[COVID-19 and endoscopy services]. / COVID-19 und Endoskopieeinheiten: Erfahrungen und Empfehlungen nach 2 Jahren Pandemie.

In 2020, the coronavirus pandemic initially led to a significant decrease in elective endoscopic examinations in Germany. The main reasons for this were the hard lockdown and the lack of personal protective equipment (PPE) and testing procedures. Since then, international recommendations from professional societies on infection control in endoscopy have been published. The extent to which these have been implemented in Germany is unclear: during the 2nd and 3rd waves in 2020/2021, most endoscopy units remained open and the level of adherence to international protection guidelines was high. A uniform "standard procedure" has not yet been published. The exact role and effectiveness of testing procedures to protect patients and staff during endoscopy was unknown, and reliable figures on staff and patient infections acquired/transmitted in endoscopy units in Germany were lacking. Thus, the most important finding of this work is the determined rate of coronavirus disease 2019 (COVID-19) in endoscopy facilities. The data show that the infection rate among staff in German clinics and practices in early 2021 averaged up to 5%; most of these were acquired in the private setting. Clinics with gastroenterological endoscopy units had significantly higher infection rates (10%) than, for example, dental and otolaryngology practices. This result indicates the need for continued PPE efforts. The most important factors for infection safety are fully vaccinated (or recovered) staff and patients, a decreasing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the use of PPE and-although controversial-the consistent use of screening tests.

[EUS-FNA: how to improve biopsy results? An evidence based review]. / EUS-geführte Feinnadelbiopsie (EUS-FNP): Wie gelingen gute Biopsien? Eine evidenzbasierte Analyse.

Endosonography with fine-needle aspiration biopsy (EUS-FNA) has become a widespreadly available clinical tool to diagnose numerous different lesions in humans. EUS-FNA is frequently used for tissue-based diagnoses such as lymphatic diseases (ranging from tuberculosis / sarcoidosis to malignant lymphoma) or solid tumors (such as pancreatic carcinoma, neuroendocrine tumors, sub-epithelial gastrointestinal tumors and others). Outcomes of EUS-FNA results, however, vary which is caused by several different factors ranging from experience of the endoscopist over technical factors such as use of stylet or suction for puncture through the skills of the cyto-pathologist who takes care of the specimen obtained by EUS-FNA. Though introduced since more than 20 years ago EUS-FNA has still not yet been perfectionized and several issues remain controversial among endoscopist. These issues include needle size and type (FNA versus TNB needles), use of a stylet and suction for FNA sampling, pure cytologic assessment versus cyto-histologic techniques, grading of the investigator´s and pathologist´s experience and improvement of EUS training for novices. In this report we briefly review the actual literature and summarize the available evidence on some controversely discussed issues. The results support the view that use of a stylet rarely aids to increase the amount of tissue obtained during EUS-FNA, whereas use of suction can be helpful in certain situations. Novel cutting needles may potentially improve number and size of core biopsies that can be rendered for special histologic tissue processing techniques. An in-room-cytopathologist not necessarily improves outcome of EUS-FNA results but may have a role during build-up of EUS units to become more successful. EUS-FNA education requires skilled endoscopists on both sides and can presumably be improved by objective testing of practical expertise by peer review and introducing objective sampling parameters. Novel techniques and equipment are about to evolve in the near future.

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy.

BACKGROUND: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. METHODS: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. RESULTS: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. CONCLUSIONS: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.

Prospective comparison of endoscopic ultrasound-guided fine-needle aspiration and surgical histology in upper gastrointestinal submucosal tumors.

STUDY AIM: To assess the accuracy of ultrasound-guided fine-needle aspiration biopsy in the differential diagnosis of gastrointestinal stroma cell tumors (GIST) from other submucosal tumors, using both cytology and histology. PATIENTS AND METHODS: We conducted a prospective study from May 2005 to September 2008 in all patients presenting with upper gastrointestinal submucosal tumors. Only patients in whom surgical resection was carried out were included in the final analysis. In cases of mesenchymal tumor, immunocytochemistry was attempted for further differentiation between GIST and non-GIST. Surgical histopathology served as the gold standard. RESULTS: A total of 47 patients were analyzable, with a final histologic diagnosis of 35 mesenchymal tumors. Sufficient tissue for conventional cytologic diagnosis was obtained only in the 35 patients with mesenchymal tumors; in this subgroup, immunocytochemistry was possible in 46 %. If and only if enough material was available for immunocytochemistry, the sensitivity for (correct recognition of) GIST tumors was 93 %. In all 12 patients with nonmesenchymal tumors and lesions, cytology was nondiagnostic and the diagnosis had to be based on clinical suspicion and the appearance on endoscopy and endoscopic ultrasound (EUS). On an intention-to-diagnose basis, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) had a positive predictive value for mesenchymal tumors of 100 %, but no value for the diagnosis of other lesions; using immunocytochemistry, a GIST tumor was recognized among the mesenchymal tumors with a sensitivity of 58 % and a specificity of 8 %. CONCLUSIONS: EUS-FNA-based cytology is safe and has only limited value for the differential diagnosis of submucosal tumors, mainly because insufficient material is harvested. Better tissue acquisition techniques are necessary for better differential diagnosis.

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study.

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.

Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome--a European perspective.

AIM: To use an evidence-based approach to evaluate the safety and tolerability of the treatments available for irritable bowel syndrome (IBS), or in clinical development, in Europe. A separate review appraises the evidence for the efficacy of these therapies. METHODS: A literature search (for 1980 to 2005) was completed for all relevant clinical trial data and other articles which included safety information on the use of pharmacological IBS therapies. Clinical trials were scored according to the level of safety information, and adverse event incidence reported when possible. RESULTS: The tolerability of many of the agents used to treat IBS in Europe is poorly understood. However, serotonergic agents, such as tegaserod and alosetron, which are currently unavailable in Europe, have undergone rigorous assessment in IBS and their benefits have been established. Following initial marketing of alosetron for use in patients with IBS with diarrhoea, concerns about severe constipation and ischaemic colitis resulted in restriction of its use to women with severe IBS symptoms. This highlights the importance of post-marketing surveillance and post-marketing studies in refining the therapeutic indication of new IBS therapies, which will help to identify appropriate recipients for the drug and establish the impact of adverse reactions in clinical practice. CONCLUSIONS: There is a significant lack of data on the safety and tolerability of the therapies currently used routinely to treat IBS in Europe. The newer agents have undergone rigorous assessment, such that their benefits and risks in treating IBS are established. Defining their place among the spectrum of available therapies remains challenging when the benefits and risks of the older treatments are so poorly characterized.

Pseudo-affective visceromotor responses and HPA axis activation following colorectal distension in rats with increased cholinergic sensitivity.

We analysed visceromotor (VMR) and corticosterone responses to colorectal stimuli under control conditions and following acoustic stress in rats selectively bred for increased sensitivity to cholinergic agonists, the Flinders Sensitive Line (FSL) rats, compared with Flinders Resistant Line (FRL) rats. FSL rats demonstrated a significant VMR response at the smallest distension pressure, whereas no response was evident in FRL controls. FSL rats also demonstrated enhanced VMR responses at both larger distension levels compared with FRL rats. Colorectal distension (CRD) produced significant increases in serum corticosterone levels, which were comparable in FRL and FSL. Noise stress induced divergent corticosterone responses in FRL and FSL, but did not affect VMR to CRD in either group. These data suggest that FSL rats show altered VMR responses to CRD and disturbed hypothalamic-pituitary-adrenal axis responses to acute stress.

[Symptomatic biliary stones at the lower end of the common duct following hepaticoduodenostomy]. / Symptomatische Steine im distalen Ductus-choledochus-Stumpf nach Hepatikoduodenostomie.

A 66-year-old patient developed episodes of severe pain due to recurrent cholangitis and pancreatitis. 2 years prior to this referral the patient had undergone an end-to-side hepaticoduodenostomy and a cholecystectomy because of choledocholithiasis and obstructive jaundice. 20 years previously a Billroth II operation had been carried out for the treatment of ulcer disease. Since the hepaticoduodenostomy the patient has suffered from recurrent epigastric pain, nausea and postprandial vomiting. An oedematous pancreatitis following a recurrent chronic cholangitis was assumed. As the intrahepatic biliary ducts appeared to be normal on radiological studies and hepatobiliary scintigraphy showed a downright transit of the tracer, recurrent cholangitis appeared at first to be a rather unlikely explanation. However, follow-up MRI and MRCP showed large calculi at the lower end of the common duct, which was also enlarged up to 1 cm. For this reason an open duodenotomy with subsequent papillosphincterotomy and retrograde choledochoscopy was carried out. The diagnosis was confirmed hereby and all calculi were removed during the operation. Since then the patient has been free of symptoms and complaints. This case shows that remaining calculi at the lower end of the common bile duct can cause severe clinical problems. Therefore the bile ducts should be inspected endoscopically and stones removed prior to, or during the primary operation.

[Clinical utility of EUS-FNA in upper gastrointestinal and mediastinal disease]. / Klinische Wertigkeit der endosonographischen Feinnadelpunktion bei Erkrankungen des oberen Gastrointestinaltrakts und Mediastinums.

BACKGROUND: Endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy (EUS-FNA) is increasingly used for the diagnosis of malignant and benign disease in the region of the upper GI tract. We prospectively investigated the clinical accuracy and safety of this method in unselected patients under routine conditions. PATIENTS AND METHODS: 101 consecutive patients (median 61.5 years; 56 female) were enrolled in the study, in whom a total of 106 tissue biopsies were obtained by using EUS-FNA. Major indications for EUS-FNA were suspicious lesions located in the mediastinum, esophagus, stomach, pancreas, liver, biliary system, adrenals or retroperitoneum. A longitudinal echoendoscope (HITACHI FG-34UX) equipped with a standard 22G -aspiration needle was used. The aspirated specimens were analyzed further by using standard cytology and/or histology. Lymph-node biopsies were additionally subjected to flow-cytometry (FACS-light-chain restriction). Surgery was used for reference (where available). In the remaining cases the final diagnosis obtained by the clinical course and all available imaging and histologic informations (ultrasound, CT, MRT) was used for reference. RESULTS: EUS-FNA caused no serious complications. In 6/106 specimen (5.6 %) no sufficient cell material could be aspirated. In the remaining 100 specimens EUS-FNA reached an overall sensitivity of 78 % and a specificity of 100 %, while the accuracy was 89 % and the positive and negative predictive values were 100 % and 81 %, respectively. The greatest diagnostic accuracy was achieved in mediastinal and retroperitoneal lesions, while the accuracy of EUS-FNA in pancreatic lesions and perigastric lymph nodes was distinctly smaller (<80 %). Addition of FACS studies in patients with suspected malignant lymphoma increased the diagnostic accuracy in the small number of patients included in the study. CONCLUSION: EUS-FNA improves the tissue-based diagnosis of suspicious lesions in locations that are difficult to access (e. g., posterior mediastinum). EUS-FNA is safe, while its diagnostic accuracy is relatively high. Our preliminary data suggest that flow-cytometry may improve the fine-needle based diagnosis of non-Hodgkin s lymphoma, which should be further investigated.

[Diagnostic utility of capsule endoscopy in occult gastrointestinal bleeding]. / Diagnostik okkulter Blutungen des oberen Gastrointestinaltraktes durch die Videokapselendoskopie.

BACKGROUND AND OBJECTIVE: The video-capsule endoscopy (CE) of the small intestine is a novel innovative procedure for outpatient use that can detect even small lesions of the mucosa of the small intestine. Aim of this retrospective clinical study was to evaluate the diagnostic value of CE in a clinical routine setting. PATIENTS AND METHODS: Between July 2001 and October 2002 we investigated 42 patients with suspected gastrointestinal bleeding by CE. In all patients, the previous upper and lower endoscopy work-up was normal. In some cases additional procedures such as bloodpool scintigraphy, angiography, small-bowel enteroclysis or push-enteroscopy were performed. RESULTS: CE detected relevant pathological findings in 23 out of 42 Patients (55 %). The majority of findings in the CE consisted of angiodysplasia (n = 16), ulcer and haemorrhagical erosions (n = 10), one Ulcus Dieulafoy and additional polyps of the small intestine (n = 2). In 4 cases an inflammatory small-bowel disease was detected. These findings could be confirmed by Re-endoscopy. The information provided was helpful to direct further diagnostic and treatment options. In 14 cases (33 %) CE-findings steered additional diagnostic and therapeutic steps. We conclude that CE is safe and has a high diagnostic yield. CONCLUSION: M2A video CE is likely to become an integral part of the algorithm of diagnostic of occult gastrointestinal bleeding after exclusion of other causes of anemia and negative upper and lower endoscopy work-up.

Diagnosis of hepatocellular carcinoma (HCC) in a high-risk patient by using transgastric EUS-guided fine-needle biopsy (EUS-FNA).

Hepatocellular carcinoma (HCC) is the most common primary malignancy arising within the liver and most often affects individuals with chronic hepatitis and/or liver cirrhosis. Patients often present at an advanced stage of disease or with poor liver function, thus limiting treatment options and resulting in a poor prognosis of the disease. Therefore, an early tissue-based diagnosis of HCC is necessary to direct further work-up and treatment. We present the case of a 70-year-old man with alcoholic cirrhosis at stage Child C, in whom a tumor nodule was found incidentally within the left lobe of the liver. Percutaneous biopsy was deemed too dangerous because a deteriorated liver function with coagulopathy was present, and a significant amount of ascites surrounded the small cirrhotic liver. To obtain a conclusive diagnosis, we performed transgastric fine-needle biopsy of the tumor under direct endosonographic guidance (EUS-FNA) without complications. Cytologic examination confirmed the presence of a well differentiated HCC. Based on this finding, super-selective CT-guided angiography and chemoembolization were subsequently performed without complications and the patient remained free of tumor relapse for the 8 months of surveillance. We conclude that EUS-guided fine-needle biopsy and cytologic examination represent a reliable alternative for tissue sampling in HCC, particularly in selected high-risk patients such as those with poor liver function and coagulation disorders; this should be assessed in prospective clinical trials.

Endoscopic ultrasound-guided fine-needle aspiration biopsy of liver lesions: histological and cytological assessment.

BACKGROUND AND STUDY AIMS: EUS-guided fine-needle aspiration biopsy (EUS-FNA) is used increasingly for the diagnosis of mediastinal, biliopancreatic, and gastric tumors. However, little is known about EUS-FNA in hepatic lesions and the best method for tissue analysis. We assessed EUS-FNA combined with histological and cytological evaluation in selected patients. PATIENTS AND METHODS: 41 patients (66 +/- 7 years) were prospectively studied, 33 of whom had clinical findings suggestive of liver malignancies. Selection for EUS-FNA was based on an increased risk of bleeding from percutaneous biopsy (coagulopathy, cirrhosis, ascites, aspirin intake; n = 15), presence of small liver tumors < 2 cm (n = 12), or liver lesions found incidentally (n = 14). Transgastric EUS-FNA of lesions located in accessible liver segments was performed using the Hitachi FG-34UX longitudinal echo endoscope and a 22-G aspiration needle. Specimens were submitted separately for standard cytological and histological evaluation. In the case of malignancies, findings at surgery with histological examination, endoscopy, or computed tomography (CT)-guided biopsy of the primary cancer served as reference results (n = 33), while in benign disorders, a combination of imaging studies (Magnetic Resonance Tomography , scintigraphy) and the clinical follow-up, as summarized in the physician's report, was used as reference. RESULTS: EUS-FNA provided appropriate biopsy specimens in 40/41 patients. It was not possible to aspirate sufficient material in one patient. On average, 1.4 needle passes were necessary to obtain sufficient amounts of tissue. With regard to malignancy, the combination of histological and cytological examination had a sensitivity of 94%, specificity of 100%, negative predictive value (NPV) of 78%, and positive predictive value (PPV) of 100%. Tissue diagnoses were in agreement in 27/41 patients (65%). In the remaining patients, only the cytological examination identified six lesions correctly, while the histological assessment was correct in another seven patients. Malignant lesions were correctly identified by cytology in 24/33 (73%) patients, while histology alone was diagnostic for malignancy in 27/33 (82%) patients. When both modalities were combined, 31 out of 33-malignancies (94%) were correctly diagnosed. Minor complications occurred in two patients and consisted of self-limiting local bleeding. CONCLUSIONS: EUS-FNA of liver tumors is a powerful, reliable, and safe procedure for the diagnosis of malignant liver lesions. Optimal diagnostic results are achieved by combining cytological with histological assessment. Hence, EUS-FNA is an alternative to percutaneous biopsy, particularly in patients at risk of bleeding or with small lesions of the liver.