Wolfgang Fischbach

Complete Remission of Primary High-Grade B-Cell Gastric Lymphoma After Cure of Helicobacter pylori Infection

PURPOSE Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases. The effect that cure of the infection has on the course of a primary high-grade gastric lymphoma is largely uncertain. The aim of this study was to report the effect of cure of H pylori infection exerted in patients with high-grade B-cell gastric lymphoma. PATIENTS AND METHODS Eight patients (4 males and 4 females; age range, 26 to 85 years) with H pylori infection and high-grade lymphoma received eradication therapy before planned treatment. The effect of H pylori eradication on the course of high-grade lymphoma was assessed by analysis of surgical specimens (n = 2) or endoscopic biopsies (n = 6). RESULTS H pylori eradication was successful in all patients and led to complete remission of the lymphoma in seven patients. One patient has experienced partial remission. Two patients were referred to surgery, one of whom (stage II(1E)) had lymph node involvement, and the histologic work-up of the resected stomach revealed residual infiltrates of a low-grade lymphoma, which prompted consolidation chemotherapy. In one patient (initially stage I(1E)), abdominal lymphoma developed 6 months after eradication therapy, which regressed completely after chemotherapy. In four patients, no further treatment was given. Six patients continue in complete remission (range, 6 to 66 months). CONCLUSION Primary high-grade B-cell gastric lymphoma in stages I(E) through II(E1) associated with H pylori may regress completely after successful cure of the infection. Prospective trials are needed to investigate this treatment in larger numbers of patients.

Primary Follicular Lymphoma of the Duodenum Is a Distinct Mucosal/Submucosal Variant of Follicular Lymphoma: A Retrospective Study of 63 Cases

PURPOSE Small series with limited follow-up have suggested primary follicular lymphoma of the duodenum (FL-D) to be an indolent disease. We report our experience on a large series of patients followed for a median time period of longer than 6 years. PATIENTS AND METHODS The study comprised 63 patients with primary FL-D defined as stage I disease. Endoscopy and detailed pathologic work-up was performed at diagnosis and at restaging to monitor the behavior of the neoplastic process. RESULTS Histologically, all 63 patients had FL, low grade (1 to 2). Duodenal endosonography demonstrated lesions confined to mucosa/submucosa in 19 of 20 patients. At an overall median follow-up of 77 months (range, 12 to 177 months), only two untreated patients had developed nodal disease, the remaining 61 patients never experienced extrasmall intestinal disease and large cell transformation did not occur at all. Among 24 patients followed by watch and wait strategy, seven showed spontaneous complete regression and 17 had stable disease; radiotherapy resulted in complete regression in all 19 patients; anti-CD20 antibody monotherapy achieved complete regression in four patients and stable disease in one patient. Various chemotherapy protocols in eight patients caused complete regression in all of them, but local relapses occurred in three. No patients required surgery or died of disease. CONCLUSION These findings characterize primary FL-D as a remarkably indolent FL variant, which, even left untreated, does not develop tumorous growth, very rarely disseminates (two of 63 patients) and does not transform to high grade disease. A watch and wait approach appears to be the most sensible strategy.

Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab

Dear Editor, Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an arteriovenous malformation of various organs and systems due to fibrovascular dysplasia. This results in recurrent and sometimes severe bleeding, of which epistaxis is the most common. Hepatic arteriovenous malformations may cause arteriovenous shunting within the liver, ischemic hepatobiliary damage, and high-output cardiac failure [1]. A 73-year-old man whose 2 brothers and 18 of 31 relatives also suffer from HHT was treated over the previous years with multiple blood transfusions for occult gastrointestinal hemorrhage but remained consistently anemic (hemoglobin level of 60 g/l). Since the last 3 years the patient also suffered from a malignant mesothelioma and therefore received six courses of chemotherapy with cisplatin/gemcitabine from March to October 2004, leading to disease stabilization. Due to disease progression, he was treated with four courses of FOLFOX4 (oxaliplatin, leucovorin, and fluorouracil) from March to June 2005 and ten courses of doxorubicin until November 2005. Due to new progression of the disease, we decided to apply pemetrexed (500 mg/m, q 3 weeks) and bevacizumab (5 mg/kg, q 2 weeks); the latter is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) and is thought to be an active drug for malignant mesothelioma [2]. Because it was suggested that increased production of VEGF is responsible for HHT [3], we also wanted to evaluate the effect of bevacizumab in transfusion frequency. The patient was treated exclusively at our institution, receiving frequent endoscopies of the upper and lower gastrointestinal tract and repeated small bowel examinations. Multiple argon beamer coagulations in the last months due to vascular malformations in the upper gastrointestinal tract were applied. As can be seen in Fig. 1 there was a dramatic decrease in transfusion frequency and improvement of hemoglobin concentration immediately after treatment with bevacizumab. Before the onset of treatment, we diagnosed multiple arteriovenous shunts in the liver by selective coeliacography. Increased cardiac output, as assessed by echocardiography, decreased from 7,800 ml/ min to 6,900 ml/min after five courses of bevacizumab. Moreover, the patient’s performance status significantly improved. In the first staging after three courses of pemetrexed and six courses of bevacizumab, there was no progression of malignant mesothelioma as assessed by computed tomography. This is the first report showing that a targeted therapy directed against VEGF has a dramatic impact on the bleeding episodes of a patient with HHT. A clinical trial with bevacizumab for patients with severe HHT is warranted. D. Flieger . S. Hainke . W. Fischbach Department of Internal Medicine II, Klinikum Aschaffenburg, Am Hasenkopf 1, Aschaffenburg, 63739, Germany

Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial

BACKGROUND Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection. METHODS In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m2 on day 1, intravenous cisplatin 60 mg/m2 on day 1, and either fluorouracil 200 mg/m2 as continuous intravenous infusion or capecitabine 1250 mg/m2 orally (two doses of 625 mg/m2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m2, intravenous oxaliplatin 85 mg/m2, intravenous leucovorin 200 mg/m2, and fluorouracil 2600 mg/m2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%]). INTERPRETATION Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma. FUNDING None.

Malignant lymphomas of the upper gastrointestinal tract. Results of a prospective study in 103 patients

Background. There is a discrepancy between the incidence of gastrointestinal involvement by malignant lymphomas, as established in postmortem studies, and the rareness of the corresponding clinical diagnosis.

Role of Pancreatic Enzymes and Their Substrates in Autodigestion of the Pancreas: In Vitro Studies With Isolated Rat Pancreatic Acini+++

Intrapancreatic activation of proteases is believed to play a major role in the pathogenesis of acute necrotizing pancreatitis. Several authors have questioned, however, the central role of trypsin in autodigestion of the pancreas. To clarify the direct effects of pancreatic enzymes and other related factors on acinar cells, we used the model of isolated pancreatic acini. Acini were prepared from male Wistar rats by collagenase digestion. Protein synthesis was measured by incubation of acini with [ 35 S]methionine. Acini were resuspended thereafter in fresh buffer and further incubated for 30–90 min under various conditions [e.g., with pancreatic homogenates, ascites (from rats with pancreatitis induced by sodium taurocholate), pure pancreatic enzymes, and other factors]. The percentage of release of newly synthesized proteins into the culture medium was regarded as a biochemical parameter of cellular integrity. A morphologic score of cellular integrity was obtained via light microscopic evaluation of acini at the end of the various incubations by measuring the degree of cell lysis, loss of cell granules, ballooning, formation of vacuoles, and karyopyknosis. When normal [31S]methionine-labeled pancreatic acini were incubated with various factors, the percentage of release of labeled proteins into the medium was as follows: incubation with HEPES/Ringers buffer, 1.8%; hemorrhagic pancreatic ascites, 3.8%; pancreatic homogenates, 2.0%; lipase, 1.8%; phospholipase A 2 , 3.0%; phospholipase A 2 + lecithin, 3.2%; trypsin, 2.5%; 5% olive oil, 1.8%; ascites + olive oil, 78.3%; ascites + homogenized epididymal fat, 79.9%; lipase + olive oil, 32.0%; pancreatic homogenates + olive oil, 28.0%; diolein, 2.65%; and oleic acid, 62.9%. The cellular release of radiolabeled proteins showed an inverse correlation with cellular integrity as shown by light microscopy. We postulate that interstitial release of degradation products from triglycerides by lipase causes cellular disruption. Whereas phospholipase A 2 and proteases do not seem to be very harmful in the early phases of cellular damage, lipase may play a major role in acute necrotizing pancreatitis.

Minimal residual low-grade gastric MALT-type lymphoma after eradication of Helicobacter pylori

Helicobacter pylori eradication is the initial treatment of choice in localised low-grade gastric MALT (mucosa-associated lymphoid-tissue)-type lymphoma. We describe the natural course of seven patients who refused further oncological treatment for persistent lymphoma after successful eradication of H pylori. Despite persistent clonality, neither lymphoma progression nor high-grade transformation arose during a mean observation period of 34 (range 22-44) months. In view of the favourable course of these patients, a watch-and-wait strategy could be a valid approach to management of this disease.

S3-guideline "Helicobacter pylori and gastroduodenal ulcer disease".

This guideline updates a prior concensus recommendation of the German Society for Digestive and Metabolic Diseases (DGVS) from 1996. It was developed by an interdisciplinary cooperation with representatives of the German Society for Microbiology, the Society for Pediatric Gastroenterology and Nutrition (GPGE) and the German Society for Rheumatology. The guideline is methodologically based on recommendations of the Association of the Scientific Medical Societies in Germany (AWMF) for providing a systematic evidence-based consensus guideline of S 3 level and has also implemented grading criteria according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Clinical applicability of study results as well as specifics for Germany in terms of epidemiology, antibiotic resistance status, diagnostics and therapy were taken into account.

Association study of a functional Toll-like receptor 4 polymorphism with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma.

Toll-like receptor 4, as part of innate immune response, is the main receptor for lipopolysaccharide on marginal zone B cells. The rare allele of TLR4 Asp299Gly attenuates receptor signaling and diminishes the inflammatory response. We genotyped 87 patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, 594 Helicobacter pylori positive controls and 358 healthy blood donors to investigate an association of TLR4 Asp299Gly in the development of gastric MALT lymphoma. Heterozygote genotype was significantly less frequent in patients with gastric MALT lymphoma compared to H. pylori-infected controls (4.6% vs. 11.6%, Fischers exact P=0.019, odds ratio=0.37, 95% confidence interval 0.13-1.03). Because 10% of caucasians are carriers of the rare allele G TLR4 Asp299Gly appears to be only one factor in the genetic susceptibility to gastric lymphoma. Further studies in larger samples are needed to confirm our findings and fully elucidate the role of TLR4 and its genetic variants in the pathophysiology of H. pylori infection and gastric lymphoma.

Differences in endoscopic and clinicopathological features of primary and secondary gastric non-Hodgkin's lymphoma ☆ ☆☆ ★ ★★

BACKGROUND Lymphomatous neoplasia of the stomach is initially seen either as primary gastric B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) or as nodal non-Hodgkin s lymphoma (NHL) secondarily involving the GI tract. One hundred seventy-six patients with primary gastric NHL (low grade, n = 65; high grade, n = 111) and 29 with secondary gastric NHL (low grade, n = 19; high grade, n = 10) were studied to evaluate whether differences in pathogenesis are associated with distinct clinical and endoscopic features. METHODS Clinical features, tumor size, localization, and growth pattern were analyzed by means of esophagogastroduodenoscopy; grading was determined with histologic examination. RESULTS The analysis of various clinical symptoms and endoscopic findings revealed a relationship between the occurrence of abdominal pain, vomiting, and unifocal growth pattern with an affiliation to the group with primary gastric NHL (p < 0.001), whereas tumor localization in the gastric fundus was predominantly found in secondary gastric NHL (p < 0.001). An equation has been generated that may help to predict affiliation to primary or secondary gastric NHL with an accuracy of 96%. CONCLUSIONS Our results indicate that careful pretreatment analysis of clinical and endoscopic findings may be helpful in the diagnosis of primary or secondary gastric involvement by NHL, although reliable discrimination still requires histologic verification.