[A Case of Mediastinal Lymph Node Metastasis from Liver Metastasis of Colon Cancer].

A 64-year-old woman underwent partial colectomy with partial resection ofthe retroperitoneum and D3 lymphadenectomy for descending colon cancer(tub2, pSS, ly0, v0, pN1, sH0, sP0, sM0, fStage III b). Three years and 6 months later, she underwent resection ofsegment 4 ofthe liver because ofliver metastasis. One year and 2 months later, her serum carcinoembryonic antigen level increased, and computed tomography showed an inferior mediastinal mass of 18mm in diameter. High FDG uptake by this tumor was seen on positron emission tomography-CT. Metachronous mediastinal lymph node metastasis from liver metastasis ofcolon cancer was diagnosed, and resection ofthe mediastinal lymph nodes was performed. Pathological examination revealed adenocarcinoma similar to the liver metastasis. After resection, the patient received antineoplastic agents(7 courses of modified FOLFOX6 followed by 3 courses of S-1). The patient is alive without recurrent disease 3 years and 4 months after resection of the mediastinal lymph nodes. Mediastinal lymph node metastasis from liver metastasis of colon cancer without lung metastasis is rare. Although the optimal treatment has not been determined, tumor resection may be associated with favorable outcomes.

[A case of advanced colon cancer with atrial fibrillation and the use of dabigatran for safe chemotherapy using fluoropyrimidine-based antitumor agents].

A 77-year-old man with colon cancer and multiple metastases to the liver and lungs underwent resection of the primary tumor and D3 lymph node dissection. He presented with chronic atrial fibrillation; therefore, warfarin was used initially as an anticoagulant. Because of the need to administer a fluoropyrimidine-based antineoplastic agent[5-fluorouracil(5-FU)] during chemotherapy, we changed the anticoagulant from warfarin to dabigatran etexilate(dabigatran)before initiating chemotherapy. No complications or excessive decrease in coagulability was observed after changing the anticoagulant; chemotherapy was safely continued. Unlike warfarin, dabigatran undergoes renal excretion, and thus, can be safely used in anticoagulant therapy without any drug interaction with 5-FU. Thus, we believe that dabigatran may be the anticoagulant of choice in the future for cancer patients who are scheduled to undergo chemotherapy using fluoropyrimidine-based antineoplastic agents.

The development of a mini-array for estimating the disease state of gastric adenocarcinoma by array CGH.

BACKGROUND: The treatment strategy usually depends on the disease state in the individual patient. However, it is difficult to estimate the disease state before treatment in many patients. The purpose of this study was to develop a BAC (bacterial artificial chromosome) mini-array allowing for the estimation of node metastasis, liver metastasis, peritoneal dissemination and the depth of tumor invasion in gastric cancers. METHODS: Initially, the DNA copy number aberrations (DCNAs) were analyzed by array-based comparative genomic hybridization (aCGH) in 83 gastric adenocarcinomas as a training-sample set. Next, two independent analytical methods were applied to the aCGH data to identify the BAC clones with DNA copy number aberrations that were linked with the disease states. One of the methods, a decision-tree model classifier, identified 6, 4, 4, 4, and 7 clones for estimating lymph node metastasis, liver metastasis, peritoneal dissemination, depth of tumor invasion, and histological type, respectively. In the other method, a clone-by-clone comparison of the frequency of the DNA copy number aberrations selected 26 clones to estimate the disease states. RESULTS: By spotting these 50 clones together with 26 frequently or rarely involved clones and 62 reference clones, a mini-array was made to estimate the above parameters, and the diagnostic performance of the mini-array was evaluated for an independent set of 30 gastric cancers (blinded - sample set). In comparison to the clinicopathological features, the overall accuracy was 66.7% for node metastasis, 86.7% for liver metastasis, 86.7% for peritoneal dissemination, and 96.7% for depth of tumor invasion. The intratumoral heterogeneity barely affected the diagnostic performance of the mini-array. CONCLUSION: These results suggest that the mini-array makes it possible to determine an optimal treatment for each of the patients with gastric adenocarcinoma.

[A case of complete response treated by gastrectomy with lymphadenectomy and combined chemotherapy of peroral S-1 and CDDP by arterial infusion for gastric cancer with multiple liver metastasis].

A 70-year-old female was admitted to our hospital with high fever about 5 days before this writing, along with anemia and hyperglycemia. Upper gastrointestinal series and endoscopy revealed type 1 gastric cancer in the greater curvature. CT and MRI showed multiple liver metastasis in the right lobe. Distal partial gastrectomy with lymphadenectomy and cannulation of hepatic artery was performed. The pathological findings revealed moderately-differentiated adenocarcinoma, T2, N0, H1, M0, stage IV. The postoperative chemotherapy with S-1 (80 mg/day) was administered for 4 weeks followed by 1 week rest and CDDP (50 mg) administered once every 4 weeks by arterial infusion. Two months after operation the tumor marker values have become normal, and CT can hardly detect the metastatic liver tumors. At 8 months after operation, CT and MRI revealed complete disappearance of these tumors. Then, 12 months after operation, FDG-PET revealed no accumulation. Now, at 18 months, the CR stage has been maintained. Combined use of peroral S-1 and CDDP by arterial infusion is effective for multiple liver metastasis after gastrectomy in gastric cancer.

Relation of DNA ploidy to genetic aberrations detected by chromosomal CGH and FISH in gastric adenocarcinomas.

We analyzed DNA copy number aberrations (DCNAs) by chromosomal comparative genomic hybridization (CGH) in 93 consecutive sporadic gastric adenocarcinomas. In addition, numerical aberrations in chromosomes 7, 11, 17, and 18 were evaluated by fluorescence in situ hybridization (FISH). Gastric cancers were divided on the basis of nuclear DNA content measured by laser scanning cytometry (LSC) into two groups, 36 DNA diploid (1.0 or= 1.2) cancers. The most frequent gain and loss of DNA copy number were found at 8q21-23 and 19p13.3, respectively, in both diploid and aneuploid cancers. Diploid cancers were further divided on the basis of genetic aberrations into major type and subtype cancers. The diploid cancer group included nine subtype cancers that showed large numbers of DCNAs; the mean number of DCNAs detected by CGH was 26.7 per tumor. This value was much larger in these diploid subtype cancers than diploid major type cancers (mean, 5.2 per tumor, p<0.0001). These nine cancers were also characterized by large intercellular variations in chromosome copy numbers that were not detected in the 27 major diploid type cancers. The aneuploid cancer group included only three subtype tumors that showed only a small number of DCNAs (mean, 3 per tumor) and minimal intercellular variations in chromosomal copy number. These data indicate that gastric adenocarcinomas can be divided into three types; aneuploid, major diploid type and diploid subtype cancers. Large-scale studies are necessary to clarify the differences in biological characteristics and underlying genetic mechanisms between these types.

UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism-directed phase II study of irinotecan with 5'-deoxy-5-fluorouridine (5'-DFUR) for metastatic colorectal cancer.

AIM: We performed a phase II study of irinotecan with 5'-deoxy-5-fluorouridine (5'-DFUR) for metastatic colorectal cancer based on UDP-glucuronosyltransferase (UGT) 1A1 polymorphism. PATIENTS AND METHODS: A total of 28 patients were enrolled. The dose of irinotecan was 150 mg/m(2) for patients with the *1/*1 wild-type genotype, and 70 mg/m(2) for those with the *1/*28 mutated genotype. The primary end-point was the response rate (RR); secondary end-points were safety, time to treatment failure (TTF), and overall survival (OS). RESULTS: In 28 patients total, genotype was wild-type in 22 and mutated in six. The RR was *1/*1 (22.7%; wild-type) vs. *1/*28 (16.7%; mutated); the median TTF was 5 months vs. 4.5 months, and the median OS was 13 months vs. 17.5 months, respectively. None of these differences were significant. Toxicities of grade 3 or higher were neutropenia (9.0% vs. 0%, respectively) and diarrhea (13.6% vs. 0%, respectively). CONCLUSION: This genotype-oriented therapy was effective and safe, and thus appears useful for patients who have complications or advanced age.

DNA copy number aberrations associated with the clinicopathological features of colorectal cancers: Identification of genomic biomarkers by array-based comparative genomic hybridization.

The aim of the present study was to investigate the chromosomal aberrations that are linked with the crucial clinicopathological features of colorectal cancer (CRC) and its prognosis by array-based comparative genomic hybridization (CGH). Fresh-frozen tumor tissues of 94 cases of CRC were analyzed by using bacterial artificial chromosome (BAC) CGH slides spotted with 4030 human BAC clones, which covered the whole range of the human genome at an average interval of 0.83 mega base pairs. DNA copy number aberrations (DCNAs) were identified in association with clinicopathological features: a gain of 8q24.3 and losses of 9q33.1 and 20p12.2 were associated with lymph node metastasis, gain of 8q24.3 and loss of 9q33.1 with disease stage, gain of 8q21.11 and loss of 10q21.3 with lymphovascular invasion and losses of 3p25.1, 10p15.3, 12q15 and 17p13.1 for venous invasion. These aberrations can be regarded as genomic biomarkers to predict the clinical outcome of patients with CRC, and are expected to serve to individualize the treatment of CRC patients.

Genomic instability and DNA ploidy are linked to DNA copy number aberrations of 8p23 and 22q11.23 in gastric cancers.

The close relationship between chromosomal instability (CIN) and aneuploidy has been reported. The purpose of this study was to identify genomic aberrations present with CIN and aneuploidy in gastric cancers. FISH and image cytometry were applied to 27 sporadic gastric adenocarcinomas to identify CIN-positive tumors and to determine DNA ploidy, respectively. In addition, array-based comparative genomic hybridization was used to identify bacterial artificial chromosome clones that displayed differences in the frequency of copy number aberrations between CIN-positive and CIN-negative tumors, and between aneuploid and diploid tumors. There were many chromosomal regions with DNA copy number aberrations, some of which were nonrandom aberrations linked to the CIN phenotype and aneuploidy. A copy number loss of 22q11.23 was more frequent in CIN-positive cancers than in others (7/12 vs. 2/15, p<0.01) and in aneuploid cancers than in diploid cancers (8/16 vs. 1/11, p<0.05). The frequency of 22q11.23 loss differed significantly between CIN-positive and aneuploid tumors and between CIN-negative and diploid cancers (7/10 vs. 1/9, p<0.01). In contrast, a DNA copy number gain of 8p23.2 was detected in 6 out of 9 CIN-negative/diploid cancers, but was not detected in CIN-positive/aneuploid cancers (p<0.01). There were no cancers carrying both aberrations (22q11.23 loss and 8p23.2 gain). The present study indicates that a 22q11.23 loss and a 8p23.2 gain are markers for both CIN and aneuploidy. This is the first report describing an inverse relationship between the 22q11.23 loss and 8p23.2 gain in terms of genomic instability and DNA ploidy in gastric cancers.