Goro Nakayama

Neoadjuvant Oxaliplatin and Capecitabine and Bevacizumab without Radiotherapy for Poor-risk Rectal Cancer: N-SOG 03 Phase II Trial

OBJECTIVE This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. METHODS Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. RESULTS Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. CONCLUSIONS Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).

Function and diagnostic value of Anosmin-1 in gastric cancer progression.

Gastric cancer (GC) is a major global health problem that urgently requires novel molecular biomarkers for patient stratification as well as therapeutic targets. Anosmin‐1 (ANOS1) gene encodes a cell adhesion molecule that plays diverse roles in multiple malignancies. We performed global expression profiling of GC cell lines and small interfering RNA (siRNA) experiments to determine the effect of ANOS1 expression on phenotype. We evaluated the association of ANOS1 mRNA and protein levels in patients’ tissue and sera with clinicopathological factors of GC subtypes. Differential expression of ANOS1 mRNA by GC cell lines correlated positively to levels of ITGAV, FOXC2 and NODAL mRNAs and inversely with those of TFPI2. Inhibiting ANOS1 expression decreased the proliferation, invasion and migration of GC cells. The mean level of ANOS1 mRNA was significantly higher in 237 GC tissues compared with the corresponding noncancerous adjacent tissues. Elevated ANOS1 levels associated significantly with the phenotypes of GC, shorter disease‐free and overall survival. ANOS1 expression was a more significant prognostic marker for diffuse and distal nondiffuse GC. ANOS1 concentrations in sera increased sequentially in sera of healthy subjects, localized GC and disseminated GCs. Prognosis was worse for patients with preoperative serum ANOS1 ≥600 pg/ml compared with those with <600 pg/ml. ANOS1 may represent a biomarker for GC phenotypes and as a target for therapy.

Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer.

Gastric cancer (GC) with hepatic metastasis remains a fatal disease. Global expression profiling was conducted using tissues from patients who had GC with synchronous hepatic metastasis, and major facilitator superfamily domain containing 4 (MFSD4) was identified as a candidate biomarker for hepatic metastasis in GC. Functional and expression analyses of this molecule in GC cell lines and clinical samples were conducted. We analyzed MFSD4 expression, DNA methylation, and copy number. RNA interference experiments evaluated the effects of MFSD4 expression on cell phenotype and apoptosis. We analyzed tissues of 200 patients with GC to assess the diagnostic performance of MFSD4 levels for predicting hepatic recurrence, metastasis, or both. Differential expression of MFSD4 mRNA by GC cell lines correlated positively with the levels of NUDT13 and OCLN mRNAs and inversely with those of BMP2. Hypermethylation of the MFSD4 promoter was detected in cells with lower levels of MFSD4 mRNA. Inhibition of MFSD4 expression significantly increased the invasiveness and motility of GC cells but did not influence cell proliferation or apoptosis. MFSD4 mRNA levels in primary GC tissues were reduced in patients with concomitant hepatic metastasis or recurrence compared with those without. Low levels of MFSD4 mRNA in primary GC tissues were an independent risk factor of hepatic recurrence and metastasis. MFSD4 expression in gastric tissues may represent a useful biomarker for identification of patients at high risk for hepatic recurrence, metastasis, or both.

Comparison of inflammation-based prognostic scores as predictors of tumor recurrence in patients with hepatocellular carcinoma after curative resection

Various inflammation‐based prognostic scores, including the Glasgow prognostic score (GPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI), have been associated with survival in patients with several types of cancer. This study compared the ability of these scores to predict recurrence‐free survival (RFS) in patients with hepatocellular carcinoma (HCC) after curative hepatectomy.

Comparison of the international consensus guidelines for predicting malignancy in intraductal papillary mucinous neoplasms

BACKGROUND This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines. METHODS Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] ≥ 10 mm, and obstructive jaundice) and worrisome features (cyst size ≥ 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5-9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically. RESULTS Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P < .0001), abrupt change in MPD diameter (OR, 3.01; P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; ΔAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79. CONCLUSION Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased.

Estrogen receptor 1 gene as a tumor suppressor gene in hepatocellular carcinoma detected by triple-combination array analysis

Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. Recent developments in the treatment of HCC remain insufficient to cure unresectable disease or to prevent HCC. Consistent efforts are, therefore, needed to deepen understanding of pathogenesis of the disease. Genome-wide gene expression profile analyses can now detect various candidate genes that are modified by HCC. We have developed a new technique to identify tumor suppressor genes, triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism and methylation arrays to identify genes with altered expression. Using HCC tissue samples, triple-combination array analysis was performed to identify a candidate tumor suppressor gene. Subsequently, samples from 48 HCC patients were subjected to quantitative polymerase chain reaction (qPCR) and methylation-specific PCR to further elucidate clinical relevance of the gene. Estrogen receptor 1 (ESR1) was detected as a candidate tumor suppressor gene. Of the 48 clinical samples, 40 (83.3%) showed ESR1 promoter hypermethylation. In 24 (50%) HCC samples, the expression levels of the ESR1 gene was decreased by >90%. The decreased expression was significantly related to high liver damage score, pathological invasion of the intrahepatic portal vein, the size of tumor (>3 cm in diameter) and hepatitis B virus infection. The present study represents another example that triple-combination array is a convenient technique for detecting genes with altered expression in disease. The ESR1 gene was identified as a candidate tumor suppressor gene in HCC and further validation is warranted.

Dihydropyrimidinase-like 3 facilitates malignant behavior of gastric cancer

BackgroundGastric cancer (GC) remains to have a poor prognosis via diverse process of cancer progression. Dihydropyrimidinase-like 3 (DPYSL3) is a cell adhesion molecule that has been reported to be involved in the metastatic process of tumor cells. The aim of this study was to identify a novel clinically-relevant biomarker of GC.MethodsExpression analysis of DPYSL3 mRNA and protein levels was conducted using GC cell lines and 238 pairs of surgically resected gastric tissues. Correlations between expression status of DPYSL3 and clinicopathological parameters were investigated.ResultsDPYSL3 mRNA expression levels positively correlated with those of potentially interacting genes (VEGF, FAK and EZR) in GC cell lines. GC tissues from tumors with distant metastases (stage IV cancer) showed elevated expression levels of DPYSL3 mRNA. The DPYSL3 staining intensity in immunochemical staining was consistent with the mRNA expression patterns in GC tissues. High DPYSL3 mRNA expression in GCs was significantly associated with more malignant phenotypes and was an independent prognostic factor. Moreover, patients with high DPYSL3 mRNA expression had a significantly shorter recurrence free survival after curative resection. In subgroup analysis based on tumor histology, similar tendency was observed between patients with differentiated and undifferentiated GCs.ConclusionsExpression status of DPYSL3 in GC tissues may represent a promising biomarker for the malignant behavior of GC.

Effectiveness of plasma treatment on pancreatic cancer cells

Non-equilibrium atmospheric pressure plasma (NEAPP) has attracted attention in cancer therapy. We explored the indirect effect of NEAPP through plasma-activated medium (PAM) on pancreatic cancer cells in vitro and in vivo. In this study, four pancreatic cancer cell lines were used and the antitumor effects of PAM treatment were evaluated using a cell proliferation assay. To explore functional mechanisms, morphological change and caspase-3/7 activation in cells were also assessed. Furthermore, reactive oxygen species (ROS) generation in cells was examined and N-acetyl cysteine (NAC), an intracellular ROS scavenger, was tested. Finally, the antitumor effect of local injection of PAM was investigated in a mouse xenograft model. We found that PAM treatment had lethal effect on pancreatic cancer cells. Typical morphological findings suggestive of apoptosis such as vacuolization of cell membranes, small and round cells and aggregation of cell nuclei, were observed in the PAM treated cells. Caspase-3/7 activation was detected in accordance with the observed morphological changes. Additionally, ROS uptake was observed in all cell lines tested, while the antitumor effects of PAM were completely inhibited with NAC. In the mouse xenograft model, the calculated tumor volume on day 28 in the PAM treatment group was significantly smaller compared with the control group [28±22 vs. 89±38 (mm3 ± SD), p=0.0031]. These results show that PAM treatment of pancreatic cancer might be a promising therapeutic strategy.

Epithelial - to - Mesenchymal Transition Predicts Prognosis in Clinical Gastric Cancer

Epithelial‐to‐mesenchymal transition (EMT) is considered to play an important role in cancer invasion and metastasis.

Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer

BackgroundIdentification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC.MethodsAssociations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes.ResultsThe expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22–3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes.ConclusionsPDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.