[Gastric MALT lymphoma - from pathogenetic insights to consequent deescalation of therapy]. / Gastrale MALT-Lymphome ­ von pathogenetischen Erkenntnissen zu konsequenter Deeskalation der Therapie.

Gastric MALT- (mucosa-associated-lymphoid-tissue) lymphoma represents the most frequent gastrointestinal lymphoma. For decades, surgery and later on radiation and chemotherapy were regarded as established therapy. Some 30 years ago, the pathogenetic role of Helicobacter pylori infection for the development of gastric MALT-lymphoma became evident. During the following years, the pathogenetic insights were consequently implemented into clinical medicine. This lead to a radical change of the therapeutic approach to these lymphoma. Nowadays, Helicobacter pylori eradication is the internationally established therapy of first choice. It is followed by lymphoma regression in most cases. The long-term prognosis of patients after exclusive eradication therapy is excellent, even if endoscopic and/or histological residuals persist and a watch-and-wait strategy is favored.The pathogenetic insights und their clinical application implicated a consequent deescalation of therapy of gastric MALT-lymphoma. This review summarizes the single steps of this development and gives a recommendation for the actual management of patients with gastric MALT lymphoma.

[Appropriateness of Proton pump inhibitor (PPI) recommendation in discharge letters of a gastroenterological department]. / Untersuchung zur indikationsgerechten Empfehlung einer Protonenpumpeninhibitor (PPI)-Medikation in Entlassungsbriefen einer gastroenterologischen Klinik.

BACKGROUND AND STUDY AIMS: Proton pump inhibitors (PPI) are one of the most often prescribed drugs worldwide. They were thought to have a great safety profile before adverse effects in case of long-term medication were discussed recently. Undoubtedly, the use of PPI has to be based on a clear indication. In this retrospective analysis, we investigated the number of patients being discharged from a gastroenterological department with a PPI medication. We also analyzed if this recommendation was based on an established indication and if dose and duration of therapy were correct. PATIENTS AND METHODS: 1612 discharge letters from the period January 1st to June 30th 2011 were evaluated. Patients being discharged with a recommendation of PPI use were assigned to one of four groups: (1) PPI recommendation correct according to guidelines indication, dose and duration of treatment; (2) PPI recommendation correct according to guidelines indication, but with failing or false dose or duration of treatment; (3) PPI recommendation rational but not based on guidelines; (4) Failing indication, wrong recommendation. For a more detailed analysis the patients of group 1 to 4 were then assigned to various subgroups according to comorbidities and concomitant medication. RESULTS: 808 of 1612 discharge letters (50,1%) recommended a PPI use. Assignment to the four groups were as follows: (1) n=344 (42,6%); (2) n=115 (14,2%); (3) n=159 (19,7%); (4) n=190 (23,5%). CONCLUSIONS: At time of discharge, PPI are frequently and partially uncritically recommended. Therefore, there is a need for a more intensive education of training interns and for a more critical review of the discharge letters by senior physicians. Even in case of optimal realization of these needs about 20% of debatable recommendations are not based on current guidelines.

[Helicobacter pylori-New aspects of forthcoming guidelines]. / Helicobacter pylori ­ neue Aspekte kommender Leitlinien.

The diagnostics and treatment of Helicobacter pylori infections are subject to continuous changes and adaptations. Due to the increase of resistance rates to frequently used antibiotics, especially clarithromycin and the lack of new antibacterial substances as well as new developments in the diagnostics, particularly new procedures for resistance testing, the guidelines have to be updated regularly. In this article new directions and trends of the forthcoming European and German guidelines are summarized, categorized and discussed by the authors involved in the compilation of future guidelines.

Acute gastrointestinal bleeding: results from the prospective German electronic registry of nearly 11 000 endoscopies (ALGK GI-bleeding registry).

BACKGROUND AND STUDY AIMS: Gastrointestinal bleeding is frequently observed in the German population. However, recent epidemiological data are not available. This study aimed to elucidate gastrointestinal bleeds under real-life conditions in 3 German hospitals. By using a standardized electronic documentation system, a large number of consecutive endoscopies could be established, thus offering representative data. PATIENTS AND METHODS: From June 2017 to December 2018, all upper and lower gastrointestinal tract endoscopies were recorded consecutively in the 3 hospitals. The electronic documentation system used included a case report form for storing data on bleeding as obligatory input for completion of the endoscopy report. In the case of gastrointestinal bleeding, specific data on the bleeding source and intensity, as well as individual characteristics, were documented. RESULTS: A total of 10 948 consecutive endoscopies were recorded, and 10 904 could be analyzed. Signs of gastrointestinal bleeding were found in 863 patients (7.9 % of all endoscopies performed), 538 patients with an intake of hemostasis-affecting drugs, and 325 patients without (62.3 % and 37.7 %, respectively). Platelet inhibitors and anticoagulants were the most frequently used hemostasis-affecting medication. There was a significant increase in age from patients without bleeding (median 68.5 years) to patients with bleeding (73.5 years) and to patients with bleeding who took hemostasis-affecting medication (80.4 years). Among the patients, 257 (29.8 %) and 606 (70.2 %) presented with major and minor bleeding, respectively. CONCLUSIONS: About 8 % of all patients undergoing upper or lower gastrointestinal endoscopy reveal signs of bleeding. A considerable number are older patients taking hemostasis-affecting drugs.

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.

Renaissance of Radiotherapy in Intestinal Lymphoma? 10-Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow-up of Two German Multicenter Consecutive Prospective Phase II Trials.

PURPOSE: This article reports on the long-term impact of radiotherapy adapted to stage, histology, and previous resection in a large cohort of patients with intestinal lymphoma (iL) treated with definitive or adjuvant curative-intent radiation therapy (RT) ± chemotherapy (CHOP, MCP, or COP). PATIENTS AND METHODS: In two consecutive prospective study designs, 134 patients with indolent (stage IE-IIE) or aggressive (stage IE-IVE) iL were referred to 61 radiotherapeutic institutions between 1992 and 2003. Patients with indolent iL received extended field (EF) 30 Gy (+10 Gy boost in definitive treatment); patients with aggressive iL received involved field (IF) (EF) 40 Gy by means of stage-, histology-, and operation-adapted radiation fields. RESULTS: The patients had median age 58 years and were predominantly male (2:1). Histology showed aggressive prevalence (1.6:1), stage IE-to-stage IIE ratio of iL 1.04:1, and localized stages-to-advanced stages ratio of aggressive lymphoma 23:1. Median follow-up was in total 11.7 years: 10.0 years in the first study, GIT (GastroIntestinal-Tract) 1992, and 11.8 years in the second study, GIT 1996. Lymphoma involvement was predominantly a single intestinal lesion (82.1%). Decrease of radiation field size from EF to IF in stage I aggressive iL from GIT 1992 to GIT 1996 resulted in a nonsignificant partial reduction of chronic toxicity while maintaining comparable survival rates (5-year overall survival 87.9 vs. 86.7%, 10-year overall survival 77.4 vs. 71.5%) with nonsignificant difference in event-free survival (5-year event-free survival 82.6 vs. 86.7%, 10-year event-free survival 69.7 vs. 71.5%) and lymphoma-specific survival (5-year lymphoma-specific survival 90.1 vs. 91.9%, 10-year lymphoma-specific survival 87.6% vs. 91.9%). Comparative dose calculation of two still available indolent duodenal lymphoma computed tomography scans revealed lower radiation exposure to normal tissues from applying current standard involved site RT (ISRT) 30 Gy in both cases. CONCLUSION: RT adapted to stage, histology, and resection in multimodal treatment of iL, despite partially decreasing field size (EF to IF), achieves excellent local tumor control and survival rates. The use of modern RT technique and target volume with ISRT offers the option of further reduction of normal tissue complication probability. IMPLICATIONS FOR PRACTICE: Although patients with intestinal lymphoma (iL) are heterogeneous according to histology and subtype, they benefit from radiotherapy. Prospective study data from 134 patients with indolent iL (stage IE-IIE) or aggressive iL (stage IE-IVE) show 100% tumor control after definitive or adjuvant curative-intent radiation therapy ± chemotherapy. Radiation treatment was applied between 1992 and 2003. Median follow-up in total was 11.7 years. No radiotherapy-associated death occurred. Relapse developed in 15.7% of the entire cohort; distant failure was more frequent than local (4:1). Normal tissue complication probability can be further improved using modern involved site radiation therapy techniques.

[3 unusual courses of gastrointestinal MALT lymphoma]. / 3 ungewöhnliche Verläufe von gastrointestinalen MALT-Lymphomen.

We report on the unusual course of disease in three patients with gastrointestinal MALT lymphoma. Special features are the primary lymphoma manifestation, the high-grade transformation during the follow up, the long-time interval between initially curative intended therapy and relapse and the occurrence of another neoplasia in one case. This demonstrates that despite their good prognosis in general, follow-up investigations of gastrointestinal MALT lymphoma are reasonable.

Acute sedation-associated complications in GI endoscopy (ProSed 2 Study): results from the prospective multicentre electronic registry of sedation-associated complications.

OBJECTIVES: Sedation has been established for GI endoscopic procedures in most countries, but it is also associated with an added risk of complications. Reported complication rates are variable due to different study methodologies and often limited sample size. DESIGNS: Acute sedation-associated complications were prospectively recorded in an electronic endoscopy documentation in 39 study centres between December 2011 and August 2014 (median inclusion period 24 months). The sedation regimen was decided by each study centre. RESULTS: A total of 368 206 endoscopies was recorded; 11% without sedation. Propofol was the dominant drug used (62% only, 22.5% in combination with midazolam). Of the sedated patients, 38 (0.01%) suffered a major complication, and overall mortality was 0.005% (n=15); minor complications occurred in 0.3%. Multivariate analysis showed the following independent risk factors for all complications: American Society of Anesthesiologists class >2 (OR 2.29) and type and duration of endoscopy. Of the sedation regimens, propofol monosedation had the lowest rate (OR 0.75) compared with midazolam (reference) and combinations (OR 1.0-1.5). Compared with primary care hospitals, tertiary referral centres had higher complication rates (OR 1.61). Notably, compared with sedation by a two-person endoscopy team (endoscopist/assistant; 53.5% of all procedures), adding another person for sedation (nurse, physician) was associated with higher complication rates (ORs 1.40-4.46), probably due to higher complexity of procedures not evident in the multivariate analysis. CONCLUSIONS: This large multicentre registry study confirmed that severe acute sedation-related complications are rare during GI endoscopy with a very low mortality. The data are useful for planning risk factor-adapted sedation management to further prevent sedation-associated complications in selected patients. TRIAL REGISTRATION NUMBER: DRKS00007768; Pre-results.

Favorable radiation field decrease in gastric marginal zone lymphoma : Experience of the German Study Group on Gastrointestinal Lymphoma (DSGL).

PURPOSE: Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT). PATIENTS AND METHODS: Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78 radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts. RESULTS: Overall collective with median age of 60 years, slight male predominance (m:f = 1.1:1) and ratio of disease stage I:stage II = 2.1:1. Median follow-up 6.4 years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2 years in the second (GIT 1996) and 4.7 years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stage I, locoregional EF in stage II) achieved the best survival outcome at the 5­year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10 patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival. CONCLUSION: Stage-adapted reduction towards IF in gMZL resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.

Patients with gastric MALT lymphoma revealing persisting endoscopic abnormalities after successful eradication of Helicobacter pylori can be safely managed by a watch-and-wait strategy.

BACKGROUND: In current guidelines, Helicobacter pylori eradication is recommended as first-line therapy in patients with gastric MALT lymphoma. This leads to complete lymphoma regression in the majority of patients. Those who show persisting histological residuals of lymphoma after eradication of the bacterium and normalization of endoscopic findings are managed by a watch-and-wait strategy. We aim to show that such an approach can be extended to patients with persisting endoscopic abnormalities. METHODS: Thirteen patients (7 female and 6 male; 62 years, range: 43 - 80) with gastric MALT lymphoma of stages I and II1 had received exclusive H. pylori eradication. Control endoscopies performed every 3 - 4 months during the first 2 years and 6 and 12 times monthly 2 - 5 and > 5 years after diagnosis, respectively, revealed successful eradication of H. pylori but persisting endoscopic abnormalities. Histologically, complete regression of the lymphoma or minor residuals were observed. RESULTS: Persisting endoscopic changes included thickened folds with or without superficial erosions, nodular mucosal surface with or without angiectasia, focal or diffuse atrophy, focal erythema, or a mixture of these findings. During a follow-up of 89.9 (12 - 329) months, the outcome of these patients was excellent with no single case of lymphoma progression. CONCLUSION: A watch-and-wait strategy can be recommended for patients with gastric MALT lymphoma showing persisting endoscopic abnormalities after eradication of H. pylori. There is no need for any oncological treatment provided that regular endoscopic-bioptic controls do not reveal any progressive changes. A standardized description of the endoscopic changes as well as a thorough bioptic technique should be included.

Colorectal MALT lymphoma: a rare clinical entity.

BACKGROUND: Data on colorectal lymphoma in general and on MALT (mucosa-associated-lymphoid tissue) lymphoma, in particular are, very rare. There are no existing recommendations from current guidelines for how to manage these patients. We here report our experience from a clinical series. AIM: The aim of this study is to present clinical features and the endoscopic appearance of colorectal MALT lymphoma and therapeutic approaches. METHODS: Seven patients (5 male and 2 female, aged 47 - 75 years) were diagnosed to have colorectal MALT lymphoma. All patients underwent a full staging work-up. A concurrent gastric MALT lymphoma was present in 2 patients. Follow-up was 37 (0 - 53) months. RESULTS: Colorectal MALT lymphoma was diagnosed by screening or staging colonoscopy in 3 and 1 patient, revealing no clinical symptoms, respectively. Two patients complained about fatigue, obstipation, and a change in bowel habits. The endoscopic appearance of the MALT lymphoma comprised obstructive tumors (n = 2), polyps (n = 3), a flat lesion (n = 1), and vascular angiectasia (n = 1). In 6 cases, colorectal MALT lymphoma presented as a solitary lesion. Following endoscopic polypectomy, surgical resection, Helicobacter pylori eradication therapy, or systemic immune-chemotherapy, complete remission of lymphoma was achieved in 5 cases, while the outcome is unknown or cannot yet be estimated in 2 cases. CONCLUSION: A treatment and management approach based on the clinical and local presentation of the lymphoma and its involvement is proposed.

[How do primary care physicians manage their patients with Helicobacter pylori infection? Results of a survey and their implementation into the German S2k guideline 2016]. / Wie behandeln Hausärzte ihre Patienten mit einer Helicobacter pylori-Infektion? Ergebnisse einer Umfrage und deren Implementierung in die deutsche S2k-Leitlinie 2016.

Background The German S3 guideline "H. pylori and gastroduodenal ulcer disease" clearly recommends how to diagnose H. pylori infection. It also states when and how eradication therapy should be done. However, there are only few data available on the management of these patients in daily routine. With this survey, we wanted to gather information on how primary care physicians are involved in the management of H. pylori infection and how they follow the guideline recommendations. From this, consequences for the update of the new S2k guideline 2016 and their communication should be derived. Methods A questionnaire with 16 items was sent to all registered primary care physicians in the district of Unterfranken, Germany. Of the 607 questionnaires sent out, 188 (31 %) were returned. Results A test for H. pylori was induced in 76 % of cases with a history of ulcers, 66 % of dyspepsia, 55 % of a family history of gastric cancer, 54 % of unspecific abdominal discomfort, and 9 % and 6 % before initiating NSAID or ASS medication, respectively. Eighty-six percent of the physicians referred their patients to a gastroenterologist for further diagnostics, 45,8 % initiated eradication therapy by themselves, and 75 % and 25 % favored the French and Italian protocol, respectively. The majority did not consider a possible primary resistance to clarithromycine. Twenty-six percent did not regularly control the success of first-line eradication therapy. In case of control, the time intervals after end of eradication treatment are nearly always considered. Second-line therapy is initiated in 99 %, and its success is checked in 87 %. Conclusion Management of patients with H. pylori infection does not always follow the recommendations of current guidelines. The reasons for that were addressed in the formulation of the updated S2k guideline and will be communicated.

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.