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The aim of this study was to evaluate the activity and the safety of a combination regimen of capecitabine and doxorubicin as salvage chemotherapy in advanced gastric cancer patients who had undergone one or two prior chemotherapy regimens. Patients received capecitabine, 2,500 mg/m2/day PO for 14 days (D1–14) and doxorubicin, 30 mg/m2 IV on day 1 every 3 weeks until disease progression. The response was evaluated according to RECIST criteria, and the toxicity was evaluated by NCI-CTC (version 2.0). Forty-five patients were enrolled. Twenty-six patients were treated as second-line chemotherapy and the remaining patients as third-line chemotherapy. A total of 152 cycles of chemotherapy (median 2, range 1–12) were administered. Median dose intensities of capecitabine and doxorubicin were 11,326 and 9.6 mg/m2/week, respectively. The overall response rate was 6.7% (95% CI, 4.1–12.5%) and the disease control rate was 46.7% (95% CI, 28.6–87.1%) according to an intent-to-treat analysis. The median progression-free survival was 11.3 weeks (95% CI, 5.6–16.7 weeks). The median overall survival was 29.1 weeks (95% CI, 18.3–39.9 weeks) with one-year survival rate of 24%. Severe (grade III/IV) hematologic and non-hematologic toxicity was uncommon and included nausea/vomiting in five (11.1%), neutropenia in two (4.4%), anemia in one (2.2%), and hand-foot syndrome in one patient (2.2%). The combination of capecitabine and doxorubicin is a feasible salvage regimen in advanced pre-treated gastric cancer. [ABSTRACT FROM AUTHOR]

Purpose: Since the combination of capecitabine and irinotecan has successfully been used as a first-line treatment in metastatic colorectal cancer (MCRC), we expected promising results when given as a second-line treatment to metastatic colorectal patients who had been pretreated with 5-Fluorouracil and Oxaliplatin.Methods: Thirty-three MCRC patients participated in this study and received an oral dose of 1,000 mg/m(2 )capecitabine twice daily on days 1-14 and a dose of 100 mg/m(2) irinotecan infused over 90 min on days 1 and 8, every 3 weeks.Results: The overall response rate in intent-to-treat was 33.3% (95% CI, 21.5-58.3%), including one complete response (3.0%) and ten partial responses (30.3%); 12 patients (36.4%) had disease stabilization and only 9 (27.3%) progressed. The median time to progression was 6.7 months (95% CI, 4.8-8.6 months). After a median follow-up time of 12 months, nine patients (27.3%) were still alive with metastatic disease. The median response duration for all patients was 6.7 months (95% CI, 3.9-9.5 months) and the median overall survival was 13.4 months (95% CI, 11.0-15.8 months) with a 1-year survival rate of 55.4%. Myelosuppression was commonly observed; NCI-CTC (v 2.0) grade 3/4 neutropenia, however, occurred in eight (24%) patients and grade 3 anemia was seen in one patient (3%). The most common (grade 3/4) non-hematological toxicity was diarrhea (15%) and the other severe grade 3/4 toxicities included nausea/vomiting in one patient (3%), stomatitis in one patient (3%), hand-foot syndrome in one patient (3%).Conclusions: The combination of capecitabine and irinotecan is an effective and well-tolerated regimen for second-line treatment of metastatic colorectal cancer. However, further phase III trials are required to clarify its use in the treatment of metastastic colorectal cancer patients who have been pretreated with 5-fluorouracil and oxaliplatin. [ABSTRACT FROM AUTHOR]

BACKGROUND: Combination chemotherapy with gemcitabine and a platinum-based agent is regarded as a standard treatment for patients with advanced biliary-tract cancer. Results of phase 2 trials of single-agent erlotinib in biliary-tract cancer and of gemcitabine plus erlotinib in pancreatic cancer have shown modest benefits. Therefore, we aimed to investigate the efficacy of gemcitabine and oxaliplatin plus erlotinib versus chemotherapy alone for advanced biliary-tract cancer. METHODS: In this open label, randomised, phase 3 trial, we randomly assigned patients (in a 1:1 ratio) with metastatic biliary-tract cancer (cholangiocarcinoma, gallbladder cancer, or ampulla of Vater cancer) to receive either first-line treatment with chemotherapy alone (gemcitabine 1000 mg/m(2) on day 1 and oxaliplatin 100 mg/m(2) on day 2) or chemotherapy plus erlotinib (100 mg daily). Treatment was repeated every 2 weeks until disease progression or unacceptable toxic effects. Randomisation was done centrally (stratified by participating centre and presence of measurable lesion). The primary endpoint was progression-free survival. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01149122. FINDINGS: 133 patients were randomly assigned to the chemotherapy alone group and 135 to the chemotherapy plus erlotinib group. The groups were balanced except for a higher proportion of patients with cholangiocarcinoma in the group given erlotinib than in the chemotherapy alone group (96 [71%] patients vs 84 [63%]). Median progression-free survival was 4·2 months (95% CI 2·7-5·7) in the chemotherapy alone group and 5·8 months (95% CI 4·6-7·0) in the chemotherapy plus erlotinib group (hazard ratio [HR] 0·80, 95% CI 0·61-1·03; p=0·087). Significantly more patients had an objective response in the chemotherapy plus erlotinib group than in the chemotherapy alone group (40 patients vs 21 patients; p=0·005), but median overall survival was the same in both groups (9·5 months [95% CI 7·5-11·5] in the chemotherapy alone group and 9·5 months [7·6-11·4] in the chemotherapy plus erlotinib group; HR 0·93, 0·69-1·25; p=0·611). All-cause deaths within 30 days of random assignment occurred in one (1%) of the patients in the chemotherapy alone group and in four (3%) of those in the chemotherapy plus erlotinib group. The most common grade 3-4 adverse event was febrile neutropenia (eight [6%] patients in the chemotherapy alone group and six [4%] in the chemotherapy plus erlotinib group). No patient died of treatment-related causes during the study. Subgroup analyses by primary site of disease showed that for patients with cholangiocarcinoma, the addition of erlotinib to chemotherapy significantly prolonged median progression-free survival (5·9 months [95% CI 4·7-7·1] for chemotherapy plus erlotinib vs 3·0 months [1·1-4·9] for chemotherapy alone; HR 0·73, 95% CI 0·53-1·00; p=0·049). INTERPRETATION: Although no significant difference in progression-free survival was noted between groups, the addition of erlotinib to gemcitabine and oxaliplatin showed antitumour activity and might be a treatment option for patients with cholangiocarcinoma. FUNDING: None. [ABSTRACT FROM AUTHOR]

Purpose: Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC)., Materials and Methods: Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity., Results: RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D., Conclusion: A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibition of LATS require further improvement in terms of both activity, selectivity and drug-like properties. Through scaffold hopping aided by docking studies and AI-assisted prediction of metabolic stabilities, we successfully identified an advanced LATS inhibitor demonstrating potent kinase activity, exceptional selectivity against other kinases, and superior oral pharmacokinetic profiles., Competing Interests: The authors declare that they have no known competing financial interests. The content and writing are solely responsible to the authors., (This journal is © The Royal Society of Chemistry.)

Background: We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification., Patients and Methods: A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test., Results: Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2., Conclusions: Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC)., Patients and Methods: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety., Results: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08)., Conclusion: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Background/aim: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents., Patients and Methods: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors., Results: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC., Conclusion: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC)., Methods: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m 2 or dose level 2, 80 mg/m 2 ) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis., Results: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival., Conclusions: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Evidence on whether prior antibiotic (pATB) administration modulates outcomes of programmed cell death protein-1 (PD-1) inhibitors in advanced gastric cancer (AGC) is scarce. In this study, we find that pATB administration is consistently associated with poor progression-free survival (PFS) and overall survival (OS) in multiple cohorts consisting of patients with AGC treated with PD-1 inhibitors. In contrast, pATB does not affect outcomes among patients treated with irinotecan. Multivariable analysis of the overall patients treated with PD-1 inhibitors confirms that pATB administration independently predicts worse PFS and OS. Administration of pATBs is associated with diminished gut microbiome diversity, reduced abundance of Lactobacillus gasseri, and disproportional enrichment of circulating exhaustive CD8 + T cells, all of which are associated with worse outcomes. Considering the inferior treatment response and poor survival outcomes by pATB administration followed by PD-1 blockade, ATBs should be prescribed with caution in patients with AGC who are planning to receive PD-1 inhibitors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Trastuzumab-containing chemotherapy is the recommended first-line regimen for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. We evaluated the safety and efficacy of trastuzumab combined with ramucirumab and paclitaxel as second-line treatment for HER2-positive G/GEJ cancer., Patients and Methods: Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line treatment with trastuzumab-containing chemotherapy were enrolled from five centers in the Republic of Korea. Patients were administered a 28-day cycle of trastuzumab (once on days 1, 8, 15, and 22: 2 mg/kg followed by 4 mg/kg loading dose), ramucirumab (once on days 1 and 15: 8 mg/kg), and paclitaxel (once on days 1, 8, and 15: dose level 1, 80 mg/m 2 ; or dose level -1, 70 mg/m 2 ). Phase II was conducted with the recommended phase II dose (RP2D). Primary end points were determination of RP2D during phase Ib and investigator-assessed progression-free survival (PFS) in patients treated with RP2D., Results: Dose-limiting toxicity at dose level 1 was not documented during phase Ib, and a full dose combination was selected as the RP2D. Among 50 patients with a median follow-up duration of 27.5 months (95% CI, 17.4 to 37.6), median PFS and overall survival were 7.1 months (95% CI, 4.8 to 9.4) and 13.6 months (95% CI, 9.4 to 17.7), respectively. Objective response rate was 54% (27 of 50, including one complete response), and disease control rate was 96% (48 of 50). Loss of HER2 expression was observed in 34.8% (8 of 23) patients after first-line treatment, and no definite association between HER2 expression and the outcome was revealed. Safety profiles were consistent with previous reports., Conclusion: Trastuzumab combined with ramucirumab and paclitaxel showed appreciable efficacy with manageable safety profiles in patients with previously treated HER2-positive G/GEJ cancer.

Bile duct cancer, or cholangiocarcinoma, is a rare disease with limited treatment options that include surgery and cytotoxic chemotherapy. The high recurrence rate and poor prognosis of this type of cancer highlights the need to identify new and more effective therapeutic targets. In this study, we found that AXL, a receptor tyrosine kinase, is highly expressed in biliary cancer patients and significantly correlated with poor patient outcomes, including metastasis and low survival rates. We also demonstrated that targeting AXL inhibits tumor progression. In vitro studies with bile duct cancer cells (SNU1196 and HUCCT1) showed that genetic knockdown of AXL significantly reduced both tumor cell growth and invasion. In addition, in vivo studies using subcutaneous and orthotopic intrahepatic models demonstrated that genetic inhibition of AXL resulted in tumor-growth delay. To further examine the possible clinical translation of AXL inhibition in the clinic, we tested the efficacy of AVB-500, a soluble AXL receptor, in reducing AXL activation and tumor growth. AVB-500 was effective at inhibiting AXL activation and decreasing the growth and invasion of SNU1196 and HUCCT1 tumors which possess high AXL expression. Most importantly, AVB-500 was highly effective at decreasing tumor dissemination of bile duct tumor cells in the peritoneal cavity. This study strongly supports the idea of using the AXL receptor as a new therapeutic target to treat the growth and progression of biliary cancer.

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC., (© 2022. The Author(s).)

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3, and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.

Background: Investigations for programmed cell death-1 (PD-1) blockade-induced hyperprogressive disease (HPD) have not been stringently conducted in patients with advanced gastric cancer (AGC). We explored the occurrence of HPD and its clinical implications in patients with AGC and treated with PD-1 inhibitors., Methods: We enrolled 169 patients with AGC and treated with either the PD-1 blockade (nivolumab or pembrolizumab; N = 112) or irinotecan monotherapy (N = 57) as a single agent. Tumour growth dynamics based on tumour growth kinetics and tumour growth rate (TGR) and time to treatment failure were analysed to define HPD. The incidence, clinical consequences and predictive markers of HPD were investigated., Results: The optimal criteria for HPD were 4-fold increases in both tumour growth kinetics and TGR ratios and a 40% increase in TGR based on the analysis for patients treated with irinotecan. In total, 10.7% (12/112) of patients experienced HPD after PD-1 inhibitor treatment. Patients with HPD had both shorter progression-free survival (hazard ratio: 2.318; 95% confidence interval: 1.205-4.460) and overall survival (hazard ratio: 2.542; 95% confidence interval: 1.314-4.918) than patients with progressive disease without HPD, losing opportunities for subsequent systemic treatments. Although other variables including PD-L1 expression were not associated with the occurrence of HPD, hypoalbuminemia (<3.25 mg/dL) at baseline was significantly associated with the occurrence of HPD (P < 0.001) and inferior survival outcomes., Conclusions: HPD occurs in a proportion of patients with AGC and treated with PD-1 inhibitors. PD-1 inhibitor-induced HPD is associated with worse outcome, loss of eligibility for subsequent treatment and hypoalbuminemia, warranting further investigation., Competing Interests: Conflicts of interest Nothing to be declared., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We investigated the predictors of survival in patients with advanced BTC according to their baseline nutritional status estimated by the Nutritional Risk Screening (NRS)-2002. From September 2006 to July 2017, we reviewed the data of 601 inpatients with BTC. Data on demographic and clinical parameters was collected from electronic medical records, and overall survival (OS) and progression-free survival were analyzed using the Kaplan-Meier method and the stepwise Cox regression analysis. Patients with an NRS-2002 score of ≤ 2, 3, and ≥ 4 were respectively classified as "no risk," "moderate risk," "high risk." Following initial NRS-2002 score, 333 patients (55%) were classified as "no-risk," 109 patients (18%) as "moderate-risk," and 159 patients (27%) as "high-risk." Survival analysis demonstrated significant differences in the median OS: "no-risk": 12.6 months (95% confidence interval [CI], 11.5-13.7); "moderate-risk": 6.1 months (95% CI, 4.3-8.0); and "high-risk": 3.9 months (95% CI, 3.2-4.6) (p < 0.001). NRS-2002 score was an independent factor for OS (hazard ratio [HR], 1.616 for "moderate-risk", 95% CI, 1.288-2.027, p < 0.001; HR, 2.121 for "high-risk", 95% CI, 1.722-2.612, p < 0.001), along with liver metastasis, peritoneal seeding, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, cholesterol, carcinoembryonic antigen, and carbohydrate antigen 19-9. In conclusion, baseline NRS-2002 is an appropriate method for discriminating those who are already malnourished and who have poor prognosis in advanced BTC patient. Significance of these results merit further validation to be integrated in the routine practice to improve quality of care in BTC patients., Competing Interests: Conflict of Interest: The authors declare that they have no competing interests., (Copyright © 2022. The Korean Society of Clinical Nutrition.)

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.

Plekha7 (Pleckstrin homology [PH] domain containing, family A member 7) regulates the assembly of proteins of the cytoplasmic apical zonula adherens junction (AJ), thus ensuring cell-cell adhesion and tight-junction barrier integrity. Little is known of Plekha7 function in cancer. In colorectal cancer (CRC) Plekha7 expression is elevated compared to adjacent normal tissue levels, increasing with clinical stage. Plekha7 was present at plasma membrane AJ with wild-type KRas (wt-KRas) but was dispersed in cells expressing mutant KRas (mut-KRas). Fluorescence lifetime imaging microscopy (FLIM) indicated a direct Plekha7 interaction with wt-KRas but scantily with mut-KRas. Inhibiting Plekha7 specifically decreased mut-KRas cell signaling, proliferation, attachment, migration, and retarded mut-KRAS CRC tumor growth. Binding of diC8-phosphoinositides (PI) to the PH domain of Plekha7 was relatively low affinity. This may be because a D175 amino acid residue plays a "sentry" role preventing PI(3,4)P 2 and PI(3,4,5)P 3 binding. Molecular or pharmacological inhibition of the Plekha7 PH domain prevented the growth of mut-KRas but not wt-KRas cells. Taken together the studies suggest that Plekha7, in addition to maintaining AJ structure plays a role in mut-KRas signaling and phenotype through interaction of its PH domain with membrane mut-KRas, but not wt-KRas, to increase the efficiency of mut-KRas downstream signaling., (Copyright © 2021. Published by Elsevier Inc.)

Background: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. We assessed the efficacy and tolerability of pemetrexed and cisplatin combination therapy in patients with refractory bone and soft tissue sarcoma (STS)., Patients and Methods: Patients were included in this multicenter, phase II study (ClinicalTrials.gov identifier NCT03809637) if they progressed after receiving one or more chemotherapy regimens containing an anthracycline and/or ifosfamide. Pemetrexed was first administered intravenously, followed by cisplatin, over a cycle of 21 days, for a maximum of six cycles. The primary endpoint was a progression-free rate (PFR) at 3 months (3-month PFR)., Results: From January 2017 to September 2019, we enrolled 37 patients; of these, 73% had previously undergone three or more rounds of chemotherapy. Five patients (13.5%) exhibited objective responses, including two patients (2/6, 33.3%) with malignant peripheral nerve sheath tumors, one patient (1/4, 25%) with synovial sarcoma, one patient (1/4, 25%) with undifferentiated pleomorphic sarcoma, and one patient (1/4, 25%) with angiosarcoma. The median progression-free survival was 2.6 months, and the 3-month PFR was 45.9% (n = 17). None of the four patients with osteosarcoma exhibited objective responses or were progression free at 3 months. The most frequent treatment-related grade 3-4 toxicities included neutropenia (16.2%), anemia (13.5%), thrombocytopenia (13.5%), and fatigue (8.1%). Among 26 patients (70.3%) available for immunohistochemical assessments, patients in the low-excision repair cross-complementation group 1 (ERCC1) and low-thymidylate synthase expression groups showed a tendency for longer overall survival., Conclusions: Combination therapy with pemetrexed and cisplatin was associated with clinically meaningful and sustained responses among patients with advanced and refractory STS. The combination therapy met its predefined primary study endpoint., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The trastuzumab biosimilar CT-P6 has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). Here, we present the first real-world comparison of CT-P6 versus RTZ with dual HER2-targeted therapy for the neoadjuvant and palliative first-line treatment with HER2-positive EBC and metastatic breast cancer (MBC) patients in two tertiary hospitals in Korea., Methods: We retrospectively investigated medical records in the Severance Breast Cancer Registry in Korea. We identified patients with HER2-positive EBC (n=254) who had received neoadjuvant chemotherapy with RTZ or CT-P6, plus pertuzumab, carboplatin and docetaxel (TCHP) and untreated stage IV MBC (n=103) who had received palliative first-line treatment with RTZ or CT-P6, plus pertuzumab and docetaxel (THP) between May 2014 and December 2019. The primary endpoints were pathologic complete response (pCR) in the EBC and progression-free survival (PFS) in the MBC cohort. Overall survival (OS), overall response rate (ORR), disease control rate (DCR), and cardiac safety were secondary endpoints., Results: A similar percentage of EBC patients achieved a pCR with CT-P6 versus RTZ (74.4% [93/125]) vs 69.8% [90/129], p =0.411). For patients with MBC, median follow-up duration was 23.0 and 41.0 months for CT-P6 and RTZ groups, respectively; median PFS did not differ significantly between two groups (13.0 vs 18.0 months, 95% confidence intervals (CIs) 0.0-26.6 vs 11.3-24.7, p =0.976). The ORR, DCR, and cardiac safety profiles did not also show significant difference efficacy outcomes between two groups., Conclusions: These real-world data suggest that biosimilar trastuzumab CT-P6 has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients, when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant or palliative setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bae, Kim, Ahn, Jeung, Sohn, Kim, Kim, Kim, Park, Park, Kim and Jeong.)

There are no means to predict patient response to neoadjuvant chemotherapy (NAC); the impact of skeletal muscle loss on the response to NAC remains undefined. We investigated the association between response to chemotherapy and skeletal muscle loss in breast cancer patients. Patients diagnosed with invasive breast cancer who were treated with NAC, surgery, and radiotherapy were analyzed. We quantified skeletal muscle loss using pre-NAC and post-NAC computed tomography scans. The response to treatment was determined using the Response Evaluation Criteria in Solid Tumors. We included 246 patients in this study (median follow-up, 28.85 months). The median age was 48 years old (interquartile range 42-54) and 115 patients were less than 48 years old (46.7%). Patients showing a complete or partial response were categorized into the responder group (208 patients); the rest were categorized into the non-responder group (38 patients). The skeletal muscle mass cut-off value was determined using a receiver operating characteristic curve; it showed areas under the curve of 0.732 and 0.885 for the pre-NAC and post-NAC skeletal muscle index ( p < 0.001 for both), respectively. Skeletal muscle loss and cancer stage were significantly associated with poor response to NAC in locally advanced breast cancer patients. Accurately measuring muscle loss to guide treatment and delaying muscle loss through various interventions would help enhance the response to NAC and improve clinical outcomes.

Background: Sarcopenia, systemic inflammation, and low muscularity significantly impact the survival of cancer patients. However, few studies have investigated how sarcopenia and systemic inflammation affect the prognosis of biliary tract cancer with distant metastasis. In this study, we investigated the association between sarcopenia with systemic inflammation and prognosis of metastatic biliary tract cancer. Materials and Methods: Data collected from 353 metastatic biliary tract cancer patients from 2007 to 2016 were analyzed. To evaluate the skeletal muscle mass, computed tomography images at the upper level of the third lumbar vertebra (L3) were used. Sarcopenia was defined using the Japan Society of Hepatology guideline; L3 muscle index <42 cm 2 /m 2 for male and <38 cm 2 /m 2 for female patients. Systemic inflammation was evaluated using the neutrophil lymphocyte ratio (NLR). Patients with NLR > 3 were categorized into the inflammatory category. The overall survival (OS) and progression free survival (PFS) were analyzed. Subgroup analysis was performed on those who received gemcitabine/cisplatin (GP) chemotherapy and depending on the presence of sarcopenia and inflammation. Results: Patients with sarcopenia showed lesser 1-year OS than those without (25.5 vs. 38.2%, p = 0.019). The patients with high NLR (NLR > 3) were associated with a shorter OS than were those with a low NLR (NLR ≤ 3) (21.0 vs. 52.8%, p < 0.001). Based on these results, we categorized the patients into three groups; sarcopenia accompanied by high NLR, no sarcopenia and low NLR, and either sarcopenia or high NLR. The OS of patients was well-stratified according to this grouping (1-year OS; 18.3 vs. 30.3 vs. 55.8%, p < 0.001). Concordant with OS results, the PFS was well-stratified based on the presence of either sarcopenia or high NLR (Sarcopenia; 9.5 vs. 19.4%, p < 0.001, NLR; 10.0 vs. 23.4%, p < 0.001). The PFS was significantly associated with high NLR and sarcopenia (1-year PFS; 7.8 vs. 13.0 vs. 27.9%, p < 0.001). Conclusion: Sarcopenia with inflammation was associated with inferior OS and PFS. In addition, sarcopenia accompanied by inflammation was associated with poor prognosis. Conservative treatments such as nutritional support, exercise, and pharmacologic intervention could help metastatic biliary tract cancer patients to overcome sarcopenia and the inflammatory status., (Copyright © 2020 Lee, Cho, Kim, Jeung and Lee.)

The Hippo pathway plays a pivotal role in tissue homeostasis and tumor suppression. YAP and TAZ are downstream effectors of the Hippo pathway, and their activities are tightly suppressed by phosphorylation-dependent cytoplasmic retention. However, the molecular mechanisms governing YAP/TAZ nuclear localization have not been fully elucidated. Here, we report that Mastermind-like 1 and 2 (MAML1/2) are indispensable for YAP/TAZ nuclear localization and transcriptional activities. Ectopic expression or depletion of MAML1/2 induces nuclear translocation or cytoplasmic retention of YAP/TAZ, respectively. Additionally, mutation of the MAML nuclear localization signal, as well as its YAP/TAZ interacting region, both abolish nuclear localization and transcriptional activity of YAP/TAZ. Importantly, we demonstrate that the level of MAML1 messenger RNA (mRNA) is regulated by microRNA-30c (miR-30c) in a cell-density-dependent manner. In vivo and clinical results suggest that MAML potentiates YAP/TAZ oncogenic function and positively correlates with YAP/TAZ activation in human cancer patients, suggesting pathological relevance in the context of cancer development. Overall, our study not only provides mechanistic insight into the regulation of YAP/TAZ subcellular localization, but it also strongly suggests that the miR30c-MAML-YAP/TAZ axis is a potential therapeutic target for developing novel cancer treatments., Competing Interests: The authors declare no competing interest.

Purpose: Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. Nutrition risk screening aims to increase awareness and allow early recognition and treatment of cancer cachexia. Therefore, screenings should be brief, inexpensive, highly sensitive, and have good specificity. Simplified Nutritional Appetite Questionnaire (SNAQ) is a simple screening tool including four questions, and validated to predict weight loss within 6 months in community-dwelling adults and nursing home residents. Our study aimed to translate the SNAQ into Korean, and to assess the validity and reliability of the translated screening tool in advanced cancer patients., Materials and Methods: The SNAQ was translated into Korean according to linguistic validation. The internal consistency of the SNAQ was evaluated by Cronbach's alpha coefficient. Test-retest reliability was evaluated using the intraclass correlation coefficient. Concurrent validity was evaluated by measuring the Pearson's correlation coefficient between the SNAQ and Mini-Nutritional Assessment (MNA) and Patient-Generated Subjective Global Assessment (PG-SGA)., Results: In the 194 patients included in full analysis set, cancer stage was predominantly metastatic (98.5%), the mean age was 60 years (range, 23 to 81 years), and the mean body mass index was 24 kg/m2 (range, 15.6 to 39.6 kg/m2). According to MNA score ≤ 11, 57 patients (29.4%) were malnourished. The mean score (±standard deviation) of the Korean version of the SNAQ was 13.8±2.5 with a range of 6-19. Cronbach's alpha coefficient was 0.737, and intraclass correlation coefficient was 0.869. The SNAQ was moderately correlated with MNA (r=0.404, p < 0.001) and PG-SGA (r=-0.530, p < 0.001). A significant weight loss of > 5% of the original bodyweightwithin 6 months occurred in 46 of the 186 patients (24.7%). SNAQ score ≤ 14 predicted > 5% weight loss with a sensitivity of 56.5% and a specificity of 44.3%., Conclusion: The Korean version of the SNAQ had high validity and reliability. SNAQ is useful for the screening tool for advanced cancer patients. The SNAQ had a limitation to predict impending weight loss in advanced cancer patients.

Purpose: This study aimed to determine the prognostic value of new quantitative parameters of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), including metabolic tumor volume (MTV), in patients with locally advanced and metastatic gallbladder cancer (GBC)., Materials and Methods: In total, 83 patients initially diagnosed with locally advanced and metastatic GBC and who underwent ¹⁸F-FDG PET/CT at the time of initial diagnosis were retrospectively reviewed. The metabolic volume-based PET parameters of primary tumors and metastatic lesions were measured, including maximum and average standardized uptake values (SUV), MTV, and total lesion glycolysis. An overall survival (OS) analysis was performed using the Kaplan-Meier method with PET and clinical parameters. A Cox proportional hazards regression analysis was performed to determine independent prognostic factors., Results: In univariate analysis, pathologic differentiation ( p <0.001), performance status (PS; p =0.003), C-reactive protein (CRP) level ( p =0.009), and PET-related SUV mt max (the highest SUV among the metastatic lesions) ( p =0.040) and MTV total (the sum of the MTVs of both the primary and metastatic lesions) ( p =0.031), were significant for OS. In multivariate analysis, MTV total (hazard ratio: 2.07; 95% confidence interval: 1.23-3.48; p =0.006) remained significant for the prediction of OS, as did differentiation ( p =0.001), PS ( p =0.001), and CRP ( p =0.039)., Conclusion: In locally advanced and metastatic GBC, volume-based PET/CT parameters of the total tumor burden of malignancy, such as MTV total , were found to be useful for the identification of patients with poor prognosis., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2019.)

Chemotherapy may negatively affect nutritional status and quality of life (QOL) in pancreatic cancer patients. Our aim was to investigate the beneficial effects of oral nutrition supplements (ONS) on pancreatic and bile duct cancer patients undergoing chemotherapy. Among patients with progressive pancreatic and bile duct cancer receiving chemotherapy, the ONS group ( n = 15) received two packs of ONS daily for 8 weeks while the non-ONS group ( n = 19) did not. Anthropometric measures, dietary intake, nutritional status, and quality of life were assessed. ONS significantly increased daily intakes of energy, carbohydrates, proteins, and lipids at 8 weeks compared to the baseline. After 8 weeks, fat mass significantly increased in the ONS group. For patients in their first cycle of chemotherapy, body weight, fat-free mass, skeletal muscle mass, body cell mass, and fat mass increased in the ONS group but decreased in the non-ONS group. Fat mass increased in second or higher cycle only in the ONS group. Patient-generated subjective global assessments (PG-SGA) and fatigue scores in the Quality of Life Questionnaire Core 30 (QLQ-C30) improved in the ONS group. ONS might improve nutritional status by increasing fat mass and/or maintaining the body composition of pancreatic and bile duct cancer patients with chemotherapy, especially those in the first cycle, and alleviate fatigue symptoms.

Background: Sarcopenia, defined as skeletal muscle loss, has been known as a poor prognosis factor in various malignant diseases The aim of this study is to investigate the effect of sarcopenia on prognosis in patients with esophageal cancer who received concurrent chemo- and radiotherapy (CCRT). Methods: We retrospectively collected clinical data of 287 patients with esophageal cancer who were treated by definite CCRT at Gangnam Severance and Severance hospital from August 2005 to December 2014. The cross-sectional area of muscle at the level of the third lumbar vertebra was measured using pre- and post-CCRT computed tomography images. Sarcopenia was defined as skeletal muscle index <49 cm 2 /m 2 for men and of <31 cm 2 /m 2 for women by Korean-specific cutoffs. Overall survival (OS) and progression free survival (PFS) were analyzed according to sarcopenia. Results: Sarcopenia identified before CCRT did not affect OS and PFS. However, patients with post-CCRT sarcopenia showed shorter OS and PFS than patients without it (median OS: 73 months vs. 28 months; median PFS: 34 months vs. 25 months, respectively). Post-CCRT sarcopenia was an independent prognostic factor of poor OS (hazards ratio: 1.697; 95% confidence interval: 1.036-2.780; P = 0.036). In multivariate analysis, male sex ( P = 0.004) and presence of CCRT-related complications, such as esophagitis or general weakness were significantly associated with post-CCRT sarcopenia ( P = 0.016). Conclusions: Sarcopenia after CCRT can be a useful predictor for long-term prognosis in patients with esophageal cancer. To control CCRT-related complications may be important to prevent skeletal muscle loss during CCRT.

Background & Aims: We investigated the predictors of overall survival (OS) among Korean patients with advanced pancreatic cancer (PC) according to their baseline nutritional status., Methods: We retrospectively reviewed the data of 412 inpatients with PC between January 2007 and February 2015 at the Department of Oncology of the Gangnam Severance Hospital, Korea. Data on demographic and clinical parameters were collected from electronic medical records, and OS was estimated using the Kaplan-Meier method. Stepwise Cox regression analysis was used to determine the factors associated with survival. Patients with a Nutritional Risk Screening (NRS) 2002 score <3 were classified as "no-risk; " those with a score of 3 were classified as "moderate-risk; " and those with a score of ≥4 were classified as "high-risk.", Results: Following nutritional screening at baseline, 194 patients (47.1%, mean age 61.8 ± 9.9 years) were classified as the "no risk" group; 81 patients (19.7%, mean age 65.4 ± 10.8 years), as the "moderate risk" group; and 137 patients (33.3%, mean age 67.8 ± 12.0 years), as the "high risk" group. Predictors of survival were NRS 2002 score (hazard ratio [HR] = 1.238; 95% confidence interval [CI] = 1.143-1.341), percentage of lymphocytes (HR = 0.973; 95% CI = 0.962-0.984), C-reactive protein level (HR = 1.003; 95% CI = 1.001-1.006), carcinoembryonic antigen level (HR = 1.000; 95% CI = 1.000-1.000), and carbohydrate antigen 19-9 level (HR = 1.000; 95% CI = 1.000-1.000). Kaplan-Meier survival analysis showed significant differences in the median OS among the NRS 2002 groups: "no risk" group: 12.3 ± 0.4 months (95% CI: 11.47-13.13 months); "moderate risk" group: 6.5 ± 0.9 months (95% CI: 4.78-8.17 months); and "high risk" group: 5.5 ± 0.6 months (95% CI: 4.31-6.69 months)., Conclusions: A good baseline nutritional status was associated with OS among Korean patients with advanced PC. An improvement in the nutritional status of patients with advanced PC through baseline nutritional interventions is therefore necessary to prolong OS., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Human epidermal growth factor 2 (HER2) gene overexpression in breast carcinoma cell lines has been shown to drive mammary carcinogenesis and tumor growth and invasion through its effects on mammary stem cells., Objective: Therefore, we investigated the mechanism by which HER2 regulates cancer stem cell (CSC) activity in gastric cancer cells., Methods: HER2 was transfected into MKN28 gastric cancer cells, and its role in regulating CSC activity was determined by characterizing the HER2-overexpressing cells., Results: The sphere formation assay revealed that the sphere sizes and frequency of sphere formation were significantly greater for the HER2-overexpressing cells than for the MKN28 control cells. The CSC markers Oct-4 and BMI1 were more highly expressed in the HER2-overexpressing cells, as were the EMT markers. This was accompanied by a significant enhancement in cellular invasion of the Matrigel and migration. The E-cadherin level was significantly downregulated, and the mesenchymal marker Snail upregulated, in the HER2-transfected cells. HER2 overexpression activated the well-characterized CSC-associated Wnt/β-catenin signaling pathway, as shown by the luciferase assay. After treatment of these cells with the Wnt signal inhibitor PRI-724, the BMI1 and Oct-4 levels were decreased for 24 h and Snail was also downregulated. Immunofluorescence staining revealed the significant restoration of E-cadherin levels in the HER2-transfected cells after PRI-724 treatment., Conclusions: These results established a role for HER2 in regulating gastric CSC activity, with Wnt/β-catenin signaling being mediated via a HER2-dependent pathway. In summary, HER2-overexpressing gastric cancer cells exhibited increased stemness and invasiveness and were regulated by Wnt/β-catenin signaling., (© 2019 S. Karger AG, Basel.)

Background: With advances in gastric cancer chemotherapy, conversion surgery has drawn attention as a new strategy to improve the outcome of stage IV disease. We investigated the efficacy of conversion surgery following chemotherapy for patients with stage IV gastric cancer., Methods: We retrospectively reviewed clinico-pathologic variables and oncologic outcomes for 101 patients with stage IV gastric cancer who were treated with systemic chemotherapy followed by gastrectomy with intension of curative resection from January 2005 to December 2012., Results: In terms of the best response from palliative chemotherapy, complete or partial response were observed in 65 patients (64.4%) in overall. Complete response of metastatic site were observed in 72 (71.3%) and 66 (65.3%) patients as best and pre-operative response, respectively. The overall complete macroscopic resection, rate was 56.4%. Eleven patients (10.9%) received combined metastasectomy. There was no postoperative surgery-related mortality for 1 month. The median overall survival time was 26.0 months. Multivariable analysis identified complete macroscopic resection, chemotherapy response (complete response/partial response) of metastatic sites, and change in CEA level as independent prognostic factors contributing to overall survival., Conclusions: Patients with stage IV gastric cancer who exhibit a good clinical response to chemotherapy might obtain greater survival benefit from gastrectomy following chemotherapy compared with patients who exhibit a poor response to chemotherapy. Prospective, randomized trials are required to determine the best strategy for combining initial chemotherapy with subsequent gastrectomy.

Purpose: With growing evidence that inflammation and low muscularity play a role in the survival of cancer patients, we evaluated the prognostic implications of sarcopenia with systemic inflammation in patients who underwent definitive chemoradiotherapy (CCRT) for locally advanced head and neck cancer. Materials and Methods: We analyzed 221 patients with head and neck cancer who received definitive CCRT between 2006 and 2015. The skeletal muscle area was measured using a single computed tomography image slice at the level of the third lumbar vertebra (L3). Sarcopenia was defined as an L3 muscle index of <49 cm 2 /m 2 for men and <31 cm 2 /m 2 for women. Results: Patients with sarcopenia ( n = 106) exhibited higher neutrophil/lymphocyte ratios (NLRs) than those without ( n = 115); the former also had an inferior 3-year overall survival (OS) rate (62%) than the latter (76%, p = 0.037). Among patients with sarcopenia, those who also had high NLRs ( n = 51) showed significantly poorer OS and progression-free survival (PFS). In the multivariate analysis, sarcopenia plus a high NLR remained the most significant predictor of poor OS and PFS. Patients with sarcopenia required more frequent interruption of RT; patients whose RT was interrupted for ≥5 days showed inferior disease control and OS. Conclusions: Sarcopenia accompanied by systemic inflammation at initial diagnosis is associated with significantly inferior OS and PFS. Additionally, patients with sarcopenia required RT interruption more frequently. Intensive nutritional support and additional treatment methods are required for these patients while undergoing RT.

Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c-MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET-negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET-related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors., (© 2018 UICC.)

Background: Lung cancer is being increasingly detected in the early stages, highlighting the importance of lung cancer screening. However, there is no consensus on the post-operative management of stage IB non-small cell lung cancer (NSCLC). Therefore, this study aimed to identify the predictive factors for prognosis of stage IB NSCLC and determine the efficacy of adjuvant chemotherapy on recurrence and survival., Methods: We enrolled 89 patients with stage IB NSCLC who underwent complete resection surgery at Gangnam Severance Hospital from Jan 2008 to Dec 2014. As per the National Comprehensive Cancer Network guidelines, patients were considered to be at high risk when they showed poorly differentiated tumors, lymphovascular invasion, tumor size >4 cm, and visceral pleural invasion (VPI)., Results: Among the 89 patients, 27 underwent adjuvant chemotherapy. Young patients or patients with squamous cell lung cancer received adjuvant chemotherapy frequently. Adjuvant chemotherapy was not a significant factor for disease-free survival and overall survival. Adjuvant chemotherapy did not show a significant protective effect for survival, even for high-risk patients. However, VPI was a significant risk factor for disease-free survival [hazard ratio (HR): 7.051; 95% confidence interval (CI): 1.570-31.659; P=0.011] and overall survival (HR: 8.289; 95% CI: 1.036-66.307; P=0.046), even after adjustment for various factors., Conclusions: Adjuvant chemotherapy does not affect the prognosis of stage IB NSCLC, even in high-risk patients. Additionally, VPI is a strong prognostic factor of stage IB NSCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Anoctamin (ANO)/transmembrane member 16 (TMEM16) proteins mediate diverse physiological and pathophysiological functions including cancer cell proliferation. The present study aimed to identify the role of ANOs in pancreatic cancer., Methods: In an initial screen of ANOs, ANO9/TMEM16J was overexpressed in pancreatic cancer cells, and its role in the pathogenesis of pancreatic cancer was evaluated using an integrated in vitro and in vivo approach. To determine clinical relevance of the experimental findings, the prognostic value of ANO9 was evaluated in patients with pancreatic cancer., Results: The ANO9 mRNA and protein levels were increased in pancreatic cancer-derived cells. Exogenous expression of ANO9 in PANC-1 cells significantly increased cell proliferation in cell cultures and in mice. In contrast, knockdown of ANO9 in AsPC-1, BxPC-3, and Capan-2 cells strongly inhibited cell proliferation. Mechanistic analysis suggested that physical association of ANO9 with epidermal growth factor receptor (EGFR) underlies ANO9-induced cell proliferation. Knockdown of ANO9 augmented the effects of the EGFR inhibitor and the cytotoxic agent on pancreatic cancer cell proliferation. In addition, high ANO9 expression is a poor prognostic factor in patients with pancreatic cancer., Conclusions: The ANO9/TMEM16J appears to be a clinically useful prognostic marker for pancreatic cancer and a potential therapeutic target.

Purpose: Metastatic biliary tract cancer (mBTC) has a dismal prognosis. In this study, an independent dataset of patients with mBTC was used to implement and validate a routine clinico-laboratory parameter-based scoring model for risk group identification., Materials and Methods: From September 2006 to February 2015, 482 patients with mBTC were assigned randomly (ratio, 7:3) into investigational (n=340) and validation datasets (n=142). The continuous variables were dichotomized using a normal range or the best cutoff values determined using the Contal and O'Quigley statistical methods. Following a Cox's proportional hazard model, the scoring model was derived by summing the rounded chi-square scores for the factors identified by multivariate analysis., Results: The performance status (Eastern Cooperative Oncology Group 3-4), hypoalbuminemia (< 3.4 mg/dL), carcinoembryonic antigen (≥ 9 ng/mL), neutrophil-to-lymphocyte ratio (≥ 3.0), and carbohydrate antigen 19-9 (≥ 120 U/mL) were identified as independent prognosticators (Harrell's C index, 0.682; integrated area under the curve, 0.653). Survival was clearly correlated with the risk groups (low, intermediate, and high, 14.0, 7.3, and 2.3 months, respectively; p < 0.001). The prognosis was also discriminative in the validation data set (median survival, 16.7, 7.5, and 1.9 months, respectively; p < 0.001). Chemotherapy did not offer any survival benefits for high-risk patients., Conclusion: These proposed prognostic criteria for mBTC can facilitate accurate patient risk stratification and treatment-related decision-making.

Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, and G2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based on BRCA2 variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively. Chemo-sensitivity, P/CAF and BubR1 expression and acetylation, BRCA2-P/CAF and BRCA2-BubR1 interactions, and HAT activities of the clones with BRCA2 variation were compared. We identified an association between chemo-sensitivity and BRCA2 N372H variation. The IC 50 of paclitaxel in heterozygous variation was higher than that of wild type. There were no differences in basic expression levels of BRCA2 among variant types. However, P/CAF expression, of BRCA2-P/CAF interaction, and HAT activity were significantly lower in heterozygous variants than in the wild type. After HDAC inhibitor treatment, HAT activity and paclitaxel sensitivity were restored in variant cells. Cell lines transformed from wild to variant or from variant to wild showed reciprocal changes in P/CAF expression, BRCA2-P/CAF interaction, HAT activity, and paclitaxel sensitivity. Forced expression of the BRCA2 heterozygous variant induced paclitaxel resistance due to altered HAT activity (p<0.001). This was reversed by the TSA combination. Restoration of wild BRCA2 from variant type improved paclitaxel sensitivity (p<0.001). Modulation of HAT activity by BRCA2 N372H variation is a new mechanism of paclitaxel resistance in breast cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Human telomerase reverse transcriptase (hTERT) expression level may not always correlate with telomerase activity. The present study analyzed hTERT splicing patterns with respect to hTERT and telomerase activity in colorectal cancer. Telomerase activity was determined by telomeric repeat amplification protocol assay, and spliced variants of hTERT were identified by reverse transcription-polymerase chain reaction in 40 colorectal cancer tissue samples. In the lower range of telomerase activity (0-100 units), the percentage of the β variant decreased with the increment in telomerase activity, whereas in the higher range of telomerase activity (>100 units), total hTERT expression level revealed a trend toward increment. There was a positive correlation between the full-length variant level and β variant level. Conversely, there was a negative correlation between the percentage of the full-length variant and β variant. Tumor-node-metastasis stage was the strongest prognostic factor in multivariate analysis and the percentage of the full-length variant was an independent prognostic factor for survival. Telomerase activity was primarily altered with changes in alternative splicing of the full-length and β variants of hTERT in colorectal cancer.

Objective: The aim of this study was to analyze the clinicopathologic characteristics and prognosis of signet ring cell carcinoma (SRC) according to disease status (early vs advanced gastric cancer) in gastric cancer patients., Background: The prognostic implication of gastric SRC remains a subject of debate., Methods: A retrospective analysis was performed using the clinical records of 7667 patients including 1646 SRC patients who underwent radical gastrectomy between 2001 and 2010. A further analysis was also performed after dividing patients into three groups according to histologic subtype: SRC, well-to-moderately differentiated (WMD), and poorly differentiated adenocarcinoma., Results: SRC patients have younger age distribution and female predominance compared with other histologic subtypes. Notably, the distribution of T stage of SRC patients was distinct, located in extremes (T1: 66.2% and T4: 20%). Moreover, the prognosis of SRC in early gastric cancer and advanced gastric cancer was contrasting. In early gastric cancer, SRC demonstrated more favorable prognosis than WMD after adjusting for age, sex, and stage. In contrast, SRC in advanced gastric cancer displayed worse prognosis than WMD. As stage increased, survival outcomes of SRC continued to worsen compared with WMD., Conclusions: Although conferring favorable prognosis in early stage, SRC has worse prognostic impact as disease progresses. The longstanding controversy of SRC on prognosis may result from disease status at presentation, which leads to differing prognosis compared with tubular adenocarinoma.

Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study. A higher frequency of chemoresistance to microtubule-modulating agents was found in cell lines with wild-type ABCB1 compared to cell lines with 2677G>T/A ABCB1 variant. Based on the pharmacogenetic association study with 2677 variant, we identified seven genes that could predict chemosensitivity to microtubule dynamics modulators. The classification accuracy with these seven genes was 90.0%, and the predicted probability was 0.73. LAMP1 was the only gene that was commonly related to chemosensitivity. LAMP1 expression levels were relatively higher in chemoresistant ABCB1 wild-type compared to chemosensitive polymorphic cells. But, there was no difference in ABCB1 expression levels between the two groups. Following LAMP1 siRNA, chemosensitivity was restored due to increased intracellular drug accumulation in wild type cell line. In conclusion, ABCB1 2677G>T/A variant enhances chemosensitivity on microtubule dynamics through LAMP1 inhibition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: This study focused on implementation of a prognostic scoring index based on clinico-laboratory parameters measured routinely on admission in metastatic pancreatic cancer patients., Materials and Methods: Records from 403 patients of metastatic disease were analyzed retrospectively. Continuous variables were dichotomized according to the normal range or the best cut-off values statistically determined by Contal and O'Quigley method, and then analyzed in association with prognosis-overall survival (OS), using Cox's proportional hazard model. Scores were calculated by summing the rounded chi-square scores for the factors that emerged in the multivariate analysis., Results: Performance status, hemoglobin, leucocyte count, neutrophil-lymphocyte ratio, and carcinoembryonic antigen were independent factors for OS. When patients were divided into three risk groups according to these factors, median survival was 11.7, 6.2, and 1.3 months for the low, intermediate, and high-risk groups, respectively (p < 0.001). Palliative chemotherapy has a significant survival benefit for low and intermediate-risk patients (median OS; 12.5 months vs. 5.9 months, p < 0.001 and 8.0 months vs. 2.0 months, p < 0.001, respectively)., Conclusion: We advocate the use of a multivariable approach with continuous variables for prognostic modeling. Our index is helpful in accurate patient risk stratification and may aid in treatment selection., Competing Interests: relevant to this article was not reported.

Purpose: We investigated the prognostic factors for recurrence in Korean patients with stage II colon cancer and evaluated their predictive significance with 5-fluorouracil (FU)-based adjuvant chemotherapy., Methods: We analyzed the relationship between clinicopathological features and relapse-free survival (RFS) of 716 stage II colon cancer patients who underwent curative resection. Predictive values were assessed using 5-year RFS and 5-year cancer-specific survival (CSS)., Results: The 5-year RFS, 5-year CSS, 5-year disease-free survival, and 5-year overall survival rates were 87.4, 94.9, 84.8, and 90.5 %, respectively. T4 stage (hazard ratio [HR], 2.342; 95 % confidence interval [CI], 1.348-4.068; p = 0.003), preoperative bowel obstruction or perforation (HR 2.428; 95 % CI 1.241-4.752; p = 0.010), and age older than 70 years (HR 1.740; 95 % CI 1.130-2.678; p = 0.012) were poor prognostic factors for recurrence in multiple Cox regression analyses. In 60 patients with T4 disease, 5-FU-based adjuvant chemotherapy was associated with improved 5-year CSS of the patients (90.3 vs. 46.7 %; HR 0.135; 95 % CI 0.035-0.517; p = 0.003)., Conclusions: We found discordance between the risk factors for recurrence and the predictive value for 5-FU-based adjuvant chemotherapy in Korean patients with stage II colon cancer. Future prospective clinical trials selectively targeting high-risk patients are needed.

Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site-directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer., (©2014 American Association for Cancer Research.)

Purpose: We conducted a phase II study evaluating safety and efficacy of combination gemcitabine and capecitabine therapy for metastatic breast cancer patients following anthracycline and taxane treatment in Korea., Methods: This was a single-arm, non-randomized phase II study. Patients received 1,000 mg/m(2) gemcitabine intravenously over 30 min on days 1 and 8, and 1,250 mg/m(2) capecitabine orally twice daily on days 1-14 until disease progression or intolerable toxicity occurred. This regimen was repeated every 3 weeks. The primary outcome assessed was overall response rate [ORR, complete response (CR) + partial response (PR) as the best response], and secondary outcomes were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) [maintenance of CR + PR + stable disease (SD) for at least 3 months], drug toxicity, and predictive factors for response to this regimen., Results: Of 41 patients, the ORR was 39.0% (CR 0%; PR 39.0%), and DCR was 78.0% using this chemotherapy. DCR for 6 and 12 months was 68.3 and 26.8%, respectively. Median PFS was 10.0 months [95% confidence interval (CI) 7.8-12.1], and median OS was 25.1 months (95% CI 18.2-32.1). Prominent toxicities were neutropenia and hand-foot syndrome. Most adverse events were well known, relatively moderate, and reversible. Taxane sensitivity [odds ratio (OR) 0.169; 95% CI 0.034-0.826; P = 0.028] and hepatic metastasis (OR 0.097; 95% CI 0.017-0.559; P = 0.009) were significantly predictive of response to gemcitabine and capecitabine combination., Conclusions: This study showed reproducible anticancer activity and tolerable toxicity of gemcitabine and capecitabine combination therapy in recurrent or metastatic Korean breast cancer patients previously treated with anthracycline and taxane.

Objective: Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer., Methods: Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles., Results: Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes., Conclusion: The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

As an angiogenic factor, thymidine phosphorylase (TP) expression in primary tumours has been thought to be a risk factor for lymph node (LN) and hepatic metastasis in patients with gastric adenocarcinoma. However, the molecular basis for the induction of metastasis by TP is largely unknown. We aim to elucidate the role of TP expression in gastric cancer neovascularisation and LN metastasis.The angiogenic and lymphangiogenic activity (CD31, D2-40, Ki-67, VEGFC, VEGFR3) and expression status of TP were detected in 103 resected human gastric carcinoma samples by immunohistochemistry. The influence of TP expression on neovascularisation and cancer cell invasion was further comparatively investigated in two groups of nude mice intraperitoneally injected with TP overexpressing MKN-45 cells (MKN-45/TP) and control cells (MKN-45/CV). In gastric cancer tissues, we found that high TP expression and various angiogenic and lymphangiogenic activities were significantly associated with poor prognostic outcomes. In addition, TP expression was also found to be associated with neovascularisation activity of gastric cancer tissues. In vivo, the MKN-45/TP group exhibited significantly increased infiltrating tumour nodules and neovascularisation activity compared to the MKN-45/CV group. TP could strongly influence gastric cancer progression via the dual activities of angiogenesis and lymphangiogenesis.

Background: Due to improved survival rate, gastric cancer (GC) patients have an increased risk of developing multiple primary cancer (MPC). The purpose of this study is to evaluate the clinicopathological features of MPC and to generate useful tools for the prediction of metachronous MPC following gastrectomy., Methods: 3066 patients who underwent curative resection of GC were reviewed retrospectively, based on the clinical information and the medical record., Results: The 5-year incidence of MPC was 2.5%. Of these, 54.3% had a metachronous MPC, while 45.7% had a synchronous MPC. The most prevalent site of metachronous MPC was the colorectum (26.3%), followed by lung (23.7%) and liver (18.4%). Multivariate logistic regression analysis revealed that old age at the time of GC diagnosis (≥60 years), early stage of GC (stage I and II), and multiplicity of GC at the time of gastrectomy were independent predictive factors for metachronous MPC. GC patients with either metachronous or synchronous MPC showed poorer survival than patients without MPC. In addition, patients with a metachronous MPC showed late survival disadvantage, while patients with a synchronous MPC showed early survival disadvantage. Furthermore, we were able to develop and internally validate a nomogram to predict the metachronous MPC after curative gastrectomy (C-index = 0.72)., Conclusion: Patients at high risk of developing metachronous MPC after curative resection of GC were identified. Individual risk of developing metachronous MPC could be predicted by a novel nomogram. Further external validation with independent patient cohorts is required to improve the accuracy of prediction.

Background: Adjuvant! Online (AOL) is a Web-accessible risk-assessment model that predicts the mortality and the benefits of adjuvant therapy for breast cancer., Methods: Using the Yonsei Tumor Registry database, patients with T1-3, N0-3, M0 breast cancer who were treated at the Yonsei Cancer Center between 1986 and 1999 were entered into AOL version 8.0 to calculate survival., Results: The median age of the study population was 45 years (range, 23-76 years) and the median follow-up duration was 10.8 years (range, 0.1-25.9 years) for all 699 patients. AOL significantly overestimated overall survival (OS) (by 11.1 %, P < 0.001), breast cancer-specific survival (BCSS) (by 11.6 %, P < 0.001), and event free-free survival (EFS) (by 9.25 %, P < 0.001) in Korean patients. Therefore, we developed a Korean version of AOL (KAOL), which is a new model for prognosis based on AOL's parameters. The observed 10-year OS (61.4 %), BCSS (62.3 %), and EFS (59.1 %) and the KAOL predicted OS (61.5 %), BCSS (63.5 %) and EFS (57.6 %) were not different (P = 0.976, P = 0.771, and P = 0.674, respectively)., Conclusions: AOL was not found to be suitable in Korean patients with breast cancer. The newly developed KAOL accurately predicted 10-year outcomes in Korean breast cancer patients.