Takumo Enomoto

Specific Enhanced Expression of Platelet-Derived Endothelial Cell Growth Factor in Submucosa of Human Colorectal Cancer

PURPOSEPlatelet-derived endothelial cell growth factor, identified to be an angiogenic factor, has been implicated in metastases of colorectal cancer. This study aimed to clarify the role and localization of platelet-derived endothelial cell growth factor associated with human colorectal cancer invasion.METHODSThirty-two patients with colorectal cancer who had undergone surgery were analyzed. Platelet-derived endothelial cell growth factor enzyme activities in the colorectal cancer specimens were measured. Cells that expressed platelet-derived endothelial cell growth factor were identified and localized by immunohistochemical analysis with anti-human platelet-derived endothelial cell growth factor antibody and by in situ hybridization with specific RNA probe.RESULTSPlatelet-derived endothelial cell growth factor enzyme activity increased significantly in cancer tissues compared with normal colonic mucosa at various distances from the cancer. Immunohistochemical analysis and in situ hybridization demonstrated platelet-derived endothelial cell growth factor expression in stromal macrophages and fibroblasts located in cancer tissues and surrounding noncancerous tissues, although the tumor cells and normal colonic mucosa were negative. The value of platelet-derived endothelial cell growth factor expression was highest at the border of the colorectal cancer (35.3 ± 8.9 percent), followed by the cancer nest (15.2 ± 9.2 percent) and normal mucosa (7.7 ± 3.4 percent). In the border area, the highest value of platelet-derived endothelial cell growth factor expression was observed in the submucosa (35.3 ± 8.9 percent), followed by the muscular propria (21.9 ± 7.7 percent) and the subserosa (14.9 ± 5.5 percent).CONCLUSIONSStromal macrophages and fibroblasts are responsible for elevated platelet-derived endothelial cell growth factor activity in colorectal cancer. The significance of enhanced expression of platelet-derived endothelial cell growth factor in the submucosa at the cancer border remains unclear. Cancer stroma may be an important factor for cancer angiogenesis and may serve as a treatment target through specific modulation of angiogenic factors.

Variations in the expression of platelet-derived endothelial cell growth factor in human colorectal polyps

Platelet-derived endothelial cell growth factor (PD-ECGF) has been identified to be an angiogenic factor, and a close relationship between the expression of PD-ECGF and tumor development has been postulated. This study was designed to assess both the role of PD-ECGF in human colorectal polyps as well as its relationship to the expression of other oncogenes during colorectal carcinogenesis. One hundred twenty patients with colon polyps who had undergone a polypectomy were studied. The polyps were classified based on the pathological findings as nonneoplastic or sporadic adenoma. The polyps were immunostained for PD-ECGF and vascular endothelial cell growth factor (VEGF), as well as for Ki-67 antigen and p53. The correlations between expression of PD-ECGF and clinicopathologic factors were examined. PD-ECGF was expressed at significant levels only in adenomas: in 4 of the 20 polyps with severe dysplasia (20%), and in 5 of the 20 cases of carcinoma in adenoma (25%). PDECGF was not detected in the nonneoplastic polyps and in adenomas with low-grade dysplasia. The intensity of immunostaining for PD-ECGF in adenomas correlated with the expression of Ki-67 antigen (P , 0.001) but not with that of p53. VEGF was not detected in any types of polyps. Angiogenic factors in colorectal adenomas might play an important role in carcinogenesis. The correlated expression of PD-ECGF and Ki-67 antigen suggests that PD-ECGF might not only act as an angiogenic factor, but also as a tumor growth factor.

Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer

Phenylbutyrate (PB) is a histone deacetylase antagonist that also exhibits antitumor activity. In this study, we used 7 breast cancer cell lines to identify biomarker candidates that predict PB sensitivity in breast cancer. Comprehensive gene expression profiles were compared using microarrays, and the importance of the identified genes to PB sensitivity was confirmed in gene transfection experiments. CRL and MDAMB453 cells were identified as PB-sensitive, while MDAMB231 cells were PB-resistant.RAB25 and ESRP1 were identified as key regulators of PB sensitivity, while ANKD1, ETS1, PTRF, IFI16 and KIAA1199 acted as PB resistance-related genes. Expression of these genes was dramatically altered by DNA demethylation treatments. RAB25 expression inhibited IFI16 and PTRF, while ESRP1 expression suppressed ANKRD1, ETS1, and KIAA1199. Both RAB25 and ESRP1 were suppressed by ZEB1, which was in turn regulated via epigenetic mechanisms. Thus, PB sensitivity is influenced by epigenetic expression alteration of ZEB1. The genes associated with PB sensitivity are downstream targets of ZEB1. Epigenetic regulation of ZEB1 may prove valuable as a critical biomarker for predicting resistance to breast cancer therapies.

The Safety of Concentrated Trastuzumab in 100 ml of Saline Solution for Administration to Patients with HER2-Positive Breast Cancer: A Phase 1 Study

Background: It is recommended that administration of trastuzumab should be carried out in a volume of 250 ml of saline solution over 90 min. Since 2011, recommendations have allowed a shortening of the administration time to 30 min at the second administration. However, the volume to be administered is still 250 ml. The purpose of this study was to evaluate the safety of trastuzumab administered in 100 ml of saline solution over 30 min. Methods: This study enrolled patients with HER2-positive breast cancer. Three dose levels of trastuzumab, each in 100 ml of saline solution, were used (2, 6 and 8 mg/kg). The primary end point was the determination of safety. Results: Nine patients were enrolled. Since no adverse events were observed, the 8 mg/kg/100 ml saline solution dose level was the recommended dose. Conclusions: A 30-min administration of trastuzumab in 100 ml of saline solution is safe in patients with HER2-positive breast cancer.

Abstract P3-09-03: Final result of randomised controlled phase II study of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3

Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute / delayed CINV. However, it has not been determined the medication schedule for DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. This is final result of current study. Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2013. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days). Eighty patients were estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting. Results: Eighty two patients were enrolled in this study. There was not inferiority about CR rate of five days after chemotherapy (81.1% of group A, 82.1% of group B). CC rate of group A (62.2%) was better than that of group B (46.2%). However, CC rate was no significant difference between group A and B. There was no significant difference about any level of nausea between group A and B. Conclusions: One day of dexamethasone with Palonosetron and Aprepitant treatment is enough to control the emesis of high emetogenic chemotherapeutic agents. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-03.

BRCAness and Prognosis in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy.

BRCAness is defined as the set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation or deletion, results in DNA repair deficiency. In the present study, we addressed BRCAness, therapeutic efficacy, recurrence, and survival in patients with triple negative breast cancer (TNBC) who were treated with neoadjuvant chemotherapy at Kitasato University Hospital, Japan, between April 2006 and October 2012. BRCAness was determined by preoperative core needle biopsy (CNB) specimens and surgical specimens. Assay was performed using Multiplex Ligation-dependent Probe Amplification (MLPA) with P376-B2 BRCA1ness probemix (MRC-Holland, Amsterdam, The Netherlands). The relative copy number ratio of each sample was compared to Human Genomic DNA (Promega, Madison, WI, USA) as reference samples was calculated with Coffalyser.NET default settings. The BRCAness score was calculated with the relative copy number ratio of various DNA sequences. Values of 0.5 or more were determined as the BRCA1-like Type (BRCAness) and those of less than 0.5 as the Sporadic Type to analyze pathological complete response (pCR) rate, recurrence, and survival. pCR (ypT0/Tis/N0) was observed in 15 patients (pCR rate: 37.5%). These patients had no recurrence. Twelve patients recurred, 8 died from breast cancer. The BRCA1-like Type were 22 and Sporadic Type were 18 in CNB specimens. No major differences were observed between the BRCA1-like Type and Sporadic Type with pCR rate, recurrence rate and survival. Twenty four surgical specimens of non-pCR patients were available and 9 were BRCA1-like Type, who had more recurrences (7/9 vs. 5/15), and their relapse-free survival was also lower (p<0.05) than that of Sporadic Type. Seven BRCA1-like Type patients remained BRCA1-like Type in surgical specimens, were worse in recurrence (p<0.01) and survival (p<0.05) compared with 6 patients whose BRCA status in surgical specimens turned to Sporadic Type. New clinical trials assessing the true recurrence (TR) rate of BRCA-type patients are expected since neither platinum-containing drugs nor poly (ADP-ribose) polymerase (PARP) inhibitors are effective against tumors with nonfunctional BRCA genes.

Superior vena cava syndrome due to mediastinal adenomatous goitre

A 60-year-old man presented with an 18-month history of deteriorating facial oedema and intermittent oedema of upper limbs. He had symptoms of headache, flush, dysphagia and coughs. He also noted hoarseness or dysphonia after standing for long periods. He had no other physical findings. MRI showed a superior to middle mediastinal mass derived from the right lobe of the thyroid, compressing the trachea to the left (figure 1, arrow heads). MR venography revealed severe stenosis of the …

Abstract P2-12-13: Results of randomised controlled phase II study (KBCSG02 trial) of the efficiency of palonosetron, aprepitant, and dexamethasone for day1 with or without dexamethasone on days2 and 3.

Background: Emesis is one of the major non-hematologic toxicity caused by chemotherapy. The control of Chemotherapy Induced Nausea and Vomiting (CINV) is conducted to a life lengthening. Recently, CINV is controlled by the second generation 5-HT3 receptor blocker (Palonosetron; PALO) and a NK-1 receptor antagonist (Aprepitant; APR). It has been shown that dexamethasone (DEX) with 5-HT3 receptor blocker improves acute/delayed CINV. However, it has not been determined the medication schedule of DEX with PALO and APR. The purpose of this study is evaluated the efficiency of palonosetron, aprepitant and dexamethasone for day1 with or without dexamethasone on days2 and 3. Methods: Breast cancer patients who administered anthracyclin drug regimen have been eligible from April, 2011 to June, 2012. The patients were randomised to group A (PALO/APR/DEX one day) and group B (PALO/APR/DEX three days). Eighty patients was estimate as study samples. The primary endpoint was a complete response (CR) rate of vomiting, the secondary endpoint was a complete control (CC) rate of vomiting. Results: Forty patients were enrolled in this study, and patient recruitment is continued. CR rate was no significant difference in both groups (76.9% of group A, 73.3% of group B). CC rate of group A (61.5%) did not show inferiority compared with group B (40.0%). Conclusions: In this current study, we suggest that one day dexamethasone treatment could reduce enough the emesis of high emetogenic chemotherapeutic agents. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-13.