Citations

SummaryDickkopf‐1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti‐DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma‐related bone disease and as an agent with potential anti‐myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose‐limiting toxicity (DLT) of escalating doses in combination with anti‐myeloma therapy and zoledronic acid. Twenty‐eight patients were enrolled and received BHQ880 at doses of 3–40 mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10 mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal‐related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti‐myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.

Introduction BO is the strongest precursor of oesophageal adenocarcinoma. Participation patterns and effectiveness of BO community screening using unsedated transnasal endoscopy (uTNE) is unknown. Feasibility of mobile van screening closer to home is also unknown. We aimed to assess the effectiveness of this technique compared to sedated endoscopy (SE). Methods A population cohort ≥50 years of age, with no history of endoscopic evaluation, was identified from a group of subjects who previously completed a validated symptom questionnaire. Patients were randomised (stratified by age, sex and reflux symptoms) and invited to undergo either uTNE in a mobile research van (muTNE), uTNE in outpatient endoscopy suite (huTNE) or SE. uTNE was performed using a portable oesophagoscope with a disposable sheath. Procedure performance characteristics and validated tolerability scales (0 = none and 10 = severe) were recorded. Results 459 subjects were contacted and 209 (46%) agreed to undergo study procedures (muTNE n = 76, huTNE n = 72, SE n = 61). Baseline characteristics were comparable among the three groups. Participation rates were numerically higher in the unsedated arms (muTNE 47.5%, huTNE 45.7%) than in the SE arm (40.7%) (p = 0.27). Patients with acid reflux symptoms ≥1/week were more likely to participate (odds ratio 2.94, 95% confidence interval 1.47, 5.88). Complete evaluation of the oesophagus was comparable using muTNE (99%), huTNE (96%) and SE (100%) techniques. Successful biopsy acquisition was lower in the muTNE (79%) and huTNE (83%) groups compared to SE (100%) (p = 0.001). Mean duration (minutes) of examination was shorter in the SE arm (4.7) than in muTNE (8.0) and huTNE (8.5) groups (p < 0.001). However, recovery time was much longer for SE (67.3) compared to muTNE (15.5) and huTNE (18.5) techniques (p < 0.001). While overall tolerability for SE was better than muTNE and huTNE (mean score 0.4 vs. 1.9 and 2.2 respectively, p < 0.001), the majority of patients who underwent muTNE and huTNE were willing to undergo the same procedure again in future (79% and 83%, respectively). No serious adverse events were reported. 16 subjects (7.6%) were diagnosed with BO. Conclusion In this first large randomised trial evaluating novel approaches for community screening for BO, unsedated mobile van and clinic screening with TNE was feasible and effective. The patients’ visit was significantly shorter with adequate tolerability, acceptability and safety profiles. Mobile and outpatient techniques may provide a cost-effective alternative to SE for BO screening. Disclosure of Interest S. Sami: None Declared, K. Dunagan: None Declared, M. Johnson: None Declared, C. Schlek: None Declared, A. Zinsmeister: None Declared, L. M. Wong Kee Song: None Declared, K. Wang: None Declared, D. Katzka: None Declared, K. Ragunath Grant/research support from: Olympus (keymed, UK) and Intromed Ltd. (Seoul, South Korea), P. Iyer: None Declared.

Background and aims Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barrett's oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO. Methods We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. Results We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose–response relationship with PPI use for >2–3 years protective against OAC or BO-HGD (three studies; PPI use >2–3 years vs <2–3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. Conclusions Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

Abstract Physical activity may be associated with reduced risk of gastric cancer. We performed a systematic review and meta-analysis to evaluate the magnitude of the association and the quality of supporting evidence. After a comprehensive search of bibliographic databases and conference proceedings through February 2013 for observational studies that examined associations between recreational and/or occupational physical activity and gastric cancer risk, we identified 16 studies (seven cohort, nine case control) reporting 11,111 cases of gastric cancer among 1,606,760 patients. Summary adjusted-OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Meta-analysis demonstrated that the risk of gastric cancer was 21% lower among the most physically active people as compared with the least physically active people (OR = 0.79; 95% CI, 0.71–0.87) with moderate heterogeneity among studies (I2 = 55%). This protective effect was seen for gastric cancers in the cardia (four studies; OR = 0.80; 95% CI, 0.63–1.00) and distal stomach (five studies; OR = 0.63; 95% CI, 0.52–0.76). The effect size was significantly smaller in high-quality studies (six studies; OR = 0.86; 95% CI, 0.75–0.99), as compared with low-quality studies (10 studies; OR = 0.74; 95% CI, 0.69–0.81). The results were consistent across sex, study quality, study design, and geographic location. In conclusion, meta-analysis of published observational studies indicates that physical activity is associated with reduced risk of gastric cancer. Lifestyle interventions focusing on increasing physical activity may decrease the global burden of gastric cancer, in addition to a myriad of other health benefits. Cancer Prev Res; 7(1); 12–22. ©2013 AACR.