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Exosomal microRNAs (miRNAs) have been attracting major interest as potential diagnostic biomarkers of cancer. The aim of this study was to characterize the miRNA profiles of serum exosomes and to identify those that are altered in colorectal cancer (CRC). To evaluate their use as diagnostic biomarkers, the relationship between specific exosomal miRNA levels and pathological changes of patients, including disease stage and tumor resection, was examined. Microarray analyses of miRNAs in exosome-enriched fractions of serum samples from 88 primary CRC patients and 11 healthy controls were performed. The expression levels of miRNAs in the culture medium of five colon cancer cell lines were also compared with those in the culture medium of a normal colon-derived cell line. The expression profiles of miRNAs that were differentially expressed between CRC and control sample sets were verified using 29 paired samples from post-tumor resection patients. The sensitivities of selected miRNAs as biomarkers of CRC were evaluated and compared with those of known tumor markers (CA19-9 and CEA) using a receiver operating characteristic analysis. The expression levels of selected miRNAs were also validated by quantitative real-time RT-PCR analyses of an independent set of 13 CRC patients. The serum exosomal levels of seven miRNAs (let-7a, miR-1229, miR-1246, miR-150, miR-21, miR-223, and miR-23a) were significantly higher in primary CRC patients, even those with early stage disease, than in healthy controls, and were significantly down-regulated after surgical resection of tumors. These miRNAs were also secreted at significantly higher levels by colon cancer cell lines than by a normal colon-derived cell line. The high sensitivities of the seven selected exosomal miRNAs were confirmed by a receiver operating characteristic analysis. Exosomal miRNA signatures appear to mirror pathological changes of CRC patients and several miRNAs are promising biomarkers for non-invasive diagnosis of the disease.

Adipocytokines are adipocyte‐secreted hormones associated with some malignancies such as colorectal, breast, and prostate cancer. We hypothesized that changes in the levels of adipocytokines may indicate the carcinogenesis and progression of colorectal cancer and adenoma, and investigated the association of the blood levels of several adipocytokines through a case‐control study. Blood levels of adiponectin, leptin, resistin, visfatin, and C‐peptide at diagnosis were measured in 115 colorectal cancer patients and 115 age‐, sex‐, and body mass index‐matched controls. The same analysis was performed in 72 colorectal adenoma patients and 72 controls. Logistic regression models were used for estimating odds ratios and 95% confidence intervals, and one‐way anova was performed to determine the prevalence of each variable between two or more groups. Resistin and visfatin levels in cancer patients were significantly higher than those of controls on multivariate analysis (P = 0.03 and P < 0.01, respectively). Stage progression significantly correlated with resistin and visfatin levels (P < 0.01 for both). The adiponectin level in adenoma patients was significantly lower than that of controls on multivariate analysis (P = 0.04). Its level was inversely correlated with the number of adenoma (P = 0.02), but not correlated with the size of adenoma. Resistin and visfatin may be good biomarkers of colorectal malignant potential and stage progression. Adiponectin level may be a good biomarker of colorectal adenoma. (Cancer Sci 2010; 101: 1286–1291)

Globally, the fifth most common cancer and the fourth leading cause of cancer-related mortality is gastric cancer (GC). Recent clinical trials on solid tumors enrolled patients who possess druggable genetic alterations, protein expression, and immune characteristics. In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Recently, immune checkpoint inhibitor (ICI) monotherapy was approved as third- or later-line treatment. Chemotherapy plus ICIs as first-line treatment exhibited improved survival compared with chemotherapy alone in HER2-negative patients according to Checkmate 649 trial results. Conversely, systemic chemotherapy prognosis remains poor. although some patients may achieve durable response to treatment and prolonged survival in advanced GC. Recently, a first-in-class, chimeric immunoglobulin G1 monoclonal antibody (zolbetuximab) that targets and binds to claudin 18 isoform 2 (CLDN18.2) has emerged as a new target therapy in GC treatment. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

The optimal medical treatment for advanced gastric cancer is currently the source of debate. Cytotoxic treatment has been shown to prolong survival and provide improved symptom control compared with best supportive care alone, but a global standard has not yet been defined. A literature research was undertaken. Results were evaluated by an international author team. The conclusions of this are presented in this paper. Combination chemotherapy with cisplatin and 5-fluorouracil was the preferred first-line chemotherapy, but oxaliplatin has shown equivalent efficacy to cisplatin. Oral fluoropyrimidines, especially S-1 and capecitabine, can substitute for 5-fluorouracil. Modern doublet regimens are preferred in the majority of patients on the basis of a balanced benefit-to-risk ratio. In selected fit and compliant patients, especially those with a high tumor burden or potential secondary resectability, a third drug may be added because triplet chemotherapy led to higher responses rates and enhanced efficacy. However, docetaxel also adds a significant increase in side effects. Monotherapy and early dose modifications should be considered in elderly and infirm patients. Beyond that, our understanding of gastric cancer tumor biology is increasing. In HER2-positive gastric cancer, the addition of the monoclononal anti-HER2 antibody trastuzumab to cisplatin and fluoropyrimidines has prolonged survival duration. Second-line chemotherapy with single agents has now become a proven treatment option. Alternatively, anti-angiogenic treatment with ramucirumab is on the horizon. In conclusion, combination chemotherapy is regarded as the global standard of care for the first-line treatment of advanced gastric cancer. Molecularly targeted treatments are being explored, preferably in combination with a backbone of chemotherapy doublets.

Purpose Adipocytokines are adipocyte-secreted hormones associated with some malignancies. We investigated the association of adipocytokines with gastric cancer. Methods The levels of body mass index (BMI) and adiponectin, leptin, resistin, visfatin, and C-peptide in blood at diagnosis were measured in 156 gastric cancer patients and 156 age- and sex-matched controls. Logistic regression models were used to estimate odds ratio, and one-way analysis of variance was performed to examine the prevalence of each variable between 2 or more groups. Results Adiponectin, C-peptide and BMI levels were significantly lower, and resistin and visfatin levels were significantly higher in the patients on multivariate analysis (P = 0.0004, 0.0006, 0.0051, 0.0006 and 0.0013, respectively). In the controls, the inverse correlation between BMI and adiponectin was comparatively strong, but was weak in the patients. The correlation between BMI and leptin was strong in both the controls and the patients. The correlation between BMI and resistin or visfatin was not clear in either the patients or the controls. The correlation between BMI and C-peptide was not clear in the controls, but might be weak in the patients. Leptin, C-peptide and BMI levels gradually decreased with stage progression, and resistin and visfatin levels gradually increased with stage progression (P < 0.0001 for all). Comparison between 38 patients with Stage I gastric cancer and the controls showed that adiponectin level tended to decrease in the patients (P = 0.0582), and BMI level was not different between two groups (P = 0.2480). Conclusions Resistin and visfatin may be good biomarkers of gastric cancer.

This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors. This phase I study showed that alpelisib, an α‐specific PI3K inhibitor, as a single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.

Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20–80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m2 oxaliplatin, 200 mg/m2l-leucovorin, 400 mg/m2 bolus fluorouracil, and 2400 mg/m2 infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m2 intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7–13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7–12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86–1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. Taiho.

The cyclin D‐CDK4/6‐INK4‐Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single‐agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single‐agent ribociclib on a 3‐weeks‐on/1‐week‐off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose‐escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose‐limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3‐weeks‐on/1‐week‐off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. Our phase 1 study aimed to determine the maximum tolerated dose and recommended dose for expansion of single‐agent ribociclib in Japanese patients with Rb+ advanced solid tumors whose disease had progressed on prior therapy. Additionally, ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were assessed. We found the RDE of single‐agent ribociclib to be 600 mg on a 3‐weeks‐on/1‐week‐off schedule. Single‐agent ribociclib exhibited an acceptable safety and tolerability profile with limited preliminary clinical activity. These findings were consistent with a phase 1 study of adult patients with solid tumors conducted in the United States and Europe.

The current histopathological risk-stratification criteria in colorectal cancer (CRC) patients following a curative surgery remain inadequate. In this study, we undertook a systematic, genomewide, biomarker discovery approach to identify and validate key EMT-associated genes that may facilitate recurrence prediction in CRC. Genomewide RNA expression profiling results from two datasets (GSE17538; N  = 173 and GSE41258; N  = 307) were used for biomarker discovery. These results were independently validated in two, large, clinical cohorts (testing cohort; N  = 201 and validation cohort; N  = 468). We performed Gene Set Enrichment Analysis (GSEA) for understanding the function of the candidate markers, and evaluated their correlation with the mesenchymal CMS4 subtype. We identified integrin subunit beta like 1 (ITGBL1) as a promising candidate biomarker, and its high expression associated with poor overall survival (OS) in stage I-IV patients and relapse-free survival (RFS) in stage I-III patients. Subgroup validation in multiple independent patient cohorts confirmed these findings, and demonstrated that high ITGBL1 expression correlated with shorter RFS in stage II patients. We developed a RFS prediction model which robustly predicted RFS (the area under the receiver operating curve (AUROC): 0.74; hazard ratio (HR): 2.72) in CRC patients. ITGBL1 is a promising EMT-associated biomarker for recurrence prediction in CRC patients, which may contribute to improved risk-stratification in CRC.

Summary Background In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic colorectal cancer (mCRC) that had progressed on all standard therapies. This post hoc analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial. Methods Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1–3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics. Results One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib ( n  = 67 and n  = 438) or placebo ( n  = 33 and n  = 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43–1.51) and 0.77 (95 % CI 0.62–0.94), respectively. Regorafenib-associated hand–foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable. Conclusion Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC.