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BACKGROUND & AIMS Atezolizumab plus bevacizumab (Ate/Bev) has demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the phase III trial. Further evaluation is necessary to investigate the safety and efficacy of Ate/Bev in real settings. METHODS This was a multicentre retrospective analysis. Between May 2020 and February 2021, 138 patients received Ate/Bev as first-line treatment for advanced HCC from 11 institutions. We excluded patients with Child-Pugh B or C and BCLC D stage, and the remaining 121 patients were included in this analysis. RESULTS According to RECIST 1.1, the objective response and disease control rates were 24.0% and 76.0%. The median follow-up duration was 5.9 months (95% confidence interval [CI], 5.4-6.4), the median progression-free survival (PFS) was 6.5 months (95% CI, 4.1-9.0), and median overall survival (OS) was not reached (95% CI, not available). The most frequent grade 3-4 adverse event was aspartate aminotransferase elevation (10.7%). In the multivariate analyses, AFP increase (P = .037), baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 5 (P = .023), and best response to stable disease or progressive disease (P = .019) were significantly associated with worse PFS. Macrovascular invasion (P = .048) and baseline NLR ≥5 (P

Galectin 3-binding protein (LGALS3BP, also known as 90K) is a multifunctional glycoprotein involved in immunity and cancer. However, its precise role in colon inflammation and tumorigenesis remains unclear. Here, we showed that Lgals3bp−/− mice were highly susceptible to colitis and colon tumorigenesis, accompanied by the induction of inflammatory responses. In acute colitis, NF-κB was highly activated in the colon of Lgals3bp−/− mice, leading to the excessive production of pro-inflammatory cytokines, such as IL-6, TNFα, and IL-1β. Mechanistically, Lgals3bp suppressed NF-κB through the downregulation of TAK1 in colon epithelial cells. There was no significant difference in the pro-inflammatory cytokine levels between wild-type and Lgals3bp−/− mice in a chronic inflammatory state, during colon tumorigenesis. Instead, Lgals3bp−/− mice showed elevated levels of GM-CSF, compared to those in WT mice. We also found that GM-CSF promoted the accumulation of myeloid-derived suppressor cells and ultimately increased colon tumorigenesis in Lgals3bp−/− mice. Taken together, Lgals3bp plays a critical role in the suppression of colitis and colon tumorigenesis through the downregulation of the TAK1-NF-κB-cytokine axis. These findings suggest that LGALS3BP is a novel immunotherapeutic target for colon inflammation and tumorigenesis.

Multidetector computed tomographic urography (MDCTU) is not yet sufficient to be used in the clinical staging of upper tract urothelial carcinoma (UTUC). This study aimed to compare the diagnostic accuracy of MDCTU T stage classification and pathologic T staging for UTUC. We retrospectively evaluated 125 patients with UTUC who underwent preoperative MDCTU. A single radiologist classified the MDCTU pattern of the tumors as either low or advanced T stage for localized or locally advanced tumors, respectively. The diagnostic values of MDCTU for locally advanced tumors and the kappa agreement between MDCTU and pathologic T stage were investigated. Among 85 pathologic low T stage (Ta–T2) tumors, 71 low T stage tumors were correctly detected by MDCTU, while 30 out of 40 advanced T stage (T3–T4) tumors were correctly diagnosed by MDCTU. MDCTU led to under-staging in 8% (10/125) tumors and over-staging in 11.2% (14/125) tumors. Therefore, the overall accuracy of MDCTU in the diagnosis of low and advanced T stage tumors was 80.8% (101/125 patients). The sensitivity for advanced T stage tumors was 75% (30/40), the specificity was 83.5% (71/85), and the positive and negative predictive values were 68.1% (30/44) and 87.6% (71/81), respectively. The kappa agreement value between the MDCTU T stage and pathologic T stage was 0.57 (95% confidence interval (CI) 0.42–0.72), which was statistically significant (P = 0.001). MDCTU T stage classification may be relatively accurate for the detection and staging of UTUC correspondence with a pathologic stage.

Fibroblast growth factor receptor 4 (FGFR4) is known to induce cancer cell proliferation, invasion, and antiapoptosis through activation of RAS/RAF/ERK and PI3K/AKT pathways, which are also known as major molecular bases of colon cancer carcinogenesis related with epidermal growth factor receptor (EGFR) signaling. However, the interaction between FGFR4 and EGFR signaling in regard to colon cancer progression is unclear. Here, we investigated a potential cross‐talk between FGFR4 and EGFR, and the effect of anti‐EGFR therapy in colon cancer treatment. To explore the biological roles of FGFR4 in cancer progression, RNA sequencing was carried out using FGFR4 transfected colon cell lines. Gene ontology data showed the upregulation of genes related to EGFR signaling, and we identified that FGFR4 overexpression secretes EGFR ligands such as amphiregulin (AREG) with consequent activation of EGFR and ErbB3. This result was also shown in in vivo study and the cooperative interaction between EGFR and FGFR4 promoted tumor growth. In addition, FGFR4 overexpression reduced cetuximab‐induced cytotoxicity and the combination of FGFR4 inhibitor (BLU9931) and cetuximab showed profound antitumor effect compared to cetuximab alone. Clinically, we found the positive correlation between FGFR4 and AREG expression in tumor tissue, but not in normal tissue, from colon cancer patients and these expressions were significantly correlated with poor overall survival in patients treated with cetuximab. Therefore, our results provide the novel mechanism of FGFR4 in connection with EGFR activation and the combination of FGFR4 inhibitor and cetuximab could be a promising therapeutic option to achieve the optimal response to anti‐EGFR therapy in colon cancer., Our study has characterized the cross‐talk between fibroblast growth factor receptor 4 (FGFR4) and epidermal growth factor receptor (EGFR)/ErbB3 signaling by the contribution of EGFR ligands secreted from FGFR4. These findings provide experimental evidence for combined treatment with FGFR4 inhibitor and anti‐EGFR therapy in colon cancer.

BACKGROUND & AIMS Regorafenib demonstrated a clinical benefit for patients with unresectable hepatocellular carcinoma (uHCC) in the phase III RESORCE trial. Considering the heterogeneity of uHCC and discrepancies in its characteristics between prospective trials and daily practice, real-life evidence is necessary. METHODS This multicentre, retrospective analysis was performed by the Korean Cancer Study Group. In total, 440 patients who received regorafenib between January 2017 and November 2019 were identified in nine tertiary referral hospitals in Korea. RESULTS All patients received prior sorafenib, and the median time-to-progression (TTP) on sorafenib was 3.9 months (range, 0.2-71.6). Regorafenib was used as the second, third and fourth to seventh lines of therapy in 305 (69.3%), 115 (26.1%) and 20 (4.5%) patients respectively. According to the RECIST v1.1, the overall response rate was 7.7% (n = 34), and the median progression-free survival (PFS) and overall survival (OS) were 3.2 (95% CI, 2.8-3.5) and 12.1 (95% CI, 9.7-14.5) months respectively. Immune checkpoint inhibitors (ICIs) were given in 115 patients (26.1%) prior to regorafenib. There were no differences in PFS and OS with regorafenib according to the prior use of ICIs (PFS, P = .61; OS, P = .63). The occurrence of hand-foot skin reaction (HFSR) was associated with a better OS (P < .001). CONCLUSIONS The real-life clinical outcomes of regorafenib for patients who progressed on prior systemic therapy including ICIs were consistent with the phase III trial results. HFSR was significantly associated with better OS with regorafenib.

Early [stage I and II (T2N0M0)] laryngeal cancer types are currently recommended to be treated with a single modality, consisting of definitive radiation therapy or larynx-preserving surgery. Although the treatment outcomes of stage I are good, the frequency of successful outcomes decreases with T2N0M0. Therefore, the present study investigated the treatment outcomes of different treatment methods in T2N0M0 laryngeal cancer. In total, 83 patients with previously untreated T2N0M0 laryngeal squamous cell carcinoma were enrolled. Patients were grouped by treatment method: Radiation therapy (RT; 27 patients); chemoradiotherapy (CRT; 46 patients) with cisplatin base; and surgery-based therapy (SBT; ten patients). The recurrence rates of the RT, CRT and SBT groups were 44.4, 19.6 and 50%, respectively. Moreover, the local control rates of the RT, CRT and SBT groups were 55.6, 87.0 and 80%, respectively. The CRT group had a significantly lower recurrence rate and higher local control rate compared with the RT group (P

BackgroundRegulatory T-cells (Treg) are essential in maintaining self tolerance, but they can also suppress anti-tumor immunity in the tumor microenvironment (TME). Treg are recruited into tumors by C-C motif chemokine ligand 17 (CCL17), and 22 (CCL22), which are produced by tumor cells and other cells in the TME. These chemokines serve as a ”homing signal” to Treg by binding to their cognate receptor, C-C chemokine receptor type 4 (CCR4), the predominant chemokine receptor on human Treg.1 2 3 FLX475, is an orally available and selective small-molecule antagonist of CCR4. In preclinical studies it has demonstrated potent inhibition of CCL17- and CCL22-induced CCR4-mediated chemotaxis, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human healthy volunteer study, the orally-available CCR4 antagonist was well tolerated, with solid safety profile. A receptor occupancy (RO) pharmacodynamic (PD) assay using peripheral blood Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors.4 The proposed mechanism of action, pharmacokinetics (PK), PD, and safety profile of FLX475 have enabled the optimized design of an ongoing Phase 2 study to assess the safety, efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer.MethodsThis clinical trial is a Phase 2, open-label study to assess the safety and efficacy of FLX475 in combination with pembrolizumab in patients with advanced or metastatic gastric cancer (NCT04768686). Approximately 90 subjects may be enrolled across 2 cohorts to examine the safety and efficacy when administered 100mg PO QD of FLX475 with 200mg IV Q3W of pembrolizumab. In cohort 1, checkpoint inhibitor naïve Epstein-Barr Virus (EBV)-negative gastric cancer subjects who have progressed on at least 2 prior systemic treatments for advanced or metastatic gastric cancer will be enrolled, and in cohort 2, checkpoint inhibitor naïve EBV-positive gastric cancer subjects who had at least 1 prior systemic treatment for advanced or metastatic gastric cancer will be enrolled. Both EBV negative and positive gastric cancer are predicted to express high levels of CCR4 ligands and enriched in Treg (i.e. ‘charged tumor’). The study is planned initially as a 2-stage design for each cohort, and an interim analysis reviewing efficacy and safety results as well as available PK and PD data for both cohorts will be performed prior to stage 2.AcknowledgementsThanks to the patients, and to their families and caregivers for allowing us to be part of the journey.RAPT Therapeutics, Inc., South San Francisco, CA, USA is providing FLX475 for the study.Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA is providing pembrolizumab for the study.Trial RegistrationNCT04768686ReferencesTalay O, et al. Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg). J Immunother Cancer 2017;5(Suppl 2):P467 (SITC 2017).Curiel, Tyler J, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine 10.9 (2004):942–949.Nakayama et al. Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus. J Virol 2004 February; 78(4):1665–74.van Marle S, et al. Pharmacokinetics, pharmacodynamics, and safety of FLX475, an orally-available, potent, and selective small-molecule antagonist of CCR4, in healthy volunteers. J Immunother Cancer 2018;6(Suppl 1):P484 (SITC 2018).

Intravesical immunotherapy or chemotherapy for non-muscle invasive bladder cancer is a well established treatment for preventing or delaying tumour recurrence following tumour resection. However, up to 70% of patients may fail and new intravesical agents with improved effectiveness are needed. Gemcitabine is a relatively new anticancer drug that has shown activity against bladder cancer. OBJECTIVES: To evaluate the effectiveness and toxicity of intravesical gemcitabine in preventing tumour recurrence and progression in non-muscle invasive bladder cancer (NMIBC). SEARCH METHODS: A search strategy was developed for MEDLINE to identify randomised trials of intravesical gemcitabine for the treatment of non-muscle invasive bladder cancer. The searches were from 1947 to May 2011. Other databases searched included EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, LILACS, SCOPUS, BNI, Biomed Central, Web of Science and BIOSIS. Handsearching of meeting proceedings, international guidelines and trial registries was also carried out. SELECTION CRITERIA: The titles and abstracts of the combined electronic and handsearching were manually screened by three authors independently to determine if they met the inclusion criteria for this review. Studies were selected if they were randomised, controlled trials or quasi-randomised clinical trials that included intravesical gemcitabine in at least one arm of a comparative study. DATA COLLECTION AND ANALYSIS: Data extraction was carried out by three reviewers. The information retrieved included the author's details, the study design, the characteristics of the recruited patients, details of the interventions and data relating to the primary, and secondary outcome measures. MAIN RESULTS: Six relevant randomised trials were identified with the number of patients randomised in each trial varying from 30 to 341 (total 704). All trials compared gemcitabine to active controls and varied in the reporting of outcomes. One study compared a single post-operative instillation of intravesical gemcitabine with a saline placebo in 341 patients and found no significant difference in the rates of tumour recurrence (28% versus 39%, respectively) or recurrence-free survival (HR (hazard ratio) 0.95, 95% CI 0.64 to1.39, P = 0.77). The rate of progression to invasive disease was greater with gemcitabine (2.4% versus 0.8%). A further trial compared gemcitabine with intravesical mitomycin C and demonstrated that the rates of recurrence (28% versus 39%) and progression (11% versus 18%) were lower with gemcitabine but did not reach statistical significance. The global incidence of adverse events was significantly less with gemcitabine (38.8% versus 72.2%, P = 0.02).Three trials compared gemcitabine with intravesical BCG but a meta-analysis was not possible due to clinical heterogeneity. In untreated patients at intermediate risk of recurrence (primary Ta-T1 no CIS) one trial showed that gemcitabine and BCG were similar with respective recurrence rates of 25% and 30% (P = 0.92) and overall progression equal (P = 1.0). Dysuria (12.5% versus 45%, P < 0.05) and frequency (10% versus 45%, P < 0.001) were significantly less with gemcitabine. In a second trial of high risk patients the recurrence rate was significantly greater with gemcitabine compared to BCG (53.1% and 28.1%, P = 0.04) and the time to recurrence significantly shorter with gemcitabine (25.5 versus 39.4 months, P = 0.042). Finally in a third trial of high risk patients who had failed previous intravesical BCG therapy, gemcitabine was associated with significantly fewer recurrences (52.5% versus 87.5%, P = 0.002) and a longer time to recurrence (3.9 versus 3.1 months, P = 0.9) compared to BCG. Progression rates were similar in both groups (33% versus 37.5%, P = 0.12) with no significant differences in grade 2 or 3 toxicities.The final trial was a marker lesion study which reported greater response rates when intravesical gemcitabine (2 g) was given as three bi-weekly doses (36%) or six weekly doses (40%) compared to a single dose (9%). AUTHORS' CONCLUSIONS: A single dose immediately following surgery is ineffective based on one study. Gemcitabine may be more active than mitomycin C with a lower toxicity profile. Compared to intravesical BCG therapy, gemcitabine had similar effects in intermediate risk patients, less effective in high risk patient and superior in BCG refractory patients. However, each randomised trial identified represents a different clinical setting in NMIBC and therefore the evidence base is limited. Consequently these data should be interpreted with caution until further corroborative evidence becomes available. The aim of intravesical therapy in NMIBC is to prevent tumour recurrence and progression and to avoid the morbidity associated with cystectomy. Intravesical gemcitabine is a promising drug that may add to the urologist's options in achieving this goal.

BACKGROUND Immunotherapy has revolutionized the clinical outcomes of intractable cancer patients. Little is known about the intestinal nonpathogenic bacterial composition of hepatocellular carcinoma (HCC) patients treated by immunotherapy. AIM To determine whether there is a correlation between gut bacterial composition and prognosis in HCC patients. METHODS From September 2019 to March 2020, we prospectively collected fecal samples and examined the gut microbiome of 8 advanced HCC patients treated with nivolumab as a second- or third-line systemic treatment. Fecal samples were collected before the start of immunotherapy. Fecal samples of patients with progression during treatment were collected at the time of progression, and fecal samples of patients who showed good response to nivolumab were collected after 5-7 mo as follow-up. Metagenomic data from 16S ribosomal RNA sequencing were analyzed using CLC Genomics Workbench. Microbiome data were analyzed according to therapeutic response. RESULTS All 8 patients were male, of which 6 had underlying chronic hepatitis B. A higher Shannon index was found in the responders than in the non-responders after nivolumab therapy (P = 0.036). The unweighted beta diversity analysis also showed that the overall bacterial community structure and phylogenetic diversity were clearly distinguished according to therapeutic response. There was no significant difference in the diversity or composition of the patient gut microbiome according to the immunotherapy used. Several taxa specific to therapeutic response were designated as follows: Dialister pneumosintes, Escherichia coli, Lactobacillus reteri, Streptococcus mutans, Enterococcus faecium, Streptococcus gordonii, Veillonella atypica, Granulicatella sp., and Trchuris trichiura for the non-responders; Citrobacter freundii, Azospirillum sp. and Enterococcus durans for the responders. Of note, a skewed Firmicutes/Bacteroidetes ratio and a low Prevotella/Bacteroides ratio can serve as predictive markers of non-response, whereas the presence of Akkermansia species predicts a good response. CONCLUSION The current presumptive study suggests a potential role for the gut microbiome as a prognostic marker for the response to nivolumab in treatment of HCC patients.

Adjuvant chemotherapy for gastric cancer, particularly stage III, improves survival after curative D2 gastrectomy. We investigated the clinical value of the lymph-node ratio (LNR; number of metastatic lymph nodes/number of lymph nodes examined) for selecting the appropriate adjuvant chemotherapy regimen in patients with D2-resected stage II/III gastric cancer.We reviewed the data of 819 patients who underwent curative D2 gastrectomy followed by adjuvant chemotherapy. Of them, 353 patients received platinum-based chemotherapy and 466 received TS-1. The patients were categorized into three groups according to their LNR (LNR 1, 0-0.1; LNR 2, 0.1-0.25; and LNR 3, 0.25), and their disease-free survival (DFS) was evaluated.The DFS curves of the patients were well separated according to stage and LNR. In multivariate analyses, an LNR 0.1 was strongly associated with the 3-year DFS (hazard ratio 2.402, 95% confidence interval 1.607-3.590, P 0.001). Platinum-based chemotherapy improved the 3-year DFS compared to TS-1 in patients with LNR 3 group in stage III gastric cancer (platinum vs. TS-1, median DFS 26.87 vs. 16.27 months, P = 0.028). An LNR 0.1 was associated with benefiting from platinum-based adjuvant chemotherapy in stage III gastric cancer patients with lymphovascular invasion (platinum vs. TS-1, median DFS 47.57 vs. 21.77 months, P = 0.011).The LNR can be used to select the appropriate adjuvant chemotherapy regimen for patients with D2-resected gastric cancer, particularly in stage III.

Background The clinical features and therapeutic strategies for gastric cancer with positive peritoneal washing cytology but without visible gross peritoneal metastasis have not been defined. The aim of this study was to evaluate the effect and clinical prognostic value of postoperative chemotherapy in gastric cancer patients with positive peritoneal washing cytology without gross peritoneal metastasis who underwent radical D2 gastrectomy in terms of disease-free survival (DFS) and overall survival (OS). Materials and Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent radical D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with positive cytology but without gross peritoneal metastasis were included in the study. In total, 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. Results Most gastric cancer patients with positive cytology without gross peritoneal metastasis demonstrated pT4 and/or pN3 disease. Postoperative chemotherapy improved DFS and OS compared to surgery only in gastric cancer patients with positive cytology without gross peritoneal metastasis (median DFS 11.63 vs. 6.98 months, p p p p

Background Extrapulmonary neuroendocrine carcinoma (EP-NEC) is an aggressive type of cancer with poor prognosis. Although several biological and histological markers are prognostic factors in NEC, the correlation between prognosis and systemic inflammation markers, such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), is unclear. This study evaluated the association between NLR or PLR and median overall survival (OS) or progression-free survival (PFS) in EP-NEC. Methods We retrospectively analyzed the clinical data from patients with unresectable or metastatic EP-NECs who received platinum-based chemotherapy at Chonnam National University Hwasun Hospital from August 2007 to March 2019. The cut-off values for NLR and PLR were 3 and 160, respectively. Results In total, 38 patients were analyzed. Both NLR and PLR at diagnosis had no significant associations with the response to initial chemotherapy. However, in the high-PLR group, median overall survival (OS) and progression-free survival (PFS) were poorer than those in the low-PLR group (high vs. low: 10.6 vs. 17.1 months, log-rank p = 0.007 and 4.1 vs. 9.3 months, log-rank p = 0.032, respectively). However, the high-NLR group had insignificantly poorer median OS and PFS than the low-NLR group. In the multivariate analysis, high PLR and LDH were independent prognostic factors for median OS and PFS. Conclusions High PLR was associated with shorter survival of EP-NEC patients receiving platinum-based chemotherapy. Therefore, PLR may be an independent prognostic factor in EP-NEC.

INTRODUCTION Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients. METHODS This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440). RESULTS The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2. CONCLUSION Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of perioperative systemic chemotherapy or immunotherapy (or both) for UTUC.

p73 is a member of the p53 family of transcription factors and, like p53, plays a role as a tumor suppressor. p73 is involved in development, proliferation, apoptosis and metastasis. However, the precise molecular mechanisms underlying its function in inhibiting metastasis remain largely unknown. Here, we show that induction of TAp73 decreased invasion and migration activity of colorectal cancer cells, whereas knockdown of TAp73 led to increased invasion and migration activity. KAI1 was identified as a transcriptional target of TAp73 and its expression is indispensable for TAp73-mediated inhibition of cell invasion and migration. Furthermore, induction of TAp73 in colorectal cancer cells elevated KAI1 expression and decreased the frequency of hepatic metastasis in vivo. Whereas, the decreased invasion and migration activities caused by TAp73 induction were abrogated by knockdown of KAI1. Interestingly, TAp73 and KAI1 are overexpressed in primary colorectal cancers and a significant correlation between TAp73 and KAI1 expression was detected, but their expressions were significantly down-regulated in metastatic cancers. Taken together, our results support a novel role for TAp73 in controlling colorectal cancer cell invasion, migration and metastasis by regulating transcription of KAI1.

Purpose Induction chemotherapy (ICT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CCRT) has the advantages of organ preservation and systemic control in head and neck cancer (HNC). Early prediction of CCRT efficacy may help identify patients who will benefit more from surgery than from CCRT. We investigated the role of interim 18-fluoro-2-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) after ICT to predict the efficacy of CCRT and clinical outcomes. Methods Tumor responses were retrospectively reviewed after CCRT based on the Response Evaluation Criteria in Solid Tumors. FDG PET-CT imaging was performed before and after three cycles of TPF. We examined the associations between the metabolic response (percentage decrease in the maximum standardized uptake value [SUVmax] and total metabolic tumor volume [MTV]) after ICT and complete response (CR) to CCRT, progression-free survival (PFS), and overall survival (OS). Results We studied 43 HNC patients with a median follow-up of 32.7 months. Lymph node (LN) SUVmax and total MTV decreases from baseline after ICT were greater in patients with a CR to CCRT than in non-CR patients (LN SUVmax, 88.8% vs. 62.5%, respectively; total MTV, 99.7% vs. 89.9%, respectively). Decreases in total MTV ≥ 78% and LN SUVmax ≥73% after ICT predicted CR to CCRT and longer OS and PFS. Conclusions Using interim FDG PET-CT to measure SUVmax and total MTV after three cycles of ICT may be a useful technique for identifying HNC patients who will benefit from CCRT and predicting survival outcomes. Electronic supplementary material The online version of this article (10.1007/s00259-017-3836-8) contains supplementary material, which is available to authorized users.

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65). Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.

// Jun Eul Hwang 1,4,* , Myung Seo Ki 1,4,* , Karham Kim 1,4 , Sung-Hoon Jung 1,4 , Hyun-Jeong Shim 1,4 , Woo-Kyun Bae 1,4 , Eu-Chang Hwang 2,4 , Young Hoe Hur 3,4 , Oh Jeong 3,4 , Seong Yeob Ryu 3,4 , Young Kyu Park 3,4 , Sang-Hee Cho 1,4 , Ju-Seog Lee 5 and Ik-Joo Chung 1,4 1 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Jeonnam, Korea 2 Department of Urology, Chonnam National University Hwasun Hospital, Jeonnam, Korea 3 Department of General Surgery, Chonnam National University Hwasun Hospital, Jeonnam, Korea 4 Chonnam National University Hwasun Hospital, Jeonnam, Korea 5 Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work as first co-authors Correspondence to: Ik-Joo Chung, email: // Keywords : gastric cancer, gastrectomy, prognosis, platinum, adjuvant chemotherapy Received : December 22, 2016 Accepted : March 01, 2017 Published : March 16, 2017 Abstract Adjuvant chemotherapy using TS-1 or capecitabine plus oxaliplatin improves survival outcomes after radical gastrectomy, with both regimens showing similar efficacies. A total of 494 patients with stage II‒III gastric cancer who underwent curative D2 gastrectomy and received adjuvant chemotherapy from April 2004 to June 2014 were included in this study. 219 patients received TS-1, and 275 received platinum-based chemotherapy. The disease-free survival associated with adjuvant chemotherapy with TS-1 was compared with that associated with fluoropyrimidine plus platinum chemotherapy to identify the subgroups that would benefit most from platinum-based chemotherapy. The platinum group consisted of younger individuals, more males and more stage III patients compared with the TS-1 group. To reduce selection bias and its effects on treatment results, we performed a propensity score-matched analysis. The matched cohort consisted of 219 TS-1 and 219 platinum treatment patients, respectively. In the matched cohort, the chemotherapeutic regimen did not affect disease-free survival according to stage (stage II: platinum vs. TS-1, P = 0.348; stage III: P = 0.132). According to the subgroup analysis, platinum-based chemotherapy resulted in an improved 3-year disease-free survival compared with TS-1 treatment (66.8% vs. 57.8%, P = 0.015) for patients with high-risk features (any two or more of pT4, pN3, and lymphovascular invasion positivity). Our results suggest that TS-1 alone is acceptable for patients without high-risk features, while platinum-based adjuvant chemotherapy should be administered to patients with high-risk features in D2-resected gastric cancer.

PURPOSE Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patients with resected colon cancer, including the underlying mechanism. MATERIALS AND METHODS FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines. RESULTS Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele. CONCLUSION The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

High metabolic activity, reflected in increased glucose uptake, is one of the hallmarks of many cancers including breast cancer. However, not all cancers avidly take up glucose, suggesting heterogeneity in their metabolic demand. Thus, we aim to generate a genomic signature of glucose hypermetabolism in breast cancer and examine its clinical relevance. To identify genes significantly associated with glucose uptake, gene expression data were analyzed together with the standardized uptake values (SUVmax) of (18)F-fluorodeoxy-glucose on positron emission tomography (PET) for 11 breast cancers. The resulting PET signature was evaluated for prognostic significance in four large independent patient cohorts (n = 5417). Potential upstream regulators accountable for the high glucose uptake were identified by gene network analysis. A PET signature of 242 genes was significantly correlated with SUVmax in breast cancer. In all four cohorts, high PET signature was significantly associated with poorer prognosis. The prognostic value of this PET signature was further supported by Cox regression analyses (hazard ratio 1.7, confidential interval 1.48–2.02; P

A good pathologic response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) is associated with a better prognosis. However, there is no effective method to predict CRT response in LARC patients. Therefore, this study used whole-exome sequencing (WES) to identify novel biomarker predicting CRT benefit in LARC. Two independent tumor tissue sets were used to evaluate the genetic differences between the good CRT response group (15 patients achieved a pathologic complete response (pCR)) and the poor CRT response group (15 patients with pathologic stage III). After applying WES to the discovery set of 30 patients, additional samples (n = 67) were genotyped for candidate variants using TaqMan or Sanger sequencing for validation. Overall, this study included a total of 97 LARC patients. In the discovery and validation set, there was no known genetic mutation to predict response between two groups, while five candidate variants (BCL2L10 rs2231292, DLC1 rs3816748, DNAH14 rs3105571, ITIH5 rs3824658, and RAET1L rs912565) were found to be significantly associated with pCR. In the dominant model, the GC/CC genotype of DLC1 rs3816748 (p = 0.032), AC/CC genotype of DNAH14 rs3105571 (p = 0.009), and TT genotype of RAET1 rs912565 (p

Purpose To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for non-muscle invasive bladder cancer (NMIBC). Materials and Methods We performed a comprehensive literature search on 11 September 2020. We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. Two review authors independently assessed the included studies and extracted data for the primary outcomes (time to recurrence, time to progression, grade III to V adverse events) and the secondary outcomes (time to death from bladder cancer, time to death from any cause, grade I or II adverse events, and disease-specific quality of life). We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. Results We found seven studies with 1,222 participants. Gemcitabine may reduce the risk of recurrence over time, but may have a similar effect on progression and grade III to V adverse events compared to saline. Gemcitabine may reduce recurrence and progression compared to mitomycin. We are uncertain about the effect of gemcitabine on the grade III to V adverse events compared to mitomycin. Gemcitabine may reduce recurrence and progression compared to giving BCG again in recurrent high-risk NMIBC after BCG treatment. Conclusions Based on the findings of this review, gemcitabine may have a favorable impact on recurrence and progression-free survival than saline and mitomycin but we are uncertain about how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high-risk diseases who have previously failed BCG., Graphical Abstract

This study was conducted to evaluate the long term complications and their risk factors including of survival outcomes in patients with locally advanced nasopharyngeal cancer (NPC) treated with docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CCRT).Among the patients who were diagnosed as NPC, we consecutively evaluated the late complications in 104 patients who completed 3 cycles of TPF induction chemotherapy followed by CCRT and received regular follow-up by otolaryngologist and oncologist. The prognostic factors for overall survival, relapse free survival and each complication were analyzed based on clinical characteristics.Over a median follow-up of 54 months (range, 7.9-152.9 months), 5-year overall survival rate was 87% for stage II, 89% for stage III, 87% for stage IV patients. The significant prognostic factor for survival is complete response rate after CCRT in multivariate analysis. The most frequent toxicity was ear complication (29.8%) including of hearing loss requiring hearing aid (6.7%) and bone necrosis (3.8%). Decreased renal function over grade 2 was occurred in only 4 patients (3.8%) regardless of the cumulative dose of cisplatin. The long term complications did not affect the survival outcome. Patients who received radiation therapy more than 5400 cGy had better survival outcome than those who did not. However, ear complication was significantly related to radiation dose (≥ 6,600 cGy) and type of radiation therapy (conventional). Age over 65 years was a significant risk factor for both ear and renal toxicity. In conclusion, close follow-up to monitor long-term complications should be performed in patients treated with TPF induction chemotherapy followed by CCRT treatment, especially in elderly patients. Reestablishing the optimal chemotherapeutic agent during CCRT and adjustment of radiation dose after induction chemotherapy could be helpful to reduce the toxicity associated with the subsequent treatment strategy for locally advance NPC patients.

Aim Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT3 receptor antagonist in a dose escalation clinical trial. Methods We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA. Results There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B-100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy. Conclusion These results suggest that the -AAG deletion variant of the 5-HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis.

Surgery is the only possible curative treatment for gastric cancer. However, the high recurrence rate makes gastric cancer difficult to cure by surgery alone. The present study was conducted to evaluate the clinical outcomes and toxicity of adjuvant treatment, including S-1/cisplatin chemotherapy followed by radiotherapy with concurrent S-1. Patients with radically D2-resected adenocarcinoma of the stomach of stage IB–IV (M0) were eligible. Patients were treated with S-1 (40–60 mg depending on the patient’s body surface area) twice daily for 3 weeks and cisplatin (60 mg/m2) intravenously on day 1 every 5 weeks. Patients received CRT (45 Gy of radiation at 1.8 Gy/day, 5 days per week, for 5 weeks with the same dose of S-1 during radiation) followed by two additional cycles of S-1/cisplatin. The primary endpoint was the 3-year disease-free survival (DFS) rate; the secondary endpoints were the 3-year overall survival rate and toxicities. Until May 2012, 46 patients were enrolled, and 34 (73.9 %) completed the planned treatment. The median age was 53 years (range: 31–69 years), and the numbers of patients with stage IB, II, III and IV disease were 0, 17, 25 and 4, respectively. Main grade 3–4 toxicities were as follows: neutropenia (28.2 %), nausea (17.4 %), vomiting (8.7 %) and anorexia (15.2 %). At the time of analysis, after a median follow-up period of 56.5 months (3.03–74.0 months), 16 recurrence events and 15 deaths were reported. The estimated 3-year DFS and survival rates were 65.2 and 76.1 %, respectively. The most common site of recurrence was the peritoneum (n = 12). The results of this phase II study show that intensified adjuvant treatment with S-1/cisplatin chemotherapy and S-1-based chemoradiotherapy was tolerable and effective in reducing disease recurrence. The addition of radiotherapy to chemotherapy may be effective in D2-resected gastric cancer. Although the data here are promising, a randomized trial is needed between patients treated with the current regimen and an appropriate comparator arm.

PURPOSE The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT). MATERIALS AND METHODS Peripheral blood samples from 244 patients treated with CRT for esophageal squamous cell carcinoma were assessed for the role of FGFR4 genotype on treatment response and survival. RESULTS A total of 94 patients were homozygous for the Gly388 allele, and 110 were heterozygous and 40 homozygous for the Arg388 allele. No significant association was found between the FGFR4 genotype and clinicopathological parameters. However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038). In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers. Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125). However, similar survival outcomes were observed for advanced-stage disease regardless of genotype. CONCLUSION This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage. It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages. In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.

4060 Background: Anti-EGFR therapy has been used as a standard treatment for metastatic colon cancer, but the innate resistance is still issues of increasing significance. Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cell proliferation, invasion and anti-apoptosis, through the pathway of MAPK-ERK and PI3K-AKT. We investigated potential crosstalk between FGFR4 and EGFR signaling to identify new resistant mechanism of anti-EGFR therapy and how to overcome it in colon cancer. Methods: RNA-Seq was used to identify the associated signal pathway and down targets induced by FGFR4. Molecular studies including RTK array, RT-qPCR, western blotting were performed to validate the interaction between FGFR4 and EGFR signaling in vitro and in vivo. Next, the effect of FGFR4 in cetuximab resistance was investigated in vitro and in colon cancer patients. Results: FGFR4 overexpression in colon cancer cells activates downstream signaling, such as, PI3K/Akt and RAS/RAF/Erk pathway. Gene Ontology (GO) analysis from RNA-seq revealed that differentially expressed genes (DEGs) altered by expression of FGFR4 were related to biological functions, including cell proliferation, epidermal growth factor receptor signaling, NIK/NF-kB signaling, interferon-gamma signaling, wound healing. RT–qRCR showed that FGFR4 promotes the EGFR and ErbB3 by inducing the expression of EGFR ligands such as AREG, BTC, EREG, HBEGF. In vivo tumorigenesis, we found that FGFR4 promotes tumor growth and high expression of AREG in xenograft tumors. FGFR4 expression reduced the sensitivity to cetuximab in colon cancer cells and synergistic effect was shown when treated with FGFR4 inhibitor with cetuximab. A positive correlation between FGFR4 and AREG expression was observed in cancer, but not in normal tissues and high FGFR4 or AREG expression showed significantly inferior overall survival than low expression in patients treated with cetuximab for metastatic colon cancer. Conclusions: We demonstrated a pivotal mechanism of FGFR4 in colon cancer progression and cetuximab resistance through inducing AREG. Our data point to FGFR4 as a new biomarker to predict cetuximab response and dual targeting of FGFR4 and EGFR may be a promising treatment modality for colon cancer.

4624 Background: There is no clear consensus on the second-line treatment for patients with metastatic pancreatic cancer (mPC). The aim of this study was to compare the efficacy and tolerability between liposomal irinotecan (nal-IRI) plus fluorouralcil/leucovorin (FL) and FOLFIRINOX (oxaliplatin/irinotecan/leucovorin/fluorouracil) in patients who failed to first-line gemcitabine-based therapy. Methods: In this retrospective study, 378 mPC patients who received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as the second-line treatment across 11 institutions from January 2015 to August 2019 were analyzed. The primary end point was progression free survival (PFS), and secondary end points were overall survival (OS), overall response rate, and tolerability. Results: There were no significant differences between the two groups in terms of baseline characteristics, except first-line regimen (previous gemcitabine/nab-paclitaxel, nal-IRI/FL, 85.6% vs. FOLFIRINOX, 51.5%; previous gemcitabine monotherapy, 5.8% vs. 24.5%). The median follow-up time was 6.0 months. The median PFS (nal-IRI/FL, 3.7 months vs. FOLFIRINOX, 5.0 months) and OS (nal-IRI/FL, 7.7 months vs. FOLFRINOX, 9.7 months) were comparable between two groups (P = 0.40 and 0.13, respectively). The overall response rate was not significantly different between two groups (nal-IRI/FL, 14% vs. FOLFRINOX, 16%; P = 0.644). In multivariate analysis, poor ECOG status, presence of liver metastasis, high NLR, and high CA19-9 were independent prognostic factors for PFS and OS, but chemotherapy regimen (nal-IRI/FL vs. FOLFRINOX) was not. In a subgroup analysis of patients with liver metastasis, FOLFIRINOX exerted significant PFS (median: 2.1 months vs. 4.1 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.02) and OS (median: 6.7 months vs. 8.4 months for nal-IRI/FL vs. FOLFIRINOX, respectively; P = 0.04) benefit compared with nal-IRI/FL. Grade 3 neutropenia or higher were more frequently observed in FOLFIRINOX (47.2%) than nal-IRI/FL (35%) (P = 0.033). Grade 3 peripheral neuropathy was also common in FOLFIRIONX (5.9%) group compared with nal-IRI/FL (1.0%) (P = 0.049). Conclusions: In second-line setting for mPC after progression on gemcitabine-based therapy, both nal-IRI/FL and FOLFIRINOX regimen showed comparable efficacy and acceptable safety outcomes. FOLFIRINOX regimen might be preferentially considered in patients with liver metastasis.

Background Although the acute toxicities during induction TPF in head and neck cancers are well known, there has been little studied about the long term complications including of outcomes in nasopharyngeal cancer (NPC). The purpose of this study is to evaluate the long term complications and survival outcomes in patients with locally advanced NPC treated with induction TPF followed by CRT. Methods From 2004 to 2016, 244 patients were diagnosed as NPC. Among them, 104 patients who completed the 3 cycles of TPF (docetaxel 75 mg/m2 and cisplatin 75/m2 day 1, plus fluorouracil 1000 mg/m2 days 1–4, every 3 wks) followed by CRT were evaluated. During CRT, cisplatin was given as either a weekly or 3 weeks regimen and RT was performed at 65–70 Gy. After completing TPF and CRT, follow up imaging and regular examination was checked by ENT specialist. Results The median follow-up duration was 60 months (range, 13-135). 5Y OS rate and 3Y PFS rate were 88.9±3.7% (95%CI 81.65-96.15) and 80.4±4.5 (95%CI 71.58-89.22). PFS was significantly associated with TNM (p = 0.001), especially N stage (N3, 3Y-PFS 42.9%, p = 0.001). The response after induction chemotherapy and postop CRT were significantly associated with PFS and OS. ENT complications such as hearing impairment, chronic infection, ear drum perforation were shown in 31 patients (30%) and renal impairment (Clcr≤60) was developed in 30 patients (30%). The incidence of both complications was significantly associated with age (>65 years, ENT Cx, p = 0.011, renal Cx, 0.032). However, age was not attenuate response rate or survival. The decreased Clcr before starting RT was associated with long term renal complication, and cumulative cisplatin dose did not affect treatment outcome. In addition, both ENT and renal toxicities were not associated with the radiation dose or cumulative cisplatin dose. Conclusions TPF followed by CCRT is an effective treatment scheme for advanced NPC. However, long term complications in ENT and decreased renal function were considerable, especially in elderly. Therefore, careful observation and management are required for high risk patients and optimal cisplatin adjustment could be prevent renal complication without affecting the treatment outcomes. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Pneumococcal vaccination (PCV13) is recommended to cancer patients undergoing systemic chemotherapy. However, the optimal time interval between vaccine administration and initiation of chemotherapy has been little studied in adult patients with solid malignancies. Methods We conducted a prospective randomized controlled trial to evaluate whether administering PCV13 on the first day of chemotherapy is non-inferior to vaccinating two weeks prior to chemotherapy initiation. Patients were randomly assigned to two study arms, and serum samples were collected at baseline and 4 weeks after vaccination to analyze the serologic response against Streptococcus pneumonia using a multiplexed opsonophagocytic killing assay. Results Of the 92 patients who underwent randomization, 43 patients in Arm A (vaccination 2 weeks before chemotherapy) and 44 patients in Arm B (vaccination on the first day of chemotherapy) were analyzed. Immunogenicity was assessed by geometric mean and fold-increase of post-vaccination titers, seroprotection rates (percentage of patients with post-vaccination titers > 1:64), and seroconversion rates (percentage of patients with > four-fold increase in post-vaccination titers). Serologic responses to PCV13 did not differ significantly between the two study arms according to all three types of assessments. Conclusions The overall antibody response to PCV13 is adequate in patients with gastric and colorectal cancer during adjuvant chemotherapy, and no significant difference was found when patients were vaccinated two weeks before or on the day of chemotherapy initiation. Clinical trial identification KCT0003379. Legal entity responsible for the study The authors. Funding National Research Foundation of Korea (NRF), Ministry of Health and Welfare of Korea. Disclosure All authors have declared no conflicts of interest.

Background Clinical features and therapeutic strategies for peritoneal washing cytology- positive (CY+) gastric cancer without gross peritoneal metastasis have not yet been defined. The aim of the study was to evaluate the clinical prognostic impacts of postoperative chemotherapy for treating gastric cancer patients with CY+ without peritoneal metastasis. Methods Intraoperative peritoneal washing cytology was performed in 285 patients who underwent curative D2 gastrectomy between April 2004 and May 2016. Of them, 88 patients with CY+ without peritoneal metastasis were included in the study. 64 patients received postoperative chemotherapy, whereas 24 patients underwent surgery only. We combined CY + 64 patients who received postoperative chemotherapy with another cohort of stage II/III gastric cancer patients (n = 819) who received adjuvant chemotherapy, for survival comparison. Results The Disease-free survival (DFS) and overall survival (OS) curves were well separated according to stage and CY+ in combined cohort (both, P Conclusions The prognosis of gastric cancer with CY+ without gross peritoneal metastasis is somewhat different from gastric cancer with overt peritoneal metastasis, and postoperative chemotherapy improves survival outcome in this patient group. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background To evaluate survival outcomes and prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who received sunitinib (SU) and pazopanib (PZ) as first-line therapy in real-world Korean clinical practice. Methods Data of 554 patients with mRCC who received SU or PZ at eight institutions between 2012 and 2016 were retrospectively reviewed. Based on the targeted therapy, the patients were divided into SU (n = 293) or PZ (n = 261) groups, and the clinicopathological variables and survival rates of the two groups were compared. A multivariable Cox proportional hazard model was used to determine the prognostic factors for OS. Results The median follow-up was 16.4 months (interquartile range, 8.3–31.3). Patients in the PZ group were older, and no significant difference was observed in the performance status (PS) between the two groups. In the SU group, the dose reduction rate was higher and the incidence of grade 3 toxicity was more frequent. The objective response rates were comparable between the two groups (SU, 32.1% vs. PZ, 36.4%). OS did not differ significantly between the two groups (SU, 36.5 months vs. PZ, 40.2 months; log-rank, P = 0.955). Body mass index, Eastern Cooperative Oncology Group PS > 2, synchronous metastasis, poor Heng risk criteria, and liver and bone metastases were associated with a shorter OS. Conclusion Our real-world data of Korean patients with mRCC suggested that SU and PZ had similar efficacies as first-line therapy for mRCC. However, PZ was better tolerated than SU in Korean patients., Graphical Abstract

Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials., There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.

There is limited data on the clinical and biological parameters that enable the prediction of the benefits derived from additional chemotherapy after disease progression compared with standard chemotherapy in patients with metastatic colorectal cancer (mCRC). The present study evaluated the role of tumor response as a clinical parameter and single nucleotide polymorphisms (SNPs) as a biomarker to predict the benefit of additional 5-fluorouracil (5-FU) rechallenge chemotherapy in patients with refractory mCRC. Tumor responses were retrospectively reviewed based on the Response Evaluation Criteria in Solid Tumors, early tumor shrinkage (ETS) and depth of response (DoR) following first-line chemotherapy in patients with stage IV CRC. Together with these parameters, SNPs known to be associated with the response to chemotherapy were analyzed with survival outcomes. In total, the tumor responses of 242 patients with mCRC were evaluated. Overall response and ETS were identified in 110 (45.4%) and 103 patients (42.6%), respectively, and the median DoR was 38.5±30.08%. ETS and DoR were significantly associated with survival outcomes, including progression-free survival, post-progression survival and overall survival. Among these patients, SNPs were analyzed in 171 patients. X-ray repair cross complementing 1 (XRCC1) (AG/AA) with a DoR >60%, good performance status and the absence of bone lesions were associated with improved overall survival. In patients receiving third-line chemotherapy with 5-FU rechallenge therapy, the methylenetretrahydrofolate reductase (MTHFR) (C677T) CC genotype and a DoR >60% were significantly associated with a good prognosis in multivariate analysis. XRCC1 (AG/AA) was also associated with a good prognosis in patients with mCRC. Patients with a DoR >60% following first-line chemotherapy and a MTHFR (C677T) CC genotype exhibited a survival benefit from 5-FU retreatment. Therefore, the DoR and MTHFR genotype are potential markers for selecting patients with refractory mCRC that would benefit from 5-FU rechallenge therapy.

Recently, several studies have shown that the De Ritis ratio (aspartate transaminase/alanine transaminase) can be a useful prognostic biomarker for certain types of malignant tumors. However, the prognostic value of the De Ritis ratio in patients with upper tract urothelial carcinoma remains largely unknown. The aim of the present study was to evaluate the prognostic significance of the De Ritis ratio in patients who had undergone radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma. In total, 1049 patients who underwent RNU at eight institutions from 2004 to 2015 were reviewed retrospectively. The De Ritis ratio and conventional clinicopathological parameters were analyzed. Survival analysis was performed using the Kaplan–Meier method and log-rank test. Multivariate analysis was carried out using the Cox proportional hazards regression model. De Ritis ratio cutoff values were derived from receiver operating characteristic (ROC) curves. ROC analysis showed the cutoff De Ritis ratio for overall death to be 1.6 (p = 0.002). The cancer-specific survival (CSS) and overall survival (OS) were significantly shorter for patients with a high De Ritis ratio (>1.6). Multivariate analysis revealed an independent relationship between an increased De Ritis ratio (>1.6) and shorter CSS (hazard ratio, HR 2.49, 95% confidence interval, CI 1.70–3.64; p = 0.001) and OS (HR 1.84, 95% CI 1.34–2.52; p = 0.001). The De Ritis ratio can be a significant predictor of oncological outcomes in patients with upper urinary tract urothelial carcinoma after surgery.

// Ho Song Yu 1,* , Jun Eul Hwang 3,* , Ho Seok Chung 1 , Yang Hyun Cho 1 , Myung Soo Kim 1 , Eu Chang Hwang 1 , Kyung Jin Oh 1 , Sun-Ouck Kim 1 , Seung Il Jung 1 , Taek Won Kang 1 , Dong Deuk Kwon 1 , Kwangsung Park 1 , Soo Bang Ryu 1,2 , Sung-Hoon Jung 3 , Young Hoe Hur 4 , Joon Hwa Noh 5 , Myung Ki Kim 6 , Ill Young Seo 7 , Chul-Sung Kim 8 , Sung Gu Kang 9 , Seok Ho Kang 9 and Jun Cheon 9 1 Department of Urology, Chonnam National University Medical School, Gwangju, Korea 2 Chonnam National University Research Institute of Medical Sciences, Gwangju, Korea 3 Department of Hemato-Oncology, Chonnam National University Medical School, Gwangju, Korea 4 Department of General Surgery, Chonnam National University Medical School, Gwangju, Korea 5 Department of Urology, Kwangju Christian Hospital, Gwangju, Korea 6 Department of Urology, Chonbuk National University Medical School, Jeonju, Korea 7 Department of Urology, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan, Korea 8 Department of Urology, Chosun University School of Medicine, Gwangju, Korea 9 Department of Urology, Korea University College of Medicine, Seoul, Korea * These authors have contributed equally to this work as first co-authors Correspondence to: Eu Chang Hwang, email: // Keywords : renal insufficiency, chronic, carcinoma, transitional cell, prognosis Received : January 02, 2017 Accepted : March 06, 2017 Published : March 15, 2017 Abstract Purpose: The aim of this study was to determine the effect of preoperative chronic kidney disease (CKD) on the prognosis of patients with upper urinary tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy (RNU). Results: The median follow-up period was 31.1 months (interquartile range: 16.2-55.7 months). Among the study patients, 224 patients in the non-CKD group were selected via propensity score matching. The median recurrence-free, cancer-specific, and overall survival were significantly shorter for patients with preoperative CKD than for non-CKD patients ( p = 0.001, p = 0.001, and p = 0.001, respectively). According to multivariable Cox regression analysis, preoperative CKD was related to worse recurrence-free (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.15-2.86, p = 0.011), cancer-specific (HR: 2.44, 95% CI: 1.44-4.14, p = 0.001), and overall survival (HR: 1.66, 95% CI: 1.15-2.40, p = 0.007). Methods: A total of 566 patients who underwent RNU at 6 institutions from 2004 to 2014 were retrospectively reviewed. Of these patients, 342 had an estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m 2 (non-CKD group) and 224 patients had an eGFR

Purpose: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer. Experimental Design: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity. Results: We identified the KITENIN/ErbB4–Dvl2–c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy. Conclusions: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.

Purpose: Systemic inflammatory responses, which are defined in terms of the Glasgow prognostic score (GPS), have been reported to be independent predictors of unfavorable outcomes in various human cancers. We assessed the utility of the GPS as a predictor of intravesical recurrence after radical nephroureterectomy (RNU) in upper urinary tract carcinoma (UTUC). Materials and Methods: We collected data for 147 UTUC patients with no previous history of bladder cancer who underwent RNU from 2004 to 2012. Associations between perioperative clinicopathological variables and intravesical recurrence were analyzed by using univariate and multivariate Cox regression models. Results: Overall, 71 of 147 patients (48%) developed intravesical recurrence, including 21 patients (30%) diagnosed with synchronous bladder tumor. In the univariate analysis, performance status, diabetes mellitus (DM), serum albumin, C-reactive protein, GPS, and synchronous bladder tumor were associated with intravesical recurrence. In the multivariate analysis, performance status (hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.41–3.85; p=0.001), DM (HR, 2.04; 95% CI, 1.21–3.41; p=0.007), cortical thinning (HR, 2.01; 95% CI, 1.08–3.71; p=0.026), and GPS (score of 1: HR, 6.86; 95% CI, 3.69–12.7; p=0.001; score of 2: HR, 5.96; 95% CI, 3.10–11.4; p=0.001) were independent predictors of intravesical recurrence. Conclusions: Our results suggest that the GPS as well as performance status, DM, and cortical thinning are associated with intravesical recurrence after RNU. Thus, more careful follow-up, coupled with postoperative intravesical therapy to avoid bladder recurrence, should be considered in these patients.

Background The platelet–lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR) have been reported as prognostic factors in various cancers, but their roles in metastatic renal cell cancer (mRCC) remain unclear. We investigated the significance of PLR and NLR, along with that of established prognostic factors, in mRCC patients receiving first-line tyrosine kinase inhibitors (TKI). Methods Data obtained from 63 mRCC patients who received first-line TKI between 2007 and 2013 were evaluated retrospectively. The association of PLR, NLR, and established prognostic factors with progression-free survival (PFS) and overall survival (OS) was analyzed using the Kaplan–Meier method. The influence of independent prognostic factors on survival was determined using multivariable Cox regression analysis. Results High NLR (>3.6) and PLR (>150) were related to shorter PFS (p = 0.001) and OS (p = 0.001). The presence of brain metastases [hazard ratio (HR) 4.94, 95% CI 1.75–13.9; p = 0.002] and high PLR (>150, HR 13.1, 95% CI 5.14–33.2; p = 0.001) were independently associated with PFS, and Eastern Cooperative Oncology Group Performance status ≥2 (HR 3.60, 95% CI 1.39–9.31; p = 0.008), lymph node metastasis (HR 2.76, 95% CI 1.11–6.86; p = 0.029), brain metastasis (HR 9.39, 95% CI 2.74–32.1; p = 0.001), and high PLR (>150, HR 16.1, 95% CI 4.41–58.4; p = 0.001) with OS. Conclusions High PLR was associated with shorter survival of mRCC patients receiving first-line TKI. The PLR may be an effective independent prognostic factor in this setting.

555 Background: Tumors expressing PD-L1 can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on these mechanism, the blockade PD-1/PD-L1 pathway based been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients. Methods: PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. Using the immunohistochemical stain, percentages of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ and ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment. Results: Strong PD-L1 expression was observed in 29% of all patients. PNI and lymphocyte response response were more frequently shown in strong PD-L1 patients. Among these patients, MSI was shown in 23 patients (12%). Although there was no significant difference between MSI and PD-L1 status, strong PD-L1 tended to better OS in MSS colon cancer (P = 0.056). In contrast, strong PD-L1 expression significantly correlated with significantly worse prognosis in disease free survival (P = 0.001) and overall survival (P < 0.001) than weak PD-L1 expression inMSI patients regardless of adjuvant chemotherapy. In MSI patients, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression patients (36.4%) than weak PD-L1 expression patients (14.3%). Conclusions: The expression of PD-L1 is differently affected on the survival according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting of immunosuppressive microenvironment in curative resected stage III colon cancer patient.

Primary angiosarcoma of the spleen is an extremely rare malignancy. Splenic angiosarcoma is difficult to diagnose, and treatment is often challenging. The prognosis is dismal, with a mean survival of less than 1 year. Currently, no standard treatment methods have been established. Anecdotal reports suggest that early diagnosis and prompt splenectomy followed by cytotoxic chemotherapy can be effective treatment modalities. We report a case of rapidly progressing primary splenic angiosarcoma with multiple liver and bone metastases and a fatal hemorrhagic outcome.

Purpose Locally advanced esophageal cancers are generally treated with neoadjuvant chemoradiotherapy, followed by surgery in operable candidates. However, even if the patients were diagnosed as operable disease, surgery could not be performed on patients with poor condition or other comorbidity. In this case, definitive chemoradiotherapy (dCRT) is the other option for localized esophageal cancer. Therefore, the purpose of this study was to evaluate the efficacy and clinical prognostic factors for dCRT in locally advanced esophageal cancer. Materials and methods We conducted a review of patients who received dCRT for locally advanced squamous esophageal cancer from 2004 to 2010, focusing on stages III and IVa. All patients received at least two cycles of platinum-based chemotherapy during radiation, and all tumor burdens were included in the radiation field. The treatment results were analyzed for patterns of failure and prognostic factors associated with survival. Results In total, 63 patients were enrolled in this study. The overall response rate was 84.1%. Relief from dysphagia after dCRT was achieved in 48 patients. The most frequent failure was local recurrence. The median overall survival (OS) was 23.0 months, and the 2-year survival rate was 45.4%. Similar results were observed for elderly study patients. Significant prognostic factors for OS were duration of smoking, high grade of dysphagia (score of 3 or 4), and shorter duration of progression-free and dysphagia-free survival. Maintenance chemotherapy after dCRT did not influence OS. However, "good risk" patients receiving maintenance chemotherapy showed better OS than those who did not receive maintenance chemotherapy (30.4 months vs. 12.0 months, p=0.002). Conclusion dCRT has a major role in improving survival and palliation of dysphagia in inoperable advanced esophageal cancer, even in elderly patients. Maintenance chemotherapy after dCRT may be effective in prolonging survival in "good risk" patients.

Two recent genome-wide association studies have identified that the rs2274223 single-nucleotide polymorphism inphospholipase C epsilon 1 and the single-nucleotide polymorphism rs13042395 in C20orf54 are involved in esophageal squamous cell carcinoma (ESCC) in Chinese populations. We hypothesized that genetic polymorphisms of phospholipase C epsilon 1 and C20orf54 are also associated with ESCC in a Korean population. The rs2274223 and rs13042395 genotyping was performed using high-resolution melting analysis. The rs2274223 GG genotype was significantly associated with an increased risk of ESCC (odds ratio [OR]=1.86, 95% confidence interval [CI]=1.08-3.25) compared with the rs2274223 AA genotype. The rs13042395 G allele showed a significantly decreased risk of ESCC in the younger age group (OR=0.71, 95% CI=0.52-0.97) and no significant association in the older group (OR=1.19, 95% CI=0.87-1.62). We observed that the rs2274223 polymorphism was associated with an increased risk of ESCC in this Korean case-control study and that age may modify the association between the rs13042395 polymorphism and the risk of ESCC.

This study evaluated the efficacy of percutaneous radiofrequency ablation (RFA) for the treatment of metachronous liver metastases of gastric cancer. We enrolled a total of 44 patients who underwent percutaneous RFA for the treatment of metachronous liver metastases after resection of a primary gastric adenocarcinoma from January 2002 to November 2011. The primary endpoint of this study was overall survival (OS) and recurrence-free survival (RFS) after RFA. Systemic chemotherapy was combined with RFA in 40 patients; the OS and RFS of the patients with liver-only metastasis who underwent RFA and chemotherapy were 20.9 months (95 % CI 18.4–23.4) and 9.8 months (95 % CI 9.2–10.5), respectively. On multivariate analysis, the factors independently, negatively associated with OS were extrahepatic metastatic lesions (HR 12.6, 95 % CI 3.7–42.9; p = 0.001), no chemotherapy (HR 43.3, 95 % CI 7.4–251.3; p = 0.001), and tumor number ≥2 (HR 2.6, 95 % CI 1.2–5.9; p = 0.015). The factors independently, negatively associated with RFS were extrahepatic metastatic lesions (HR 3.6, 95 % CI 1.6–7.8; p = 0.003) and bilobar intrahepatic distribution (HR 3.9, 95 % CI 1.5–9.9; p = 0.001). The efficacy of percutaneous RFA for metachronous liver metastases of gastric cancer is limited to patients with a single, unilobar metastasis without extrahepatic metastatic lesions. Combined systemic chemotherapy is very important for the prolongation of OS.

Background Clinical studies, with a proper scientific design, on the impact of disclosing a prognosis on a patient's psychological or physical conditions are rare. We investigated the effect of patient awareness of terminal status on survival and quality of life (QoL) in a palliative care setting. Methods This is a prospective cohort study of patients with terminal cancer. Patients with cancer at a palliative care unit were enrolled consecutively. The patients' awareness of their terminal status was determined using a semistructured interview. Sociodemographic and clinical characteristics, including Eastern Cooperative Oncology Group performance status, depressed mood, and QoL, were investigated. To determine the independent effects of awareness of illness on survival and QoL, multivariate Cox proportional-hazards regression and multivariate linear regression were used, respectively. Results For the 262 cases analyzed, the median survival time (interquartile range) was 28.5 (15.8–55.3) days, and 76 (29.0%) patients were unaware of their prognosis. Patients who were aware survived for a shorter period than did those who were unaware (HR, 1.44; 95% CI, 1.07–1.93, p = 0.015) after adjusting for clinical variables including physical status and depression. Also, patients who were aware reported lower subjective QoL compared with patients who were unaware in a multivariate linear regression analysis (B, −0.10; 95% CI, −0.17 to −0.03, p = 0.008). Conclusions Awareness of prognosis may negatively impact survival and QoL in terminally ill cancer patients. Therefore, the patient's preference for and individual susceptibility to receiving such information should be assessed carefully before disclosure. Copyright © 2013 John Wiley & Sons, Ltd.

Purpose Hypoxia-inducible factor-1α (HIF-1α) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1α. Recent reports suggested that HIF-1α also mediated the induction of class III β-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1α and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro. Materials and Methods The protein expression levels of HIF-1α and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel. Results Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1α and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1α and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1α and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. Conclusion We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.

PURPOSE The purpose of this study is to evaluate the effect of diabetes mellitus (DM) and preoperative glycemic control on prognosis in Korean patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). MATERIALS AND METHODS A total of 566 patients who underwent RNU at six institutions between 2004 and 2014 were reviewed retrospectively. Kaplan-Meier and Cox regression analyses were performed to assess the association between DM, preoperative glycemic control, and recurrence-free, cancer-specific, and overall survival. RESULTS The median follow-up period was 33.8 months (interquartile range, 41.4 months). A total of 135 patients (23.8%) had DM and 67 patients (11.8%) had poor preoperative glycemic control. Patients with poor preoperative glycemic control had significantly shorter median recurrence-free, cancer-specific, and overall survival than patients with good preoperative glycemic control and non-diabetics (all, p=0.001). In multivariable Cox regression analysis, DM with poor preoperative glycemic control showed association with worse recurrence-free survival (hazard ratio [HR], 2.26; 95% confidence interval [CI], 1.31 to 3.90; p=0.003), cancer-specific survival (HR, 2.96; 95% CI, 1.80 to 4.87; p=0.001), and overall survival (HR, 2.13; 95% CI, 1.40 to 3.22; p=0.001). CONCLUSION Diabetic UTUC patients with poor preoperative glycemic control had significantly worse oncologic outcomes than diabetic UTUC patients with good preoperative glycemic control and non-diabetics. Further investigation is needed to elucidate the exact mechanism underlying the impact of glycemic control on UTUC treatment outcome.