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Background: Patients achieving pathological complete response (pCR) post-neoadjuvant chemoradiotherapy (nCRT) and surgery for locally advanced esophageal squamous cell carcinoma (ESCC) have a favorable prognosis. However, recurrence occurs in approximately 20-30% of all patients, with few studies evaluating their prognostic factors. We identified these prognostic factors, including inflammation-based markers, in patients with ESCC showing pCR after nCRT and surgery., Patients and Methods: Patients with ESCC undergoing esophagectomy post-nCRT (January 2007-August 2017) were studied. Survival analysis evaluated 5-year overall (OS) and recurrence-free survival (RFS). Risk factors, including inflammation factors, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR), were analyzed using Cox-proportional hazards model., Results: Overall, 123patients participated herein. After a median follow-up duration of 67 months (44-86 months), 17 patients (12.3%) had recurrent disease. The 5-year OS and RFS rates were 71.6% and 68.0%, respectively. In the multivariable analysis, older age ( ≥ 60 years) [hazard ratio (HR) 3.228, 95% confidence interval (CI) 1.478-7.048, p = 0.003], higher pretreatment T stage (≥ T3; HR 2.563, 95% CI 1.335-4.922, p = 0.005), nonapplication of induction chemotherapy (HR 2.389, 95% CI 1.184-4.824, p = 0.015), and higher post-nCRT PLR (≥ 184.2; HR 2.896, 95% CI 1.547-5.420, p = 0.001) were poor independent prognostic factors for 5-year RFS. The patient group with three to four identified factors with poor outcomes exhibited a 5-year RFS rate of 46.2%., Conclusions: Significant prognostic factors include higher post-nCRT PLR, older age, higher clinical T stage, and nonapplication of induction chemotherapy. Identifying higher recurrence risk patients is crucial for tailored follow-up and treatment., (© 2024. Society of Surgical Oncology.)

Background: Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib., Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1., Results: The median age was 60 years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively., Conclusion: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs., (© 2024. Asian Pacific Association for the Study of the Liver.)

Key Message: Bulked segregant RNA seq of pools of pepper accessions that are susceptible or resistant to Broad bean wilt virus 2 identifies a gene that might confer resistance to this devastating pathogen. The single-stranded positive-sense RNA virus Broad bean wilt virus 2 (BBWV2) causes substantial damage to pepper (Capsicum annuum) cultivation. Here, we describe mapping the BBWV2 resistance locus bwvr using a F 7:8 recombinant inbred line (RIL) population constructed by crossing the BBWV2-resistant pepper accession 'SNU-C' with the susceptible pepper accession 'ECW30R.' All F 1 plants infected with the BBWV2 strain PAP1 were susceptible to the virus, and the RIL population showed a 1:1 ratio of resistance to susceptibility, indicating that this trait is controlled by a single recessive gene. To map bwvr, we performed bulked segregant RNA-seq (BSR-seq). We sequenced pools of resistant and susceptible lines from the RILs and aligned the reads to the high-quality 'Dempsey' reference genome to identify variants between the pools. This analysis identified 519,887 variants and selected the region from 245.9-250.8 Mb of the Dempsey reference genome as the quantitative trait locus region for bwvr. To finely map bwvr, we used newly designed high-resolution melting (HRM) and Kompetitive allele specific PCR (KASP) markers based on variants obtained from the BSR-seq reads and the PepperSNP16K array. Comparative analysis identified 11 SNU-C-specific SNPs within the bwvr locus. Using markers derived from these variants, we mapped the candidate bwvr locus to the region from 246.833-246.949 kb. SNU-C-specific variants clustered near DEM.v1.00035533 within the bwvr locus. DEM.v1.00035533 encodes the nitrate transporter NPF1.2 and contains a SNP within its 5' untranslated region. The bwvr locus, which contains four genes including DEM.v1.00035533, could represent a valuable resource for global pepper breeding programs., (© 2024. The Author(s).)

Decidualization of the endometrial stromal cells (ESCs) is essential for successful embryo implantation. It involves the transformation of fibroblastic cells into epithelial-like cells that secrete cytokines, growth factors, and proteins necessary for implantation. Previous studies have revealed altered expression of miR-375 in the endometrium of patients with recurrent implantation failure and the ectopic stromal cells of patients with endometriosis. However, the exact molecular mechanisms, particularly the role of microRNAs (miRNAs) in the regulation of decidualization, remain elusive. In this study, we investigated whether decidualization is affected by miR-375 and its potential target(s). The findings demonstrated the downregulation of the expression of miR-375 in the secretory phase compared to its expression in the proliferative phase of the endometrium in normal donors. In contrast, it was upregulated in the secretory phase of the endometrium in infertility patients. Furthermore, during decidualization of ESCs in vitro, overexpression of miR-375 significantly reduced the transcript-level expression of forkhead box protein O1 (FOXO1), prolactin (PRL), and insulin-like growth factor binding protein-1 (IGFBP1), the well-known decidual cell markers. Overexpression of miR-375 also resulted in reduced decidualization-derived intracellular and mitochondrial reactive oxygen species (ROS) levels. Using the luciferase assay, we confirmed that NADPH oxidase 4 (NOX4) is a direct target of miR-375. Collectively, the study showed that the miR-375-mediated NOX4 downregulation reduced ROS production and attenuated the decidualization of ESCs. It provides evidence that miR-375 is a negative regulator of decidualization and could serve as a potential target for combating infertility., (© 2022. The Author(s).)

The vascular endothelial growth factor (VEGF)/VEGFR and hepatocyte growth factor (HGF)/c-MET signaling pathways act synergistically to promote angiogenesis. Studies indicate VEGF inhibition leads to increased levels of phosphorylated c-MET, bypassing VEGF-mediated angiogenesis and leading to chemoresistance. We conducted a phase 1 clinical trial with 32 patients with refractory solid tumors to evaluate the safety, pharmacokinetics, and pharmacodynamics of combinations of VEGF-targeting pazopanib and the putative c-MET inhibitor ARQ197 (tivantinib) at 5 dose levels (DLs). Patients either took pazopanib and tivantinib from treatment initiation (escalation phase) or pazopanib alone for 7 days, with paired tumor sampling, prior to starting combination treatment (expansion phase). Hypertension was the most common adverse event. No more than 1 dose limiting toxicity (DLT) occurred at any DL, so the maximum tolerated dose (MTD) was not determined; DL5 (800 mg pazopanib daily and 360 mg tivantinib BID) was used during the expansion phase. Twenty of 31 evaluable patients achieved stable disease lasting up to 22 cycles. Circulating VEGF, VEGFR2, HGF, and c-MET levels were assessed, and only VEGF levels increased. Tumor c-MET levels (total and phosphorylated) were determined in paired biopsies before and after 7 days of pazopanib treatment. Total intact c-MET decreased in 6 of 7 biopsy pairs, in contrast to previously reported c-MET elevation in response to VEGF inhibition. These results are discussed in the context of our previously reported analysis of epithelial-mesenchymal transition in these tumors., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Perception has recently been highlighted as a critical determinant for participation in clinical trials (CTs) among cancer patients. We evaluated cancer patients' current perceptions of CTs using the PARTAKE questionnaires, focusing on differences between patients with common and rare cancers. From November 2015 to May 2017, we prospectively surveyed patients who had received anti-cancer treatment at Asan Medical Center. Among 333 respondents, 70.9% had common and 29.1% had rare cancers. In the cohort, 87.7% of patients with common cancers and 75.3% of patients with rare cancers answered that they heard of and knew about CTs. However, willingness to participate in CTs was expressed only in approximately 56% of patients, although it was significantly associated with awareness and perception. Surprisingly, patients with rare cancers when compared with patients with common cancers showed significantly lower levels of awareness and perception (64.2% vs 79.9%, p = 0.003 and 77.3% vs 91.9%, p < 0.001), and consequently less willingness to participate in CTs (47.4% vs 58.9%, p = 0.06). In addition, cancer patients still harbored fear and concerns about safety and reward of CTs, and demonstrated substantial lack of knowledge about the voluntary nature of CTs, which was more obvious in patients with rare cancers. We identified relatively modest willingness of cancer patients to participate in CTs regardless of generally favorable perception. These findings are highlighted by the more negative perception of CTs among patients with rare cancers relative to those with common cancers. Further education and encouragement by research and public entities seem essential to improve motivation of CTs in cancer patients beyond good perception, especially for patients with rare cancers.

Caffeic acid phenethyl ester (CAPE) exhibits various pharmaceutical properties, including anti-bacterial, anti-inflammatory, anti-viral, anti-cancer, and anti-oxidative activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been a promising anti-cancer agent that preferentially induces cancer cell apoptosis with negligible cytotoxicity toward normal cells. Therefore, the present study investigated whether CAPE promotes TRAIL-mediated cytotoxicity in hepatocarcinoma Hep3B cells. The present study demonstrated that CAPE sensitized TRAIL-mediated cell death in Hep3B carcinoma cells. The percentages of the apoptotic cells and annexin-V(+) cells significantly increased in combined treatment with CAPE and TRAIL (CAPE/TRAIL). Treatment with pancaspase inhibitor, z-VAD-fmk, attenuated CAPE/TRAIL-induced apoptosis, suggesting that the combined treatment triggers caspase-dependent apoptosis. Additionally, we found that CAPE stimulated the expression of death receptor 5 (DR5) and treatment with DR5/Fc chimera protein significantly blocked CAPE/TRAIL-induced apoptosis, which indicates that CAPE/TRAIL stimulated apoptosis through the binding of TRAIL to DR5. Moreover, expression of transcription factor C/EBP homologous protein (CHOP) markedly increased in response to CAPE and transient knockdown of CHOP abolished CAPE/TRAIL-mediated apoptosis. These results suggest that CHOP is a key regulator in CAPE/TRAIL-mediated apoptosis. Taken together, the present study found that CAPE significantly enhanced TRAIL-mediated apoptosis in Hep3B carcinoma cells and suggested that CAPE has promising potential in chemoprevention of hepatocellular carcinomas.

Background: This study aimed to validate the prognostic relevance of macroscopic serosal changes in patients with resected gastric cancer. Prospectively collected databases of two multicenter randomized phase III trials of adjuvant chemotherapy were analyzed., Methods: For this study, 655 patients in the control groups of AMC 0101 and 0201 trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time to peritoneal recurrence were analyzed., Results: Macroscopic serosal changes were identified intraoperatively in 432 patients (66 %) and found to be significantly associated with multifocal or diffuse involvement (p = 0.001), Borrmann type 4 (p = 0.005), advanced pathologic T (p < 0.001), N (p < 0.001), overall stage (p < 0.001), and total gastrectomy (p < 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopic serosal changes were significantly associated with poor RFS [hazard ratio (HR) 2.0; 95 % confidence interval (CI), 1.4-2.7; p < 0.001] and OS (HR 2.1; 95 % CI 1.5-3.0; p < 0.001). The changes also were significantly related to shorter time to peritoneal recurrence (HR 2.9; 95 % CI 1.7-5.0; p < 0.001)., Conclusions: Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence for patients with curatively resected gastric cancer. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected gastric cancer in terms of prognosis and peritoneal recurrence.

The characteristics of volatile organic compounds (VOCs) emitted from several consumer and commercial products (body wash, dishwashing detergent, air freshener, windshield washer fluid, lubricant, hair spray, and insecticide) were studied and compared. The spray products were found to emit the highest amount of VOCs (~96 wt%). In contrast, the body wash products showed the lowest VOC contents (~1.6 wt%). In the spray products, 21.6-96.4 % of the VOCs were propane, iso-butane, and n-butane, which are the components of liquefied petroleum gas. Monoterpene (C10H16) was the dominant component of the VOCs in the non-spray products (e.g., body wash, 53-88 %). In particular, methanol was present with the highest amount of VOCs in windshield washer fluid products. In terms of the number of carbon, the windshield washer fluids, lubricants, insecticides, and hair sprays comprised >95 % of the VOCs in the range C2-C5. The VOCs in the range C6-C10 were predominantly found in the body wash products. The dishwashing detergents and air fresheners contained diverse VOCs from C2 to C11. Besides comprising hazardous VOCs, VOCs from consumer products were also ozone precursors. The ozone formation potential of the consumer and commercial spray products was estimated to be higher than those of liquid and gel materials. In particular, the hair sprays showed the highest ozone formation potential.

Background: Anti-angiogenic therapies such as bevacizumab upregulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of drug resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. We hypothesized that co-administration of pegylated SN-38 (EZN-2208) may offset the induction of HIF-1α following bevacizumab treatment, resulting in synergistic antitumor effects., Patients and Methods: Patients with refractory solid tumors were enrolled. Objectives were to evaluate the modulation of HIF-1α protein and target genes in tumor biopsies following administration of the combination of EZN-2208 administered weekly × 3 (days 1, 8, 15) and bevacizumab administered every 2 weeks, in 28-day cycles, and to establish the safety and tolerability of the combination. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) were obtained following bevacizumab alone (before EZN-2208) and after administration of both study drugs., Results: Twelve patients were enrolled; ten were evaluable for response. Prolonged stable disease was observed in 2 patients, one with HCC (16 cycles) and another with desmoplastic round cell tumor (7 cycles). Reduction in HIF-1α protein levels in tumor biopsies compared to baseline was observed in 5 of 7 patients. Quantitative analysis of DCE-MRI from 2 patients revealed changes in K(trans) and k(ep). The study closed prematurely as further clinical development of EZN-2208 was suspended by the pharmaceutical sponsor., Conclusion: Preliminary proof-of-concept for modulation of HIF-1α protein in tumor biopsies following administration of EZN-2208 was observed. Two of 10 patients had prolonged disease stabilization following treatment with the EZN-2208 and bevacizumab combination.

Background: Self-expandable metallic stents are used widely to relieve malignant gastric outlet obstruction (GOO). However, restenosis or migration of first stents is a frequent complication. The purpose of this retrospective cohort study was to evaluate the effectiveness of second stents as an approach to manage failure of first stents in patients with malignant GOO., Methods: A total of 222 patients with gastric cancer received first stents due to inoperable GOO at National Cancer Center in Korea between January 2008 and June 2011. Monthly follow-up interviews were performed, and second stents (stent-in-stent or stent-after-migration) were inserted in 59 patients by June 2012. Technical and clinical successes and long-term complications were evaluated., Results: The technical and immediate clinical success rates were 98.3 % (58/59) and 91.5 % (54/59), respectively. Patients who received a second stent due to late complications involving the first stent (migration, restenosis, and fracture) showed a higher clinical success rate (95.8 % [46/48]) than patients who received a second stent due to immediate clinical failure of the first stent (72.7 % [8/11], p = 0.04). The immediate clinical success rate of stent-after-migration (100 % [11/11]) was not different from that of stent-in-stent (89.6 % [43/48], p = 1.0). The stent dysfunction rate of stent-after-migration (27.3 % [3/11]) also was similar to that of stent-in-stent (29.2 % [14/48], p = 1.0). The median patencies of stent-in-stent and stent-after-migration were 27.4 and 58.4 weeks, respectively (p = 0.177). There were no significant prognostic factors for patency of second stents., Conclusions: Insertion of a second stent is effective for treating the first-stent failure in gastric cancer patients with GOO, especially if the immediate outcome of the first stent was successful.

Background: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC)., Methods: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity., Results: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively., Conclusions: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

Background and Aims: The best therapeutic modality has not been established for gastric low-grade adenomas or dysplasia (LGD), which can progress to invasive carcinoma despite a low risk. This study aims to investigate the clinical efficacy, safety, and local recurrence after argon plasma coagulation (APC) treatment of gastric LGD compared with endoscopic submucosal dissection (ESD)., Patients and Methods: A total of 320 patients with gastric LGD ≤ 2.0 cm treated with APC or ESD between 2004 and 2011 were retrospectively analyzed. We compared local recurrence rate, complication rate, procedure time, and admission to hospital between APC and ESD groups., Results: Of the 320 patients, 116 patients were treated with APC and 204 with ESD. During follow-up, local recurrence was more common in the APC group (3.8 %, 4/106) than the ESD group (0.5 %, 1/188; log-rank test P = 0.036). However, all patients with local recurrence (n = 5) were treated by additional APC, and followed up without further recurrences. ESD was complicated by two perforations (1.0 %, 2/204) compared with no perforations in the APC group (0 %, 0/116). Bleeding complications were not different between the APC (1.7 %, 2/116) and ESD (2.0 %, 4/204) groups. Procedure time was shorter in the APC (7.8 ± 5.1 min) than the ESD (53.1 ± 38.1 min) group (P < 0.001). The proportion of hospitalization was less in the APC group (31.0 %, 36/116) than the ESD group (100.0 %, 204/204) (P < 0.001)., Conclusions: APC can be a good treatment option for patients with LGD ≤ 2.0 cm.

Purpose: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments., Experimental Design: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks., Results: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without., Conclusions: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.

Pectobacterium carotovorum subsp. carotovorum causes soft rot disease in various plants, including Chinese cabbage. The simple extracellular leucine-rich repeat (eLRR) domain proteins have been implicated in disease resistance. Rice leucine-rich repeat protein (OsLRP), a rice simple eLRR domain protein, is induced by pathogens, phytohormones, and salt. To see whether OsLRP enhances disease resistance to bacterial soft rot, OsLRP was introduced into Chinese cabbage by Agrobacterium-mediated transformation. Two independent transgenic lines over-expressing OsLRP were generated and further analyzed. Transgenic lines over-expressing OsLRP showed enhanced disease resistance to bacterial soft rot compared to non-transgenic control. Bacterial growth was retarded in transgenic lines over-expressing OsLRP compared to non-transgenic controls. We propose that OsLRP confers enhanced resistance to bacterial soft rot. Monitoring expression of defense-associated genes in transgenic lines over-expressing OsLRP, two different glucanases and Brassica rapa polygalacturonase inhibiting protein 2, PDF1 were constitutively activated in transgenic lines compared to non-transgenic control. Taken together, heterologous expression of OsLRP results in the activation of defense response and enhanced resistance to bacterial soft rot.

Background: Self-expandable metallic stents (SEMSs) provide effective palliation for inoperable malignant gastric outlet obstruction (GOO). The objective of this study was to evaluate the effectiveness of SEMSs in patients with recurrent gastric cancer after radical gastrectomy., Methods: We retrospectively analyzed data from patients with gastric cancer who underwent endoscopic SEMS placement. The patients had obstructive symptoms due to recurrent gastric cancer after curative-intent subtotal or total gastrectomies. Technical and clinical success rates of stent placement were evaluated and clinical outcomes were compared according to operation types., Results: A total of 15 patients underwent total gastrectomies with esophagojejunostomies and Roux-en-Y reconstructions, 8 underwent subtotal gastrectomies with Billroth I reconstructions, and 12 underwent subtotal gastrectomies with Billroth II reconstructions. Four patients in the Billroth II group received stents in afferent and efferent loops, so a total of 39 stents were placed. Technical success was achieved with 92% (36/39) of stents, and clinical success occurred with 90% (35/39) of stents, with no significant differences among surgery groups or between stent types (covered vs. uncovered). The GOO score (preprocedure: 0.45±0.62) increased by 1 week (2.06±0.51, p<0.001) and was maintained up to 1 month (1.71±1.15, p<0.001 compared with initial score). Complications occurred with 17 of 39 stents (44%) and included 2 perforations, 3 migrations, and 12 restenoses. Median stent patency duration was 10.7 weeks and median survival was 21.3 weeks; these did not significantly differ by surgery group (p=0.25 and 0.93, respectively) or stent type (covered vs. uncovered, p=0.51 and 0.96, respectively)., Conclusion: Endoscopic SEMS placement for obstruction due to recurrent cancer after total or subtotal gastrectomy is feasible and provides effective short-term palliation, independent of the type of surgical procedure or stent (covered vs. uncovered) used.

Recently, many studies have shown that granulocyte macrophage-colony stimulating factor (GM-CSF) has anti-apoptotic activity and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. This study investigated detailed mechanism of GM-CSF involved in its anti-apoptotic activity and regulation of Bcl-2 expression in neural progenitor cells (NPCs) as a model. NPCs were cultured from the brain of E13 ICR mouse. When NPCs were treated with staurosporine at 1 μM, apoptosis occurred in more than 30% of cells in TUNEL assay. However, apoptosis was significantly inhibited by pre-treatment with GM-CSF at 10 ng/ml. Under the same experimental condition, the expression of both Bcl-2 and Bcl-xl was clearly induced by GM-CSF regardless of staurosporine treatment in RT-PCR and Western blot analyses. GM-CSF was shown to induce the expression of Bcl-2 and Bcl-xl via Janus tyrosine kinase (JAK) but not via phosphatidylinositol 3-kinase (PI3K) or RAS-mitogen activated protein kinase kinase-1 (MEK-1) using specific signal pathway inhibitors. Further analyses showed that the expression of Bcl-2 and Bcl-xl was induced by GM-CSF via signal transducers and activators of transcription 5 (STAT5) and STAT3, respectively. In addition, JAK/STAT5-Bcl-2 pathway but not JAK/STAT3-Bcl-xl pathway was responsible for the anti-apoptotic activity of GM-CSF in NPCs in TUNEL assay. To our knowledge, this study is the first report that shows differential roles of Bcl-2 and Bcl-xl, and their regulation mechanism involved in the anti-apoptotic activity of GM-CSF in NPCs.

Background: While clinicians routinely follow up gastric cancer patients after curative resection to detect recurrence, the effectiveness of regular follow-up has not been proven, and no consensus has been reached regarding follow-up programs., Methods: Of the 1,767 patients who underwent curative resection for gastric cancer from 2001 to 2004, 310 (17.5%) developed recurrence during follow-up. The oncologic effectiveness of follow-up was evaluated using recurrence detection rates during follow-up and survivals. Clinicopathologic characteristics, the detection tools used, and times lapsed between recurrence and previous examinations were also investigated., Results: Two hundred thirty-three (75.2%) of the 310 patients who developed recurrence were detected by regular follow-up (detected group). The frequencies of undifferentiated and diffuse-type recurrences were higher in patients with recurrence detected based on patient-initiated findings (undetected group) than in the detected group. Computed tomography and tumor markers were the first detection tools that yielded positive findings. Times between recurrence detection and previous examinations ranged from 2.8 to 5.3 months over the first 2 years. No difference in overall survival was found between the detected and undetected groups (log rank, P = 0.2)., Conclusions: The oncologic effectiveness of regular follow-up after curative resection for gastric cancer was found to be unsatisfactory. A large-scale randomized controlled trial is required to identify the effectiveness of regular follow-up in terms of its oncologic, functional, psychological, and economical aspects.

Background: We conducted the current study to investigate the clinical outcomes of metastatic gastric carcinoma (MGC) patients who experienced gastrointestinal (GI) perforation during palliative chemotherapy and to examine the prognostic factors associated with survival after perforation., Methods: We reviewed the medical records of patients at the Center for Gastric Cancer of the National Cancer Center, Korea who developed GI perforation during palliative chemotherapy between January 2001 and December 2008., Results: Of the 1,856 patients who received palliative chemotherapy for MGC, 32 patients (1.7%) developed GI perforation during chemotherapy. Patients with perforation at the primary gastric site were more likely to have ulcerative gastric cancer lesion (90.5 vs. 40.0%, P = 0.034) or gastric tumor bleeding (28.6 vs. 0%, P = 0.298), and less likely to have Bormann type IV (14.3 vs. 60.0%, P = 0.062), than patients with perforation at nongastric sites. In 14 patients (43.8%) who resumed chemotherapy after perforation, the disease control rate was 57.1%, and median overall survival (OS) after perforation was 7.5 months [95% confidence interval (CI), 6.0-9.0 months]. In all patients, median OS following perforation was 4.0 months (95% CI, 1.5-6.6 months), and multivariate analysis revealed that differentiated tumor histology, response to chemotherapy before perforation, and absence of septic shock at time of perforation were significantly associated with favorable OS after perforation., Conclusions: As patients experiencing GI perforation during palliative chemotherapy have heterogeneous clinical presentation, we need to adopt different approaches in the management of the patients that are compatible with the favorable prognostic factors.

Background: The technical difficulty of lymph node dissection in laparoscopy-assisted distal gastrectomy (LADG) remains a barrier for extending the indication for this modality and limits its widespread clinical practice. The aim of this study was to evaluate our institutional guidelines for LADG, limiting the indications for this modality to only clinical stage T1N0 or T1N1 gastric cancer., Methods: From January 2002 to October 2006, a total of 294 cases of LADG and 664 cases of open distal gastrectomy (ODG) for clinical T1N0 or T1N1 gastric cancer were performed at the National Cancer Center, Korea. The two groups' clinicopathologic characteristics, surgical outcome, morbidity, and survival were compared., Results: The mean operating time for the LADG group was significantly longer than that for the ODG group (265.8 +/- 56.3 vs. 171.4 +/- 43.1 minutes, P < .001). The mean number of retrieved lymph nodes in the LADG group was higher than that of the ODG group (39.5 +/- 14.7 vs. 37.2 +/- 12.9, P = .017). The postoperative hospital stay was shorter in the LADG group (8.0 +/- 3.3 vs. 10.5 +/- 4.1 days, P < .001). The complications rate was lower for the LADG group than that for the ODG group (6.8% vs. 11.3%, P = .032). The overall survival rate was not significantly different between the two groups (P = .880)., Conclusions: Before considering expanding the indications for LADG, developing a carefully thought-out guideline and conducting an audit are mandatory.

Background: Benign strictures at esophagojejunostomy sites may develop after total gastrectomy, and through-the-scope balloon dilation (TTS-BD) can relieve them. The aim of this study was to evaluate effective and safe balloon diameter for benign stricture after total gastrectomy., Methods: From June 2001 to December 2006, 930 gastric cancer patients underwent total gastrectomy with Roux-en-Y esophagojejunostomy in a cancer center hospital. We performed TTS-BD when benign strictures developed. Initial success rate, complication rate, and restenosis rate were evaluated. We classified the patients into three groups according to final dilation diameter and number of sessions., Results: A total of 58 patients (6.2%) developed a benign stricture at the esophagojejunostomy site. We classified them into three groups based on the final luminal diameter of the balloon used and the number of sessions, as follows: group A (n = 20), 13.5-15 mm in one or two sessions; group B (n = 13), 16.5-20 mm in one session; group C (n = 25), 16.5-20 mm in two sessions. The initial success rates were 100% for groups A and B and 96% for group C. A perforation occurred in one patient (7.7%) in group B. Restenosis occurred in two patients (10%) in group A, one patient (7.7%) in group B, and in no patients in group C (p = 0.29). Restenosis was resolved by one or two further TTS-BDs., Conclusion: TTS-BD to 15 mm was a safe and effective treatment for benign esophagojejunostomy strictures following total gastrectomy. Restenosis was not common and could be resolved by one or two further TTS-BD sessions.

Objectives: This study was designed to identify the characteristics of patients with early gastric cancers that have skip metastases., Background: The possibility of lymph node metastasis is the most important factor to consider when deciding on the resection procedure for patients with early gastric cancer., Methods: From February 2003 through July 2008, 739 patients with early gastric adenocarcinoma underwent gastric resection at the National Cancer Center, Korea, and were included in this study. Patients with skip metastases were analyzed and compared with those without skip metastases., Results: Skip metastases were found in 2.8% of patients with early gastric cancer. Tumor size and the presence of lymphatic invasion were associated with skip metastases by both univariate and multivariate analysis. All skip metastases were metastases to the extraperigastric lymph nodes that skipped across the perigastric lymph nodes. Sixteen patients (66.7%) with these metastases had metastatic lymph nodes at No. 7, 8, and 9 stations., Conclusions: Tumor size should be considered during sentinel lymph node mapping to prevent false-negative results in patients with early gastric cancer. If sentinel nodes are not found in the perigastric lymph nodes, No. 7, 8, and 9 stations should be explored for prevention of false-negative sentinel node mapping results.

Background: There is a prevailing belief that both obesity and abdominal shape influence abdominal accessibility, and thus affect short-term surgical outcomes of gastric cancer surgery., Methods: We measured the thickness of subcutaneous fat (SCF), abdominal anterior-posterior diameter (APD), transverse diameter (TD), and intra-abdominal fat volume (IFV) at the umbilicus level by using the abdominal CT scans of 291 gastric cancer patients who had undergone subtotal gastrectomy and D2 lymph node dissection. Clinicopathological factors including body mass index (BMI), APD, TD, IFV, and SCF and surgical outcomes, i.e., dissected lymph node number, morbidity, and mortality were analyzed., Results: SCF thickness, APD, TD, IFV, and BMI mean values were 20.0 mm (range 2.0-64.0), 188.4 mm (range 128.0-332.0), 301.4 mm (range 160.0-651.0), 198.3 mm(2) (range 123.4-312.1), and 23.9 kg/m(2) (range 16.6-34.6), respectively. In male patients, APD was found to correlate with the number of retrieved lymph nodes (P = 0.045). Whereas in female patients, this was not the case (P = 0.093). Twenty-one patients experienced postoperative complications but no postoperative mortality occurred. Female patients who experienced postoperative complications had higher APD (32.9 +/- 10.0 mm versus 26.1 +/- 7.9 mm, P = 0.044) and BMI (27.3 +/- 4.1 kg/m(2) versus 24.3 +/- 3.5 kg/m(2), P = 0.049) values than those who did not., Conclusions: We conclude that obesity and abdominal shape of gastric cancer patients both influence the short-term surgical outcomes of subtotal gastrectomy with D2 lymph node dissection.

Background: This study was conducted to evaluate the leaning curve of D2 lymph node dissection for patients with gastric cancer in a high-volume center., Methods: The authors prospectively reviewed the data of all patients who underwent total gastrectomy with D2 lymph node dissection during a 4-year period. Retrieved lymph node number was used as a surrogate marker of oncological outcome. The retrieved lymph node number cut-off value required for satisfactory D2 lymph node dissection was defined as >25. Cumulative sum analysis was used to examine the learning curves of individual surgeons at target accuracy rates of 85%, 90%, 92.5%, 95%, and 98%., Results: Two junior staff surgeons performed 198 curative-intent total gastrectomies with D2 lymph node dissections during the study period; their success rates exceeded 90%. Operating time decreased with operative experience (Pearson correlation coefficient = -0.515, P < 0.001). The learning period for total gastrectomy with D2 lymph node dissection for these two junior members of staff was calculated as 23-35 cases, presuming a 92.5% success rate., Conclusions: The current study suggests that the surgical learning period for D2 lymph node dissection extends to at least 23 cases or 8 months. In clinical trials containing gastric cancer surgery, the learning curve for qualified surgery from the standpoint of oncological outcome should be considered to minimize bias due to surgeon-associated factors.

Background: The aim of this study was to determine how to select potential candidates for curative resection among advanced gastric patients with equivocal findings of para-aortic lymph node metastasis on computed tomography (CT)., Methods: We analyzed the clinicopathologic results of 23 advanced gastric cancer patients who were diagnosed as having equivocal findings of para-aortic lymph node metastasis on a CT scan and who underwent gastrectomy with D2 and para-aortic lymph node dissection., Results: Twenty-two patients were male, and one patient was female. The median age of all study subjects was 52 years (range, 31-75 years). Sixteen underwent total gastrectomy, and seven underwent subtotal gastrectomy. The median number of A2 (suprarenal) lymph nodes harvested was 2 (range, 1-5), and that of B1 (infrarenal) lymph nodes was 6 (range, 1-17). Ten (43.5%) of the 23 patients were proven pathologically to have metastasis to para-aortic lymph nodes. Two patients with cT2 cancer had no metastatic para-aortic lymph node, whereas three patients with cT4 disease had metastatic para-aortic lymph nodes (P = .021). Seven (70.0%) of 10 patients with pathologic para-aortic lymph node metastasis experienced recurrence, whereas only 2 (15.4%) of 13 patients without experienced recurrence (P = .008). The Lauren classification was found to be an independent predictor of para-aortic lymph node metastasis (relative risk; .13; 95% confidence interval, .02-.83; P = .03)., Conclusions: More than half of gastric cancer patients with equivocal findings of para-aortic lymph node metastasis on CT are potential candidates for curative resection. The Lauren classification of gastric cancer in patients with equivocal CT findings of para-aortic lymph node metastasis would be helpful when deciding on clinical stage and treatment plans in these patients.

The aim of this study was to develop a method for fractionation of articular chondrocytes from the entire thickness of the tissue. Isolated chondrocytes from rabbit articular cartilage fractionated by centrifugation in a discontinuous Percoll gradient resulted in four cell fractions with two differing properties. The lowest-density fraction consisted mainly of large cells with small nuclei proliferated actively, maintained the chondrocytic phenotype, and secreted larger amounts of proteoglycan. In contrast, the highest-density fraction consisted of small cells with large nuclei proliferated slowly, did not express the chondrocytic phenotype, and produced larger amounts of interleukin 1-induced nitric oxide. Comparing our results with other previous reports, we find that fraction 1 cells are likely originated from the deep layer of the articular cartilage, whereas fraction 4 cells are tentatively categorized as chondrocytes from the superficial layer of cartilage. Centrifugal fractionation of articular chondrocytes via Percoll density gradient permits clear separation of these heterogeneous cells into different phenotypic populations and allows distinguishing of cells from the different layers of articular cartilage. This simple novel method will provide ready separation of articular chondrocytes for the investigation of the pathogenesis of articular cartilage.