Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Submacular hemorrhage and grape-like polyp clusters: factors associated with reactivation of the lesion in polypoidal choroidal vasculopathy.

PurposeThe purpose of this study is to investigate the factors associated with reactivation of the lesion during the first year in patients with polypoidal choroidal vasculopathy (PCV) treated with intravitreal ranibizumab.Patients and methodsThis retrospective observational study included 84 eyes diagnosed with PCV and treated with 3-monthly ranibizumab injections. Only those patients who exhibited complete resolution of fluid after initial treatment and were followed up at least 12 months were included. The baseline characteristics of the patients, including their age and sex, location of the polyps, greatest linear dimensions of the lesions, largest polyp diameter, choroidal vascular hyperpermeability, submacular hemorrhages ≥1 disc area in size, presence of grape-like polyp clusters, central foveal thickness, and best-corrected visual acuity were compared between patients with and without reactivation of the lesion.ResultsDuring the 12-month follow-up period, reactivation of the lesion was observed in 60 patients (71.4%). The first reactivation was noted at a mean duration of 3.9±1.7 months after the third ranibizumab injection. Cox regression analysis revealed that the absence of submacular hemorrhages ≥1 disc area (P=0.009), presence of grape-like polyp clusters (P=0.002), and greatest linear dimension of the lesions (P=0.019) were associated with reactivation of the lesion.ConclusionThe absence of submacular hemorrhages, presence of grape-like polyp clusters, and large lesion size at diagnosis were associated with a high risk of reactivation of PCV in patients treated with intravitreal ranibizumab. Patients exhibiting these characteristics may require close monitoring.

Acute endophthalmitis after cataract surgery: 164 consecutive cases treated at a referral center in South Korea.

PurposeTo identify prognostic factors in patients referred with endophthalmitis after cataract surgery, and to evaluate the efficacy of primary vitrectomy as an initial management.MethodsOver an eight-year study period, we retrospectively reviewed the medical records of 164 patients who were referred with endophthalmitis following cataract surgery. Treatment generally conformed to standard guidelines, although primary vitrectomy was performed in several eyes with a visual acuity of hand motion or better, depending on the patient's status. Using multivariate analysis, we analyzed outcomes to determine the effect on final visual outcome.ResultsA final visual acuity of ≥20/40 was achieved in 92/164 (56.1%) cases after treatment. Bacterial cultures showed bacterial growth in 89/164 cases (54.3%). Among the various baseline characteristics, old age (P=0.028), poor visual acuity at presentation (P=0.004), gram-negative bacterial infection (P=0.030), and short time between cataract surgery and signs of endophthalmitis (P=0.021) were associated with poor visual outcome. The visual outcome showed no significant difference, in terms of initial treatment feature, between the primary vitrectomy with intraocular antibiotics injection (IOAI) and IOAI-only groups. However, reintervention was significantly less frequent in the primary vitrectomy group than in the IOAI group (12.5 and 32.7%, respectively; P=0.002).ConclusionOld age, poor visual acuity at presentation, type of cultured organism (gram-negative bacteria), and early onset of endophthalmitis after cataract surgery were significantly related to poor visual outcome after endophthalmitis treatment. Primary vitrectomy may decrease the need for reintervention to control infection, although the treatment showed no benefits with regard to visual outcome.

Cytokeratin19 induced by HER2/ERK binds and stabilizes HER2 on cell membranes.

Cytokeratin19 (KRT19) is widely used as a biomarker for the detection of disseminated tumors. Using an LC-MS/MS proteomics approach, we found that KRT19 was upregulated in HER2-overexpressing cells and tissues. KRT19 expression was induced by HER2-downstream ERK at the transcriptional level. Another HER2-downstream kinase, Akt, was found to phosphorylate KRT19 on Ser35 and induce membrane translocation of KRT19 and remodeling of KRT19 from filamentous to granulous form. KRT19 phosphorylated by Akt could bind HER2 on the plasma membrane and stabilized HER2 via inhibition of proteasome-mediated degradation of HER2. Silencing of KRT19 by shRNA resulted in increased ubiquitination and destabilization of HER2. Moreover, treatment of KRT19 antibody resulted in downregulation of HER2 and reduced cell viability. These data provide a new rationale for targeting HER2-positive breast cancers.

Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study.

BACKGROUND: Metformin use has been associated with a decreased incidence and mortality of various cancers. AIM: To evaluate the association between metformin use and gastric cancer. METHODS: We randomly selected 100 000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39 989 patients (aged 30-97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26 690 patients had used metformin out of 32 978 diabetics who had not regularly used insulin (insulin non-users), and 5855 patients had used metformin out of 7011 regular insulin users. RESULTS: Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P = 0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53-1.01) with borderline statistical significance (P = 0.059). Duration of metformin use was associated with the reduction in gastric cancer risk (AHR, 0.88; 95% CI 0.81-0.96, P = 0.003), especially in patients who used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37-0.87; P = 0.009). CONCLUSION: Metformin use >3 years in type 2 diabetics who do not use insulin is associated with a significantly reduced gastric cancer risk.

Lentiviral modification of enriched populations of bovine male gonocytes.

Undifferentiated germ cells have the capacity to develop into sperm capable of fertilizing oocytes and contributing genetic material to subsequent generations. The most primitive prepubertal undifferentiated germ cells include gonocytes and undifferentiated spermatogonia, including spermatogonial stem cells (SSC). Gonocytes, present in the testis at birth, differentiate into SSC, which maintain spermatogenesis for the remainder of the male's life. Because of their capacity to contribute to lifelong spermatogenesis, undifferentiated germ cells are attractive targets for genetic modification to produce transgenic animals, including cattle. To maximize the efficiency of genetic modification of bovine gonocytes and SSC, effective enrichment techniques need to be developed. Selection of bovine gonocytes using differential plating was improved 8-fold (P < 0.001) when using a combination of extracellular matrix proteins, including laminin, fibronectin, collagen type IV, and gelatin, compared to using laminin and gelatin alone. Selected cells labeled with PKH26 formed colonies of donor-derived germ cells after transplantation into recipient mouse testes, indicating putative stem cell function. Significantly more colonies (P < 0.001) per 1 × 10(5) viable transplanted cells were formed from isolated nonadherent cells (203 ± 23.2) compared to adherent (20 ± 2.7) or Percoll (45.5 ± 4.5) selected cells. After selection, some gonocytes were transduced using a lentiviral vector containing the transgene for the enhanced green fluorescent protein. Transduction efficiency was 17%. Collectively, these data demonstrate effective methods for the selection and genetic modification of bovine undifferentiated germ cells.

Staging of intestinal- and diffuse-type gastric cancers with the OLGA and OLGIM staging systems.

BACKGROUND: Operative link on gastritis assessment (OLGA) and Operative link on gastric intestinal metaplasia assessment (OLGIM) staging systems have been proposed for gastric cancer (GC) risk estimation. AIM: To validate the OLGA and OLGIM staging systems in a region with high risk of GC. METHODS: This retrospective study included 474 GC patients and age- and sex-matched health screening control persons in a cancer centre hospital. We classified gastritis patterns according to the OLGA and OLGIM systems using the histological database that a pathologist prospectively evaluated using the updated Sydney system. GC risk according to the OLGA and OLGIM stages was evaluated using logistic regression analysis. RESULTS: More GC patients had OLGA stages III-IV (46.2%) than controls (26.6%, P < 0.001), particularly among patients with intestinal-type GCs (62.2%) compared with diffuse-type GCs (30.9%). OLGA stages III and IV were significantly associated with increased risk of GC [odds ratios (ORs), 2.09; P = 0.008 and 2.04; P = 0.014 respectively] in multivariate analysis. The association was more significant for intestinal-type (ORs, 4.76; P = 0.001 and 4.19; P = 0.002 respectively), but not diffuse-type GC. OLGIM stages from I to IV were significantly associated with increased risk of both intestinal-type (ORs, 3.64, 5.15, 7.89 and 13.20 respectively) and diffuse-type GC (ORs, 1.84, 2.59, 5.08 and 6.32 respectively) with a significantly increasing trend. CONCLUSION: As high OLGA and OLGIM stages are independent risk factors for gastric cancer, the staging systems may be useful for risk assessment in high-risk regions, especially for intestinal-type gastric cancer.

Randomised clinical trial: the effects of Helicobacter pylori eradication on glandular atrophy and intestinal metaplasia after subtotal gastrectomy for gastric cancer.

BACKGROUND: Helicobacter pylori eradication is recommended for early gastric cancer (GC) patients after resection. AIM: To evaluate whether H. pylori eradication improves glandular atrophy and intestinal metaplasia (IM) in GC patients undergoing subtotal gastrectomy. METHODS: This randomised, double-blind trial was performed in tertiary care setting. Distal GC patients with H. pylori infection were randomised to receive proton pump inhibitor-based triple therapy or placebo. The histology was evaluated using the updated Sydney system before and at 36 months after surgery. The endpoints were the comparison of atrophy and IM score changes between the allocated groups and according to final H. pylori status. RESULTS: Overall, 190 patients were randomised to the treatment and placebo groups. For lesser curvature of the corpus, mean atrophy and IM scores did not differ between the treatment and placebo groups. However, the H. pylori-eradicated patients had significantly lower mean scores than the H. pylori-persistent patients regarding atrophy (0.55 ± 0.95 vs. 1.05 ± 1.10 respectively; P = 0.0046) and IM (0.66 ± 0.99 vs. 1.05 ± 1.16 respectively; P = 0.0284). The percentage change from baseline was more marked in the H. pylori-negative than in the H. pylori-positive groups (-58.6% vs. -11.0% for atrophy and -60.5% vs. -35.6% for IM respectively). For greater curvature, mean atrophy score was lower in the H. pylori-negative group than in the H. pylori-positive group (0.14 ± 0.50 vs. 0.41 ± 0.75 respectively; P = 0.0281). The percentage change was -36.4% vs. 86.3%. CONCLUSION: Helicobacter pylori eradication in GC patients is beneficial, as reflected by lower scores of atrophy and IM at 36 months after subtotal gastrectomy. (ClinicalTrials.gov number, NCT01002443).

Effect of chemotherapy on the outcome of self-expandable metallic stents in gastric cancer patients with malignant outlet obstruction.

BACKGROUND AND STUDY AIM: Chemotherapy has been suggested to affect the outcome of pyloric stent placement. This study aimed to investigate the association between the response to chemotherapy and pyloric stent outcome. PATIENTS AND METHODS: Data from 113 patients with inoperable gastric cancer who received chemotherapy after pyloric stent placement at the National Cancer Center hospital were analyzed retrospectively. Chemotherapy response was assessed using the Response Evaluation Criteria in Solid Tumors. A Cox proportional hazards model was used to evaluate the effect of chemotherapy response on the complications of stents. RESULTS: The stent migration rate was 15.9% (18/113) and the re-stenosis rate was 30.1% (34/113). The response rates to chemotherapy were higher in the first-line group than in the salvage chemotherapy group (second-line or more) (44.8% [26/58] vs. 3.6% [2/55], respectively; P < 0.001). The proportion of patients with long time-to-progression (> 8 weeks) was also higher in the first-line than the salvage chemotherapy group (81.0% [47 /58] vs. 61.8% [34 /55], respectively; P = 0.036). Although, the response to chemotherapy was not associated with stent migration or re-stenosis, a long time-to-progression (adjusted hazard ratio [aHR] = 0.29, 95% confidence interval [CI] 0.13-0.67) and first-line chemotherapy (aHR = 0.45, 95%CI 0.22-0.93) were protective factors against re-stenosis in the multivariate analysis. In patients who received first-line chemotherapy, the median duration of patency of covered and uncovered stents was 20 weeks (95%CI 11-29) and 33 weeks (95 %CI 18-48), respectively (P = 0.317). CONCLUSIONS: A long time-to-progression and first-line chemotherapy were significant protective factors against re-stenosis. In chemotherapy-naïve gastric cancer patients with pyloric obstruction, placement of an uncovered stent followed by chemotherapy can be considered to increase stent patency.

Aspirin use and bleeding risk after endoscopic submucosal dissection in patients with gastric neoplasms.

BACKGROUND AND STUDY AIM: The risk of bleeding after endoscopic submucosal dissection (ESD) in patients with early gastric neoplasms who do not discontinue aspirin for the procedure has not been established. We aimed to investigate whether post-ESD gastric bleeding is increased in patients who take aspirin. PATIENTS AND METHODS: Patients who underwent ESD for early gastric neoplasms at the National Cancer Center Hospital, Korea, between November 2008 and January 2011 were enrolled. The risk of post-ESD bleeding was evaluated using Poisson regression analysis. RESULTS: We categorized 514 patients into three groups according to aspirin intake at the time of the procedure: patients who never used aspirin (n=439), patients who interrupted aspirin use for 7 days or more (n=56), and patients who continuously used aspirin (n=19). Post-ESD bleeding occurred in 4.1% (21/514) overall, and was more frequent in continuous aspirin users (4/19 [21.1%]) than in those who never used aspirin (15/439 [3.4%]) (P=0.006) and those with interrupted aspirin use (2/56 [3.6%]) (P=0.033). Multivariate analysis showed that use of aspirin by itself was associated with post-ESD bleeding (relative risk [RR] 4.49; 95% confidence interval [95%CI] 1.09-18.38). The resumption of clopidogrel combined with aspirin use (RR 26.71, 95%CI 7.09-100.53), and increased iatrogenic ulcer size (RR 1.52, 95%CI 1.14-2.02), were significantly associated with post-ESD bleeding. CONCLUSIONS: Continuous aspirin use increases the risk of bleeding after gastric ESD. Aspirin use should be stopped in patients with a low risk for thromboembolic disease to minimize bleeding complications.

Intravitreal bevacizumab and ranibizumab injections for patients with polypoidal choroidal vasculopathy.

PURPOSE: To compare the effectiveness of intravitreal injection of bevacizumab and ranibizumab in patients with treatment-naïve polypoidal choroidal vasculopathy (PCV). METHODS: A total of 66 and 60 eyes of 121 consecutive patients who received intravitreal bevacizumab (1.25 mg) or ranibizumab (0.5 mg) injection for treatment of PCV were retrospectively reviewed. After initial three loading injections by month, injection was performed as needed. Main outcome measures included best corrected visual acuity (BCVA), foveal center thickness (FCT) as assessed by spectral domain optical coherence tomography (SD-OCT), and change in polypoidal lesion on indocyanine green angiography (ICGA). RESULTS: At 12 months, average number of injections was 4.72±1.84 in the bevacizumab group and 5.52±1.54 in the ranibizumab group. Mean logarithm of the minimum angle of resolution of BCVA from baseline at 12 months after injection improved by 0.11 in the bevacizumab group (P=0.02) and by 0.14 in the ranibizumab group (P=0.01). Average FCT decreased from 368±62.48 to 298±40.77 µm in the bevacizumab group (P=0.01) and from 371±50.79 to 286±36.93 µm in the ranibizumab group (P=0.01). Polyp regression rate was 24.2% (16 eyes out of 66 eyes) in the bevacizumab group and 23.3% (14 eyes out of 60 eyes) in the ranibizumab group. There was no statistically significant difference in BCVA improvement achieved, FCT improvement achieved, and polyp regression rate between groups. CONCLUSION: Intravitreal injections of bevacizumab and ranibizumab have similar effects in stabilization of visual acuity, macular edema, and regression of polypoidal complex with PCV eyes.

Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy.

To identify transcriptional profiles predictive of the clinical benefit of cisplatin and fluorouracil (CF) chemotherapy to gastric cancer patients, endoscopic biopsy samples from 96 CF-treated metastatic gastric cancer patients were prospectively collected before therapy and analyzed using high-throughput transcriptional profiling and array comparative genomic hybridization. Transcriptional profiling identified 917 genes that are correlated with poor patient survival after CF at P<0.05 (poor prognosis signature), in which protein synthesis and DNA replication/recombination/repair functional categories are enriched. A survival risk predictor was then constructed using genes, which are included in the poor prognosis signature and are contained within identified genomic amplicons. The combined expression of three genes-MYC, EGFR and FGFR2-was an independent predictor for overall survival of 27 CF-treated patients in the validation set (adjusted P=0.017), and also for survival of 40 chemotherapy-treated gastric cancer patients in a published data set (adjusted P=0.026). Thus, combined expression of MYC, EGFR and FGFR2 is predictive of poor survival in CF-treated metastatic gastric cancer patients.

Comparison of surgical performance and short-term clinical outcomes between laparoscopic and robotic surgery in distal gastric cancer.

AIMS: The authors aimed to compare the surgical performance and the short-term clinical outcomes of robotic assisted laparoscopic distal gastrectomy (RADG) with laparoscopy-assisted distal gastrectomy (LADG) in distal gastric cancer patients. METHOD: From April 2009 to August 2010, 62 patients underwent LADG and 30 patients underwent RADG for preoperative stage I distal gastric cancer by one surgeon at the National Cancer Center, Korea. Surgical performance was measured using lymph node (LN) dissection time and number of retrieved LNs, which were viewed as surrogates of technical ease and oncologic quality. RESULTS: In clinicopathologic characteristics, mean age, depth of invasion and stage were significantly different between the LADG and RADG group. Mean dissection time at each LN station was greater in the RADG group, but no significant intergroup difference was found for numbers of retrieved LNs. Furthermore, proximal resection margins were smaller, and hospital costs were higher in the RADG group. In terms of the RADG learning curve, mean LN dissection time was smaller in the late RADG group (n = 15) than in the early RADG group (n = 15) for 4sb/4d, 5, 7-12a stations, but numbers of retrieved LNs per station were similar. CONCLUSION: With the exception of operating time and cost, the numbers of retrieved LNs and the short-term clinical outcomes of RADG were found to be comparable to those of LADG, despite the surgeon's familiarity with LADG and lack of RADG experience. Further studies are needed to evaluate objectively ergonomic comfort and to quantify the patient benefits conferred by robotic surgery.

CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients.

BACKGROUND: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. METHODS: Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). RESULTS: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. CONCLUSION: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Risk of high-grade dysplasia or carcinoma in gastric biopsy-proven low-grade dysplasia: an analysis using the Vienna classification.

BACKGROUND AND AIMS: Therapeutic guidelines have not yet been established for low-grade gastric adenomas/dysplasias (LGD), which have a low risk of progression to high-grade adenomas/dysplasias (HGD) or to invasive carcinomas. This study aimed to evaluate risk factors for HGD/carcinoma that indicate a need for resection in biopsy-proven LGD lesions. PATIENTS AND METHODS: In total, 236 LGD lesions from 208 consecutive patients treated with endoscopic resection (ER) were retrospectively studied between 2004 and 2008. The Vienna classification was used for histological diagnosis. A generalized estimating equation (GEE) logistic regression model was used for multivariate analysis. RESULTS: Among the 236 LGD lesions, the final pathology diagnosed 9 (3.8 %) as invasive carcinoma (category 5), 71 (30.1 %) as HGD (category 4), 148 (62.7 %) as LGD (category 3), and 8 (3.4 %) as negative/indefinite for dysplasia (category 1/2). Lesions ≥ 1 cm were classified as HGD/carcinoma in 39.4 % of patients (65/165). Multivariate analysis indicated that size of ≥ 1 cm (OR 1.93 [95 % CI, 1.06 - 3.52]), depressed morphology (OR 3.81 [95 % CI, 1.22 - 11.9]), and erythema (OR 2.49 [95 % CI, 1.31 - 4.72]) were significantly associated with HGD/carcinoma. The OR increased to 47.6 (95 % CI, 4.27 - 530.65) when the risk factors were all positive. The sensitivity and negative predictive value for ≥ 1 risk factors were 93.8 % and 90.9 %, respectively. As the number of risk factors of a lesion increased, the specificity and positive predictive value also increased. CONCLUSIONS: Endoscopic resection can be recommended if a low-grade dysplastic lesion has at least one of the following risk factors: depressed morphology, surface erythema, or a size of 1 cm or greater. For lesions that have none of the three risk factors, follow-up endoscopy is recommended.

Phase II study of a triplet regimen of S-1 combined with irinotecan and oxaliplatin in patients with metastatic gastric cancer: clinical and pharmacogenetic results.

BACKGROUND: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. PATIENTS AND METHODS: Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. RESULTS: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). CONCLUSIONS: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

Risk of hemorrhagic gastropathy associated with colonoscopy bowel preparation using oral sodium phosphate solution.

BACKGROUND AND STUDY AIMS: Oral sodium phosphate (NaP) solution is widely used for colonoscopy bowel preparation and it may cause aphthous ulcers in the colon. Our aim was to evaluate whether oral NaP solution is associated with gastric mucosal lesions. METHODS: A total of 20 070 individuals underwent esophagogastroduodenoscopy (EGD) with colonoscopy, and 4271 individuals underwent EGD without colonoscopy, for cancer screening. Oral NaP solutions were used for bowel preparation prior to colonoscopy. Hemorrhagic gastropathy was graded using a five-point scale for erosive mucosal injury. The effect of NaP bowel preparation on hemorrhagic gastropathy was estimated using multiple logistic regression analysis with odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS: The incidence of hemorrhagic gastropathy was 1.6 % (70/4271) in the EGD only group and 4.0 % (809/20 070) in the EGD with colonoscopy group ( P < 0.001, unadjusted OR 2.55, 95 %CI 1.99 - 3.27). The ORs for mild (grade 1 - 2), moderate (grade 3), and severe (grade 4) hemorrhagic gastropathy according to NaP use were 1.92 (95 %CI 1.45 - 2.54), 4.72 (95 %CI 2.65 - 8.47), and 5.99 (95 %CI 1.46 - 24.63), respectively. After adjustment for confounding factors, NaP solution was a significant risk factor for acute hemorrhagic gastropathy in the multivariate analysis (OR 1.92, 95 %CI 1.34-2.74). In addition, male sex, a body mass index (kg/m (2)) of less than 20, concurrent use of antihypertensive or nonsteroidal anti-inflammatory drugs, and duodenal ulcers were independently associated with the development of hemorrhagic gastropathy. HELICOBACTER PYLORI infection and atrophic gastritis were negatively associated with hemorrhagic gastropathy. CONCLUSION: Oral NaP bowel preparation for colonoscopy was associated with hemorrhagic gastropathy.

Decomposition of 1,4-dioxane by photo-Fenton oxidation coupled with activated sludge in a polyester manufacturing process.

The cyclic ether 1,4-dioxane is a synthetic industrial chemical that is used as a solvent in producing paints and lacquers. The EPA and the International Agency for Research on Cancer(IARC) classified 1,4-dioxane as a GROUP B2(probable human) carcinogen. 1,4-dioxane is also produced as a by-product during the manufacture of polyester. In this research, a polyester manufacturing company (i.e. K Co.) in Gumi, Korea was investigated regarding the release of high concentrations of 1,4-dioxane (about 600 mg/L) and whether treatment prior to release should occur to meet with the level of the regulation standard (e.g., 5 mg/L in 2010). A 10 ton/day pilot-scale treatment system using photo-Fenton oxidation was able to remove approximately 90% of 1,4-dioxane under the conditions that concentrations of 2800 ppm H(2)O(2) and 1,400 ppm FeSO(4) were maintained along with 10 UV-C lamps (240 microW/cm(2)) installed and operated continuously during aeration. However, the effluent concentration of 1,4-dioxane was still high at about 60 mg/L where TOC concentration in the effluent had been moreover increased due to decomposed products such as aldehydes and organic acids. Thus, further investigation is needed to see whether the bench scale (reactor volume, 8.9 L) of activated sludge could facilitate the decomposition of 1,4-dioxane and their by-products (i.e., TOC). As a result, 1,4-dioxane in the effluent has been decreased as low as 0.5 mg/L. The optimal conditions for the activated sludge process that were obtained are as follows: DO, 3-3.5 mg/L; HRT, 24 h; SRT 15 d; MLSS, 3,000 mg/L. Consequently, photo-Fenton oxidation coupled with activated sludge can make it possible to efficiently decompose 1,4-dioxane to keep up with that of the regulation standard.

Obesity and weight gain as risk factors for erosive oesophagitis in men.

BACKGROUND: Although obesity and weight gain increase the risk for symptoms of gastro-oesophageal reflux disease, their association with erosive oesophagitis is still unclear in the male population. AIM: To evaluate, in men, the association of body mass index (BMI) and weight gain with endoscopically proven erosive oesophagitis. METHODS: A total of 8571 Korean men in a comprehensive screening cohort were enrolled. Effects of BMI and abdominal obesity on erosive oesophagitis were estimated with odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression analysis. We also evaluated the association between erosive oesophagitis and BMI change after 1-3 years. RESULTS: The prevalence of erosive oesophagitis was 6.4% (552/8571). In univariate analysis, the ORs for erosive oesophagitis increased as BMI or waist circumference increased (P for trend <0.001, both). In multivariate analysis, OR for erosive oesophagitis increased as BMI increased (P for trend = 0.002), while the significance of waist circumference was attenuated (P for trend = 0.13). Increase in BMI (>or=1 kg/m2) was associated with persistence of erosive oesophagitis (OR = 2.83, 95% CI: 1.01-7.92, P = 0.04) and new development of the disease (OR = 2.13, 95% CI: 1.38-3.28, P = 0.001) compared with BMI change less than 1 kg/m2. CONCLUSIONS: Elevated BMI and weight gain have a significant association with erosive oesophagitis.

Learning curve for identification of sentinel lymph node based on a cumulative sum analysis in gastric cancer.

BACKGROUND/AIMS: Lymph node metastasis is the most important point to consider when deciding on the modality of resection in patients with early gastric cancer. This study was conducted to evaluate the learning curve for identification of sentinel lymph nodes in patients with gastric cancer. METHODS: The investigators included the results from 2 prospective series of sentinel lymph node mapping. Cumulative sum (CUSUM) analysis was performed to assess the learning curves for identification of sentinel lymph nodes at CUSUM target success rates of 95%. RESULTS: One surgeon performed 135 sentinel lymph node mappings for 2 prospective series. The success rate exceeded 90%. The learning period for gastric cancer sentinel node mapping was calculated to be 26 cases for achieving a 95% success rate. Multiple logistic regression analysis for successful detection of sentinel nodes showed that surgical experience of sentinel lymph node mapping was an independent factor for successful detection of sentinel nodes. CONCLUSIONS: This study suggests that the learning period for identification of sentinel lymph nodes in gastric cancer would be 26 cases. In clinical trials for gastric cancer with sentinel lymph node mapping, the learning curve should be considered to minimize bias due to surgical factors.