Summary Background Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Methods This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. Findings From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10–39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. Interpretation In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. Funding Merck & Co.

https://thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(16)00175-3.pdf

Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.

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Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED)

BACKGROUND & AIMS
A cascade of precursor lesions (eg, atrophic gastritis, intestinal metaplasia, and dysplasia) precedes most gastric adenocarcinomas. Quantification of gastric cancer risk in patients with premalignant gastric lesions is unclear, however. Consequently, endoscopic surveillance is controversial, especially in Western populations.


METHODS
To analyze current surveillance practice and gastric cancer risk in patients with premalignant gastric lesions, all patients with a first diagnosis between 1991 and 2004 were identified in the Dutch nationwide histopathology registry (PALGA); follow-up data were evaluated until December 2005.


RESULTS
In total, 22,365 (24%) patients were diagnosed with atrophic gastritis, 61,707 (67%) with intestinal metaplasia, 7616 (8%) with mild-to-moderate dysplasia, and 562 (0.6%) with severe dysplasia. Patients with a diagnosis of atrophic gastritis, intestinal metaplasia, or mild-to-moderate dysplasia received re-evaluation in 26%, 28%, and 38% of cases, respectively, compared with 61% after a diagnosis of severe dysplasia (P < .001). The annual incidence of gastric cancer was 0.1% for patients with atrophic gastritis, 0.25% for intestinal metaplasia, 0.6% for mild-to-moderate dysplasia, and 6% for severe dysplasia within 5 years after diagnosis. Risk factors for gastric cancer development were increasing severity of premalignant gastric lesions at initial diagnosis (eg, severe dysplasia, hazard ratio 40.14, 95% confidence interval 32.2-50.1), increased age (eg, 75-84 years, hazard ratio 3.75, 95% confidence interval 2.8-5.1), and male gender (hazard ratio 1.50, 95% CI 1.3-1.7).


CONCLUSIONS
Patients with premalignant gastric lesions are at considerable risk of gastric cancer. As current surveillance of these patients is inconsistent with their cancer risk, development of guidelines is indicated.

Gastric cancer risk in patients with premalignant gastric lesions

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy, the European Helicobacter Study Group, the European Society of Pathology, and the Sociedade Portuguesa de Endoscopia Digestiva have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach. A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia and the need for adequate staging in the case of high-grade dysplasia, and they focus on treatment and surveillance indications and methods.

/pdf/management-of-precancerous-conditions-and-lesions-in-the-28d5wxyibk.pdf

Authors M. Moehler, S.-E. Al-Batran, T. Andus, M. Anthuber, J. Arends, D. Arnold, D. Aust, P. Baier, G. Baretton, J. Bernhardt, H. Boeing, E. Böhle, C. Bokemeyer, J. Bornschein, W. Budach, E. Burmester, K. Caca, W. A. Diemer, C. F. Dietrich, M. Ebert, A. Eickhoff, C. Ell, J. Fahlke, H. Feußner, R. Fietkau, W. Fischbach, W. Fleig, M. Flentje, H. E. Gabbert, P. R. Galle, M. Geissler, I. Gockel, U. Graeven, L. Grenacher, S. Groß, J. T. Hartmann, M. Heike, V. Heinemann, B. Herbst, T. Herrmann, S. Höcht, R. D. Hofheinz, H. Höfler, T. Höhler, A. H. Hölscher, M. Horneber, J. Hübner, J. R. Izbicki, R. Jakobs, C. Jenssen, S. Kanzler , M. Keller, R. Kiesslich, G. Klautke, J. Körber, B. J. Krause, C. Kuhn, F. Kullmann, H. Lang, H. Link, F. Lordick, K. Ludwig, M. Lutz, R. Mahlberg, P. Malfertheiner, S. Merkel, H. Messmann, H.-J. Meyer, S. Mönig, P. Piso, S. Pistorius, R. Porschen, T. Rabenstein, P. Reichardt, K. Ridwelski, C. Röcken, I. Roetzer, P. Rohr, W. Schepp, P. M. Schlag, R. M. Schmid, H. Schmidberger, W.-H. Schmiegel, H.-J. Schmoll, G. Schuch, C. Schuhmacher, K. Schütte, W. Schwenk, M. Selgrad, A. Sendler, J. Seraphin, T. Seufferlein, M. Stahl, H. Stein, C. Stoll, M. Stuschke, A. Tannapfel, R. Tholen, P. Thuss-Patience, K. Treml, U. Vanhoefer, M. Vieth, H. Vogelsang, D. Wagner, U. Wedding, A. Weimann, H. Wilke, C. Wittekind und die Mitglieder der Autorengruppe

[German S3-Guideline "Diagnosis and Treatment of Esophagogastric Cancer"]

Gastric cancer continues to be an important healthcare problem from a global perspective. Most of the cases in the Western world are diagnosed at late stages when the treatment is largely ineffective. Helicobacter pylori (H. pylori) infection is a well-established carcinogen for gastric cancer. While lifestyle factors are important, the efficacy of interventions in their modification, as in the use of antioxidant supplements, is unconvincing. No organized screening programs can be found outside Asia (Japan and South Korea). Although several screening approaches have been proposed, including indirect atrophy detection by measuring pepsinogen in the circulation, none of them have so far been implemented, and more study data is required to justify any implementation. Mass eradication of H. pylori in high-risk areas tends to be cost-effective, but its adverse effects and resistance remain a concern. Searches for new screening biomarkers, including microRNA and cancer-autoantibody panels, as well as detection of volatile organic compounds in the breath, are in progress. Endoscopy with a proper biopsy follow-up remains the standard for early detection of cancer and related premalignant lesions. At the same time, new advanced high-resolution endoscopic technologies are showing promising results with respect to diagnosing mucosal lesions visually and targeting each biopsy. New histological risk stratifications (classifications), including OLGA and OLGIM, have recently been developed. This review addresses the current means for gastric cancer primary and secondary prevention, the available and emerging methods for screening, and new developments in endoscopic detection of early lesions of the stomach.

Gastric cancer: prevention, screening and early diagnosis.

Objective. Helicobacter pylori-associated atrophic gastritis is known to be a significant risk factor for gastric cancer. Among the well-known parameters of atrophic gastritis are the levels of serum gastrin-17 (G-17) and pepsinogen I (PG1), which are biomarkers of gastric antral and corpus mucosal activity, respectively. The aim of study was to compare the production of G-17 and PG1 in patients with or without stomach mucosal atrophy and to investigate the utility of serum PG1 and/or G-17 concentrations for the objective evaluation of atrophic gastritis. Material and methods. . A total of 178 dyspeptic Helicobacter pylori-positive patients underwent diagnostic upper gastrointestinal endoscopy with biopsy. The degree of histologic gastric mucosal atrophy was compared with the fasting levels of PG1, and to the postprandial levels of G-17 detected by enzyme immunoassay. Results. . A decrease in serum G-17 levels along with worsening of the antral atrophy was observed; the serum levels of PG1 were reduced du...

Invasive and non-invasive diagnosis of Helicobacter pylori-associated atrophic gastritis: A comparative study

AIM: To assess the possibility of non-invasive screening of atrophic chronic gastritis for preventing further development of gastric cancer.

METHODS: One hundred and seventy-eight consecutive Helicobacter pylori (H pylori)-positive dyspeptic patients after detection of serum levels of pepsinogen-1 (PG-1) and gastrin-17 (G-17) by enzyme immunoassay were proposed for endoscopy and histology. The serologic and morphologic results were compared with estimating the sensitivity, specificity and prognostic values of the tests.

RESULTS: There was statistically significant reverse dependence between the grade of stomach mucosal antral or corpus atrophy and the proper decreasing of serum G17 or PG1 levels. The serologic method was quite sensitive in the diagnosis of non-atrophic and severe antral and corpus gastritis. Also, it was characterized by the high positive and negative prognostic values.

CONCLUSION: Detection of serum G-17 and PG1 levels can be offered as the screening tool for atrophic gastritis. The positive serologic results require further chromoendoscopy with mucosal biopsy, for revealing probable progressing of atrophic process with development of intestinal metaplasia, dysplasia or gastric cancer.

Possibility of non-invasive diagnosis of gastric mucosal precancerous changes.

Background. Saving lives and preventing patients from dropping out of the waiting list for liver transplantation due to the progression of portal hypertension and the development of complications is an urgent task of transplantology in conditions of a donor organ shortage, which causes long waiting times for this operation. Aim. To study the efficacy of endoscopic band ligation versus no intervention in the primary prevention of upper gastrointestinal bleeding and assess the impact on survival of patients with ascites listed in the liver transplantation waiting list. Material and methods. A retrospective comparative study was conducted in patients with decompensated liver diseases with severe ascites and varicose veins, without a history of bleeding, when included in the waiting list for liver transplantation. Primary prevention of bleeding from varices was carried out in patients by means of endoscopic ligation of varicose veins (n=92, group 1); this intervention was not performed in other patients (n=89, group 2). Results. The compared groups were comparable in demographics, clinical parameters, MELD and Child-TurcottePugh scores, or the incidence of severe ascites. The study groups of patients did not have significant differences in the numbers of medium-size and large varices. The incidence of bleeding was significantly lower in the group of patients with endoscopic band ligation as a method of primary prevention than in the group of patients without this intervention (23.9% and 78.7%, respectively, p=0.0001). Patient survival was significantly higher in the group of patients who underwent endoscopic band ligation than in the group of patients without interventions, which was established using the Kaplan-Meier method (Log Rank=0.0001). Conclusion. Primary prevention of bleeding from the upper digestive tract through endoscopic band ligation is an effective method of saving lives and preventing patients with ascites from dropping out of the liver transplantation waiting list in conditions of a donor organ shortageб which causes a long waiting period for surgery.

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The use of endoscopic band ligation in the primary prevention of bleeding in patients with ascites listed in the liver transplantation waiting list

Objective: to determine the efficacy of non-selective beta-blockers (NSBBs) in the primary prevention of bleeding esophageal varices and to assess their impact on the survival of patients with ascites enrolled in the liver transplant waiting list (LTWL).Materials and methods. We carried out a retrospective comparative study of cirrhotic patients with severe ascites and esophageal varices without bleeding before enrollment in the LTWL. Primary prophylaxis of variceal bleeding included the use of NSBBs (n = 97, group 1). These drugs were not used in the other patients (n = 91, group 2).Results. There were no significant differences between the groups in terms of clinical, laboratory and demographic parameters, MELD scores and Child-Turcotte-Pugh (CTP) classes for cirrhosis. Patient groups included in the study had no significant differences with respect to incidence of medium- and large-sized varices and incidence of severe ascites. Bleeding incidence was significantly lower in the NSBBs group than in the non-NSBBs group (52.6% and 95.6%, respectively, p = 0.0001).Conclusion. NSBBs constitute an efficacious therapy in primary prophylaxis of esophageal variceal bleeding, thereby saving life and preventing delisting of patients with ascites from the LTWL.

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Victor D. Pasechnikov

Papers

Gastric cancer: prevention, screening and early diagnosis.

Invasive and non-invasive diagnosis of Helicobacter pylori-associated atrophic gastritis: A comparative study

Possibility of non-invasive diagnosis of gastric mucosal precancerous changes.

The use of endoscopic band ligation in the primary prevention of bleeding in patients with ascites listed in the liver transplantation waiting list

Nonselective beta-blockers in primary prophylaxis of esophageal variceal bleeding in patients with ascites waitlisted for liver transplantation