S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma-final results of the randomized AIO MATEO phase II trial.

PURPOSE: Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. DESIGN: MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. RESULTS: From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). CONCLUSIONS: S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas.

PURPOSE: Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs. METHODS: Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression. RESULTS: Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4+ T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4+ T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs. CONCLUSION: In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4+ cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.

Better prognosis of gastric cancer patients with high levels of tumor infiltrating lymphocytes is counteracted by PD-1 expression.

The prognostic potential of anti-tumor immune responses is becoming increasingly important in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S) especially regarding the use of immune checkpoint inhibitors. This study analyzes for the first time the prognostic impact of tumor-infiltrating lymphocytes (TILs) and checkpoint inhibitors in a large Caucasian cohort in patients with AGE/S. We screened tissue samples from 438 therapy-naïve patients with AGE/S undergoing surgery between 1992 and 2005, examined in a tissue microarray (TMA) and stained against human CD3, CD4, CD8, PD-1, and PD-L1. Out of 438 tissue samples, 210 were eligible for multivariate analysis. This revealed that high infiltration with CD3+, CD4+, or CD8+ TILs was associated with an increased overall survival in AGE/S patients, which could only be confirmed in multivariate analysis for CD3 (HR: 0.326; p = .023). Independent improved survival was limited to gastric cancer patients and to early tumor stages as long as TILs did not express PD-1 (HR: 1.522; p = .021). Subgroup analyses indicate that TIL-dependent anti-tumor immune response is only effective in gastric cancer patients in early stages of disease in PD-1 negative TILs. Combined analysis of PD-1 and CD3 could serve as a prognostic marker for the clinical outcome of gastric cancer patients and could also be of interest for immunotherapy.

Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas.

INTRODUCTION: The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). METHODS: This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. RESULTS: Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. CONCLUSION: In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype.

Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry.

Small molecule inhibitors such as Larotrectinib have been recently approved in the treatment of patients with fusions of the neurotrophic-tropomyosin receptor tyrosine kinase (NTRK) genes 1-3. These genomic rearrangements have been reported across different tumor subtypes with a high prevalence in rare tumors. However, in gastric and esophageal adenocarcinoma (AGE) NTRK fusions have also been described in a subset of Asian patients. In order to study the prevalence of this alteration in Caucasian patients with AGE we performed immunohistochemistry for pan-NTRK in 438 formalin-fixed paraffin embedded (FFPE) tumor samples. While we found NTRK expression in gastric glands and tumor adjacent nerve tissue, we did not detect this marker in the tumor compartment. Based on our findings NTRK fusions do not seem to play a role in the molecularpathology of Caucasian AEG patients, so that other treatment options are required.

Development of a Novel Imaging Agent for Determining Albumin Uptake in Solid Tumors.

PURPOSE: The purpose of this study was to investigate the albumin-binding compound 111In-C4-DTPA as an imaging agent for the detection of endogenous albumin accumulation in tumors. METHODS: 111In-C4-DTPA was injected in healthy nude mice for pharmacokinetic and biodistribution studies (10 min, 1, 6, 24, and 48 h, n = 4) and subsequently in tumor-bearing mice for single-photon emission computed tomography/X-ray-computed tomography (SPECT/CT) imaging studies. Four different human tumor xenograft models (LXFL529, OVXF899, MAXFTN401, and CXF2081) were implanted subcutaneously unilaterally or bilaterally (n = 4-8). After intravenous administration of 111In-C4-DTPA, SPECT/CT images were collected over 72 h at 4-6 time points. Additionally, gamma counting was performed for the blood, plasma, lungs, heart, liver, spleen, kidneys, muscle, and tumors at 72 h post-injection. RESULTS: 111In-C4-DTPA bound rapidly to circulating albumin upon injection, and the radiolabeled albumin conjugate thus formed was stable in murine and human serum. SPECT/CT images demonstrated a time-dependent uptake with a maximum of 2.7-3.8% ID/cm3 in the tumors at approximately 24 h post-injection and mean tumor/muscle ratios in the range of 3.2-6.2 between 24 and 72 h post-injection. The kidneys and bladder were the predominant elimination organs. Gamma counting at 72 h post-injection showed 1.3-2.5% ID/g in the tumors and mean tumor/muscle ratios in the range of 4.9-9.4. CONCLUSION: 111In-C4-DTPA bound rapidly to circulating albumin upon injection and showed time-dependent uptake in the tumors demonstrating a potential for clinical application as a companion imaging diagnostic for albumin-binding anticancer drugs.

Pharmacological effect of aminoferrocene in mice with L1210 leukemia.

AIM: To study the cytostatic and some biological effects of aminoferrocene using mice with L1210 lymphoid leukemia. MATERIALS AND METHODS: Experiments were performed on BDF1 male mice (DBA/2, female × C57Bl/6, male) with transplantable L1210 lymphoid leukemia. Determination of antitumor activity of Benzyl-Fc Boron (Bn), it was injected intraperitoneally 6 times daily, starting on day 2 after L1210 leukemia cell transplantation. Doses of Bn such as 26; 260 and 2600 µg/kg were used. The determination of intracellular content of cardiolipin, thiols, reactive oxygen species (ROS) and also analysis of Annexin V positivity and mitochondrial transmembrane potential (JC-1 staining) were performed with use of flow cytometry. The levels of "free iron" complexes, transferrin active forms and the rate of NO generation were measured by EPR-specroscopy. RESULTS: Six daily injections of Bn at a dose of 26 µg/kg resulted in an increased survival of mice with L1210 leukemia by 28% (p < 0.05). Bn led to an increase of apoptotic cells number and ROS amount in leukemia cells. Besides, Bn caused a decrease of cardiolipin and nonprotein thiol compounds content. The membrane electrochemical potential of cell mitochondria was decreased also after Bn administration. Studies using EPR-spectroscopy revealed a significant increase in a level of "free iron", content of transferrin active species and generation rate of NO by inducible NO-synthase in L1210 cells after aminoferrocene administration. CONCLUSION: Our data indicate that Benzyl-Fc Boron can be promising candidate for realizing a new strategy of anticancer therapy with the use of ROS-inducing agents.

Diffuse gastric cancer with peritoneal carcinomatosis can mimic Crohn's disease.

In some cases the diagnosis of gastric cancer is difficult and the endoscopic presentation may be misleading. Diffuse type gastric carcinoma with peritoneal metastasis may present primarily with abdominal pain, colonic infiltration and/or diarrhea, thus other differential diagnoses like Crohn's disease (CD) may be considered at first. Therefore intensive diagnostic work-up is important. We report two cases of gastric cancer with ascites due to peritoneal carcinomatosis who were first diagnosed as CD. The patients were hospitalized in different institutions for weight loss, abdominal pain and nausea. The first colonoscopy, upper endoscopy with multiple biopsies and ascites puncture were negative for malignant disease, but macroscopic lesions resembling CD were described. Both patients were released on a prednisolone-based treatment for suspected CD. They presented to our hospital for further evaluation due to persistent symptoms. Neither lower nor upper endoscopy were suggestive of CD and endoscopic ultrasound was suspicious of malignancy in one case. Histology was diagnostic and showed gastric infiltration by a poorly differentiated adenocarcinoma. Diffuse type gastric cancer (gastric linitis plastica) with peritoneal metastasis may mimic certain clinical, endoscopic and CT imaging features of CD. Repeated biopsies and endoscopic investigations are often necessary to confirm a malignant process, especially in case of an inconclusive clinical and endoscopic picture. Endoscopic ultrasound may be useful to evaluate the risk of malignancy in patients with macroscopic suspicion of malignancy and negative biopsies.

Locally recurrent colorectal cancer: results of surgical therapy.

PURPOSE: Up to 20 % of colorectal cancer patients develop recurrent disease despite standardized surgical techniques and multimodal treatment strategies. Radical resection is the central component of curative therapy in these cases. The aim of this study was to evaluate treatment results in patients with locoregionally recurrent colorectal cancer. METHODS: From January 1995 to December 2007, surgery was performed for recurrent colorectal cancer in 82 patients who had undergone curative (R0) resection of their primary tumor. Assessment included patient, tumor and treatment characteristics, postoperative complications, and time without re-recurrence; recurrence-free and overall survival rates were calculated according to the Kaplan-Meier method. RESULTS: Resection was performed in 60 of the 82 patients (73 %), repeat R0 resection in 52 % (31/60). Patients had a postoperative morbidity of 39 % (31/82), a relaparotomy rate of 13 % (11/82), and a lethality of 7 % (6/82). Forty-eight percent of all surgically-treated patients received a permanent stoma. Re-recurrence was seen in 52 % (16/31). R0 resection was associated with a 5-year survival rate of 35 % (11/31). CONCLUSIONS: Extensive reinterventions often enable repeat R0 resection. Despite relevant morbidity, the lethality appears to be acceptable. Decisive for the prognosis is re-recurrence.

Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO){dagger}.

BACKGROUND: This prospective multicentre phase II trial assessed the feasibility and efficacy of perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in patients with gastro-oesophageal adenocarcinoma. METHODS: Patients with curatively resectable adenocarcinoma of the stomach, the gastro-oesophageal junction or the lower third of the oesophagus were enrolled. Patients received docetaxel 75 mg/m(2) plus cisplatin 60 mg/m(2) (day 1), followed by oral capecitabine 1875 mg/m(2) divided into two doses (days 1-14) every 3 weeks. There were three cycles preoperatively and three cycles postoperatively. The primary end point was the R0 resection rate. RESULTS: Fifty-one patients were recruited and assessed for feasibility and efficacy. 94.1% of patients received all three planned cycles preoperatively, and 52.9% received three cycles postoperatively. The R0 resection rate was 90.2%. 13.7% of patients showed complete pathological remission (pCR). Toxicity was acceptably tolerable. Without prophylactic granulocyte colony-stimulating factor administration, neutropenic fever developed in 21.5% of patients preoperatively (grade 3 or 4) and in 11.1% of patients postoperatively. CONCLUSIONS: DCX is a safe and feasible perioperative regimen in the treatment of gastro-oesophageal adenocarcinoma with a high percentage of cycles delivered pre- and postoperatively, compared with standard practice. The high efficacy in terms of R0 resection rate and pCR is very promising.

Diagnostic value of confocal endomicroscopy in celiac disease.

BACKGROUND: Improved endoscopic screening with targeted biopsies might enhance diagnostic yield in celiac disease. Confocal endomicroscopy (CEM) allows high-resolution in vivo histological analysis. We compared the endomicroscopic findings during ongoing endoscopy with the histological findings graded according to the Marsh classification. METHODS: Twenty-four patients with celiac disease and six patients with celiac disease that was refractory on a gluten-free diet were examined using CEM. The duodenal mucosa was evaluated by CEM and by conventional histological analysis in respect of villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40 / 100 enterocytes). The CEM results were assessed as to sensitivity, specificity, and interobserver variability. A Marsh classification score determined by CEM was compared to that obtained by histology. Thirty patients undergoing routine upper gastrointestinal endoscopy were used as controls. RESULTS: Conventional histology showed villous atrophy and crypt hyperplasia in 23 and increased numbers of IELs in 27 of the 30 patients with celiac disease. With CEM, villous atrophy, crypt hyperplasia, and increased IELs were respectively identified in 17, 12, and 22 of the 30 patients. The agreement of the findings on CEM with those of conventional histology was good in relation to villous atrophy (sensitivity 74 %) and increased numbers of IELs (sensitivity 81 %), but inadequate in relation to crypt hyperplasia (sensitivity 52 %). The kappa values for determination of interobserver variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. In the 30 control patients, normal duodenal architecture was found by both histology and endomicroscopy, indicating an overall specificity of 100 %. CONCLUSION: The assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but insufficient in respect of crypt hyperplasia. For routine use of CEM in patients with celiac disease, the technique would need to be improved.

Immune modulation by non-hodgkin lymphoma in a patient with two primary intestinal T-cell lymphomas and long-standing celiac disease.

Tumors may influence immunologic reactions. Here, we report on a 72-year-old patient who suffered from celiac disease (CD) that had been diagnosed 20 years before. Under a normal diet but without any evidence of enteropathy or CD-associated antibodies, the patient developed a jejunal T-cell lymphoma. It was resected due to perforation and four courses of IMVP-16 were added. The patient started and kept a strict gluten-free diet (GFD). Two years later, he presented with weight loss and a clonally divergent refractory sprue type II with loss of antigen (CD8; T-cell receptor-beta) expression in intraepithelial lymphocytes. At this time point, he showed high titers of CD-associated antibodies, although he was on a strict GFD. This case report highlights several questions: the missing enteropathy under a gluten-containing diet supports the notion of immune suppression in malignant diseases, especially non-Hodgkin lymphoma. Secondly, the patient developed an early form of a second independent T-cell lymphoma (refractory sprue type II) under a strict GFD, then with CD-associated antibodies, which raises the question whether the clonal intraepithelial lymphocytes were stimulating antibody production. Thus, the single detection of CD-associated antibodies in patients with CD is not itself proof of noncompliance with GFD.

A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: The combination of irinotecan with 5-fluorouracil demonstrates efficacy with tolerable safety in the first-line treatment of metastatic gastroesophageal cancer (mGC). This randomized phase II trial compared for the first time capecitabine with irinotecan or cisplatin in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive 3-week cycles of capecitabine 1000 mg/m(2), twice daily for 14 days, with on day 1 either irinotecan 250 mg/m(2) (XI) or cisplatin 80 mg/m(2) (XP). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Of 118 patients recruited, 112 were eligible for safety analysis and 103 for efficacy analysis. In the XI and XP treatment arms, there were no marked differences in ORR, 37.7% versus 42.0%, and median PFS, 4.2 versus 4.8 months, although median OS was longer, 10.2 versus 7.9 months, respectively. Grade 3/4 toxicity was higher in the XP regimen for thrombocytes (18.2% versus 1.8%), nausea (23.6% versus12.3%) and vomiting (16.4% versus 1.8%) and in the XI arm for diarrhea (22.8% versus 7.3%). CONCLUSION: The comparable activity and safety of the XI and XP regimens establish XI as a relevant platinum-free first-line treatment choice for patients with mGC.

Aberrant T-lymphocytes in refractory coeliac disease are not strictly confined to a small intestinal intraepithelial localization.

BACKGROUND: Refractory coeliac disease (RCD) is characterized by persisting mucosal pathology in spite of a strict gluten free diet (GFD). In RCD type II, phenotypically aberrant (CD7+CD3-CD4/8-cytoplasmicCD3+) T-lymphocytes are present within the intraepitelial lymphocyte (IEL) population in the small intestine, and 50-60% of these patients develops an enteropathy associated T-cell lymphoma (EATL). AIM: To investigate whether aberrant T-lymphocytes in RCD II can be detected in other parts of the small intestinal mucosa besides the intraepithelial compartment. Additionally, the presence of aberrant T-lymphocytes was analyzed in two RCD II patients that developed atypical skin lesions. METHODS: Multiparameter flow cytometric immunophenotyping was performed on both IEL and lamina propria lymphocyte (LPL) cell suspensions, isolated from small bowel biopsy specimens of RCD II patients (n = 14), and on cutaneous lymphocytes isolated from skin-lesion biopsy specimens of RCD II patients (n = 2). In addition, immunofluorescence analysis of frozen RCD II derived small intestinal biopsies was performed. RESULTS: Our results clearly show that aberrant T-lymphocytes may be present in both the IEL and the LPL compartments of RCD II derived small intestinal biopsies. Although the highest percentages are always present in the IEL compartment, aberrant LPL can exceed 20% of total LPL in half the RCD II patients. Interestingly, cutaneous lymphocytes isolated from atypical skin lesions that developed in some RCD II patients showed a similar aberrant immunophenotype as found in the intestinal mucosa. CONCLUSIONS: In RCD II, the aberrant T-lymphocytes may also reside in the subepithelial layer of the small intestinal mucosa, in the lamina propria, and even in extraintestinal localizations including the skin. Whether this phenomenon represents a passive overflow from the intestinal epithelium or active trafficking towards other anatomical localizations remains to be elucidated. RCD II appears to be a disseminated disease, which may impose the risk of EATL development outside the intestine.

[Immune reconstitution inflammatory syndrome (IRIS) of the small bowel in an immunocompromised patient suffering from systemic lupus erythematosus and non-tuberculous mycobacteriosis]. / Immunrekonstitutionssyndrom des Dünndarms bei einer immunsupprimierten Patientin mit systemischem Lupus erythematodes und nichttuberkulöser Mykobakteriose.

An overwhelming immune reaction resulting in granulomatous inflammation after infection with opportunistic pathogens is termed immune reconstitution inflammatory syndrome (IRIS). It has mainly been described in patients with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy (HAART) who show a significant increase of low CD4 T cells (initially <50/microl). IRIS may lead to organ damage and differential diagnosis is often difficult. We report the case of a 38-year-old female patient who developed a Mycobacteria genavense infection of the liver and the bowel after several immunosuppressive therapies for systemic lupus erythematosus. CD4 T cell counts as low as 17/microl were found and immunosuppressive therapy was stopped. Despite several courses of antibiotic treatment and rising CD4 T cell counts, severe malabsorption persisted. Upper endoscopy revealed a continuous inflammation with pseudopolyps of the small bowel and histologically, a granulomatous infiltrate was detected. After exclusion of a persisting infection by Mycobacteria genavense, IRIS of the small bowel was suspected and treatment with prednisolone was started. The clinical and histological picture improved significantly, the number of CD25(+)CD4(+) cells decreased in the lamina propria of the duodenum under treatment with prednisolone and Foxp3+ regulatory T cells (Treg) accumulated around granulomas. This case shows that IRIS is not restricted to HIV patients but may also occur in otherwise immunosuppressed patients. Due to different treatment strategies, distinguishing IRIS from infectious diseases is essential. The role of Treg in IRIS has to be elucidated.

Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue.

BACKGROUND AND AIMS: The alpha(2)-gliadin-33mer has been shown to be important in the pathogenesis of coeliac disease. We aimed to study mechanisms of its epithelial translocation and processing in respect to transcytotic and paracellular pathways. METHODS: Transepithelial passage of a fluorescence-labelled alpha(2)-gliadin-33mer was studied in Caco-2 cells by using reverse-phase high-performance liquid chromatography, mass spectrometry, confocal laser scanning microscopy (LSM) and fluorescence activated cell sorting (FACS). Endocytosis mechanisms were characterised with rab-GFP constructs transiently transfected into Caco-2 cells and in human duodenal biopsy specimens. RESULTS: The alpha(2)-gliadin-33mer dose-dependently crossed the epithelial barrier in the apical-to-basal direction. Degradation analysis revealed translocation of the 33mer polypeptide in the uncleaved as well as in the degraded form. Transcellular passage was identified by confocal LSM, inhibitor experiments and FACS. Rab5 but not rab4 or rab7 vesicles were shown to be part of the transcytotic pathway. After pre-incubation with interferon-gamma, translocation of the 33mer was increased by 40%. In mucosal biopsies of the duodenum, epithelial 33mer uptake was significantly higher in untreated coeliac disease patients than in healthy controls or coeliac disease patients on a gluten-free diet. CONCLUSION: Epithelial translocation of the alpha(2)-gliadin-33mer occurs by transcytosis after partial degradation through a rab5 endocytosis compartment and is regulated by interferon-gamma. Uptake of the 33mer is higher in untreated coeliac disease than in controls and coeliac disease patients on a gluten-free diet.

Capsule endoscopy in refractory celiac disease.

BACKGROUND AND STUDY AIMS: Patients with refractory celiac disease (RCD) are at risk of intestinal T-cell lymphoma, which is difficult to diagnose because it often develops in the small bowel. We therefore studied whether wireless capsule endoscopy was able to detect ulcerative jejunitis or intestinal T-cell lymphomas that were missed by standard endoscopic and imaging procedures in patients with RCD. PATIENTS AND METHODS: Detection of ulcerative jejunitis and overt T-cell lymphoma by capsule endoscopy or by upper and lower endoscopy, abdominal computed tomography (CT) or abdominal magnetic resonance tomography (MRT) was compared in 14 consecutive patients with RCD: in seven patients who showed loss of T-cell antigens on intraepithelial lymphocytes and/or clonality of the T-cell receptor gene (i. e. type II RCD) and in seven patients who did not have these features (i. e. type I RCD). RESULTS: Complete evaluation of the small bowel by capsule endoscopy was achieved in 9/14 patients. Signs of ulcerative jejunitis or intestinal T-cell lymphoma, affecting further clinical management, were found in two patients with type II RCD: in one patient these signs were found only by capsule endoscopy (ulcerations and stenosis) and in another patient the abnormalities were identified by CT/MRT (mesenteric lymph nodes harboring lymphoma). No clinically relevant abnormalities were found in patients with type I RCD by lower endoscopy or by small-bowel imaging (capsule endoscopy, CT, or MRT). CONCLUSIONS: In patients with type II RCD, capsule endoscopy can detect additional cases with ulcerative jejunitis and could be included in the diagnostic armamentarium, subject to confirmation by larger series. In patients with type I RCD, our study confirmed the low diagnostic yield of imaging procedures, including wireless capsule endoscopy.

[An unusual case of upper GI bleeding: esophageal cancer metastasis at a percutaneous endoscopic gastrostomy site--case report and review of the literature]. / Ungewöhnlicher Fall einer akuten oberen gastrointestinalen Blutung: PEG-Implantationsmetastase eines Osophaguskarzinoms--Fallbericht und Literaturübersicht.

We present the case of a patient with an esophageal squamous cell carcinoma, who was treated primarily by radiotherapy. Due to dysphagia, the patient received a percutaneous endoscopic gastrostomy (PEG) without any sign of tumour at that time. Five months later the patient presented with an upper GI bleeding from a gastric ulcer, which histologically turned out to be a metastasis of the previously diagnosed squamous cell carcinoma. So-called "implantation metastases" at the percutaneous endoscopic gastrostomy site are rare and most of the cases have been described in patients with head and neck tumours. Moreover, the presentation as an upper GI bleed is very uncommon and needs the attention of both endoscopists as well as gastrointestinal oncologists. Clinicopathological features of this case with a brief review of the literature are presented.