Katsuhiko Saito

Detection of the four sequence variations of MDR1 gene using TaqMan® MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects

OBJECTIVESnP-glycoprotein (P-gp) is significant from the viewpoint of pharmacokinetics/pharmacodynamics (PK/PD). MDR1 gene encodes P-gp and has a wide variety of SNPs. As the SNPs may be one of the factors that induce pharmacogenetic individual difference, haplotype analysis is necessary to evaluate the PK/PD.nnnDESIGN AND METHODSnThe SNPs of the detected MDR1 were -129T>C, 325G>A, 2677G>T/A, and 3435C>T. For the analysis of linkage disequilibrium (LD) and haplotype analysis, and for the reconstruction of the haplotype pair, ARLEQUIN and PHASE were employed.nnnRESULTSnThe result of the chi(2) test detected significant LD between -129 and 2677, -129 and 3435, and 2677 and 3435. There were 9 haplotypes: T-G-C, T-T-C, C-T-C, T-A-C, C-A-C, T-G-T, T-T-T, C-G-T, and C-T-T.nnnCONCLUSIONSnLD was found among the positions -129, 2677 and 3435. As a result, 9 haplotypes exists in the Japanese population. These results suggest that it would be necessary to give consideration to haplotype for the purpose of evaluating the PK/PD of the drugs transported by P-gp.

Detection of incidental breast tumors by noncontrast spiral computed tomography of the chest.

PurposeThe aim of this study was to investigate the frequency of breast tumors and breast cancers with noncontrast spiral chest computed tomography (CT).Material and methodsA clinical study was conducted to evaluate findings in the mammary region of 1008 consecutive patients with no mammary symptoms or signs who underwent noncontrast spiral CT of the chest from April 2003 to March 2006.ResultsSix cases of breast abnormality were detected among the 1008 women. Three were primary breast cancers, one was metastatic breast cancer, and two were benign tumors. All four breast cancer patients were over 70 years old. The characteristics of the tumor margins on CT scans corresponded to the mammography and ultrasonography findings. The mammographic background density ranged from inhomogeneous high-density breast to fatty breast. The detection rate of primary breast cancer by noncontrast spiral CT was 0.30%.ConclusionNoncontrast spiral chest CT occasionally detects nonsymptomatic breast cancers, especially in elderly patients.

Characterization of a genotype previously designated as cyp2a6 D-type: cyp2a6 * 4b , another entire gene deletion allele of the cyp2a6 gene in Japanese

CYP2A6 is known as an enzyme responsible for the metabolism of several clincally used drugs such as tegafur. Previously, we found two novel genotypes of the CYP2A6 gene, D-type and E-type, and the E-type was clarified to be homozygous for the CYP2A6*4A allele. On the other hand, since the D-type was reported to lack regions from at least intron 5 to a part of exon 9 of the CYP2A6 gene, it caused a misunderstanding that the D-type would be a partial CYP2A6 gene-deleted allele. In this paper, we demonstrate that the D-type is a genotype heterozygous for the CYP2A6*4A and another novel entire CYP2A6 gene-deleted allele, CYP2A6*4B, by analyzing a Japanese family including parents genotyped as the CYP2A6*4A/4A and CYP2A6*1A/*4B, respectively.

Association of SLC22A4/5 Polymorphisms with Steroid Responsiveness of Inflammatory Bowel Disease in Japan

PurposeWe investigated the association between steroid responsiveness and single nucleotide polymorphisms of SLC22A4/A5 located within inflammatory bowel disease 5 locus. Our goal is personalized steroid therapy adjusted to match individual variations in drug responsiveness in each inflammatory bowel disease patient.MethodsUnrelated Japanese cohorts of 94 patients with Crohn’s, 94 patients with ulcerative colitis, and 257 healthy control subjects were consecutively enrolled in this study. Genotyping and haplotype analysis focusing on steroid responsiveness was performed by using 15 single nucleotide polymorphisms.ResultsThe G allele of −368Tu2009>u2009G in SLC22A5, in which strong linkage disequilibrium was observed and the limited diversity of three haplotypes was estimated, was significantly associated with steroid resistance in Japanese patients with Crohn’s disease (Pu2009=u20090.016). Haplotype analysis between −446Cu2009>u2009T and −368Tu2009>u2009G in the SLC22A5 promoter region showed that the CG allele appeared to be a risk haplotype for steroid resistance (CG: odds ratio, 4.13; 95 percent confidence interval, 1.41–12.1; Pu2009=u20090.016).ConclusionsThis extensive linkage disequilibrium may form a general risk haplotype for steroid resistance in Crohn’s disease in Japanese. Further analyses of the pharmacogenomics of steroid responsiveness are warranted to achieve the goal of individualized steroid therapy against inflammatory bowel disease.

Association of μ-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.

AbstractnGenetic variants, such as single-nucleotide polymorphisms (SNPs), of the μ-opioid receptor gene (OPRM1) might be associated with individual differences in opioid sensitivity, as well as with the incidence and severity of postoperative nausea and vomiting (PONV). The goal of the present study was to determine, in a cohort of Japanese surgical patients, genotypes and haplotypes of several SNPs in the OPRM1 gene, and their association with PONV during the early (first 24xa0h) postoperative period. We examined the incidence and severity of PONV, during the first 24xa0h after surgery, in 85 Japanese patients receiving intravenous patient-controlled analgesia fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene (rs1799971, A/G; rs510769, G/A; rs4870266, G/A; rs3798683, G/A; rs1323042, A/C; rs609623, C/T; rs9397685, A/G; and rs644261, C/G) were selected based on their minor allele frequency (>10xa0%) and linkage disequilibrium strength (<80xa0%), and genotyped for haplotype analysis and determination of associations with PONV. Only one out of eight investigated SNPs, rs9397685, in the intronic part of the OPRM1 gene was associated with differences in the occurrence and severity of PONV. We also found four common haplotypes with a frequency of >10xa0% in the investigated patients, including GGGAACAC (33xa0%), AGGGACAC (19xa0%), GGGAACGC (12xa0%), and AGAGACAC (10xa0%). The severity of PONV in carriers of the GGGAACGC haplotype was significantly lower than in the carriers of the other haplotypes (Pxa0<xa00.05). One intronic SNP, rs9397685, and haplotypes constructed from eight SNPs within the OPRM1 gene locus might be involved in the severity of PONV associated with general anesthesia and opioid administration. This novel finding, if validated and verified in larger and additional ethnic cohorts, might contribute to better knowledge of the contribution of the OPRM1 gene to PONV.n

Metastatic gastric carcinoma from breast cancer mimicking primary linitis plastica: A case report

Metastases to the gastrointestinal tract rarely occur in breast cancer except in invasive lobular carcinoma. The present study reports a rare case of metastatic gastric cancer from invasive ductal carcinoma (IDC) of the breast mimicking primary gastric linitis plastica. A 51-year-old premenopausal female, who had a history of partial mastectomy for right breast cancer at the age of 40, was referred to Toyama City Hospital (Toyoma, Japan) for an endoscopic diagnosis of gastric linitis plastica. Abdominal computed tomography (CT) revealed left hydronephrosis, while peritoneal metastasis and malignant ascites were not detected. Chest CT detected a left lung tumor, which had invaded the left upper bronchus. Biopsy specimens were obtained and the histopathological findings on both the gastric tumor and lung tumor demonstrated poorly differentiated adenocarcinoma, whereas the histology of the original breast cancer was IDC with a solid-tubular type. Immunohistochemistry revealed that the biopsied specimens of the gastric and lung tumors were positive for estrogen receptor (ER), progesterone receptor (PgR) and negative for human epithelial growth factor receptor-2 (HER2). These molecular characteristics indicated the case was metastatic gastric carcinoma from the breast cancer with lung metastasis, since the statuses of ER, PgR and HER2 were concordant with those of the original breast cancer. However, the possibility of primary gastric cancer could not be completely ruled out. Therefore, a total gastrectomy was performed for the purpose of both diagnosis and treatment. Pathological examination of the resected specimen provided a definite diagnosis of multiple metastatic gastric carcinomas from the breast. To the best of our knowledge, metastatic gastric cancer derived from the breast presenting as linitis plastica 11 years following the surgical removal of IDC has not been described previously.

Massive pneumoretroperitoneum arising from emphysematous cholecystitis: a case report and the literature review.

BackgroundEmphysematous cholecystitis is a severe variant of acute cholecystitis caused by anaerobic bacteria. Although intraperitoneal air as a complication has been described in association with emphysematous cholecystitis, pneumoretroperitoneum arising from emphysematous cholecystitis is extremely rare. Herein, we describe a rare case of pneumoretroperitoneum arising from emphysematous cholecystitis that was successfully treated with emergency surgery.Case presentationAn 84-year-old male was transported to the Emergency Department of our hospital for acute abdomen. Computed tomography revealed acute cholecystitis accompanied by emphysematous change. Computed tomography also revealed massive pneumoretroperitoneum complicated with pneumobilia and gas in the hepatoduodenal ligament. Clinical findings fulfilled the diagnostic criteria for systemic inflammatory response syndrome and sepsis. Emergency surgery was carried out with a diagnosis of both emphysematous cholecystitis and gastrointestinal perforation. Intraoperative findings revealed acute gangrenous cholecystitis and pneumoretroperitoneum presenting with an odor-free foamy abscess along the loose connective tissue behind the ascending colon and mesocolon. No evidence of gastrointestinal perforation was found during surgery. Therefore, cholecystectomy and lavage drainage were performed. Bacterial culture examination isolated a single species of anaerobe, Klebsiella pneumoniae, which was considered to be the cause of emphysematous cholecystitis, pneumobilia, and pneumoretroperitoneum.ConclusionsEmphysematous cholecystitis should be considered as a possible cause of pneumoretroperitoneum. The present case is the first report of massive pneumoretroperitoneum extending to the dorsal side of the ascending mesocolon as a complication of emphysematous cholecystitis.

The Association Between Heterozygosity for UGT1A1*6, UGT1A1*28, and Variation in the Serum Total-Bilirubin Level in Healthy Young Japanese Adults

AIMSnConsiderable variations in the serum total-bilirubin concentrations are observed in healthy subjects. Both sex and the UGT1A1 homozygous genotypes,*6/*6 and *28/*28, are known to influence this variation. However, currently, there is no consensus on the relationship of the heterozygous genotypes *1/*6, *1/*28, or *6/*28 and interindividual variation in the serum total-bilirubin levels. In the present study, we sought to clarify the involvement of heterozygous alleles *6 and *28 in the interindividual difference in the serum total-bilirubin levels among healthy young Japanese adults.nnnMETHODSnWe enrolled 92 healthy Japanese aged 20-30 years (37 men and 55 women). The serum total-bilirubin levels were compared between men and women and with different UGT1A1 genotypes. Multiple regression analysis was used to investigate the relationships between individual differences in the serum total-bilirubin levels, UGT1A1 genetic variants, and sex.nnnRESULTSnSerum total-bilirubin levels were significantly lower in women than in men. There were also significant differences in the serum total-bilirubin levels between the *1/*1 and *1/*28 genotype, the *1/*1 and *6/*28 genotype, the *1/*6 and *1/*28 genotype, and also the *1/*6 and *6/*28 genotype. Multiple regression analysis showed significant relationships between the serum total-bilirubin level, the UGT1A1 genotypes *1/*28 and *6/*28, and sex. This model explained 42.3% of the interindividual variation in serum total-bilirubin levels.nnnCONCLUSIONSnWe found that the UGT1A1 genotypes *1/*28 and *6/*28 as well as sex contributed to interindividual variations in the serum total-bilirubin levels. In contrast, UGT1A1*1/*6 showed only minimal involvement in individual differences in serum total-bilirubin levels.

Association between the low‑dose irinotecan regimen‑induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22–38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.

Sigmoid colon cancer arising in a diverticulum of the colon with involvement of the urinary bladder: a case report and review of the literature

BackgroundColon cancer can arise from the mucosa in a colonic diverticulum. Although colon diverticulum is a common disease, few cases have been previously reported on colon cancer associated with a diverticulum. We report a rare case of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder, which presented characteristic radiographic images.Case presentationA 73-year-old man was admitted to our hospital for macroscopic hematuria. Computed tomography and magnetic resonance imaging revealed a sigmoid colon tumor that protruded into the urinary bladder lumen. The radiographs showed a tumor with a characteristic dumbbell-shaped appearance. Colonoscopy showed a type 1 cancer and multiple diverticula in the sigmoid colon. A diagnosis of sigmoid colon cancer with involvement of the urinary bladder was made based on the pathological findings of the biopsied specimens. We performed sigmoidectomy and total resection of the urinary bladder with colostomy and urinary tract diversion. Histopathological findings showed the presence of a colovesical fistula due to extramurally growing colon cancer. Around the colon cancer, the normal colon mucosa was depressed sharply with lack of the muscular layer, suggesting that the colon cancer was arising from a colon diverticulum.ConclusionThe present case is the first report of sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder. Due to an accurate preoperative radiological diagnosis, we were able to successfully perform a curative resection for sigmoid colon cancer arising in a diverticulum with involvement of the urinary bladder.