Publications

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    ABSTRACT: PurposeAmino acid transporters play an important role in the tumor progression and survival of cancer cells. But, it remains unclear about the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC). The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC.Material and Methods We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34.ResultsLAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery.ConclusionLAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery.
    Hepatology Research 10/2014; · 2.07 Impact Factor
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    ABSTRACT: The results of several pulmonary resections using a uniportal approach have been published. However, there are no reports of uniportal thoracoscopic anatomic segmentectomy in Japan. We have a fundamental belief in "reduced-port surgery" and therefore routinely perform uniportal thoracoscopic surgery for patients with pneumothorax. This report describes a successful case of uniportal thoracoscopic anatomic segmentectomy through a 3.5-cm incision in a 76-year-old woman with primary lung cancer. The patient was pathologically diagnosed with multiple primary adenocarcinomas stage IA (T1aN0M0). Postoperatively, no analgesics were needed. The operative procedure is described in detail and includes technical tips such as the pulley method, extra-vessel exposure, the shaft-on-shaft technique, one-hand encircling, and one-hand exposure. The selection criteria for uniportal thoracoscopic segmentectomy limit its use.
    09/2014;
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    ABSTRACT: Murine double minute 2 (MDM2) is a negative regulator of p53. A single-nucleotide polymorphism (SNP) (rs2279744: c.309T>G) in the promoter region of the MDM2 gene has been shown to result in higher levels of MDM2 RNA and protein. Regarding the contribution of c.309T>G in the MDM2 gene to the lung cancer risk, previous studies are conflicting. In order to evaluate the association between c.309T>G and the lung cancer risk, a case-control study was performed. The MDM2 genotypes were determined in 762 lung cancer patients and in 700 cancer-free control subjects using the Smart Amplification Process. Statistical adjustment was performed for gender, age and pack-years of smoking. The distributions of c.309T>G (T/T, T/G, G/G) were 20.1, 49.7, 30.2% in the case group and 21.7, 47.9, 30.4% in the healthy-control group. There were no overall associations between the MDM2 genotypes and the risk of lung cancer [T/G genotype: Adjusted odds ratio (AOR), 1.30; 95% confidence interval (CI), 0.88-1.93; and G/G genotype: AOR, 1.18; 95% CI, 0.78-1.80]. The subgroup analysis of gender, histology, smoking status and epidermal growth factor receptor mutation status also indicated that there was no association with lung cancer. Additionally, the genotypes did not have an effect on the age at the time of diagnosis of lung cancer (P=0.25). In conclusion, the G allele frequency in the lung cancer cases was 0.551, which was similar to other studies. The results of the present study suggest that the c.309T>G is not significantly associated with lung cancer.
    Biomedical reports. 09/2014; 2(5):719-724.
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    ABSTRACT: Molecular-targeted therapy has not been established in non-adenocarcinoma lung cancer (non-AdLC), as no targets that affect the clinical efficacy of molecular-targeted drugs have yet been identified. In this study, we investigated the frequency of genetic variations in discoidin domain receptor 2 (DDR2), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-AdLC patients, in order to evaluate the possibility of genetic mutations in these genes being used as therapeutic targets for the treatment of patients with non-AdLC. For this purpose, we enrolled 150 non-AdLC patients who had undergone surgery at the Gunma University Hospital between December, 2003 and December, 2012. Genetic mutations in the EGFR, KRAS, DDR2 and BRAF genes were detected by a sequencing method or probe assay using DNA derived from cancer tissues. No somatic mutations in DDR2 or BRAF were detected in non-AdLC patients. Conversely, genetic mutations in EGFR exon 19 were found in 3 squamous cell carcinoma (SCC) and 3 adenosquamous carcinoma patients, whereas KRAS codon 12 mutations were also found in 3 SCC patients and 1 large-cell neuroendocrine carcinoma patient. EGFR and KRAS mutations were mutually exclusive. This study indicated that, although DDR2 and BRAF mutations may only rarely be used as therapeutic targets, EGFR and KRAS mutations may represent candidate therapeutic targets, at least in the non-AdLC patients investigated.
    Molecular and clinical oncology. 09/2014; 2(5):714-718.
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    ABSTRACT: Somatic mutations of the catalytic subunit of the cyclic AMP-dependent protein kinase (PRKACA) gene have recently been identified in about 35% of cortisol-producing adenomas (CPAs), with the affected patients showing overt Cushing's syndrome. Since we recently reported higher prevalence of mutations of the KCNJ5 gene and associations with autonomous cortisol secretion in Japanese aldosterone-producing adenomas than in Western countries, there might be different features of CPAs between Japan and the West. We therefore investigated mutations of the PRKACA gene in Japanese patients with several adrenal tumors secreting cortisol, including overt Cushing's syndrome, subclinical Cushing's syndrome, and aldosterone-producing adenomas (APAs) co-secreting cortisol operated on at Gunma University Hospital. Of the 13 patients with CPA who showed overt Cushing's syndrome, 3 (23%) had recurrent somatic mutations of the PRKACA gene, p.L206R (c.617 T>G), and there were no mutations in subclinical Cushing's syndrome. Among 33 APAs, 24 had somatic mutations of the KCNJ5 gene, either G151R or L168R, 11 (33%) had autonomous cortisol secretion, but there were no mutations of the PRKACA gene. We established a PCR-restriction fragment length polymorphism assay and revealed that the mutated allele was expressed at a similar level to the wild-type allele. These findings demonstrated that 1) the prevalence of Japanese patients with CPA who showed overt Cushing's syndrome and whose somatic mutations in the PRKACA gene was similar to that in Western countries, 2) the mutation might be specific for CPAs causing overt Cushing's syndrome, and 3) the mutant PRKACA allele was expressed appropriately in CPAs.
    Endocrine Journal 07/2014; · 2.23 Impact Factor
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    ABSTRACT: To date, more than 100 reports of several major pulmonary resections through a uniportal approach have been published. However, there have been no reports of uniportal thoracoscopic lobectomy in Japan. We present herein a successful case of uniportal thoracoscopic right lower lobectomy through a 3.5-cm incision for 84- year-old female patient with primary lung cancer (clinical stage I A). Postoperativecourse was uneventful and she discharged from the hospital on day 5 postoperatively. Pathological diagnosis was primary adenocarcinoma of T1aN0M0, stage I A.
    Kyobu geka. The Japanese journal of thoracic surgery 07/2014; 67(7):540-543.
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    ABSTRACT: In recent years, there has been significant progress in systemic chemotherapy for metastatic or recurrent colorectal cancer. We investigatedthe clinical efficacy andfeasibility of the bevacizumab andcapecitabine /oxaliplatin(CapeOX)combination for untreatedcolorectal cancer. From October 2009 to June 2012, 38 patients were included, 18 receiving CapeOX alone and 20 receiving CapeOX plus bevacizumab. The response rate andd isease-control rate were 16% and5 0%, respectively, in the CapeOX arm, and5 5% and8 5%, respectively, in the CapeOX plus bevacizumab arm. Median progression-free survival was 8.0 months in the CapeOX arm and1 2.8 months in CapeOX plus bevacizumab arm. The median overall survival was 21.6 months in the CapeOX arm and3 4.0 months in CapeOX plus bevacizumab arm. Our results suggest that CapeOX treatment can be useful in the outpatient setting andmore effective when combinedwith bevacizumab. Except in cases of bevacizumab intolerance, addition of bevacizumab to CapeOX treatment is considered useful as first-line therapy for metastatic or recur- rent colorectal cancer.
    Gan to kagaku ryoho. Cancer & chemotherapy 06/2014; 41(6):737-741.
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    ABSTRACT: ASCT2 is highly expressed in cancer cells. However, the clinicopathological significance of ASCT2 expression in pancreatic cancer remains unclear. The aim of this study was to investigate the clinical significance of ASCT2 expression in pancreatic cancer.
    Histopathology 05/2014; · 2.86 Impact Factor
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    ABSTRACT: A 58-year-old man underwent low anterior resection for type 2 rectal cancer with liver metastasis. An abdominal computed tomography(CT)scan showed multiple hepatic tumors(in S2, S3, S4, and S6)and a filling defect in the left portal vein. Pathological examination revealed a moderately differentiated adenocarcinoma, pSS, pN0, ly0, v3, with a tumor thrombus in the portal vein. After surgery, the patient was treated with combined chemotherapy of bevacizumab/Leucovorin and fluorouracil with oxaliplatin(FOLFOX4). After 11 courses of chemotherapy, tumor marker levels normalized, and the sizes of the liver metastases and thrombus in the left portal vein remarkably decreased. Resection of the left hepatic lobe and a partial resection of S6 were performed. Pathological examination revealed no residual cancer cells and indicated that the histological classification due to the chemotherapy regimen was Grade 3. The patient was alive for 5years after the initial surgery, without recurrence.
    Gan to kagaku ryoho. Cancer & chemotherapy 05/2014; 41(5):657-60.
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    ABSTRACT: Aortocaval fistula (ACF) is a well-known but uncommon complication of ruptured abdominal aortic aneurysm (AAA). Even with attentive care, oversight of ACFs may occur in emergency cases. Because mortality due to ACF is high, a rapid, multidirectional analysis of the preoperative state leading to a correct diagnosis is essential. Here, we report the case of an 82-year-old man with a ruptured AAA and ACF. He presented with multiple organ failure that was initially attributed to congestive heart failure. He underwent emergent surgery and was diagnosed intraoperatively as having an AAA with ACF. He left the hospital 1 month after the operation without complications.
    Annals of Vascular Surgery 03/2014; · 0.99 Impact Factor
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    ABSTRACT: Background:ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.Methods:One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.Results:ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.Conclusions:ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.British Journal of Cancer advance online publication, 6 March 2014; doi:10.1038/bjc.2014.88 www.bjcancer.com.
    British Journal of Cancer 03/2014; · 5.08 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the prognosis of pulmonary adenocarcinoma patients following postoperative recurrence, according to epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) gene mutation status and recurrence site. In total 58 adenocarcinoma patients with recurrence following surgical resection were retrospectively evaluated between 2002 and 2011. The patients were divided into groups according to the presence or absence of EGFR and KRAS mutations and the clinicopathological characteristics, recurrence sites and postrecurrence survival were compared. EGFR and KRAS mutations were detected in 26 (45%) and 11 patients (19%), respectively. Initial recurrence was distant in 25 (43%), local in 17 (29%) and both distant and local in 16 cases (28%). In EGFR-mutant (EGFR+) cases, bilateral/contralateral lung recurrence was a frequent finding. EGFR+ cases exhibited significantly better outcomes compared to KRAS+ and EGFR-KRAS- (wild-type) cases. The 2-year post-recurrence survival rates were 81, 18 and 47% in EGFR+, KRAS+ and wild-type cases, respectively. The patients with distant organ recurrence exhibited significantly worse survival compared with those without distant recurrence in wild-type, but not in the EGFR+ cases or the entire cohort. Multivariate analysis revealed that EGFR mutations and a number of recurrent lesions were the only statistically significant independent predictors of postrecurrence prognosis. Our results indicated distinct survival differences in recurrent adenocarcinoma patients according to driver mutations. Patients with EGFR-mutated tumors exhibited increased survival, regardless of recurrence at distant sites, whereas patients with KRAS-mutated adenocarcinoma exhibited poor outcome following postoperative recurrence. Therefore, the assessment of driver mutations is essential for predicting postrecurrence survival following surgical resection.
    Molecular and Clinical Oncology 03/2014; 2(2):187-196.
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    The Journal of thoracic and cardiovascular surgery 02/2014; · 3.41 Impact Factor
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    ABSTRACT: Breast hamartoma is an uncommon benign tumor characterized by the variety of component tissues. Adipose tissue, mammary glands, and fibrous tissue in various proportions are the main components and form a well-circumscribed mass. Myoid (muscular) hamartoma is an extremely rare subtype of breast hamartoma, which contains an additional smooth muscle component. Inadequate breast contour and nipple-areola complex malposition and expansion can occur after resection of a large myoid hamartoma. Immediate mammaplasty for the affected breast, using the dermoglandular flap technique, is required to provide symmetry of the bilateral breasts. We report a case of myoid hamartoma that was larger than ever documented before. An acceptable aesthetic result was achieved by resection and application of reduction mammaplasty in a single-stage operation.
    Surgery Today 01/2014; · 0.96 Impact Factor
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    ABSTRACT: Extraperitoneal colostomy is considered to be more effective at preventing post-colostomy complications than intraperitoneal colostomy. However, this operation is difficult via laparoscopic surgery alone. We present an extraperitoneal colostomy technique using a hand inserted from the perineal side. Extraperitoneal colostomy was performed in five patients. After the rectum was resected, a hand was inserted into the abdominal cavity from the perineal side, and pneumoperitoneum was created. The peritoneum was dissected to make the extraperitoneal route, and the proximal colon was passed along this route with fingers and laparoscopic manipulation. All procedures were completed without tissue damage or hemorrhage. No patient developed a hernia or ileus postoperatively. Laparoscopic abdominoperineal resection for an extraperitoneal colostomy is difficult via laparoscopic ports only. It can be simplified by operating with manual assistance via the perineal wound.
    Asian Journal of Endoscopic Surgery 01/2014; 7(1):89-92.
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    ABSTRACT: The mesenteric vessels have many branching patterns. This study clarified the anatomic relationship between the superior mesenteric vein (SMV), the right colic artery (RCA), and the ileocolic artery (ICA) using 3-dimensional computed tomography (3D-CT). The relationship between the RCA and the right colic vein (RCV) was also examined. Between April 2006 and July 2011, all patients with colorectal cancer underwent multidetector computed tomography (MDCT) before laparoscopic surgery. The 100 most recent consecutive cases were analyzed. 3D-CT images were made by combining arterial angiography, venous angiography, colonography, tumor, lymph node, and duodenal images. The RCA branched from the SMA in 37 cases (37%); of these, 21 had an ICA that crossed anterior to the SMV and 16 had an ICA that crossed posterior. When the ICA crossed anterior to the SMV, all had an RCA that crossed anterior to the SMV, and no posterior RCA was seen. Furthermore, the RCV joined the SMV in 10 cases (27%) and the gastrocolic trunk in 27 cases (73%). Our study clarified the anatomic variety of the vessels in right-sided colon cancer. Preoperative 3D-CT is useful for understanding the anatomy to ensure a safe, precise operation.
    Surgical laparoscopy, endoscopy & percutaneous techniques 12/2013; 23(6):536-9. · 0.88 Impact Factor
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    ABSTRACT: Purpose: We have reported, in a randomized, controlled study, that tegafur-uracil(UFT)and protein-bound polysaccharide K(PSK)combination therapy significantly improves the 5-year disease-free survival rate and reduces the risk of recurrence compared to UFT alone for Stage II or III colorectal cancer. In this study, we examined the efficacy of PSK by stratifying patients according to the preoperative lymphocyte ratio(Lym). Methods: In a randomized, controlled study, 205 patients were eligible(137 in the UFT/PSK group and 68 in the UFT group). Of these, 193 patients with available preoperative Lym data were analysed(131 in the UFT/PSK group and 62 in the UFT group). Results: Among patients with a preoperative Lym of <35%, the relapse-free survival(RFS)rate was 76.5% in the UFT/PSK group and 55.8% in the UFT group(p=0.008). However, in patients with a preoperative Lym of ≥35%, the RFS rate did not differ between the 2 groups. Similarly, overall survival was significantly higher in the UFT/PSK group than in the UFT group in patients with a preoperative Lym of <35%, whereas no intergroup difference was found among patients with a preoperative Lym of ≥35%. Conclusion: This study suggests that a low preoperative Lym is a good predictor for response to PSK in patients with Stage II or III colorectal cancer.
    Gan to kagaku ryoho. Cancer & chemotherapy 12/2013; 40(13):2525-2528.
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    ABSTRACT: The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer. A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line. In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU. High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.
    BMC Cancer 10/2013; 13(1):482. · 3.33 Impact Factor
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    ABSTRACT: S-1 is a novel oral anticancer agent consisting of tegafur, a prodrug of 5-fluorouracil, and 2 modulators. A phase I study of sequential S-1 and cyclophosphamide(CPA)therapy was conducted to determine the dose-limiting toxicities(DLTs)and recommended doses(RDs)in patients with metastatic or recurrent breast cancer(MBC). Patients with MBC received sequential S-1 and CPA. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at escalating doses of 40, 50, 65, and 80mg/m2/day and CPA at 100 mg/body/day on days 15-28. The schedule was repeated twice at a 4-week interval. The purposes of this study were to determine the RDs, safety, and efficacy of the regimen. A total of 12 patients were registered. No patients experienced DLTs, and the RDs of S-1 and CPA were 80mg/m2/day and 100 mg/body/day, respectively. The response rate was 50. 0%. In conclusion, sequential therapy with S-1 and CPA could be safely and effectively used for the treatment of MBC, and the RDs for this regimen were determined to be 80mg/m2/day for S-1 and 100 mg/m2/day for CPA.
    Gan to kagaku ryoho. Cancer & chemotherapy 09/2013; 40(9):1175-80.

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