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.

[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.

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.

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.

Defect of a complement receptor 3 epitope in a patient with systemic lupus erythematosus.

Complement receptor 3 (CR3) is expressed on cells of the reticuloendothelial system and involved in the clearance of immune complexes. In this article a patient with a deficiency of the C3bi binding site of this receptor is described. Clinically this patient exhibited predominantly cutaneous manifestations of a systemic lupus erythematosus with an immune vasculitis and panniculitis. The deficiency of the CR3 epitope was demonstrated using flow cytometry. The functional relevance of this defect was demonstrated in a rosetting assay with C3bi-loaded erythrocytes. C3bi binding was found to be significantly decreased. Furthermore, there was an impairment of phagocytosis of opsonized Escherichia coli. The CR3 defect is not due to an autoantibody but is assumed to have a genetic basis. These data suggest that the defect of the CR3 may be involved in the pathogenesis of the immune vasculitis in this patient.

Differential Regulation of Calcitonin Gene-related Peptide (CGRP) in Regenerating Rat Facial Nucleus and Dorsal Root Ganglion.

The content of calcitonin gene-related peptide (CGRP) and CGRP-mRNA were determined in axotomized rat facial motor nucleus and sensory fifth lumbar dorsal root ganglion (L5 DRG) using radioimmunoassay and Northern blot analysis. After facial nerve transection CGRP levels in the facial nucleus showed a biphasic, approximately five-fold increase. A first peak occurred at postoperative day 3 and, after a transient decrease to normal levels at day 9, another increase was observed reaching a peak around the time of reinnervation (postoperative day 21). CGRP-mRNA showed a similar, biphasic increase. The first peak in CGRP mRNA preceded the peptide peak by 2 days, the second peak was approximately day 21. In contrast, a decrease in CGRP levels is seen in L5 DRG after sciatic nerve section, reaching minimal levels of 45% of control during the second postoperative week. CGRP-mRNA in axotomized DRG also decreases preceding the decrease in peptide levels. No recovery to normal levels is seen for either peptide or mRNA levels in regenerating DRG up to 45 days after injury. Thus, axotomy leads to a differential regulation of both CGRP and CGRP-mRNA in regenerating facial motor nucleus and sensory L5 DRG. This difference may be due to different regulating factors present in both the respective target tissues and the CNS regions and could reflect different functions of CGRP in regenerating motor and sensory neurons.

Semiquantitation of human chemokine mRNA levels with a newly constructed multispecific competitor fragment.

Chemokines are a group of inducible, locally acting proinflammatory cytokines which have been implicated in the pathogenesis of a variety of diseases. Important members of the group include monocyte chemoattractant protein (MCP)-1, -2, -3, macrophage inhibitory protein (MIP)-1alpha, -1beta and RANTES (regulated upon activation, normal T expressed and secreted). To facilitate further investigation of the human chemokines, we have constructed a novel multispecific competitor fragment containing primer binding sites for the CC-chemokines MCP-1, MCP-2, MCP-3, MIP-1alpha, MIP-1beta and RANTES, the CXC-chemokines MIP-2alpha, MIP-2beta as well as for the housekeeping gene beta-actin. Using this competitor fragment we can demonstrate reliable semiquantitation of reverse transcribed chemokine mRNAs. The assay should be useful for further studies, in particular for the semiquantitation of chemokine mRNA species from small cell or tissue specimens.

Semi-quantification of human C-C chemokine mRNAs with reverse transcription/real-time PCR using multi-specific standards.

A reverse transcription/real-time polymerase chain reaction (PCR) assay was established to semi-quantify the mRNA levels of the human C-C chemokines RANTES, MIP-1beta and MCP-1 relative to the housekeeping gene beta-actin. The assay showed a high sensitivity (below 60 cDNA molecules/10 microl reaction) and dynamic range (8 log units); both within-assay and inter-assay variability were below 0.06 log units and the accuracy was +/-0.06 log units for all four chemokines. Moreover, it is demonstrated that a multi-specific DNA fragment, which had previously been constructed for competitive PCR, can be used as a reliable external standard. This allows a direct semi-quantitative comparison of different chemokine mRNA levels and is a convenient alternative to the use of different sets of homologous external standards. The method was successfully applied to the semi-quantification of chemokines in human liver specimens and should be useful in further studies on steady state mRNA levels of C-C chemokines from low cell numbers or small tissue specimens.

Calcitonin gene-related peptide (CGRP) in the regenerating rat sciatic nerve.

Calcitonin-gene related peptide (CGRP) is a neuromodulatory peptide present in motoneurons and a subpopulation of sensory neurons of the adult peripheral nervous system. Here we have investigated the changes in axonal transport of CGRP and CGRP receptor expression in the injured and regenerating rat sciatic nerve using CGRP-immunocytochemistry, radioimmunoassay and quantitative in situ receptor autoradiography techniques. Axotomy led to a gradual and prolonged, 2.5- to 3.5-fold increase in specific CGRP binding to the distal part of the crushed sciatic nerve, beginning 4-6 days after axotomy. An even stronger, up to 30-fold increase was observed after 30-42 day denervation in the distal part of the transected sciatic nerve, where neurite reinnervation was prevented by retroversion and ligation of the proximal nerve stump. Reconnection of the proximal and distal nerve stumps 21 days after transection did not lead to a major reduction in specific CGRP binding but prevented a further increase that occurred between 21 and 42 days after transection without reconnection. In contrast, the anterograde axonal transport of CGRP decreased after axotomy to 40-50% of the control values 6-8 days after nerve crush but recovered towards normal levels during successful regeneration. Interestingly, the retrograde axonal transport of CGRP appeared to amount to only 10-20% of the anterograde transport, suggesting that the peptide may be released by the regenerating neurites into the endoneurium of the injured peripheral nerve. In view of the persistent upregulation in endoneural CGRP binding after axotomy these data indicate that axonal CGRP could play a regulatory role in mediating axonal-endoneural cell interaction during peripheral nerve regeneration.

Calcitonin gene-related peptide increases in rat facial motoneurons after peripheral nerve transection.

The rat facial nerve was transected and the retrograde reaction studied in the facial nucleus using light and electron microscopic immunohistochemistry and radioimmunoassay for calcitonin gene-related peptide (CGRP). An initial increase of CGRP-immunoreactivity (IR) was noted at 15 h after axotomy, thereafter CGRP-IR continued to rise to maximal levels around day 6 after which it gradually decreased and reached normal levels again after 5-6 weeks. Immunoreactive CGRP was found to fill the perikarya of facial motoneurons extending into dendrites and axons. Possible functional implications of CGRP as a neuroregulatory molecule during nerve regeneration are discussed.

Hepatitis C virus-associated mixed cryoglobulinaemia.

Symptomatic mixed cryoglobulinaemia may dominate the course of hepatitis C virus infection. While conventional treatment of mixed cryoglobulinaemia relied on immunosuppression, the discovery of the close association to HCV infection has prompted treatment studies with interferon-alpha. Although symptomatic improvement is achieved in most patients during therapy, the rate of sustained response is low.

Autoimmunity induced by interferon-alpha therapy for chronic viral hepatitis.

Type I interferons, which are mostly alpha-interferons (either as single agents or in combination with antiviral drugs), are currently the standard therapy for chronic viral hepatitis B, B/D, and C. Side-effects are not uncommon and include exacerbation of pre-existing autoimmune disorders or the de novo induction of autoimmunity. These adverse effects are attributed to the immunomodulatory properties of type I interferons, and should be distinguished from autoimmunity associated with chronic viral hepatitis in which interferon treatment may indeed be beneficial. The major autoimmune side-effects of interferon therapy for chronic viral hepatitis are thyroid or liver disease. Therefore, screening for thyroid antibodies and auto-antibodies indicative of autoimmune hepatitis both before, during, and after interferon therapy is strongly recommended. The presence of high concentrations of thyroid auto-antibodies or antibodies associated with autoimmune hepatitis can be contraindicative to interferon therapy. However, treatment is not contraindicated in viral hepatitis (in particular chronic hepatitis C) associated with autoimmune phenomena--including low-titer thyroid antibodies or other non-organ specific auto-antibodies. If interferon-induced autoimmunity occurs, the necessity of therapy has to be balanced carefully against the risks of autoimmune disease. Further research is needed to identify the factors which determine susceptibility to interferon-associated autoimmunity in individual patients.

[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.

[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.