Endoscopic Submucosal Dissection in Europe: Results of 1000 Neoplastic Lesions From the German Endoscopic Submucosal Dissection Registry.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) enables the curative resection of early malignant lesions and is associated with reduced recurrence risk. Due to the lack of comprehensive ESD data in the West, the German ESD registry was set up to evaluate relevant outcomes of ESD. METHODS: The German ESD registry is a prospective uncontrolled multicenter study. During a 35-month period, 20 centers included 1000 ESDs of neoplastic lesions. The results were evaluated in terms of en bloc, R0, curative resection rates, and recurrence rate after a 3-month and 12-month follow-up. Additionally, participating centers were grouped into low-volume (≤20 ESDs/y), middle-volume (20-50/y), and high-volume centers (>50/y). A multivariate analysis investigating risk factors for noncurative resection was performed. RESULTS: Overall, en bloc, R0, and curative resection rates of 92.4% (95% confidence interval [CI], 0.90-0.94), 78.8% (95% CI, 0.76-0.81), and 72.3% (95% CI, 0.69-0.75) were achieved, respectively. The overall complication rate was 8.3% (95% CI, 0.067-0.102), whereas the recurrence rate after 12 months was 2.1%. High-volume centers had significantly higher en bloc, R0, curative resection rates, and recurrence rates and lower complication rates than middle- or low-volume centers. The lesion size, hybrid ESD, age, stage T1b carcinoma, and treatment outside high-volume centers were identified as risk factors for noncurative ESD. CONCLUSION: In Germany, ESD achieves excellent en bloc resection rates but only modest curative resection rates. ESD requires a high level of expertise, and results vary significantly depending on the center's yearly case volume.

Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness.

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

[Surgical interventions in patients with mast cell activation disease. Aspects relevant for surgery using the example of a cholecystectomy]. / Chirurgische Eingriffe an Patienten mit Mastzellüberaktivitätserkrankung. Operationsrelevante Aspekte am Beispiel einer Cholezystektomie.

BACKGROUND: Systemic mast cell activation disease (MCAD) is characterized by an increased and unregulated release of mast cell mediators which can evoke a multifaceted clinical picture often resembling irritable bowel syndrome or fibromyalgia. Because of the considerable prevalence (~ 17 %) of MCAD surgeons are frequently unwittingly confronted with MCAD patients in whom unexpected intraoperative and postoperative complications may occur. Therefore, knowledge of the particular requirements is of relevance for surgical treatment of MCAD patients. OBJECTIVE: The present paper outlines a concept of surgical treatment of MCAD patients based on the literature which is illustrated by a case report on emergency laparoscopic cholecystectomy. CONCLUSIONS: Due to the high prevalence of MCAD in the general population it can be assumed that the frequency in the surgical patient population is similar. If a patient has MCAD, specific characteristics should be taken into account in the surgical procedure to avoid increased operative and complication risks resulting from MCAD.

[How safe is sedation in gastrointestinal endoscopy? A multicentre analysis of 388,404 endoscopies and analysis of data from prospective registries of complications managed by members of the Working Group of Leading Hospital Gastroenterologists (ALGK)]. / Wie sicher ist die Sedierung in der gastrointestinalen Endoskopie? Eine multizentrische Auswertung von 388 404 Endoskopien und Auswertung der Daten aus prospektiv geführten Komplikationsregistern von Mitgliedern der Arbeitsgemeinschaft leitender Gastroenterologen im Krankenhaus (ALGK).

BACKGROUND: Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. METHODS: Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). RESULTS: Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty-one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class ≥ 3. CONCLUSIONS: Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class ≥ 3.

[Endoscopic resection of a rare gastric adenoma (pyloric gland adenoma) with transition into a well-differentiated adenocarcinoma]. / Endoskopische Resektion eines seltenen Magenadenoms (Pyloric-gland-Adenom) mit Übergang in ein gut differenziertes Adenokarzinom.

We present the case of a 76-year-old lady in whom the work-up for iron-deficiency anaemia resulted in the finding of a giant gastric polyp. The polyp could be completely removed endoscopically. The final histology showed the rare entity of a pyloric gland adenoma with focal transition into a well-differentiated adenocarcinoma. The patient is well after a follow-up of 12 months. Pyloric gland adenoma was first described in 1990. In spite of its benign histological appearance, a transition into adenocarcinoma has been reported in up to 30 % of the cases. Thus, although relatively rare, the gastroenterologist/endoscopist, as well as the pathologist should be aware of the entity of pyloric gland adenoma.

Orthogonally bifunctionalised polyacrylamide nanoparticles: a support for the assembly of multifunctional nanodevices.

Polyacrylamide nanoparticles bearing two orthogonal reactive functionalities were prepared by reverse microemulsion polymerisation. Water-soluble photosensitisers and peptide or carbohydrate moieties were sequentially attached to the new nanospecies by orthogonal conjugations based on copper-catalysed azide-alkyne cycloaddition and isothiocyanate chemistry.

Fatal acute liver failure due to reactivation of hepatitis B following treatment with fludarabine/cyclophosphamide/rituximab for low grade non-Hodgkin's lymphoma.

BACKGROUND: Reactivation of chronic hepatitis B in HBsAg carriers is a well known complication of chemo?therapy. The clinical spectrum ranges from asymptomatic hepatitis to fatal hepatic failure. Although it impairs the prognosis of cancer treatment, it may be overlooked due to other possible causes of liver damage. CASE REPORT: The patient presented with acute liver failure after 6 cycles of rituximab, fludarabine, and cyclophosphamide for low grade non-hodgkin's lymphoma. Differential diagnoses were chemotherapy-induced liver failure, autoimmune hepatitis, phenprocoumon-induced liver failure and infiltration of the liver by lymphoma. Finally, reactivation of hepatitis B with a fibrosing cholestatic pattern was identified. CONCLUSION: This case reminds clinicians that patients receiving high-intensive chemotherapy or immunosuppressive therapy should be screened for HBsAg. HbsAg positive patients should obtain prophylactic antiviral therapy with lamivudine or another substance active against HBV.

[Palliative locoregional therapy for hilar cholangiocarcinoma: photodynamic therapy and brachytherapy]. / Palliative lokoregionäre Therapie des hilären Gallengangskarzinoms: photodynamische Therapie und Brachytherapie.

In hilar cholangiocarcinoma, only 20-30% of the patients are candidates for curative surgical resection, leaving the majority with merely palliative treatment options. Since the natural history of hilar cholangiocarcinoma is dominated by local complications rather than metastatic disease, local palliative treatment seems a reasonable option. Here, endoluminal photodynamic therapy has emerged as a promising treatment with several prospective observational studies and 2 prospective randomised studies published which included nearly 200 patients. With low complication rate and morbidity, PDT achieves an increased median survival as well as an increased quality of life even in patients with reduced performance status. Radiotherapy is an alternative local treatment option applied as brachytherapy, external beam radiotherapy or combined modality treatment. To date, however, sufficient data from controlled clinical trials are lacking, thus palliative radiotherapy has to be considered an experimental treatment option.

Detection of human aspartyl (asparaginyl) beta-hydroxylase and homeobox B7 mRNA in brush cytology specimens from patients with bile duct cancer.

BACKGROUND AND STUDY AIMS: The diagnosis of bile duct cancer is hampered by the low sensitivity of intraductal brush cytology and forceps biopsy. In the present study real-time reverse transcription polymerase chain reaction (RT-PCR) assays for the detection of human aspartyl (asparaginyl) beta-hydroxylase (HAAH) and homeobox B7 (HoxB7) mRNA from intraductal brush cytology specimens were established. Both markers are overexpressed in biliary cancer cell lines and possibly involved in the pathogenesis of bile duct cancer. PATIENTS AND METHODS: RT-PCR assays were validated for detection limit, in-assay variability, and inter-assay variability. Target gene expression was determined in brush cytology specimens from 16 patients with biliary strictures (11 with histologically proven cholangiocarcinomas and five with benign biliary strictures). RESULTS: The assay was quick (about 3 h), highly sensitive (with detection limits between 3 and 106 molecules), and reproducible (maximum in-assay variability 10.3 %, maximum inter-assay variability 11.8 %). The sensitivity of routine brush cytology alone was 36 % (four of 11 cases), with 100 % specificity. A combination with detection of HoxB7 and HAAH mRNA increased the overall diagnostic sensitivity to 82 %. CONCLUSIONS: Detection of these markers using the RT-PCR assays from brush cytology specimens described here may prove to be a useful additional tool for the diagnosis of bile duct carcinoma.

Development of a liquid chromatography/tandem mass spectrometry method for the quantification of fumonisin B1, B2 and B3 in cornflakes.

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of fumonisin B1 (FB1), B2 (FB2) and B3 (FB3) in cornflakes is described. During method development, special attention was paid to the selection of a suitable internal standard (IS) in order to offer a good alternative for deuterated FB1. In this respect, the C12-sphinganine analogue (2S,3R)-2-aminododecane-1,3-diol was chosen because of its structural similarity to the fumonisin backbone and its chromatographic elution between the target analytes. For the extraction of the fumonisins from the cornflakes matrix, MeOH/H2O (adjusted to pH 4 with 0.1 M HCl; 70:30, v/v), ACN/MeOH/H(2)O (25:25:50, v/v/v) and acidified ACN/MeOH/H2O (25:25:50, v/v/v; pH 4) were evaluated. Preference was given to acidified MeOH/H2O (70:30, v/v) with mean recoveries (n=12) for FB1, FB2 and FB3 of, respectively, 84+/-10, 78+/-7 and 85+/-9%. Cleanup was performed using immunoaffinity columns (FumoniTest, VICAM). The chromatography was performed under isocratic conditions at a flow of 0.3 mL min-1 with a mobile phase consisting of ACN/H2O (60:40, v/v) containing 0.3% formic acid. The mass spectrometer was operated in the positive electrospray ionization (ESI+) mode using multiple reaction monitoring (MRM). An intralaboratory validation was conducted with fortified samples determining limits of detection (LOD), limits of quantification (LOQ), precision, trueness, specificity and measurement uncertainty. The LOD concentrations for FB1, FB2 and FB3 were 20, 7.5 and 12.5 microg/kg. The LOQs were 40 microg/kg for FB1, 15 microg/kg for FB2 and 25 microg/kg for FB3. The coefficients of variation (CVs) under repeatability conditions varied from 11 to 13% for FB1, from 9 to 14% for FB2 and from 7 to 10% for FB3. Under within-laboratory reproducibility conditions, the CVs ranged from 12 to 17% for FB1, from 9 to 16% for FB2 and from 7 to 13% for FB3. The percent bias for FB1 varied from -12 to -10%, while for FB2 and FB3 bias ranged, respectively, from -4 to -2% and from -12 to -5%. The expanded measurement uncertainties for FB1, FB2 and FB3 were, respectively, 19, 18 and 22%.

[Malaria in the emergency room. Results of the emergency treatment of 137 patients with symptomatic malaria]. / Malaria in der Notaufnahme. Ergebnisse der Notfallbehandlung bei 137 Patienten mit symptomatischer Malaria.

OBJECTIVE: To assess characteristics and outcome of emergency patients with acute malaria. PATIENTS AND METHODS: We retrospectively assessed the clinical and laboratory parameters of 137 consecutive patients (87 males, 50 females; median age 37 years, range 17 - 67 years) presenting with acute malaria to our tertiary care center between 1992 and 2002. RESULTS: Falciparum malaria was diagnosed in 116/137 and tertian malaria in 19/137 patients; a single patient was infected with both parasites while in another case the type of parasite remained unclear. Infections were acquired in Africa (121), Asia , and in the Americas . One traveler visited multiple continents. Only 36 % (50/137) of patients had used malaria chemoprophylaxis. 128/137 patients were treated as in-patients; 22 of these had to be treated on an intensive care unit. According to the criteria of the German Society of Tropical Medicine, 44/137 (32 %; 95 % confidence interval (CI): 25 - 40 %) patients suffered from complicated malaria. The overall mortality rate was 2/137 (1.5 %; 95 % CI: 0,4 - 5.2 %); the mortality rate of complicated malaria tropica was 2/44 (4,5 %; 95 % CI 1,3 - 15 %). Patients with complicated malaria were significantly older than those with uncomplicated malaria. Median length of hospital stay was 4 days in uncomplicated and 9 days in complicated cases. Based on costs of EUR 2500 per case, an attack rate of > 3 % in East African travelers and a cost of EUR 55 for a chemoprophylaxis with mefloquine, chemoprophylaxis is cost-effective. CONCLUSION: In our retrospective analysis, complicated malaria tropica was associated with older age. Although malaria causes considerable morbidity, the overall mortality from severe malaria is low. Reinforcement of chemoprophylaxis especially in travelers to Africa could reduce malaria cases and is cost-effective.

Quantitative determination of ochratoxin A in kidneys by liquid chromatography/mass spectrometry.

A sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the quantitative determination of ochratoxin A (OTA) in kidney samples was developed. Ochratoxin B (OTB) was used as internal standard. Extraction of homogenized kidney samples was done by adding a chloroform/phosphoric acid mixture. Due to restriction of the sample size, less chloroform could be used than in previously described methods. Two different columns for clean-up were compared: strong anion exchange (Bond Elut SAX) and Extrelut NT columns. The high-performance liquid chromatography (HPLC) was used with gradient elution consisting of variable mixtures of formic acid (0.3%) in acetonitrile and formic acid (0.3%) in water. The mass spectrometer was operated in the positive ESI mode using multiple reaction monitoring. For OTA the precursor ion was m/z 404 while the product ions were at m/z 239 and m/z 341. For OTB the precursor ion was m/z 370 while the product ions were at m/z 205 and at m/z 324. A calibration curve of fortified kidney samples was used to quantify OTA. Method validation was performed according to Commission Decision 2002/657/EC. Decision limit (CCalpha), detection capability (CCbeta), precision, bias, trueness, specificity and measurement uncertainty were determined. In general, the best results were obtained using SAX clean-up. CCalpha and CCbeta were 0.11 and 0.25 microg kg(-1), respectively. Within-laboratory reproducibility (% CV) was 9, 9, and 5% for OTA-fortified kidney samples of 0.5, 1, and 2.5 microg kg(-1), respectively. Trueness (%) was 75, 69, and 57% for OTA-fortified kidney samples at 0.25, 0.5, and 1 microg kg(-1), respectively. Measurement uncertainty and expanded uncertainty were 14.85 and 29.70%, respectively. All criteria as laid down in Commission Decision 2002/657/EC were fulfilled. Therefore, this LC/ESI-MS/MS method can be used to monitor kidneys for OTA in the framework of Council Directive No. 96/23/EC.

[Endemic celiac sprue and Hodgkin's disease in a 72-year-old patient]. / Einheimische Sprue und Morbus Hodgkin bei einem 72-jährigen Patienten.

HISTORY AND CLINICAL FINDINGS: A 72-year-old man was admitted with diarrhea, loss of weight and anemia. The diarrhea started after antibiotic treatment of a pneumonia and persisted for 6 months at admission. Monoclonal gammopathy was found on external examination. INVESTIGATIONS AND DIAGNOSIS: The work-up yielded iron deficiency anemia, monoclonal gammopathy (IgG kappa) and elevated polyclonal IgA due to Gliadin- and endomysium-antibodies. Duodenal mucosa biopsies showed villous atrophy and increased intraepithelial lymphocytes. Celiac disease was diagnosed. Unexpectedly, mediastinal lymphomas were found and the concomitant diagnosis of Hodgkin's disease was made. TREATMENT AND COURSE: On gluten free diet all symptoms of malabsorption resolved. Therapy for the Hodgkin lymphoma with chemotherapy was initiated. As Bleomycin associated lung disease occurred during therapy, radiotherapy was not administered. A complete remission could be achieved. CONCLUSIONS: The association of celiac disease and malignancy is well known. The pathogenesis is not fully understood, but a correlation between the duration of gluten exposure and the rate of malignancy was found. Thus, the chronic immunologic stimulation might also have contributed to the development of Hodgkin's disease in our patient, which to date has been reported only anecdotally.

Intrahepatic mRNA levels of interferon gamma and tumor necrosis factor alpha and response to antiviral treatment of chronic hepatitis C.

OBJECTIVES: The impact of intrahepatic messenger RNA (mRNA) levels of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) on the outcome of antiviral treatment of chronic hepatitis C was evaluated. METHODS: Semiquantitative mRNA determination was performed on 36 pretreatment liver biopsies by reverse transcription/competitive polymerase chain reaction. RESULTS: Sustained response (normal aminotransferase levels and negative hepatitis C virus [HCV] RNA for more than 6 months) was achieved in 13 patients, whereas 23 of 36 patients did not achieve sustained response (12 partial responders, 11 complete nonresponders). In sustained responders, pretreatment intrahepatic mRNA levels of IFN-gamma and TNF-alpha were lower than in nonsustained responders (IFN-gamma, 0.23 +/- 0.10 vs. 0.35 +/- 0.07, respectively; p = 0.024 and TNF-alpha, 1.2 +/- 0.7 vs. 2.3 +/- 1.4, respectively; p= 0.009); similarly, HCV viral load was lower in sustained responders than in nonresponders (663,424 +/- 756,389 copies/mL vs. 1,656,713 +/- 1,517,683 copies/mL, respectively; p = 0.037). In addition, TNF-alpha mRNA levels were correlated to HCV viral load and liver fibrosis scores. CONCLUSIONS: Higher intrahepatic mRNA levels of IFN-gamma and TNF-alpha may reflect interferon resistance of HCV strains and may contribute to tissue damage in patients refractory to antiviral treatment.