Subjective and objective olfactory abnormalities in Crohn's disease.

The pathogenesis of Crohn's disease (CD) is still unknown, but the involvement of the olfactory system in CD appears possible. No study to date has systematically assessed the olfactory function in CD patients. We investigated the olfactory function in CD patients in active (n = 31) and inactive disease (n = 27) and in a control group of age- and sex-matched healthy subjects (n = 35). Subjective olfactory testing was applied using the Sniffin' Sticks test. For olfactory testing, olfactory event-related potentials (OERPs) were obtained with a 4-channel olfactometer using phenyl ethyl alcohol (PEA) and hydrogen sulfide (H(2)S). Carbon dioxide (CO(2)) was employed as control stimulus, and chemosomatosensory event-related potentials (CSSERPs) were registered. Results of the Sniffin' Sticks test revealed significantly different olfactory hedonic judgment with increased olfactory hedonic estimates for pleasant odorants in CD patients in active disease compared with healthy subjects. A statistical trend was found toward lower olfactory thresholds in CD patients. In objective olfactory testing, CD patients showed lower amplitudes of OERPs and CSSERPs. Additionally, OERPs showed significantly shorter N1- and P2 latencies following stimulation of the right nostril with H(2)S in CD patients in inactive disease compared with controls. Our study demonstrates specific abnormalities of olfactory perception in CD patients.

Determinants of physician empathy during medical education: hypothetical conclusions from an exploratory qualitative survey of practicing physicians.

BACKGROUND: Empathy is an outcome-relevant physician characteristic and thus a crucial component of high-quality communication in health care. However, the factors that promote and inhibit the development of empathy during medical education have not been extensively researched. Also, currently there is no explicit research on the perspective of practicing physicians on the subject. Therefore the aim of our study was to explore physicians' views of the positive and negative influences on the development of empathy during their medical education, as well as in their everyday work as physicians. METHOD: We administered a written Qualitative Short Survey to 63 physicians in seven specialties. They were able to respond anonymously. Our open-ended question was: "What educational content in the course of your studies and/or your specialist training had a positive or negative effect on your empathy?" We analyzed the data using thematic content analysis following Mayring's approach. RESULTS: Forty-two physicians took part in our survey. All together, they mentioned 68 specific factors (37 positive, 29 negative, 2 neutral) from which six themes emerged: 1. In general, medical education does not promote the development of empathy. 2. Recognizing the psycho-social dimensions of care fosters empathy. 3. Interactions with patients in medical practice promote empathy. 4. Physicians' active self-development through reflective practice helps the development of empathy. 5. Interactions with colleagues can both promote and inhibit empathy through their role modeling of empathic and non-empathic behavior. 6. Stress, time pressure, and adverse working conditions are detrimental to empathy development. CONCLUSIONS: Our results provide an overview of what might influence the development of clinical empathy, as well as hypothetical conclusions about how to promote it. Reflective practice seems to be lacking in current medical curricula and could be incorporated. Raising physicians' awareness of the psycho-social dimension of disease, and of the impact of peer influence and role modeling, seems promising in this regard, too. Stress and well-being seem to be closely related to physician empathy, and their modulation must take into account individual, social, and organizational factors. Further research should investigate whether or how these hypothetical conclusions can deepen our understanding of the determinants of physician empathy in order to help its promotion.

Position paper on postgraduate medical education on the occasion of hospital reform - postgraduate medical education must be considered. A joint position paper by Bündnis Junge Ärztinnen und Ärzte and AG Junge Gastroenterologie of the DGVS as well as the Young DGN.

The Bündnis Junger Ärztinnen und Ärzte (BJÄ, Alliance of Young Physicians in Germany) has presented a position paper (PP) on Postgraduate Medical Education (PGME) against the background of an unfolding hospital reform in Germany, and they describe existing deficits of PGME in Germany. Based on this, demands were made of legislators, employers and medical associations which could result in a sweeping reformation of PGME. Hospital reforms can only be accomplished with well trained and motivated physicians. In this respect the BJÄ regards the reform of hospitals and the health-care system as a chance for a reform of PGME, which is long overdue. Legislative competence for PGME lies with the States of the Federal Republic of Germany and this warrants an adjustment of state medical association laws to accommodate the demands of the BJÄ. Generally PGME must be taken into consideration in all health-care legislation, in analogy to the meanwhile globally adopted principle of "Health in all Politics (HiAP)". The BJÄ has made every endeavour to produce this PP. The responsible stakeholders and actors in the health-care system would be well-advised to take the position paper seriously with a dwindling physician work force in hospitals and serious quality deficits in PGME. Hence, the BJÄ must be comprehensively supported. They need congenial partners to define the scientific foundation of all their demands, to test their application under real life conditions in hospital and outpatient care, to pursue research on the impact on patient care and on the intended transformation of the health-care system. This might best be accomplished by partnering with a scientific Association for Postgraduate Medical Education as has been the case in many countries for decades.

Strategies for training in diagnostic upper endoscopy: a prospective, randomized trial.

BACKGROUND: Training simulators have been used for decades with success; however, a standardized educational strategy for diagnostic EGD is still lacking. OBJECTIVE: Development of a training strategy for diagnostic upper endoscopy. STUDY DESIGN: Prospective, randomized trial. SETTINGS: A total of 28 medical and surgical residents without endoscopic experience were enrolled. Basic skills evaluations were performed following a structured program involving theoretical lectures and a hands-on course in diagnostic EGD. Subsequently, stratified randomization to clinical plus simulator training (group 1, n = 10), clinical training only (group 2, n = 9), or simulator training only (group 3, n = 9) was performed. Ten sessions of simulator training were conducted for groups 1 and 3 during the 4-month program. Group 2 underwent standard training in endoscopy without supplemental simulator training. The final evaluation was performed on the simulator and by observation of 3 clinical cases. Skills and procedural times were recorded by blinded and unblinded evaluators. MAIN OUTCOME MEASUREMENTS: Time to reach the duodenum, pylorus, or esophagus. RESULTS: All trainees demonstrated a significant reduction in procedure time during a simple manual skills test (P < .05) and significantly better skills scores (P = .006, P = .042 and P = .017) in the simulator independent of the training strategy. Group 1 showed shorter times to intubate the esophagus (61 ± 26 seconds vs 85 ± 30 seconds and 95 ± 36 seconds) and the pylorus (183 ± 65 seconds vs 207 ± 61 seconds and 247 ± 66 seconds) during the clinical evaluation. Blinded assessment of EGD skills showed significantly better results for group 1 compared with group 3. Blinded and unblinded evaluations were not statistically different. LIMITATIONS: Small sample size. CONCLUSIONS: Structured simulator training supplementing clinical training in upper endoscopy appears to be superior to clinical training alone. Simulator training alone does not seem to be sufficient to improve endoscopic skills.

The WFME global standards for quality improvement of postgraduate medical education: Which standards are also applicable in Germany? Recommendations for physicians with a license for postgraduate training and training agents.

Background: In Germany, the (model) regulation for postgraduate medical education 2018, the professional codes of conduct of the regional medical councils and the health professions chamber laws of the federal states are the formal basis of postgraduate medical education, but say little about its structure, processes and results. The World Federation for Medical Education (WFME) has developed global standards for improving the quality of postgraduate medical education and published them in a revised edition in 2015. A German version which takes the specifics of medical training in Germany into account has not been published to date. Objective: The Committee for Postgraduate Medical Education (PGME) of the Society for Medical Education (GMA) has set itself the goal of firstly translating the WFME standards into German and secondly making recommendations for physicians with a license for post-graduate training (PLT) and training agents (TA) in clinics and practices which have been adapted to the German context. Methods: The WFME standards were translated into German by a working group of the GMA Committee for PGME, the terminology adapted to PGME in Germany and checked by an interdisciplinary panel of experts made up of 9 members of the committee. In a second step, the WFME basic standards and quality standards for PGME relevant to PLTs and TAs in Germany were iteratively determined by this panel of experts using the Nominal Group Technique (NGT) and compiled in the form of recommendations. Results: The translation of the WFME guidelines was approved by the expert group without any changes to the content, taking into account the terminological system of PGME in Germany. In a second step, 90 standards were identified which were considered helpful for PGME in Germany, especially for PLTs and TAs (such as development of a professional identity, a more patient-centered approach or support of self-directed learning). Care was taken to only give recommendations which can be influenced by PLTs and TAs. These standards have been summarized as recommendations to PLTs and TAs and take into account all chapters of the WFME standards. Conclusion: The WFME standards selected here are recommended to PLTs and TAs in clinics and practices to achieve high-quality PGME. Empirical longitudinal studies will be required to examine both the implementation and the results of applying the modified WFME criteria in Germany.

Cleaning of occluded pancreatic duct endoprostheses: a new indication for extracorporeal shock wave lithotripsy?

BACKGROUND: Pancreatic duct stenting is widely performed for bridging main pancreatic duct obstruction in patients with chronic pancreatitis. The major limitation is early stent occlusion, making regular stent exchange necessary. OBJECTIVE: To date, no measures are available to prevent stent occlusion. The aim of this study was to evaluate the cleansing effect of shock wave application (SWA) on occluded pancreatic duct stents in vitro. DESIGN: In vitro study. PATIENTS: We analyzed occlusion rates of 25 plastic endoprostheses removed from 21 patients with chronic pancreatitis. INTERVENTION: We administered 350 shock wave pulses every 10 mm along the prosthesis, which was stored in a latex balloon filled with gas-free physiologic saline solution, by using a pressure of 42 megapascals. MAIN OUTCOME MEASUREMENTS: After SWA, the occlusion rate was measured again, and the cleansing rate was calculated in comparison with the native prosthesis. RESULTS: The mean (± SD) occlusion rate was significantly reduced (64.7 ± 28.7 [15%-100%]) before SWA vs 9.8 ± 25.3 [0-100%]) after SWA; P = .038). In 16 of 25 prostheses (64%), cleaning was complete. Four of the remaining 9 prostheses (16%) showed satisfactory cleaning of 95%, on average. Residual clogging material was found mainly at the duodenal tip and the middle of the stent. No significant association was found between patient-related or stent-related parameters and the cleansing effect of SWA. LIMITATIONS: In vitro study design. CONCLUSION: SWA is effective in cleaning occluded pancreatic endoprostheses in vitro. Prolongation of stent placement seems possible if regular SWA is performed. Extracorporeal shock wave lithotripsy therefore might become a new indication for patients under treatment with pancreatic endoprostheses.

Hemodynamic efficacy of sequential hemoclip application using the Olympus HX-110/610 reloadable clipping device in spurting bleedings.

BACKGROUND: Hemoclip application in GI-hemorrhage has proven to be effective. Clinical experience shows that multiple clips are frequently necessary. In 2005, an easily reloadable clip-applicator was introduced. We evaluated the hemodynamic efficacy of this new device. MATERIAL/METHODS: We prospectively compared the new clipping device (Olympus HX 110/610) in a validated experimental setting using the compactEASIE®-simulator for GI bleeding. The artificial blood circulation system in the simulator was connected to a pressure transducer. Four investigators of different endoscopic experience (1000-6000 endoscopies) treated 12 bleeding sources each, with up to 6 clips for each bleeding location. Pressures were recorded to objectify the additive effects of sequential clip application on the reduction in vessel diameter. The intervention was abandoned if a maximum measurable pressure of 300 mmHg was achieved. RESULTS: Hemoclip application led to a significant increase of peak pressure (91±100 mmHg, p<0.001) and mean pressure (95±99 mmHg, p<0.001), representing a significant reduction in vessel diameter. Pooled data showed a significant stepwise increase in mean and maximum system pressure, resulting in reduction of vessel diameter up to the fifth hemoclip. On average, 5 clips (range 1-6) were used. More experienced endoscopists achieved a higher increase in mean pressure (167 and 118 mmHg vs 72 and 23 mmHg, p<0.05). Mean reloading time was 39 seconds (19-49 sec). CONCLUSIONS: Sequential application of multiple hemoclips led to an increasing effect, comparable to the results of previous clinical trials. The number of hemoclips applied correlated inversely, but not significantly, with the endoscopist´s experience. Expensive single-use clips appear dispensable in view of the short reloading time.

Palliative first-line therapy with weekly high-dose 5-fluorouracil and sodium folinic acid as a 24-hour infusion (AIO regimen) combined with weekly irinotecan in patients with metastatic adenocarcinoma of the stomach or esophagogastric junction followed by secondary metastatic resection after downsizing.

BACKGROUND: The aim of this retrospective study was to evaluate the efficacy and safety of weekly high-dose 5-fluorouracil (5-FU)/folinic acid (FA) as 24-h infusion (AIO regimen) plus irinotecan in patients with histologically proven metastatic gastroesophageal adenocarcinoma (UICC stage IV). MATERIAL/METHODS: From 08/1999 to 12/2008, 76 registered, previously untreated patients were evaluable. Treatment regimen: irinotecan (80 mg/m²) as 1-h infusion followed by 5-FU (2000 mg/m²) combined with FA (500 mg/m²) as 24-h infusion (d1, 8, 15, 22, 29, 36, qd 57). RESULTS: Median age: 59 years; male/female: 74%/26%; ECOG ≤1: 83%; response: CR: 1%, PR: 16%, SD: 61%, PD: 17%, not evaluable in terms of response: 5%; tumor control: 78%; median OS: 11.2 months; median time-to-progression: 5.3 months; 1-year survival rate: 49%; 2-year survival rate: 17%; no evidence of disease: 6.6%; higher grade toxicities (grade 3/4): anemia: 7%, leucopenia: 1%, ascites: 3%, nausea: 3%, infections: 12%, vomiting: 9%, GI bleeding of the primary tumor: 4%, diarrhea: 17%, thromboembolic events: 4%; secondary metastatic resection after downsizing: 16 patients (21%), R-classification of secondary resections: R0/R1/R2: 81%/6%/13%, median survival of the 16 patients with secondary resection: 23.7 months. CONCLUSIONS: Combined 5-FU/FA as 24-h infusion plus irinotecan may be considered as an active palliative first-line treatment accompanied by tolerable toxicity; thus offering an alternative to cisplatin-based treatment regimens. Thanks to efficient interdisciplinary teamwork, secondary metastatic resections could be performed in 16 patients. In total, the patients who had undergone secondary resection had a median survival of 23.7 months, whereas the median survival of patients without secondary resection was 10.1 months (p≤0.001).

Neoadjuvant treatment with weekly high-dose 5-fluorouracil as a 24h-infusion, folinic acid and biweekly oxaliplatin in patients with primary resectable liver metastases of colorectal cancer: long-term results of a phase II trial.

BACKGROUND: In 2003 Wein et al. published data after a short median follow up (23 months). Here we report on the long-term results. MATERIAL/METHODS: The patients (n=20) received a neoadjuvant treatment regimen comprising biweekly 85 mg/m2 oxaliplatin (L-OHP) (2h-infusion, d 1, 15, 29 qd 57) and 500 mg/m2 calcium folinic acid (FA) (1-2h-infusion, d 1, 8, 15, 22, 29, 36 qd 57) followed by 2600 mg/m2 5-Fluorouracil (5-FU) (24h-infusion, d 1, 8, 15, 22, 29, 36 qd 57). Two cycles of chemotherapy were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted. RESULTS: After neoadjuvant therapy, imaging procedures revealed complete remission in 2 patients (10%) and partial remission in 18 patients (90%). Diarrhea (Common Toxicity Criteria toxicity grade 3) was observed in 6 patients (30%) as main symptom of toxicity, followed by vomiting in 3 patients (15%). Higher grade sensomotoric neuropathy did not present. The curative resectability rate (R0) was 80%. In 9 out of 18 patients (50%) undergoing surgical intervention minor postoperative complications occurred. No postoperative mortality was observed. Over a median follow up of 45,5 months the median survival of all patients is 3.0 years and the 5-year overall survival rate is 40%. The 5-year disease-free survival rate is 25%. CONCLUSIONS: Neoadjuvant treatment with 5-FU combined with FA and L-OHP proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising.

Palliative first-line treatment with weekly high-dose 5-fluorouracil as 24h-infusion and gemcitabine in metastatic pancreatic cancer (UICC IV).

BACKGROUND: The aim of this study was to evaluate the efficacy and toxic side effects of combined gemcitabine plus weekly high-dose 5-Fluorouracil (5-FU) as 24h-infusion in patients with metastatic pancreatic cancer (UICC IV) as validation group of an earlier phase II study. Primary endpoints were to assess the response and tumour control rate. MATERIAL/METHODS: This study comprised 60 prospectively registered patients with metastatic pancreatic cancer (UICC IV). A locally advanced disease was defined as exclusion criteria. The treatment schedule was weekly gemcitabine (1.000 mg/m(2)) as a 0.5h-infusion combined with 5-FU (2.000 mg/m(2)) as a 24h-infusion on day 1, 8 and 15 every 28 days. RESULTS: Response rate (CR+PR) was achieved in 7% of the patients, tumour control rate (CR+PR+SD) was achieved in 59%. Median time-to-progression was 4 months, median overall survival was 7.3 months (95% CI 5.4-9.1). The median survival of patients with normal CEA value was 10.6 months (95% CI 7.8-13.4); with a normal CA 19-9 median survival was 10.1 months (95% CI 4.6-15.7) and with ECOG performance status 0 median survival was 10.1 months (95% CI 8.6-15.3). As higher grade toxicity (grade 3/4) leukopenia (15%), anaemia (10%) and thrombopenia (5%) were observed. Nausea and diarrhea (grade 3/4) occurred in 5% of the patients and vomiting in 2%. CONCLUSIONS: The administration of gemcitabine and 5-FU as a 24h-infusion is feasible and offers good tumour control rate accompanied by tolerable toxicity. The subgroup of patients with a good performance status (ECOG 0) and tumour markers within the normal range benefit from the gemcitabine combination therapy.

Adherence to continuous positive airway pressure therapy for obstructive sleep apnea: impact of patient education after a longer treatment period.

BACKGROUND: Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea (OSA) but it is often cumbersome so that adherence to CPAP therapy is limited. OBJECTIVES: We evaluated adherence to CPAP therapy after an additional educative intervention in OSA patients after a longer treatment period. METHODS: A short patient information program covering many aspects of symptoms, consequences and treatment of OSA was created, and standardized information sessions were developed to be given by an experienced sleep physician to >6,000 participants of patient support group meetings throughout Germany. They also received a booklet containing the essential information of the lectures. Of the 526 randomly selected members of these support groups receiving the anonymized questionnaire by mail, 475 CPAP patients sent the questionnaire back. Of these CPAP patients, 243 participated in a lecture und and had received a booklet (information group) and 232 CPAP patients had not attended a lecture (control group). RESULTS: In the information group, a significantly higher daily usage of CPAP devices (6.9 +/- 0.9 h/day) was reported compared with the control group (5.7 +/- 1.3 h/day; p < 0.001). Furthermore, the score in the Epworth Sleepiness Scale (ESS) was found to be significantly lower in the information group (median ESS = 6, interquartile range, IQR, 4-8 vs. median = 11, IQR 8-13; p < 0.001). CONCLUSIONS: Patients who attended our short information program showed a higher daily usage and a lower subjective daytime sleepiness. These results suggest that patients on CPAP therapy may benefit from education even after a longer treatment period.

Entrance barriers and integration obstacles of NOTES.

Natural orifice transluminal endoscopic surgery (NOTES) changes the paradigm of endoscopy and even surgery. The artificial perforation of abdominal hollow organs is now welcome and no longer avoided under all circumstances. Surgeons as well as gastroenterologists face a lot of problems, barriers and integration obstacles. The interdisciplinary approach for the introduction of a new technique appears promising and opens a lot of perspectives. This paper illustrates and discusses medical, technical, financial and professional barriers and integration obstacles for the introduction of NOTES into clinical practice.

In vitro differentiation of human monocytes into dendritic cells by peptic-tryptic digest of gliadin is independent of genetic predisposition and the presence of celiac disease.

INTRODUCTION: This study was done to further reveal the role of the innate immune system in celiac disease. METHODS: Dendritic cells were matured from venous blood of patients with active or treated celiac disease and DQ2-DQ8-positive or negative controls. Dendritic cells were treated with a peptic-tryptic digest of gliadin (500 microg/ml) and their activation was analyzed by fluorescent-activated cell sorting analysis, cytokine secretion, and their ability to elicit T cell proliferation. RESULTS AND DISCUSSION: Gliadin upregulated interleukin (IL)-6, IL-8, and IL-12 (p40) secretion in dendritic cells and induced strong expression of the maturation markers human leukocyte antigen (HLA)-DR, CD25, CD83, and CD86 of all subjects irrespective of their genotype or the presence of disease, whereas the digest of bovine serum albumin showed no effect. However, gliadin-stimulated dendritic cells from active celiac showed enhanced stimulation of autologous T cells compared to the other groups. CONCLUSION: Further research should be aimed at identifying the mechanisms that control inflammation in healthy individuals.

Activation of tumor-specific T lymphocytes after laser-induced thermotherapy in patients with colorectal liver metastases.

PURPOSE: To asses if laser-induced thermotherapy (LITT) induces a specific cytotoxic T cell response in patients treated with LITT for colorectal cancer liver metastases. METHODS: Eleven patients with liver metastases of colorectal cancer underwent LITT. Blood was sampled before and after LITT. Peripheral T cell activation was assessed by an interferon gamma (IFNg) secretion assay and flow cytometry. Test antigens were autologous liver and tumor lysate obtained from each patient by biopsy. T cells were stained for CD3/CD4/CD8 and IFNg to detect activated T cells. The ratio of IFNg positive to IFNg negative T cells was determined as the stimulation index (SI). To assess cytolytic activity, T cells were co-incubated with human colorectal cancer cells (CaCo) and cytosolic adenylate kinase release was measured by a luciferase assay. RESULTS: IFNg secretion assay: before LITT SI was 12.73 (+/-4.83) for CD3+, 4.36 (+/-3.32) for CD4+ and 3.64 (+/-1.77) for CD8+ T cells against autologous tumor tissue. Four weeks after LITT SI had increased to 92.09 (+/-12.04) for CD3+ (P < 0.001), 42.92 (+/-16.68) for CD4+ (P < 0.001) and 47.54 (+/-15.68) for CD8+ T cells (P < 0.001) against autologous tumor tissue. No increased SI was observed with normal liver tissue at any time point. Cytotoxicity assay: before LITT activity against the respective cancer cells was low, with RLU = 1,493 (+/-1,954.68), whereas after LITT cytolytic activity had increased to RLU = 7,260 [+/-3,929.76 (P < 0.001)]. CONCLUSION: Patients with liver metastases of colorectal cancer show a tumor-specific cytotoxic T cell stimulation and a significantly increased cytolytic activity of CD3+, CD4+ and CD8+ T cells after LITT against an allogenic tumor (CaCo cell line).

Cellular plasticity of trans- and dedifferentiation markers in human hepatoma cells in vitro and in vivo.

Tumor cells have the capability to trans- and to dedifferentiate, for example by reactivating embryonic development genes and stem cell characteristics. The aim of our study was to show the differential expression of stem- and progenitor cell markers in human hepatocellular carcinoma cell lines (HCC). Different human HCC cell lines (HUH7, HUH7 5-15, HUH7 pcDNA3.1, Hep3B and HepG2) were cultured under standard conditions in vitro or implanted subcutaneously (5x10(6) cells) in male NMRI mice. Specimens were characterized by quantitative real-time PCR, Western blotting, methylation-specific PCR and immunohistochemistry for markers of differentiation (cytokeratins, vimentin), embryonic development or stem cells (PTC, PDX-1, SHH, Thy1, c-kit, CD34, beta-catenin, Ki-67). The investigated HCC cell lines showed different patterns of marker expression allowing to distinguish four distinct groups: the classical cholangiocellular type (Huh-7, Huh-7 pcDNA3.1, Hep3B) with expression of CK7/19, beta-catenin and CD34; a dedifferentiated mesenchymal-proliferative type (Huh-7 5-15) characterized by CK19, Vimentin and Ki-67; a dedifferentiated embryonic-development type (Hep3B implanted in matrigel) with expression of CK19, beta-catenin and PTC and a classical HCC type (HepG2) showing CK18/19 and beta-catenin expression. HCC cell lines showed significantly different expression patterns of differentiation markers in a xenograft model. Furthermore, direct association of some markers was observed. The groups differ from each other in expression patterns, but also show that environmental factors play an important role in the behaviour of cells.

The expression pattern of PDX-1, SHH, Patched and Gli-1 is associated with pathological and clinical features in human pancreatic cancer.

BACKGROUND AND AIMS: Pancreatic cancer cells have been shown to possess stem-cell-like properties, especially by reactivating embryonic transcription factors involved in tissue differentiation. We therefore investigated if and to what extent developmental genes of the human pancreas are expressed in pancreatic ductal adenocarcinomas and precursor lesions, pancreatic intraepithelial neoplasia (PanIN), and if this correlates or predicts response to treatment and overall survival. MATERIAL AND METHODS: Invasive ductal adenocarcinomas of the pancreas [UICC pT3pN0 (n = 13) vs. pT3pN1 (n = 25)] and tumors after neoadjuvant chemotherapy [5-fluorouracil (FU)/folic-acid and gemcitabine; UICC ypN0 (n = 7) vs. ypN1 (n = 6)] resected between 1997 and 2003 were characterized histochemically and immunohistochemically [pancreas duodenum homeobox 1 (PDX-1), Sonic hedgehog protein (SHH), Patched (Ptc) and Gli-1]. Gene distribution was compared with morphological patterns of the pancreatic carcinoma and PanIN as well as with peritumorous reactions of normal pancreas. RESULTS: The overall expression of PDX-1, SHH, Ptc and Gli-1 was low, but showed a distinctive and topographic linkage inside pancreatic carcinomas as well as inside PanINs. Additionally, a topographic and significant association of these markers with nodal status (PDX-1, Ptc, Gli-1), tumor size (PDX-1, Gli-1) and R status (PDX-1) was found. After stratification with the strongest outcome predictor, grading, survival analysis revealed that Ptc expression in grade 2 and PDX-1 expression in grade 3 carcinomas are independent survival factors. CONCLUSIONS: Markers of pancreas development are reexpressed in invasive ductal adenocarcinomas and their expression is essentially associated with general clinical and pathological features such as survival or nodal status.

Comparability of microarray data between amplified and non amplified RNA in colorectal carcinoma.

Microarray analysis reaches increasing popularity during the investigation of prognostic gene clusters in oncology. The standardisation of technical procedures will be essential to compare various datasets produced by different research groups. In several projects the amount of available tissue is limited. In such cases the preamplification of RNA might be necessary prior to microarray hybridisation. To evaluate the comparability of microarray results generated either by amplified or non amplified RNA we isolated RNA from colorectal cancer samples (stage UICC IV) following tumour tissue enrichment by macroscopic manual dissection (CMD). One part of the RNA was directly labelled and hybridised to GeneChips (HG-U133A, Affymetrix), the other part of the RNA was amplified according to the "Eberwine" protocol and was then hybridised to the microarrays. During unsupervised hierarchical clustering the samples were divided in groups regarding the RNA pre-treatment and 5.726 differentially expressed genes were identified. Using independent microarray data of 31 amplified vs. 24 non amplified RNA samples from colon carcinomas (stage UICC III) in a set of 50 predictive genes we validated the amplification bias. In conclusion microarray data resulting from different pre-processing regarding RNA pre-amplification can not be compared within one analysis.

Weekly high-dose 5-fluorouracil as a 24-h infusion and sodium folinic acid (AIO regimen) plus irinotecan in patients with locally advanced nonresectable and metastatic adenocarcinoma or squamous cell carcinoma of the oesophagus: a phase II trial.

In the majority of patients with oesophageal carcinoma, curative treatment proves to be impossible when diagnosis was established; therefore, most of the patients are candidates for palliative chemotherapy. The aim of this phase II study was to evaluate the efficacy and safety of 5-fluorouracil/folinic acid (AIO regimen) plus irinotecan in patients with locally advanced or metastatic carcinoma of the oesophagus. The methods used a prospective phase II trial, start: November 2002; patients: n=25; chemotherapy: irinotecan (80 mg/m2) as a 1-h infusion and 5-fluorouracil (2000 mg/m2) with sodium folinic acid (500 mg/m2) as a 24-h infusion on days 1, 8, 15, 22, 29 and 36, repeated on day 57. Last date of evaluation: 28 February 2007; n=24; adenocarcinoma: n=13, squamous cell carcinoma (SCC): n=11; UICC III/IV: 3/21; grading G1/G2/G3/G4: 0/8/12/4; median age: 58 years (range 44-75); men/women: 19/5; Eastern Cooperative Oncology Group index 0/1/2: 3/17/4; applications: 460. Higher-grade toxicity: grade 3 diarrhoea: n=2, grade 4 diarrhoea: n=1, grade 4 vomiting: n=1, grade 4 nausea: n=1, grade 3 fatigue: n=1, grade 3 hyponatraemia: n=2, grade 4 elevation of creatinine: n=1, thrombosis of the vena subclavia: n=1, ischaemic lesion of the brain stem: n=1. Three patients died after two chemotherapeutic applications because of high tumour burden. Evaluable for response: n=19. Partial response: n=8 (33%), stable disease: n=9 (38%), progressive disease: n=2 (8%), not evaluable: n=5 (21%). Time-to-progression: 6.6 months (range 1.6-24.6). Total median survival: 13.6 months (median survival of adenocarcinoma: 20.3 months, median survival of SCC: 10.0 months). Secondary resection (R0): n=3. In oesophageal carcinomas, the AIO regimen plus irinotecan is excellently manageable as an outpatient treatment and shows efficacy in adenocarcinomas and SCCs of the oesophagus.

Characteristics of metachronous colorectal adenomas found during long-term follow-up: analysis of four subsequent generations of adenoma recurrence.

OBJECTIVE: Because of the high recurrence rates of colorectal adenomas, regular surveillance by colonoscopy has been recommended, but there is still a dearth of information on the long-term results of follow-up colonoscopy after polypectomy. The aims of this study were to determine the differences between initial adenomas and metachronous lesions, to evaluate the effect of long-term surveillance and to describe the hypothetical origin of the colorectal adenoma-carcinoma sequence. MATERIAL AND METHODS: Between 1978 and 2003 a total of 1091 patients undergoing periodic surveillance examinations were prospectively documented at the Erlangen Registry of Colorectal Polyps. Differences between initial and metachronous lesions found during long-term follow-up were studied. Statistical analysis using chi(2) testing of adenoma characteristics found in four subsequent recurrence periods was carried out, and the relative risk (RR) for the development of metachronous adenomas of advanced pathology was calculated. RESULTS: In comparison with the initial findings, metachronous adenomas are generally significantly smaller lesions (p<0.00001), usually tubular in shape (p<0.00001) and bearing high-grade dysplasia less often (p<0.00001) and are usually located in the right colon (p<0.00001). These differences are found between the initial and four subsequent generations of metachronous adenomas. The number of synchronous adenomas is reduced only in the first recurrence (p<0.001); in the further generations equal proportions of multiplicity are found, as in the baseline examination. Patients with adenomas of advanced pathology, i.e. large, tubulovillous or villous adenomas at baseline, have a significantly higher risk for large (RR 2.73; 95% CI 1.77-4.20), tubulovillous or villous (RR 1.55; 95% CI 1.06-2.25) or multiple (RR 2.45; 95% CI 1.83-3.29) metachronous adenomas at the first recurrence. CONCLUSIONS: Metachronous adenomas show the uniform characteristics of being small tubular lesions rarely bearing high-grade dysplasia, usually located in the right colon. Thus regular follow-up colonoscopy can provide sufficient colorectal carcinoma prevention.

Peginterferon alfa-2a relapse rates depend on weight-based ribavirin dosage in HCV-infected patients with genotype 1: results of a retrospective evaluation.

OBJECTIVE: The cumulative dosage of ribavirin per kilogram of body-weight prevents relapse and thus is a significant predictor of sustained virological response (SVR). Comparison of peginterferon (peg-IFN) alfa-2b/ribavirin and peg-IFN alfa-2a/ribavirin shows that the rates of SVR are similar, but the rates of relapse are significantly lower under the peg-IFN alfa-2b regimen. Depending on the weight-based ribavirin dose, patients with >105 kg reach a maximum of 13.2 mg/kg body-weight ribavirin in the peg-IFN alfa-2b regimen as opposed to only 11.3 mg/kg in the peg-IFN alfa-2a regimen. The aim of these investigations was to determine relapse rates in a retrospective analysis of 98 patients chronically infected with hepatitis C virus (HCV) genotype (GT) 1 in relation to the weight-based ribavirin dose. MATERIAL AND METHODS: All patients completed treatment with peg-IFN alfa-2a/ribavirin (1000 mg/d or 1200 mg/d for patients weighing <75 kg or > or =75 kg) for 48 weeks. Classification of a low ribavirin dose with <13.2 mg/kg body-weight was used. Patients with a ribavirin dose > or =13.2 mg/kg were compared with those with a dose <13.2 mg/kg. RESULTS: Patients with a ribavirin dose > or = 13.2 mg/kg (n=84) showed a relapse rate of 19.0% in contrast to 71.4% in patients with a ribavirin dose of <13.2 mg/kg (n=14) (p=0.0013). The SVR rate was significantly higher in the > or =13.2 mg/kg ribavirin dosed group (59.5% versus 28.6%). CONCLUSIONS: Weight-adapted ribavirin dosing in combination with peg-IFN alfa-2a to avoid giving low doses of ribavirin should be evaluated. This will minimize relapse, especially in HCV GT 1 patients.