Itaru Omoto

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study

Anemia in oncology patients is often considered a side effect of cancer therapy; however, it may occur before any antineoplastic treatment (cancer-related anemia). This study was aimed to evaluate the prevalence of cancer-related anemia in a large cohort of oncology patients and whether inflammation and malnutrition were predictive of its development and severity. The present study included 888 patients with cancer at different sites between May 2011 and January 2014. Patients were assessed at diagnosis before any cancer treatment. The prevalence of anemia according to the main clinical factors (tumor site, stage and performance status) was analyzed. In each patient markers of inflammation, iron metabolism, malnutrition and oxidative stress as well as the modified Glasgow prognostic score, a combined index of malnutrition and inflammation, were assessed and their role in predicting hemoglobin level was evaluated. The percentage of anemic patients was 63% with the lowest hemoglobin levels being found in the patients with most advanced cancer and compromised performance status. Hemoglobin concentration differed by tumor site and was lowest in patients with ovarian cancer. Hemoglobin concentration was inversely correlated with inflammatory markers, hepcidin, ferritin, erythropoietin and reactive oxygen species, and positively correlated with leptin, albumin, cholesterol and antioxidant enzymes. In multivariate analysis, stage, interleukin-6 and leptin were independent predictors of hemoglobin concentration. Furthermore, hemoglobin was inversely dependent on modified Glasgow Prognostic Score. In conclusion, cancer-related anemia is a multifactorial problem with immune, nutritional and metabolic components that affect its severity. Only a detailed assessment of the pathogenesis of cancer-related anemia may enable clinicians to provide safe and effective individualized treatment.

Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Recently developed molecular targeted therapies are not available for patients with ESCC. After curative surgical resection, patients frequently suffer distant metastasis and recurrence. Exploration of novel ESCC metastatic pathways may lead to the development of new treatment protocols for this disease. Accordingly, we have sequentially identified microRNA (miRNA)-mediated metastatic pathways in several cancers. Our past studies of miRNA expression signatures have shown that microRNA-375 (miR-375) is frequently reduced in several types of cancers, including ESCC. In the present study, we aimed to investigate novel miR-375-mediated metastatic pathways in ESCC cells. The expression of miR-375 was downregulated in ESCC tissues, and ectopic expression of this miRNA markedly inhibited cancer cell migration and invasion, suggesting that miR-375 acted as an antimetastatic miRNA in ESCC cells. Our strategies for miRNA target searching demonstrated that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells. Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness. Moreover, oncogenic genes, including CENPF, KIF14 and TOP2A, were shown to be regulated downstream of MMP13. Taken together, these findings demonstrated that the antitumor miR-375/oncogenic MMP13 axis had a pivotal role in ESCC aggressiveness. These results provide novel insights into the potential mechanisms of ESCC pathogenesis.

Expression of vascular endothelial growth factor‑C and vascular endothelial growth factor receptor‑3 in esophageal squamous cell carcinoma

Lymph node metastasis is one of the most important prognostic factors in esophageal squamous cell carcinoma (ESCC). Vascular endothelial growth factor (VEGF)-C and its receptor, VEGF receptor-3 (VEGFR-3), are key in the process of lymphangiogenesis. The present study immunohistochemically examined the expression of VEGF-C, VEGFR-3 and D2-40 in 119 patients with ESCC, and microlymphatic vessel density (MLVD) was calculated based on D2-40 expression counts. Positive expression of VEGF-C was found to correlate significantly with depth of tumor invasion, lymphatic invasion and lymph node metastasis (P<0.001, P<0.0001 and P<0.0001, respectively). Patients with deeper tumor invasion showed higher positivity of VEGFR-3 expression (P<0.05), while patients with lymph node metastasis showed higher MLVD (P<0.05). When patients were divided into three groups according to the expression of VEGF-C and VEGFR-3, patients with coexpression of VEGF-C and VEGFR-3 exhibited poorer prognosis and higher MLVD. The VEGF-C/VEGFR-3 axis is important in tumor lymphangiogenesis.

Clinical course and outcome after esophagectomy with three-field lymphadenectomy in esophageal cancer

BackgroundEsophagectomy with three-field lymphadenectomy has been performed for esophageal cancer. Detailed analysis of cause of death and mode of recurrence is required to determine the need for further adjuvant therapy and follow-up.Materials and methodsA total of 208 patients who underwent esophagectomy through right thoracotomy with three-field lymphadenectomy were enrolled into the present study. Mode of first recurrence was divided into four groups: lymph node, hematogenous, mixed, and local recurrence.ResultsExcluding 16 hospital deaths, the number of deaths and 5-year survival rates were 104 patients and 7.8% for cancer recurrence, 12 patients and 53.8% for second primary cancers in other organs, and 34 patients and 31.0% for causes of death unrelated to carcinoma. In the 104 patients with relapse, 5-year survival rate of patients was 14.3% with lymph node recurrence (n = 29), 9.1% with hematogenous recurrence (n = 32), 3.1% with mixed recurrence (n = 35), and 12.5% with local recurrence (n = 8).ConclusionTo improve outcomes for esophagectomy with three-field lymphadenectomy, early detection of recurrent disease and regular examination of the entire body for secondary cancer is necessary.

Clinical implication of CD166 expression in gastric cancer

CD166 is one of the cell‐surface immunoglobulins, and is well known to regulate leukocyte mobility. Its expression is associated with aggressive tumor behavior. CD166 expression is a prognostic marker in several cancers, but the predictive value of CD166 expression in gastric cancer has not been clarified yet.

Endoscopic ultrasonography is useful for monitoring the tumor response of neoadjuvant chemoradiation therapy in esophageal squamous cell carcinoma

BACKGROUND Recently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings. METHODS There were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining. RESULTS Azan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect. CONCLUSIONS Preoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients.

Clinical and biological impact of cyclin-dependent kinase subunit 2 in esophageal squamous cell carcinoma

Cyclin-dependent kinase subunit 2 (CKS2) is a cyclin-dependent kinase subunit (CKS) family member that participates in cell cycle regulation. Few studies have investigated its involvement in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to assess the clinical significance of CKS2 in ESCC. We used immunohistochemistry to study the clinicopathologic significance of CKS2 protein expression in 121 patients with ESCC. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we examined the expression of CKS2 mRNA in tumors and the corresponding normal esophageal tissues that were obtained from 62 patients. Finally, siRNA-mediated attenuation of CKS2 expression was examined in vitro. CKS2 protein expression was significantly correlated with depth of tumor invasion, clinical stage, lymphatic invasion and distant metastasis (p=0.033, 0.028, 0.041 and 0.009, respectively). CKS2 mRNA expression was higher in cancer tissue than in corresponding normal tissue (p<0.001). Patients with positive-CKS2 protein expression had a poorer five year survival frequency than patients who did not express CKS2 protein (p=0.025). In vitro, siRNA-mediated suppression of CKS2 slowed the growth rate of ESCC cells compared to control cells (p<0.001). The evaluation of CKS2 expression is useful for predicting the cause of malignant tumors and the prognosis of patients with ESSC.

Clinical Significance of 18F-fluorodeoxyglucose Positron Emission Tomography in Superficial Esophageal Squamous Cell Carcinoma

PurposeTo assess the clinical usefulness and significance of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC).MethodsWe examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically.ResultsThe FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake–positive patients, depth of tumor invasion and histology were prognostic factors.ConclusionsFDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake–positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

Regulation of SPOCK1 by dual strands of pre- miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma

Analysis of our microRNA (miRNA) expression signatures of human cancers based on RNA sequencing have shown that both strands of pre-miR-150, miR-150-5p (the guide strand) and miR-150-3p (the passenger strand), are significantly reduced in cancer tissues. We have investigated the functional significance of both strands of pre-miR-150 in cancer cells. The aim of this study was to investigate the antitumor function of these miRNAs and how these miRNAs regulated oncogenic targets in esophageal squamous cell carcinoma (ESCC). Ectopic expression studies demonstrated that both strands of pre-miR-150 miRNA inhibited ESCC cancer cell migration and invasion, indicating that both miR-150-5p and miR-150-3p acted as antitumor miRNAs. A combination of genome-wide gene expression analyses and in silico database searches showed that SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was a candidate target of miR-150-5p and miR-150-3p in ESCC cells. Luciferase reporter assays showed that SPOCK1 was directly regulated by these miRNAs. Silencing of SPOCK1 by small interfering RNA inhibited cancer cell migration and invasion. Overexpression of SPOCK1/SPOCK1 was confirmed by real-time PCR methods and immunohistochemistry. Taken together, downregulation of both strands of pre-miR-150 and overexpression of SPOCK1 are involved in ESCC pathogenesis. The involvement of passenger strand miRNAs in the regulation of cancer cell aggressiveness is a novel concept in RNA research.

Programmed death-ligand 1 is a promising blood marker for predicting tumor progression and prognosis in patients with gastric cancer

Immune checkpoint inhibitor therapy has been clinically introduced for several malignancies, and its effectiveness has been confirmed by clinical trials. In particular, programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) are widely known as important immune checkpoint molecules associated with the mechanisms of immune escape by malignant tumor cells. In addition, liquid biopsy of blood specimens has the clinical benefit of providing a simple, repeatable sampling tool. Non‐invasive liquid biopsy has recently been spotlighted as a promising approach to predicting tumor progression and prognosis. This study assessed the clinical significance of PD‐L1 mRNA expression in blood specimens obtained from patients with gastric cancer. Peripheral blood specimens were collected before treatment from 124 patients with gastric cancer. The PD‐L1 mRNA expression was evaluated by quantitative RT‐PCR. Programmed death‐ligand 1 mRNA expression was significantly higher in patients with advanced gastric cancer than in patients with early gastric cancer (P = .002). Moreover, PD‐L1 expression correlated significantly with depth of tumor invasion, distant metastasis, and stage (P = .001, P < .001, and P < .001, respectively). Patients with high PD‐L1 expression showed significantly poorer prognosis than those with low PD‐L1 expression (P < .0001). Multivariate analysis indicated PD‐L1 expression as an independent prognostic factor. Expression of PD‐L1 in peripheral blood may offer an immunological predictor of tumor progression and disease outcome in patients with gastric cancer.