Relapse free survival by receipt of adjuvant chemotherapy.

<p>Relapse free survival by receipt of adjuvant chemotherapy.</p

Early relapses after adjuvant chemotherapy suggests primary chemoresistance in diffuse gastric cancer

<div><p>Background</p><p>Survival from gastric cancer remains poor, particularly in Western populations. Previous pre-clinical and subgroup analyses of clinical trials have suggested differing benefits from fluoropyrimidine-based chemotherapeutics for diffuse and intestinal gastric cancer. This analysis examines patterns of relapse with and without adjuvant chemotherapy after curative resection for gastric cancer in these subtypes to explore the Lauren classification as a predictive marker of benefit for fluoropyrimidine-based adjuvant chemotherapy.</p><p>Patients and methods</p><p>Gastric cancer patients enrolled in an ongoing tissue banking study were analysed, 164 patients who would currently be considered for adjuvant therapy after curative resection were included in the analysis. Patients who did and did not receive adjuvant chemotherapy were compared. The primary end point was relapse free survival.</p><p>Results</p><p>Approximately 50% of patients received adjuvant chemotherapy, the majority receiving a fluoropyrimidine-based regimen. The comparison of Kaplan-Meier curves for patients who did and did not receive adjuvant chemotherapy are different between patients with intestinal and diffuse gastric cancer, and suggest that there may be a benefit in intestinal gastric cancer. The hazard ratio for adjuvant chemotherapy for intestinal gastric cancer was 0.56, (95% CI 0.27–1.17), suggesting a trend towards benefit that was lacking in diffuse gastric cancer patients (1.26, 95% CI 0.70–2.38). The patterns of relapse after adjuvant chemotherapy also differed between diffuse and intestinal gastric cancer. More than 50% of diffuse gastric cancer patients who received adjuvant chemotherapy relapsed within 12 months of surgery despite similar surgical parameters.</p><p>Conclusions</p><p>Lauren classification is prognostic in gastric cancer. This analysis adds further evidence that it may also be predictive of benefit for fluoropyrimidine-based chemotherapeutics, with lower chemosensitivity seen in diffuse gastric cancer. Treating diffuse and intestinal gastric cancer as separate entities, with identification of efficacious treatments for diffuse gastric cancer will help in improving outcomes from gastric cancer.</p></div

Consort diagram of patient eligibility, Lauren classification subtype and receipt of adjuvant chemotherapy.

<p>Consort diagram of patient eligibility, Lauren classification subtype and receipt of adjuvant chemotherapy.</p

Description of patients by receipt of adjuvant chemotherapy.

<p>Description of patients by receipt of adjuvant chemotherapy.</p

Kaplan-Meier estimates of relapse free survival among patients eligible for adjuvant therapy after curative resection of gastric cancer.

<p>(A) By Lauren classification subtype. (B) By receipt of adjuvant chemotherapy in all patients. (C) By receipt of adjuvant chemotherapy in patients with intestinal gastric cancer only. (D) By receipt of adjuvant chemotherapy in patients with diffuse gastric cancer only.</p

Description of patients by Lauren classification subtype.

<p>Description of patients by Lauren classification subtype.</p

Increased apoptosis in liver of <i>Sod</i>^−/− mice but not in <i>Ku80</i>^−/− liver tissue.

<p>Representative images are shown from livers of <i>Ku80</i>^−/− and wt mice at 12 months and <i>Sod1</i>^−/− and wt mice at 4 months. Cells undergoing apoptosis were detected by <i>in situ</i> labeling of nuclear DNA fragmentation (TUNEL) as described in the text.</p

Persistent DNA damage foci in <i>Ku80</i>^−/− MEFs.

<p>(A) Persistent DNA damage foci were visualized by immunofluorescence. Wt and <i>Ku80</i>^−/− MEFs were treated with bleomycin or H₂O₂ and stained 3 d later for the presence of 53BP1 foci. Top panels–53BP1 in red and nuclei counterstained with DAPI (blue). Bottom panels–53BP1 in grayscale. (B) Quantification of DNA damage foci (53BP1) shown in A, in untreated cells and 3 d after treatment of wt and <i>Ku80</i>^−/− MEFs.</p

Spontaneous mutant frequencies in different organs from <i>Ku80</i>^−/− and wt mice.

<p>Error bars indicate standard deviations (n = 5–8). Statistical tests were applied as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003458#s4" target="_blank">materials and methods</a> to compare mutant frequencies between <i>Ku80</i>^−/− and wt mice.</p

Point mutations in brain of Ku80^−/− or wt mice.

<p>Point mutations in brain of Ku80^−/− or wt mice.</p