Sapporo, Japan
Sapporo, Japan

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Nakahara Y.,Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital | Nakahara Y.,Kitasato University | Takagi Y.,Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital | Takagi Y.,Sharp Corporation | And 9 more authors.
OncoTargets and Therapy | Year: 2016

Background: Repetitive genotyping is useful to assess the genetic evolution of non-small-cell lung cancer (NSCLC) during treatment, but the need for sampling by biopsy is a major obstacle. Digital polymerase chain reaction (PCR) is a promising procedure for the detection of mutant alleles in plasma of cancer patients. Methods: This prospective study enrolled patients with NSCLC and known epidermal growth factor receptor (EGFR) mutations and who had experienced disease progression during ongoing EGFR-tyrosine kinase inhibitor (TKI) therapy. Eligible patients received daily gefitinib and either pemetrexed or S-1 every 3 weeks until disease progression or the development of unacceptable toxicity. Peripheral blood was collected before and after the combination therapy for digital PCR and hepatocyte growth factor measurement. Results: From May 2012 to January 2014, nine patients with a median age of 67 (range 52–80) years were enrolled. Patterns of disease progression during adjacent EGFR-TKI therapy were acquired resistance, observed in seven patients, and primary resistance, observed in two patients. Known EGFR mutations were detected in plasma samples of six (67%) patients at study enrollment. Of these, T790M mutation was concurrently detected in three (50%) patients. Four patients underwent gefitinib plus pemetrexed therapy, and five patients underwent gefitinib and S-1 therapy. The median number of cycles delivered was five, and the median progression-free survival was 5.7 months. Efficacy outcomes did not differ between treatments. After the combination therapy, plasma T790M status changed to positive in two patients. Hepatocyte growth factor level did not significantly change through the combination therapy. Conclusion: The usefulness of monitoring the genetic evolution of EGFR-driven tumors using noninvasive procedures was demonstrated. Since continuation of EGFR-TKI therapy with cytotoxic agents has an acceptable tolerability and a possibility of inducing T790M mutation, the combination therapy may be useful for EGFR-mutant NSCLC resistant to EGFR-TKI therapy without T790M mutation. © 2016 Nakahara et al.


Kamimae S.,Sapporo Medical University | Yamamoto E.,Sapporo Medical University | Yamano H.-O.,Red Cross | Nojima M.,Sapporo Medical University | And 18 more authors.
Cancer Prevention Research | Year: 2011

Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. ©2011 AACR.


Ishizu A.,Hokkaido University | Tomaru U.,Hokkaido University | Murai T.,GeneticLab Co. | Yamamoto T.,GeneticLab Co. | And 10 more authors.
PLoS ONE | Year: 2013

The JMAAV study was an open-labeled prospective clinical trial, which proposed severity-based treatment protocols for patients with microscopic polyangiitis (MPA). The results suggest that the proposed protocols are useful (remission rate: 89.4%), but are also indicative of relapse or patient demise regardless of the treatment (recurrence rate: 19.0%; mortality rate: 10.6%). The aim of this study is to develop the method to predict response to the treatment in patients with MPA. In the present study, transcriptome analysis was performed using peripheral blood from patients enrolled in the JMAAV study before and 1-week after the beginning of treatment. The gene expression profile before treatment was not directly related to the response to the treatment. However, when the samples from 9 patients with good response (persistent remission for 18 months) were examined, the expression of 88 genes was significantly altered by the treatment. Thirty statistically reliable genes were selected, and then the alteration of expression by the treatment was examined among 22 patients, including 17 with good response, which was defined as persistent remission for 18 months and 5 with poor response, which was defined as relapse after remission or no remission. Discrimination analysis between the alteration of expression of the 30 genes by the treatment and the response identified a combination of 16 genes as the most valuable gene set to predict the response to the treatment. This preliminary study identified IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2 as the important genes that can predict the response to the treatment in patients with MPA at an early point during the therapy. © 2013 Ishizu et al.


Matsumoto Y.,Fukushima Medical University | Saito T.,Fukushima Medical University | Hoshi K.,Fukushima Medical University | Ito H.,Fukushima Medical University | And 9 more authors.
Journal of Biochemistry | Year: 2015

We previously found that a lectin, Sambucus sieboldiana agglutinin (SSA), bound to α2,6-sialylated glycan epitopes on transferrin and inhibited anti-transferrin antibody binding to the antigen in ELISA (SSA inhibition). Here we report that SSA inhibition is applicable to immunohistochemistry, localizing α2,6-sialylated transferrin in the liver. Immunohistochemistry using anti-transferrin polyclonal antibody revealed that transferrin was detected in hepatocytes near interlobular veins. Addition of SSA lectin markedly attenuated the staining. Sialidase treatment of a liver section abolished SSA binding and concomitantly cancelled SSA inhibition, suggesting that SSA binding to glycan epitopes on the section was essential for the inhibition. To examine the importance of proximity between antigen epitopes and SSA-binding (glycosylation) sites, we prepared two anti-peptide antibodies against partial amino acid sequences of transferrin. One antibody (Tf-596Ab) is against a peptide sequence, Cys596-Ala614, which is proximal to N-glycosylation sites (Asn-432 and Asn-630). The other (Tf-120Ab) is against a peptide sequence, Val120-Cys137, distal to the sites. The staining signals of Tf-596Ab were reduced by the addition of SSA, whereas those of Tf-120Ab were reduced only a little. This result suggests that proximity of the antigen epitope to SSA binding sites is critical for SSA inhibition in immunohistochemistry. © 2014 Crown copyright 2014.


Muto M.,Engaru Kosei General Hospital | Ichiki K.,Engaru Kosei General Hospital | Ishikawa C.,Engaru Kosei General Hospital | Inoue M.,Engaru Kosei General Hospital | Kondo N.,GeneticLab Co.
Gastroenterological Endoscopy | Year: 2014

An 80-year-old woman visited our hospital with a complaint of constipatioa Colonoscopy revealed a submucosal tumor-like elevated lesion in the appendix orifice which had a depression in the center. A biopsy material taken from the epithelia of the appendix orifice revealed signet ring cell carcinoma, and ileocecal resection was carried out Microscopically, most of the lesion was occupied by signet ring cells, but tub2 and muc coexisted in the same lesion. It is suggested that signet ring cell carcinoma had originated from tubular adenocarcinoma.


Maruyama K.,Asahikawa University | Chinda J.,Asahikawa University | Kuroshima T.,Asahikawa University | Kabara M.,Asahikawa University | And 6 more authors.
Internal Medicine | Year: 2015

Minimal change nephrotic syndrome (MCNS) is a common form of nephrotic syndrome (NS). We herein present the case of a 57-year-old woman with advanced lung adenocarcinoma treated with the tyrosine kinase inhibitor (TKI) gefitinib who developed NS. A renal biopsy revealed minor glomerular abnormalities, and the patient’s symptoms improved exclusively with the discontinuation of gefitinib. Therefore, we diagnosed her with MCNS associated with gefitinib treatment. A few months later, however, she developed recurrent lung tumors. Following the challenging initiation of the TKI erlotinib, she achieved remission without proteinuria. We thus conclude that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy. © 2015 The Japanese Society of Internal Medicine.


Matsuzawa F.,Social Welfare Corporation Hokkaido Social Work Association Obihiro Hospital | Kuraya D.,Social Welfare Corporation Hokkaido Social Work Association Obihiro Hospital | Hamaguchi J.,Social Welfare Corporation Hokkaido Social Work Association Obihiro Hospital | Abe H.,Social Welfare Corporation Hokkaido Social Work Association Obihiro Hospital | And 4 more authors.
Japanese Journal of Gastroenterological Surgery | Year: 2013

A 32-year-old man was transferred to our hospital because of small intestinal obstruction. At the time of admission, blood test revealed the WBC was 12,350/μl and CRP was negative. Four days after admission, he underwent exploratory laparotomy under the diagnosis of intestinal obstruction due to an unknown cause because the symptom did not improve by conservative treatment. A nodule was found in the retroperitoneum where a chord from the nodule to the mesentery of the small intestine was strangulating one part of the small intestine. The obstruction was treated by excision of the strand and nodule. Microscopic findings of the nodule showed the necrosis and an anisakis with typical pathological findings of anisakiasis, a lateral chord, intestine and Renette cells. Although reports on anisakiasis have increased in recent years, adhesive intestinal obstruction induced by extra-gastrointestinal anisakiasis is rare. A preoperative diagnosis of this disease is difficult, however, we must be attentive to this as a possible cause of intestinal obstruction. © 2013 The Japanese Society of Gastroenterological Surgery.

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