BACKGROUND:In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n ¼ 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n ¼ 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n ¼ 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P ¼ .015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P ¼ .049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P ¼ .008 for classification by K-means clustering analysis; P ¼ .040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings.

LBA4509 Background: Advanced GC is an incurable disease; new and less toxic treatments are needed. HER2 overexpression has been reported in 6–35% of stomach and gastroesophageal tumors. Trastuzumab (H; Herceptin), a monoclonal antibody against HER2, has shown survival benefits when given with CT in patients (pts) with HER2-positive early and metastatic breast cancer. The ToGA study is the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of H in HER2- positive GC. Methods: Pts with HER2-positive gastroesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were randomized to receive H+CT (5-fluorouracil or capecitabine and cisplatin) q3w for 6 cycles or CT alone. H was given until disease progression. The primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival, time to progression, duration of response, and safety. An interim analysis was planned at 75% of deaths and the Independent Data Monitoring Committee recommended releasing the data as the pre-specified boundary was exceeded and median follow-up of pts was 17.1 months. Results: Tumors from 3,807 pts were centrally tested for HER2 status: 22.1% were HER2 positive (abstract #4556). 594 pts were randomized 1:1 at sites in Europe, Latin America, and Asia. Baseline characteristics were well balanced across arms. Median OS was significantly improved with H+CT compared to CT alone: 13.5 vs. 11.1 months, respectively (p=0.0048; HR 0.74; 95% CI 0.60, 0.91). ORR was 47.3% in the H+CT arm and 34.5% in the CT arm (p=0.0017). Safety profiles were similar with no unexpected adverse events in the H+CT arm. There was no difference in symptomatic congestive heart failure between arms. Asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of pts in the H+CT arm and 1.1% in the CT arm. Conclusions: This first randomized trial investigating anti-HER2 therapy in advanced GC showed that H+CT is superior to CT alone. The OS benefit indicates that H is a new, effective, and well-tolerated treatment for HER2-positive GC. [Table: see text]

Lysosomal membrane protein 2 (LAMP-2) is a target of antineutrophil cytoplasmic autoantibodies (ANCA) in addition to the more commonly known targets proteinase 3 and myeloperoxidase. The prevalence of anti-LAMP-2 antibodies and their relationship to disease in ANCA glomerulonephritis are not well described. We measured anti-LAMP-2 reactivity in 680 sera samples (two academic centers) from patients with ANCA glomerulonephritis (n=329); those with ANCA-negative glomerulonephritis (n=104); those with fimbriated, gram-negative Escherichia coli urinary tract infection (n=104); disease controls (n=19); and healthy volunteers (n=124). With levels in healthy controls used to define a reference range, anti-LAMP-2 reactivity was present in 21% of ANCA sera from two of the centers; reactivity was present in 16% of the control group with urinary tract infection. Western blotting and immunofluorescence microscopy did not verify positivity. Titers of anti-myeloperoxidase and anti-proteinase 3 antibodies were 1500-fold and 10,000-fold higher than anti-LAMP-2 titers, respectively. There was no correlation between anti-LAMP-2 antibodies and disease activity. Furthermore, Wistar Kyoto rats injected with anti-LAMP-2 antibodies did not develop glomerulonephritis. In conclusion, antibodies that react with LAMP-2 may exist at very low titers in a minority of patients with ANCA disease. These data do not support a mechanistic relationship between anti-LAMP-2 antibodies and ANCA glomerulonephritis.

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Extracellular volume expansion, measured by MFBIA, does not help preserve residual renal function, and is harmful for the technical and patient survival in Korean peritoneal dialysis patients.

Renal disease is a worldwide health issue. Besides transplantation, current therapies revolve around dialysis, which only delays disease progression but cannot replace other renal functions, such as synthesizing erythropoietin. To address these limitations, cell‐based approaches have been proposed to restore damaged kidneys as an alternative to current therapies. Recent studies have shown that stem cell‐derived secretomes can enhance tissue regeneration. However, many growth factors undergo rapid degradation when they are injected into the body in a soluble form. Efficient delivery and controlled release of secreting factors at the sites of injury would improve the efficacy in tissue regeneration. Herein, we developed a gel‐based delivery system for controlled delivery of trophic factors in the conditioned medium (CM) secreted from human placental stem cells (HPSCs) and evaluated the effect of trophic factors on renal regeneration. CM treatment significantly enhanced cell proliferation and survival in vitro. Platelet‐rich plasma (PRP) was used as a delivery vehicle for CM. Analysis of the release kinetics demonstrated that CM delivery through the PRP gel resulted in a controlled release of the factors both in vitro and in vivo. In an acute kidney injury model in rats, functional and structural analysis showed that CM delivery using the PRP gel system into the injured kidney minimized renal tissue damage, leading to a more rapid functional recovery when compared with saline, CM, or vehicle only injection groups. These results suggest that controlled delivery of HPSC‐derived trophic factors may provide efficient repair of renal tissue injury. stem cells translational medicine 2019;8:959&970

PurposeTo identify potential predictive factors of incidental prostate cancer (IPca) in patients considering tissue-ablation treatment for benign prostatic hyperplasia (BPH).Materials and MethodsFrom the 11 centers, 1,613 men who underwent transurethral resection of the prostate (TURP) or open prostatectomy were included. Before surgery, prostate biopsy was performed in all patients with prostate-specific antigen (PSA) ≥4.0 ng/ml or with abnormal digital rectal examination (DRE) findings. The patients with prostate cancer preoperatively or with PSA >20 ng/ml were excluded. As predictive factors of IPca, age, body mass index, PSA, DRE, and transrectal ultrasonography (TRUS) findings, including total prostate volume (TPV), transition zone volume (TZV), and the presence of hypoechoic lesions, were reviewed. PSA density (PSAD) and PSAD in the transition zone (PSAD-TZV) were calculated.ResultsIPca was diagnosed in 78 patients (4.8%). DRE findings, PSA, and TZV were independent predictive factors in the multivariate analysis. In the receiver operating characteristic curve analysis of PSA, PSAD, and PSAD-TZV, the area under the curve (AUC) was the largest for PSAD-TZV (AUC, 0.685).ConclusionsIPca was detected in 4.8% of the population studied. In addition to DRE findings, the combination of TZV and PSA can be useful predictive factors of IPca in patients considering tissue-ablation treatment as well as TURP.