could lead to new clinical applications

Relevance of Primitive Carotidobasilar Anastomosis for Internal Carotid Artery Stenosis

Primitive carotido-basilar anastomoses (PCA) are persistent fetal vessels. The aim of the study was to compare the clinical characteristics of patients operated on for internal carotid artery (ICA) stenosis with or without PCA in order to evaluate the impact of PCA on the treatment. Material and methods. Consecutive patients operated on for ICA stenosis at our university hospital were included. Surgical treatment consisted in carotid endarterectomy (CEA) with patch plastic. Results. Of the 380 CEA performed between 2006 and 2012, PCA were found in six patients (1.6%). All patients with PCA were symptomatic vs. 54% of patients without PCA (p=0.035). Significantly less posterior collateral flow was present in patients with PCA (33%) compared to those without PCA (85%, p=0.01). Only two of the six patients with PCA were diagnosed prior to surgery, none was ligated intraoperatively. PCA was not associated with stroke and restenosis at long-term follow up. Conclusions. PCA are rarely diagnosed prior to surgery in patients with ICA stenosis and need not to be ligated during CE

Post-exercise pulsatility index indicates treatment effects in peripheral arterial occlusive disease (PAOD)

Background!#!Hypothesis: Post-exercise measurements better discriminate PAOD-patients from healthy persons and they more sensitively detect hemodynamic improvements after treatment procedures than resting measurements.!##!Methods!#!A total of 19 healthy volunteers and 23 consecutive PAOD-patients underwent measurements of peak systolic velocity (PSV), end-diastolic velocity (EDV), minimal diastolic velocity (MDV), time-averaged maximum velocities (TAMAX), resistance index (RI) and pulsatility index (PI) before and after a standard exercise test (at 1, 2, 3, 4 and 5 min) before and after treatment (incl. epidemiological data, PAOD risk factors and comorbidities).!##!Results!#!In resting values, healthy persons and PAOD-patients did not differ significantly in any of the hemodynamic parameters. PSV increased after treatment in PAOD-patients by 5 cm/s (paired t‑test, p: 0.025); however, when the amplitude of autoregulatory changes related to the resting values were calculated, PAOD-patients showed clearly less hemodynamic changes after exercise than healthy persons (p: 0.04; 0.002; <0.001 for PSV, TAMAX and PI, resp.). The time course after exercise was compared by repeated measures of ANOVA. Healthy persons differed significantly in PI, RI and PSV from PAOD patients before and after treatment (p<0.001 each). The PAOD-patients revealed a significantly improved PI after treatment (p: 0.042). The only factor contributing significantly to PI independently from grouping was direct arterial vascularization as compared to discontinuous effects by an obstructed arterial tree.!##!Conclusion!#!Healthy persons cannot be well differentiated from PAOD-patients solely by hemodynamics at rest but by characteristic changes after standard exercise. Treatment effects are reflected by higher PI-values after exercise

German Bowel Cancer Center: An Attempt to Improve Treatment Quality

Background. Colorectal cancer remains the second most common cause of death from malignancies, but treatment results show high diversity. Certified bowel cancer centres (BCC) are the basis of a German project for improvement of treatment. The aim of this study was to analyze if certification would enhance short-term outcome in rectal cancer surgery. Material and Methods. This quality assurance study included 8197 patients with rectal cancer treated between 1 January 2008 and 31 December 2010. We compared cohorts treated in certified and noncertified hospitals regarding preoperative variables and perioperative outcomes. Outcomes were verified by matched-pair analysis. Results. Patients of noncertified hospitals had higher ASA-scores, higher prevalence of risk factors, more distant metastases, lower tumour localization, lower frequency of pelvic MRI, and higher frequencies of missing values and undetermined TNM classifications (significant differences only). Outcome analysis revealed more general complications in certified hospitals (20.3% versus 17.4%, p=0.03). Both cohorts did not differ significantly in percentage of R0-resections, intraoperative complications, anastomotic leakage, in-hospital death, and abdominal wall dehiscence. Conclusions. The concept of BCC is a step towards improving the structural and procedural quality. This is a good basis for improving outcome quality but cannot replace it. For a primary surgical disease like rectal cancer a specific, surgery-targeted program is still needed

In Vitro Chemo-Sensitivity Assay Guided Chemotherapy is Associated with Prolonged Overall Survival in Cancer Patients

The overall survival (OS) of patients suffering From various tumour entities was correlated with the results of in vitro-chemosensitivity assay (CSA) of the in vivo applied drugs. Material and methods. Tumour specimen (n=611) were dissected in 514 patients and incubated for primary tumour cell culture. The histocytological regression assay was performed 5 days after adding chemotherapeutic substances to the cell cultures. n=329 patients undergoing chemotherapy were included in the in vitro/in vivo associations. OS was assessed and in vitro response groups compared using survival analysis. Furthermore Cox-regression analysis was performed on OS including CSA, age, TNM classification and treatment course. Results. The growth rate of the primary was 73-96% depending on tumour entity. The in-vitro response rate varied with histology and drugs (e.g. 8-18% for methotrexate and 33-83% for epirubicine). OS was significantly prolonged for patients treated with in vitro effective drugs compared to empiric therapy (log-rank-test, p=0.0435). Cox-regression revealed that application of in vitro effective drugs, residual tumour and postoperative radiotherapy determined the death risk independently. Conclusions. When patients were treated with drugs effective in our CSA, OS was significantly prolonged compared to empiric therapy. CSA guided chemotherapy should be compared to empiric treatment by a prospective randomized trial

Disease knowledge and patient education are key players for a better quality of life in vascular surgery patients

<jats:title>Summary</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The aim of this prospective investigation was to determine factors that influence the verbal disease knowledge level of the patient after the informed consent (IC) talk and to assess whether it can be improved by additional education. Furthermore, the factors underlying quality of life (QoL) after treatment, among them knowledge, education, and ambulatory care, were investigated.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Consecutive patients who had undergone vascular surgical intervention for abdominal aortic aneurysm (AAA), thrombendarteriectomy (TEA) of the femoral bifurcation, or digital subtraction angiography (DSA) with or without endovascular intervention for arterial occlusive disease (AOD) were included over a defined study time period. They were divided randomly into (i) standard IC talk, (ii) extended IC talk with a PowerPoint lecture (PP; Microsoft Inc., Redmond, WA, USA), and (iii) extended IC talk with a walking diary (WD). The patients filled out questionnaires before and after treatment and a RAND36 Health Survey during follow-up. The disease knowledge level was quantified by six verbal items. Group comparisons were performed by matched-pair analysis (MPA) and factor analysis by multiple regression analysis and multivariate analysis of variance (MANOVA).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>From January 2015 until November 2016, <jats:italic>n</jats:italic> = 198 patients were enrolled. Remembrance and comprehension rates were in general low and did not improve significantly with additional PP or WD. Age was inversely associated with disease knowledge. Age was also inversely and WD/PP and knowledge level directly associated with mid-term QoL. However, other factors such as care provision and social status were important as well.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Communication with and education of vascular surgery patients is one of the mainstays of treatment and should be continued beyond the legal and formal requirements during treatment and after discharge from hospital in order to keep the QoL as high as possible.</jats:p> </jats:sec&gt

Surgical teaching at the Medical School Otto-von-Guericke University of Magdeburg – basic conceptual description

Teaching in surgery, one of the classical big clinical and main disciplines beside internal medicine, needs to be also associated with great attention in regard to a valuable final result at the end of the study of human medicine. In particular, surgery is not only the subject to a large number of lectures it also represents one third (four months) of the compulsory internship (practical year – in German, “Praktisches Jahr”) at the end of the study of medicine. Therefore, medical teaching of students should be always part of serious and steady attempts to optimize course und contents as a component of guiding activities focussing onto the substantial improvement of the study of medicine. In detail, the classical and traditionally established type of teaching, the (oral) lecture, has to be further developed and reasonably completed by numerous interactive and practice-oriented teaching, learning and examining modalities (obligatory or facultative seminars / courses, training in [very] small groups of students, bed-side teaching, individual practical exercises within the SkillsLab, groups of young researchers, research projects in teaching, scientific publications on topics and recommendable experiences ot teaching including students, ”Teach-the-teacher“ projects etc.). Although many novel concepts have been inaugurated and considerable advances have been achieved, there is a steady need for further improvement. In the presented representative but medical school-specific overview, the current complex surgical teaching concept, which has been continuously optimized over the last couple of years, at the Otto-von-Guericke University Medical School with University Hospital of Magdeburg (Germany) is described as a scientific and systematizing document as well as a manuscript associated with the ongoing preparation of an institutional “Teaching Manual” on surgical teaching and training for medical students. It should – last but not least – provide the basis for a public discussion, which vice versa might hopefully and possibly result in further structural reforms of (surgical) teaching in the near future

Nauczanie chirurgii na Uniwersytecie Ottona von Guericke w Magdeburgu - podstawowy opis koncepcyjny

Nauczanie chirurgii jako jednej z klasycznych, rozległych dyscyplin klinicznych oraz głównych dziedzin obok medycyny chorób wewnętrznych powinno otrzymywać należytą uwagę w kontekście możliwości uzyskania wysokiego wyniku końcowego na zakończenie studiów medycznych. Chirurgia jest nie tylko przedmiotem wielu wykładów, lecz także stanowi również jedną trzecią (cztery miesiące) obowiązkowego stażu (rok praktyczny – w języku niemieckim Praktisches Jahr) na koniec studiów medycznych. Dlatego też nauczanie medyczne studentów powinno zawsze stanowić część rzetelnych i stałych prób optymalizacji programu nauczania i treści jako elementu przewodnich działań, które koncentrują się na znacznej poprawie studiów medycznych. Co więcej, klasyczny i tradycyjnie ustanowiony format nauczania, tj. wykład (ustny), wymaga dalszego rozwoju i racjonalnego uzupełnienia poprzez liczne formy nauczania interakcyjnego, zorientowanego na praktykę, metody przekazywania wiedzy i egzaminowania (obligatoryjne lub fakultatywne seminaria/kursy, szkolenia w małych grupach uczniów, nauczanie przy łóżku pacjenta, indywidualne ćwiczenia praktyczne w ramach SkillsLab, grupy młodych badaczy, projekty badawcze w toku nauczania, publikacje naukowe na wszelkie tematy i cenne doświadczenia związane z nauczaniem, w których mogą uczestniczyć studenci, metoda „Nauczaj nauczyciela”, projekty itp.). Chociaż zainicjowanych zostało wiele nowatorskich koncepcji i dokonano znacznych postępów, istnieje ciągła potrzeba dalszej poprawy. W prezentowanym ogólnym zarysie specyficznym dla indywidualnych uczelni, mającym charakter reprezentacyjny, obecna złożona koncepcja nauczania chirurgicznego, która w ostatnich latach podlegała nieustannej optymalizacji na Uniwersytecie Ottona von Guerickego w Magdeburgu ze Szpitalem Uniwersyteckim (Niemcy), opisana jest jako dokument naukowy i systematyzujący, a także jako manuskrypt związany z ciągłym przygotowywaniem instytucjonalnego „Podręcznika nauczania” na temat rozwijania wiedzy o chirurgii i szkolenia studentów medycyny. Na koniec temat powinien stanowić podstawę do publicznej dyskusji, która, miejmy nadzieję, może doprowadzić do dalszych reform strukturalnych nauczania (chirurgii) w najbliższej przyszłości

Prognostic Relevance of hTERT mRNA Expression in Ductal Adenocarcinoma of the Pancreas12

Telomerase is thought to play an essential role in tumorigenesis and progression. Its activity is directly correlated with the expression of its catalytic subunit, human telomerase reverse transcriptase (hTERT). A correlation of transcript expression with a poor prognosis has been detected in different human malignancies. However, data on hTERT in pancreatic ductal adenocarcinoma (PDAC) are purely descriptive so far. Therefore, we evaluated the impact of hTERT expression on patients' prognosis. Human telomerase reverse transcriptase mRNA isolates from 56 human microdissected PDAC tissues were analyzed by quantitative reverse transcription-polymerase chain reaction and multivariate Cox regression hazard test. Elevated hTERT transcript levels were measured in 23 of 56 PDAC tissues, 33 patients showed no detectable transcripts. Unexpectedly, a low expression of hTERT mRNA levels was associated with a worse prognosis for overall survival (relative risk = 5.33; P = .013) when compared to high levels, whereas undetectable expression showed an intermediate risk of tumor-related death. These data challenge previous findings outlining hTERT's negative impact on overall survival. The risk pattern obtained in PDAC suggests a more complex regulation of hTERT

Current diagnostics and treatment of fibrosarcoma -perspectives for future therapeutic targets and strategies

Adult-type fibrosarcoma is a rare and highly aggressive subtype of soft tissue sarcomas. Due to the existence of other spindle-cell shaped sarcomas, its diagnosis is always one of exclusion. The likelihood of misdiagnoses between similar tumour entities is high, and often leads to inappropriate tumour treatment. We summarize here the main features of fibrosarcoma. When fibrosarcoma is appropriately diagnosed, the patient's overall prognosis is generally quite poor. Fibrosarcoma is characterized by its low sensitivity towards radio-and chemotherapy as well as by its high rate of tumour recurrences. Thus it is important to identify new methods to improve treatment of this tumour entity. We discuss some promising new directions in fibrosarcoma research, specifically focusing on more effective targeting of the tumour microenvironment. Communication between tumour cells and their surrounding stromal tissue play a crucial role in cancer progression, invasion, metastasis and chemosensitivity. The therapeutic potential of targeting the tumour microenvironment is addressed