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.

Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis.

PURPOSE: In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. METHODS: Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. RESULTS: MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13-3.37, P = 0.63) and 1.44 (95% CI 0.66-3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14-0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89-1.58, P = 0.26). CONCLUSION: Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.

BACKGROUND: Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding. AIM: To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs. METHODS: Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis. RESULTS: Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users. CONCLUSIONS: Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non-aspirin antiplatelet agents. H. pylori-positive patients on combined antiplatelet therapy carry the highest risk for peptic ulcer bleeding.

Predictive Value of Asphericity in Pretherapeutic [111In]DTPA-Octreotide SPECT/CT for Response to Peptide Receptor Radionuclide Therapy with [177Lu]DOTATATE.

PURPOSE: The purpose of this study was to assess the value of the spatial heterogeneity of somatostatin receptor (SSR) volume, quantified as asphericity (ASP), and to predict response to peptide receptor radionuclide therapy (PRRT) in patients with metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). PROCEDURES: From June 2011 to May 2013, patients suffering from GEP-NEN who underwent pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®) prior to [177Lu-DOTA0-Tyr3]octreotate ([177Lu]DOTATATE)-PRRT were enrolled in this retrospective evaluation. SSR expression in 20 NEN patients was qualitatively and quantitatively assessed using the Krenning score, the metastasis to liver uptake ratio (M/L ratio), and ASP at baseline. Response to PRRT was evaluated based on lesions, which were classified as responding lesions (RL) and non-responding lesions (NRL) after 4- and 12-month follow-ups. The values of the Krenning score, M/L ratio, and ASP for response prediction were compared by using the Mann-Whitney U test, Kruskal-Wallis test, and receiver operating characteristic (ROC) curves. RESULTS: Seventy-seven metastases (liver, n = 40; lymph node, n = 24; bone, n = 11; pancreas, n = 2) showed SSR expression. A higher ASP level was significantly associated with poorer response at both time points. ROC analyses revealed the highest area under the curve (AUC) for discrimination between RL and NRL for ASP after 4 months (AUC 0.97; p = 0.019) and after 12 months (AUC 0.96; p < 0.001), followed by the Krenning score (AUC 0.74; p = 0.082 and AUC 0.85; p < 0.001, respectively) and M/L ratio (AUC 0.77; p = 0.107 and AUC 0.82; p < 0.001). The optimal cutoff value for ASP was 5.12 % (sensitivity, 90 %; specificity, 93 %). CONCLUSION: Asphericity of SSR-expressing lesions in pretherapeutic single-photon emission computed tomography with integrated computed tomography (SPECT/CT) is a promising parameter for predicting response to PRRT in gastroenteropancreatic neuroendocrine neoplasms.

Leukotriene receptor expression in esophageal squamous cell cancer and non-transformed esophageal epithelium: a matched case control study.

BACKGROUND: Leukotriene B4 (LTB4R and LTB4R2) and cysteinyl leukotriene receptors (CYSLTR1 and CYSLTR2) contribute to malignant cell transformation. We aimed to investigate the expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 in esophageal squamous cell carcinoma and adjacent non-transformed squamous epithelium of the esophagus, as well as in control biopsy samples from esophageal squamous epithelium of patients with functional dyspepsia. METHODS: Expression of LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 was analyzed by immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in biopsy samples of 19 patients with esophageal squamous cell cancer and 9 sex- and age-matched patients with functional dyspepsia. RESULTS: LTB4R, LTB4R2, CYSLTR1 and CYSLTR2 were expressed in all biopsy samples. Major findings were: 1) protein levels of all leukotriene receptors were significantly increased in esophageal squamous cell cancer compared to control mucosa (p < 0.05); 2) CYSLTR1 and CYSLTR2 gene expression was decreased in cancer tissue compared to control at 0.26-fold and 0.23-fold respectively; 3) an up-regulation of LTB4R (mRNA and protein expression) and a down-regulation of CYSLTR2 (mRNA expression) in non-transformed epithelium of cancer patients compared to control (p < 0.05) was observed. CONCLUSIONS: The expression of leukotriene receptors was deregulated in esophageal squamous cell cancer. Up-regulation of LTB4R and down-regulation of CYSLTR2 gene expression may occur already in normal squamous esophageal epithelium of patients with esophageal cancer suggesting a potential role of these receptors in early steps of esophageal carcinogenesis. Larger studies are warranted to confirm these observations.

[Sealing of the hepatic resection area using hemostat devices does not improve results of adequate surgery]. / Versiegelung der Leberresektionsfläche mit Gewebsklebematerialien bewirkt keine weitere Verbesserung adäquater Chirurgie.

PURPOSE: In hepatic resections, there has been a high quality demand. The aim of this systematic clinical, prospective, unblinded unicenter observational study with two arms in an unselected patient cohort was to investigate whether hemostat device can significantly improve outcome in resective liver surgery, in particular, in high risk patients. METHODS: All consecutive patients (mean age, 60.5 [range, 17 - 96] years) who underwent hepatic resection (ntotal = 770) were prospectively documented in a computer-based registry at a university hospital (tertiary center) over a time period of 10 years and retrospectively evaluated specifically with regard to the use (-/+; in daily practice and intraoperative decision-making) of hemostat device (Tissucol(®), n = 59/Tachocomb(®), n = 202/combination, n = 55) indicated (among others) by drainage volume, inflammatory parameters and rate of specific complications (nvalidated = 541 [100 %]). RESULTS: Most frequently, (a-)/typical segmental resections were used: n = 192/90 (3-segment resection, only n = 38). 1) For the assignment of patients to the two different groups (-/+ hemostat device), weight loss and type of resection were found as significant factors (trend: ASA, cirrhosis), for the amount of drainage volume, ASA, sex, Karnofsky Performance Scale and also type of resections using independent distributed statistical tests (such as χ(2), U test [Mann/Whitney]; H test [Kruskal-Willis]; correlation coefficient by Spearman) - no impact: smoking, diabetes, BMI, ethanol. 2) Not taking into account these parameters, the use of hemostat device was characterized by an increased drainage volume (negative control < Tissucol = Tachocomb < combination). 3) Using multifactorial analysis of variance, it was found even under correction by the factors with significant impact elucidated in the single test that the application of hemostat device onto the hepatic resection area resulted unexpectedly rather in an increase than a decrease of the drainage volume but 4) under accompanying more pronounced increase of the white blood cell count (leucocytosis). 5) General and specific complications such as postoperative bleeding, biliary fistula and subhepatic abscess were not further lowered in a significant manner using hemostat device. CONCLUSION: Adequate surgery in the operative management of hepatic resection area cannot further be improved or optimized using hemostat device. In this context, drainage volume may not be considered a sufficient rather an orienting parameter. However, there is an inflammatory response detectable most likely indicated by a(n un-)specific effusion and increase of white blood cell count, which can be interpreted as a) being characteristic for the problematic group of patients, in whom hemostat device was decided to be useful and was finally used in daily prectice, or b) reactive inflammation to foreign material.

[S2k-guideline Helicobacter pylori and gastroduodenal ulcer disease]. / S2k-Leitlinie Helicobacter pylori und gastroduodenale Ulkuskrankheit.

In the line "bismuth-containing quadruple therapy" of Table 7 (p 342), in the column "dosage" incorrectly at the three antibiotics respectively 1-1-1-1. The correct is: 3-3-3-3.

Helicobacter pylori infection is associated with a reduced risk of developing eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) represents a chronic immune-antigen-mediated allergic disease of the oesophagus of still unknown aetiology. Environmental exposure has been postulated to play a pathogenetic role. Helicobacter pylori (H. pylori) infection has been inversely associated with allergic diseases including atopic dermatitis, asthma and allergic rhinitis and H. pylori may play a protective role in these conditions. Little is known about the relationship between EoE and H. pylori. AIM: To investigate in a case-control study whether H. pylori infection is associated with a reduced risk of developing EoE. METHODS: H. pylori infection was evaluated by serology in 58 [11(19%) female, 47 (81%) male, median age: 36.5 years, range 20-72 years] patients with a clinical and histologically proven diagnosis of EoE and 116 age and sex-matched controls (1 case: 2 controls). Antibodies against H. pylori were identified by enzyme-linked immunosorbent assay. Patients with H. pylori-specific IgG ≥ 30 enzyme immunounits were classified as H. pylori-positive. RESULTS: 3/58 (5.2%) patients with EoE had serological evidence of H. pylori infection (EoE - H. pylori current infection) and 5/58 (8.6%) reported prior eradication therapy for H. pylori infection (EoE - H. pylori former infection). The control group demonstrated significantly higher seroprevalence of H. pylori (37.9%, P < 0.0001) when compared to patients with EoE. EoE was inversely associated with H. pylori infection [odds ratio (OR) 0.24, 95% confidence interval (CI) 0.11-0.50]. CONCLUSION: Helicobacter pylori infection is inversely associated with EoE. Our results may contribute to further understanding the pathogenesis and evolving aetiology of EoE.

Autoimmune gastritis in autoimmune thyroid disease.

BACKGROUND: Autoimmune gastritis leads to oxyntic gastric atrophy, a condition at increased risk for gastric cancer. Autoimmune gastritis in conjunction with autoimmune thyroid disease has been reported previously. AIM: In a case-control study in patients with autoimmune thyroid disease to evaluate the usefulness of serum pepsinogens for the identification of oxyntic gastric atrophy, and to determine the relationship of Helicobacter pylori with oxyntic gastric atrophy. METHODS: Patients with autoimmune thyroid disease (cases) and goitre (controls) were prospectively enrolled in the study. Pepsinogen (PG) I levels ≤25 µg/mL and PG I/II ratio ≤3 were indicative for oxyntic gastric atrophy. Antibodies against H. pylori, CagA and parietal cells were also determined. Esophagogastroduodenoscopy with biopsies was offered to patients with serological oxyntic gastric atrophy. RESULTS: In total, 34 autoimmune thyroid disease patients and 30 controls were enrolled. Serological oxyntic gastric atrophy was present only in autoimmune thyroid disease patients (8/34, 23.5%, OR 8.3, 95% CI = 1.9-36.2). In all eight patients oxyntic gastric atrophy was confirmed by histology. OLGA stage I, II, III and IV was described in 0%, 33%, 50% and 17% of the cases, respectively. About, 89% and 11% of oxyntic gastric atrophy patients were seropositive for antibodies against parietal cells or H. pylori infection, respectively. Gastric atrophy involved the angulus/antrum in 50% of patients with autoimmune gastritis. CONCLUSIONS: The seroprevalence of oxyntic gastric atrophy is high in patients with autoimmune thyroid disease, and testing of serum pepsinogens should be included in the clinical assessment of these patients. H. pylori infection is unlikely to be a principal factor in the pathogenesis of oxyntic gastric atrophy in patients with autoimmune thyroid disease. In autoimmune gastritis, gastric atrophy can spread from the oxyntic towards the antral mucosa.

Helicobacter pylori related and non-related lesions in the stomach.

Gastric lesions may arise in gastric mucosa of patients with gastritis or gastropathies due to different etiopathogenic factors. As most lesions of the stomach result from a chronic infection of gastric mucosa with Helicobacter pylori (H. pylori), a possible classification of gastric lesions based on etiology may distinguish H. pylori-related lesions from those arising in a gastric mucosa not colonized from the bacterium. The repertoire of lesions one may find in the stomach is limited and different pathologies may present with a similar macroscopic aspect. Clinically relevant lesions of the stomach that are or are not associated with H. pylori infection include gastric ulcer, gastric atrophy, gastric neoplasia, and metastasis from other cancers. The detection or exclusion of an H. pylori infection in patients with gastric lesions has important consequences for the clinical management. In the present review we focus on H. pylori-related and non-related peptic lesions in the stomach.

[Dilemma between gastroprotection and cardiovascular prevention]. / Dilemma zwischen Magenschutz und Kardioprotektion.

Long-term low-dose aspirin intake leads to a 2 - 4-fold risk of risk for upper gastrointestinal bleeding. The additional intake of clopidogrel further increases the risk of upper GI bleeding (OR 7.4). Because of the potential interaction between proton pump inhibitors (PPI) and clopidogrel that compromises the efficacy of clopidogrel on platelet aggregation, there has been a warning in the product information by health authorities in the US and in Europe who discourage the concomitant use of PPI and clopidogrel. In the present study we performed a selected review of the published literature on the indications for gastric protection with PPI in patients on mono- or dual antiplatelet therapy focussing on the possible interaction between clopidogrel and PPI. In ex vivo analyses of platelet function, a reduced efficacy of clopidogrel was observed in patients on comedication with omeprazole. This was not the case with the comedication of other PPIs. To date, clear evidence is missing to state that comedication with PPI reduces the efficacy of clopidogrel IN VIVO. If both Clopidogrel and PPI need to be prescribed, a split dosage regimen of PPI in the morning and clopidogrel in the evening can be recommended. The short half-life of both medications explains the rationale of this recommendation.

[Non steroidal anti-inflammatory drugs (NSAIDs) - balancing gastrointestinal complications and the cardiovascular risk]. / Nichtsteroidale Antirheumatika (NSAR) - an der Schnittstelle gastrointestinaler Nebenwirkungen und kardiovaskulärer Risiken.

Because of their anti-inflammatory, analgesic and antipyretic properties non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed throughout all medical fields. Both gastrointestinal as well as cerebro- and cardiovascular risk needs to be considered. Especially before starting a long-term medical treatment with NSAIDs the individual gastrointestinal and cardiovascular risk of the patient has to be assessed carefully.

Feasibility of double-balloon enteroscopy-assisted chromoendoscopy of the small bowel in patients with familial adenomatous polyposis.

BACKGROUND AND STUDY AIMS: Patients with familial adenomatous polyposis (FAP) are at increased risk of developing duodenal and jejunal adenocarcinomas. The aim of this study was to assess the usefulness of double-balloon enteroscopy- (DBE-) assisted chromoendoscopy for the detection and characterization of small-bowel polyps in patients with FAP. PATIENTS AND METHODS: We performed a prospective evaluation of patients with clinically and genetically proved FAP who were enrolled in an endoscopic surveillance program. DBE was performed using a Fujinon intestinoscope (FN 450P 5/20; Fujinon Corp., Omiya, Japan), and chromoendoscopy was performed using indigo carmine. The severity of small bowel polyposis was based on the Spigelman-Saurin classification. RESULTS: Nine patients underwent DBE-assisted chromoendoscopy. Small-bowel polyps (including papillary adenomas) were detected in seven patients (88 %). The mean depth of small-bowel insertion was 180 cm (range 120-320 cm). The mean Spigelman-Saurin score was 4.6 (range 0-8). Jejunal polyps were detected in six patients (67 %). Chromoendoscopy aided in the detection of additional polyps in two patients. In one patient the polyps were flat and only visible with chromoendoscopy (biopsy confirmed these to be adenomas). Jejunal polyps and advanced neoplasms were more frequent in patients with APC gene mutations in exon 15. The following endoscopic therapies were performed: polypectomy (n = 1), duodenal mucosectomy (n = 1), and ablation therapy with argon plasma coagulation (n = 2). CONCLUSIONS: DBE was found to be a helpful method for the evaluation of small-bowel polyps in patients with FAP. DBE-assisted chromoendoscopy was of further assistance for the detection of jejunal polyps.

Effects of low-dose aspirin on gastric erosions, cyclooxygenase expression and mucosal prostaglandin-E2 do not depend on Helicobacter pylori infection.

BACKGROUND: The mechanisms by which Helicobacter pylori and low-dose aspirin induce gastric damage are not completely elucidated. AIM: To evaluate the effects of low-dose aspirin on gastric damage, mucosal prostaglandin-E(2) levels and cyclooxygenase-enzyme expression in relation to the H. pylori status. METHODS: Twenty healthy volunteers (H. pylori positive, n = 10; H. pylori negative, n = 10) received aspirin 100 mg/die for 1 week. At days 0, 1, 3 and 7, gastric mucosal lesions were studied by oesophagogastroduodenoscopy and histology. COX-1 and COX-2 were determined by immunohistochemistry and reverse-transcriptase polymerase chain reaction, and mucosal prostaglandin-E(2) levels by enzyme-linked immunosorbent assay. Nine H. pylori-positive subjects repeated the protocol after H. pylori eradication. RESULTS: All groups developed a similar number of erosions. COX-1 and COX-2 expression, as well as mucosal prostaglandin-E(2) levels were not influenced by H. pylori status and aspirin medication. Helicobacter pylori-negative and H. pylori-eradicated subjects who developed aspirin-induced erosions had significant lower pre-treatment antral prostaglandin-E(2) levels than those without erosions (3.6 ng/microg vs. 6.3 ng/microg protein and 3.6 ng/microg vs. 6.0 ng/microg protein, respectively, P < 0.01 Mann-Whitney U-test). CONCLUSIONS: In healthy subjects, low-dose aspirin for 1 week does neither affect cyclooxygenase expression nor mucosal prostaglandin-E(2) levels. Antral prostaglandin-E(2)-basal levels appear to be critical for development of aspirin-induced gastric damage in subjects without H. pylori infection.