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A 41-year-old female complained of epigastric pain and was referred to our hospital. Gastrofiberscopy revealed that type 4 gastric cancer located at the whole gastric body. Although abdominal computed tomography showed that no distant metastasis but regional lymph node metastasis existed, staging laparoscopy and cytological diagnosis revealed that there were intraperitoneal free cancer cells without overt peritoneal metastasis(P0CY1). She received neoadjuvant chemotherapy with S-1 plus cisplatin for consecutive 21 days followed by 7 days of rest as a course. After 3 courses of the chemotherapy, intraperitoneal free cancer cells were not found, and she underwent curative gastrectomy. Pathological examination showed that the therapeutic effect was Grade 2. S-1 as postoperative chemotherapy had been prescribed for 10 months without relapse. However, she suffered from anorexia and abdominal distension and peritoneal metastasis was confirmed on the 575th day after curative operation. She has received a weekly paclitaxel therapy as second-line chemotherapy.

The most common treatment for patients of peritoneal dissemination of gastric cancer is a systemic chemotherapy, but the prognosis of these patients is very poor. For these diseases, some have reported the usefulness of intraperitoneal chemotherapy with cisplatin (CDDP), because of the direct cytotoxicity. Here, we report an effective treatment by chemotherapy with S-1 plus CDDP, intraperitoneal administration for the patients of peritoneal dissemination of gastric cancer. The patient was a 41-year-old male with upper abdominal pain. Upper gastrointestinal endoscopy showed a large type 3 gastric cancer from the cardia to antrum. Intraoperative peritoneal lavage cytology and dissemination was positive, thus we performed the total gastrectomy and implanted the intraperitoneal (IP) port in the Douglas's pouch. S-1 was given orally twice daily for the first 3 weeks of a 5-week cycle. CDDP was given as an intraperitoneal infusion on day 8 of each cycle. After 10 courses, he was treated with S-1 alone because he had an allergic reaction of CDDP. In 35 courses, he had survived for 5 years as disease free. Intraperitoneal chemotherapy may be a promising treatment for the patients who have peritoneal dissemination from gastric cancer.

Gastric endocrine cell carcinoma is known to be highly malignant with a poor prognosis, and no standard treatment has been established. We experienced a case of gastric endocrine cell carcinoma with liver and lymph node metastases. The lesions became resectable after chemotherapy with S-1/cisplatin (CDDP). The patient was a 68-year-old male. He had gastrointestinal endoscopy for screening without complains. The endoscopy findings showed that a type 3 gastric cancer on lesser curvature of ventricular angle of the stomach, and was histologically diagnosed as an endocrine cell carcinoma by the biopsy specimen. A computed tomography (CT) scan showed metastatic lesions at S2 and S3 of the liver, and No.6 lymph node enlargement. Thus he was diagnosed as gastric endocrine cell carcinoma with liver and lymph node metastases. He was treated chemotherapy with S-1/CDDP every 5 weeks. After these courses of treatment, liver and lymph node metastatic lesions had reduced in size, but the primary lesion was still remained. Then he suffered from a drug induced eruption due to S-1. We changed the chemotherapy to biweekly CPT-11/CDDP. After 21 courses, he underwent distal gastrectomy with lymph node dissection and a partial liver resection. Histological findings revealed that there were no cancer cells in removed specimens. He had treated 8 courses of CPT-11/CDDP therapy after the surgery, and survived for 5 years without recurrence.

The number of surgeries for colorectal cancer in elderly patients is increasing in correspondence to Japan's aging society. It is important to evaluate the patient's condition in order to carry out operations safely. The Onodera index (Onodera index in order (PNI: prognostic nutritional index)=serum alb value × 10+the lymphocyte counts of peripheral blood) is a simple and useful tool for choosing the method of operation. In our experience, 75% of elderly patients had pre-operative complications. Respiratory and circulatory complications occurred more frequently after operations. Pre- and post-operative adequate management can help facilitate a safer operation. Even if a curative operation was carried out for an elderly patient, both the cancer-specific survival rate and the 5-year relative survival rate were good. If the operation is tolerable for the elderly patient, curative resection should be performed. Chemotherapy in elderly should be also evaluated by the patient's activities of daily living and the regimen of chemotherapy should be selected.

A 55-year-old male patient with epigastralgia was diagnosed as type 3 gastric cancer at the lower gastric region. Total gastrectomy and D3 lymph node dissection were performed in our hospital. Pathological findings showed pT2N2M0, pStage IIIA. He was treated with 5'-DFUR and PSK therapy as adjuvant chemotherapy for 18 months after surgery. At 24 months after the operation, paraaortic lymph node recurrence was confirmed by computed tomography. He was treated with single agent S-1 in 10 courses on a 4-week dosing regimen with a 2-week interval. After 4 courses, CT showed a disappearance of paraaortic lymph node. He was obtained a complete response. Now the patient is disease-free for 11 years after operation.

A 61-year-old man admitted to our hospital for diarrhea and general fatigue was found in endoscopic and radiological examination to have sigmoid colon cancer with multiple liver metastases. The patient underwent sigmoidectomy (S, type 2, 105x78 mm, sSI (urinary bladder), sN0 (0/22), sH3 (Grade C), sP0, sM0, sStage IV). Pathological report was following: tub2, pSI (urinary bladder), ly0, v1, pN0(0/22), PM0, DM0, RM0. After operation, the patient received systemic chemotherapy (CPT-11+UFT/LV) with hepatic arterial infusion therapy(HAI). We could not observe any severe adverse events. We conducted hepatectomy because of partial response by chemotherapy. As of this writing 41 months after surgery, the patient continues to do well with no signs of recurrence. The combination chemotherapy of CPT-11+UFT/LV with HAI was safe and effective treatment for the patients with unresectable liver metastases from colorectal cancer.

The patient was a 58-year-old man who had been performed a low anterior resection for an advanced upper rectal cancer (T3N0M0, Stage II). At fourteen months after primary operation, follow-up CT scan, MRI and FDG-PET showed a pelvic recurrence located at upper presacral region. Following radiotherapy combined with S-1, we performed a curative surgical resection. Pathologically, an extensive fibrosis was shown without a tumor cell. Complete surgical removal of the recurrent disease remains the best chance of cure after a local recurrence. But in the case of recurrent tumor located in upper presacral region and extended to the pelvic side-wall, it is very difficult to achieve negative resection margins. So selection of patients is very important to reduce the risk of positive surgical margins. We experienced a resected case of pathologically complete response of a pelvic recurrence from rectal cancer after chemoradiotherapy with S-1. This case suggests the neoadjuvant chemoradiotherapy has potential to improve management of locally recurrent rectal cancer.

To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases.Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140 mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300 mg/m² per day) and LV (75 mg/body per day) on days 1-7 of each cycle, and with HAI 5-FU (2,000 mg/week) on days 8-14 of each cycle.Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140 mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2 months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection.Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.

A 48-year-old man, who had undergone a low anterior resection for advanced lower rectal cancer on May 27, 2003, was admitted to our hospital with anastomosis recurrence in November 2004. After chemo-radiotherapy (5-FU 250 mg/ body continuous infusion, 5 Gy each 5 fragments), an abdomino-perineal resection was performed on December 1, 2004. A follow-up CT scan showed pelvic local recurrences located dorsal to prostate in January, and the presacral region in July 2006. Because of presence of complication of acute promyelocytic leukemia (APL), this patient had a poor general condition. So radiofrequency ablation (RFA) therapy was performed as a palliative therapy. A presacral relapse was revealed in three months after RFA. As a complication, two weeks after RFA for the presacral region, a vesicoctaneous fistula occurred, and it required a urinary diversion. He died of APL on August 27, 2007. CT-guided radiofrequency ablation is useful for pelvic recurrence from rectal cancer of poor-risk patient.

Cdc4 (Fbxw7) is a potential tumor suppressor that regulates ubiquitination and proteolysis of multiple targets such as cyclin E, c-Myc, c-Jun and Notch. CDC4 mutations were investigated in 194 colorectal carcinomas and adenomas for comparison between sporadic and hereditary cancers.Mutations of the CDC4 gene were analyzed by PCR-SSCP and sequencing, and loss of heterozygosity (LOH) was analyzed by microsatellite marker analysis.Somatic CDC4 mutations were detected in 9% (3 of 33) of hereditary nonpolyposis colorectal cancer (HNPCC), 9% (3 of 33) of familial adenomatous polyposis (FAP) carcinomas, and 10% (7 of 73) of sporadic carcinomas. CDC4 mutations were also detected in adenomas at frequencies of 6% (2 of 31) and 4% (1 of 24) in FAP and sporadic cases, respectively. Frameshift mutations were observed in HNPCC tumors, while single-base substitutions predominantly occurred in FAP and sporadic tumors. LOH at the chromosome 4q region was rarely detected in tumors with CDC4 mutations.The results indicate that the frequency of CDC4 mutations in colorectal tumors is similar in patients with HNPCC and FAP compared to patients with sporadic carcinomas. Moreover, infrequent LOH suggests that the CDC4 gene does not follow the general 2-hit model.

Although numerous authors have reported various prognostic factors for liver metastases from colorectal cancer, there is not yet a general classification.A total of 478 colorectal cancer patients from 18 institutes were studied. Prognostic factors were investigated using univariate and multivariate analyses.Independent prognostic factors for colorectal liver metastases were number of liver metastases, size of the largest liver metastases, mesenteric lymph node metastases (pN0/1:or =3 lesions, pN2:or =4 lesions), and extrahepatic metastases (EM0: absence of extrahepatic metastasis, EM1: presence of extrahepatic metastases). We defined the following classification system; Stage A: HT1 (or =4 lesions andor =5cm) and pN0/1, Stage B: HT2 (or =5 lesions or5cm) and pN0/1, or HT1 and pN2, Stage C: HT2 and pN2, HT3 (or =5 lesions and5cm) with any pN, or any HT and any pN with EM1. Five-year survival rates were 53.5% for Stage A patients, 25.4% for Stage B patients, and 5.8% for Stage C patients. Median survival time was 70.4 months, 31.4 months, and 17.2 months, respectively.Our classification was advocated to evaluate prognoses for liver metastases from colorectal cancer. It can help guide decision making in terms of liver resection and assessing patient prognosis.

To clarify the differences in characteristics of adenomatous polyposis coli (APC) mutations between colorectal tumors from various phenotypes of familial adenomatous polyposis (FAP) and between colorectal and extracolonic tumors, we analyzed APC mutations in 86 colorectal tumors from FAP patients including profuse, sparse and attenuated types, 23 sporadic colorectal tumors and 40 FAP extracolonic tumors including duodenal, gastric and desmoid tumors. In all tumors, 1 allele of the truncated APC gene retained armadillo repeats, 15-amino-acid (aa) repeats and various numbers of 20-aa repeats, but lacked SAMP repeats, as a result of germline and somatic mutations. Regarding 20-aa repeats, the truncated APC gene retained 1 repeat due to allele loss in 96% (27/28) of colorectal tumors from profuse-type FAP, 69% (36/52) of sparse-type retained 2 repeats due to somatic mutation, and 100% (6/6) of attenuated-type retained 2 or 3 repeats due to the third or second hit. In sporadic colorectal tumors 74% (17/23) retained 1 or 2 repeats. The truncated APC gene retained 3 repeats in 88% (7/8) of FAP duodenal tumors, 100% (26/26) of gastric tumors retained 2 or 3 repeats and 83% (5/6) of desmoid tumors retained 2 repeats. These data suggest that the number of β-catenin downregulating 20-aa repeats in truncated APC gene associated with colorectal tumorigenesis is different in profuse, sparse and attenuated types of FAP, and that the association with tumorigenesis is also different between colorectal and extracolonic tumors. © 2008 Wiley-Liss, Inc.

We have experienced a successful case of liver metastasis from gastric cancer treated with S-1 plus induced hypertensive hepatic arterial infusion chemotherapy. A 50-year-old man had undergone distal gastrectomy with extended lymphadenectomy for advanced gastric cancer. Although he was given 100 mg/day of S-1 for postoperative adjuvant therapy, an abdominal CT scan showed a liver metastasis at the hepatic segment 6 after 3 courses of adjuvant chemotherapy. Then, intra-arterial hepatic cannulation connecting to a subcutaneously implanted port system was indwelt via left subclavial artery. Mitomycin C (10 mg) was injected through out the induced hypertension with intravenously-administered angiotensin II once a month. After he received three courses of this combination chemotherapy, the liver metastasis has disappeared on CT scan and a complete response (CR) has been maintained.

Somatic mutations of the PIK3CA gene have recently been detected in various human cancers, including sporadic colorectal cancer. However, mutations of the PIK3CA gene in hereditary colorectal cancers have not been clarified. To elucidate the mutation status in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), which are the most common hereditary colorectal cancers, we investigated PIK3CA mutations in 163 colorectal tumors, including adenomas, intramucosal carcinomas and invasive carcinomas. For comparison, we also analyzed mutations of the same gene in 160 sporadic colorectal tumors at various histopathological stages. Analysis at exons 1, 7, 9 and 20 of the PIK3CA gene revealed somatic mutations in 21% (8 of 39) of FAP invasive carcinomas, 21% (7 of 34) of HNPCC invasive carcinomas, 15% (8 of 52) of sporadic invasive carcinomas, and 14% (7 of 50) of sporadic colorectal metastases in the liver. Mutations in FAP and HNPCC carcinomas predominantly occurred in the kinase domain (exon 20), while the majority of mutations in sporadic cases occurred in the helical domain (exon 9). Adenomas and intramucosal carcinomas from all patients exhibited no mutations (0 of 148). Our data suggest that PIK3CA mutations contribute to the invasion step from intramucosal carcinoma to invasive carcinoma in colorectal carcinogenesis in FAP and HNPCC patients at a similar extent to that seen in sporadic patients.

We examined the expression of sVEGFR1 in colorectal cancer tissue and corresponding normal colorectal mucosa to assess the clinical significance of sVEGFR1 in colorectal cancer. We also assessed the relationship between sVEGFR1 levels and various clinicopathologic factors and prognoses. sVEGFR1 and VEGF levels were measured in fresh-frozen tumor extracts from 84 primary colorectal cancer tissues and 27 corresponding normal mucosa using ELISA. Mean of sVEGFR1 levels were 3.17 ng/mg protein. sVEGFR1 levels increased significantly in cancer tissue compared with normal mucosa. Although VEGF levels increased in cancer tissues, the ratio of sVEGFR1/VEGF in cancer tissue was significantly lower than that in normal tissue. No significant correlation between sVEGFR1 or VEGF levels and any clinicopathologic parameter was found. Overexpression of sVEGFR1 was significantly associated with a favorable prognosis. Based on sVEGFR1 levels in colorectal cancer without distant metastases, patients with higher sVEGFR1 levels (≥1.5 ng/mg protein) demonstrated significant longer recurrence-free survival than patients with lower sVEGFR1 levels (

582 Background: Associations of EGFR gene copy number (GCN) and EGFR CA-SSR1 polymorphism with clinical outcome still remain controversial in mCRC pts treated with cet. Interethnic differences in the repeat number of EGFRCA-SSR1 have been reported between Caucasian and Asians, however, there have been few reports about the associations with clinical outcome in Japanese pts. The aim of this study was to evaluate the predictive value of two biomarkers in Japanese mCRC pts treated with cet. Methods: This study enrolled 77 pts with tumor available from two prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in mCRC pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Genomic DNA isolated by macro-dissection from tissue was screened for the EGFR GCN determined by FISH on FFPE tumor specimens with the cut-off value of 2.9, adopted as previously reported (Cappuzzo F, et al., 2008), and the EGFR CA-SSR1 short (S; ≤19) / long (L; ≥20) determined by PCR amplification and fragment length analysis using capillary electrophoresis. Associations of the biomarkers with efficacy, including response, progression-free survival, and overall survival, were evaluated. Additional analysis was addressed at a possible association between the EGFRCA-SSR1 and ST. Results: The frequency of the L alleles of the EGFR CA-SSR1 was 64%. There was no significant association between two biomarkers and efficacy. However, the EGFR CA-SSR1 variant significantly correlated with ST evaluated on 8 weeks after initial administration. The rate of ST with grade 2 or 3 was 33% (10/30), 19% (5/26), and 64% (7/11) in LL, SL, and SS genotype, respectively (fisher's exact test p=0.03). Conclusions: Our study provides first evidence that the EGFR CA-SSR1 variant was associated with cet-induced ST in Japanese mCRC pts. No predictive value for cet treatment could be identified in our screened biomarkers, however, extended RAS mutations analysis is warranted (UMIN000010635).

Dihydropyrimidine dehydrogenase (DPD) is a reducing enzyme for fluoropyrimidine which is a widely-used anti-cancer agent, and its deficiency leads to serious toxicities. We report a rare patient with a DPD deficiency. A 39-year-old man was suspected to have a gastric cancer recurrence from the elevation of CEA. Although TS-1 was administered for five days, it was stopped due to the development of grade 2 anorexia and nausea. Although we administered UFT at his request after a one-month drug rest, grade 1 stomatorrhagia besides the former adverse events developed after five days. Therefore he discontinued it and was admitted to our hospital. After 19 days, he died from multiple brain hemorrhage despite the intensive therapies. We considered that the congenital DPD deficiency caused the development of these adverse events because the DPD value was less than 5 pmol/mg/min in mononuclear cells of peripheral blood.

Objectives: To clarify the role of the KLF6 (Kruppel-like factor 6) locus in multistep colorectal carcinogenesis, we analyzed loss of heterozygosity (LOH) at 10p15 (KLF6 locus) and mutations of the KLF6gene in 298 colorectal tumors at various pathological stages of sporadic and familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) patients. Methods: 10p15 LOH was analyzed using KLF6M1 and KLF6M2, and KLF6 gene mutation was analyzed using PCR-SSCP and sequencing. Results: It was found that the frequencies of LOH (sum of M1 and M2) were 4% in adenomas, 0% in intramucosal carcinomas, 35% in invasive carcinomas, and 33% in liver metastases in sporadic cases. Invasive carcinomas from FAP patients showed only 6% LOH, and invasive carcinomas from HNPCC patients exhibited 0% LOH. Mutation analysis of the KLF6 gene in 298 colorectal tumors detected no somatic mutations. Conclusions: The present data suggest that LOH of the KLF6 locus at chromosome 10p15 contributes to the invasion step from an intramucosal carcinoma to an invasive carcinoma specifically in sporadic colorectal carcinogenesis, but is rarely involved in the carcinogenesis of FAP and HNPCC cases. Moreover, the absence of somatic mutations suggests the uncertainty of the KLF6 gene as a classical tumor suppressor gene at the lost 10p15 region in colorectal carcinogenesis.

As the frequency of chemotherapy was increasing at an out-patient clinic, chemotherapy centers for an outpatient clinic have been established. When chemotherapy was carried out for 25 patients in a day at an outpatient clinic, the mean time was 27.6 minutes from ordering the drugs to the drugs' arrival. When the line was crowded, the drug arrival time was more than one hour, and at least 90 minutes was necessary to begin the chemotherapy. As the number of patients increases, it is necessary to have the effective use of a chemotherapy room and the patients have to be divided according to the duration of time required for chemotherapy. It appears that a continuation of infusion chemotherapy will be frequently carried out and the chemotherapy with an IVH port and a portable pump system will be popular in the future. It is necessary to make the system which supports a continuous infusion like this.

If the chemotherapy at home is as effective as the chemotherapy at an outpatient clinic, QOL of the patients will be improved. In this paper the future of chemotherapy at home was clarified from the outcome of the chemotherapy for advanced and recurrent colorectal cancer.Hepatic arterial infusion chemotherapy (HAI) (5-FU 2,000 mg/w, continuous infusion for 7 days, n=123) for unresectable liver metastases and FL chemotherapy (5 FU 1,500 mg + l-LV 375 mg/w, continuous systemic chemotherapy for 7 days, n=32) for extra hepatic recurrence were carried out at home by a portable pump system every other week.The response rates were 61.2% in HAI and 18.8% in FL. MST were 14.7 months in HAI and 10.8 months in FL. It was important to establish a surveillance network system to continue the chemotherapy at home.It was suggested that the chemotherapy at home was effective and to maintain the patient's QOL as one of the options.

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.

The patient is a 66-year-old male who underwent gastrojejunostomy at another hospital with the diagnosis of type 3 unresectable gastric cancer. He was admitted to our hospital for adjuvant chemotherapy. A CT scan revealed both peritoneal dissemination and a large tumor directly invading the pancreas and liver. After 7 courses of combined chemotherapy with 5-FU, Leucovorin, cis-platinum and methotrexate, an effective response, tumor reduction and the disappearance of peritoneal dissemination, was verified by CT scan. Pancreatoduodenectomy with transverse colectomy was carried out and the pathological diagnosis was also curative (pT3, pN1, pP0, HO: stage III A). Although he unfortunately died from peritoneal recurrence after 9 months, he maintained good quality of life after re-operation. We think this case shows the possibility of NAC for patients with far advanced gastric cancer with peritoneal dissemination to improve their prognosis or QOL.

We analyzed the significance of the measurement of urine di-acetyl spermine (DiAcSpm) as a cancer marker for colorectal cancer treatment. We measured both the urine DiAcSpm(ELISA, normal range: 0-0.25 mumol/creatinine) and serum CEA (normal range: 0-5.0 ng/ml) of preoperative and postoperative colorectal cancer patients every month. We compared the positive rate from the cancer stage and the power of prognostic prediction. We divided the colorectal cancer patients into 4 groups: Group A: both levels were high; Group B: only the CEA level was high; Group C: only the DiAcSpm level was high; Group D: both levels were within a normal range. The positive rates of DiAcSpm and CEA from cancer staging were as follows: Stage 0: 62% and 9.5%, Stage I: 60% and 10%, Stage II: 70% and 42%, Stage III: 82% and 47%, and Stage IV: 88% and 63%, respectively. There was a significant difference (p0.0001) between both levels, especially for early-stage cases. The two-year survival rate was 0% in Group A, 100% in Group B, 72.7% in Group C and 100% in Group D. The difference among the 4 groups was significant (p0.0001). This showed that urine DiAcSpm predicted the prognosis after colorectal cancer surgery more exactly than serum CEA.

We report 2 patients with metastatic ovarian tumors of gastric origin who underwent oophorectomy with paraaortic and intrapelvic lymph node dissection, and showed a relatively good outcome. Case 1 A 40-year-old female with gastric cancer located in the MULE area underwent total gastrectomy with D3 lymph node dissection on June 2, 1989. Pathological Stage was IIIB and curability was B according to the JGCA classification. In month 56 after surgery, a left ovarian tumor was detected, and bilateral oophorectomy with paraaortic and intrapelvic lymph node dissection was performed. Signet ring cell carcinoma from the stomach was confirmed in both left ovary and lymph node around the left external iliac artery. In month 51 after the oophorectomy, the patient died from carcinomatous peritonitis. Case 2 A 23-year-old female with gastric cancer located in the M area underwent distal gastrectomy with D3 lymph node dissection on November 1, 2000. Pathological Stage was IV and curability was B according to the JGCA classification. In month 19 after surgery, a left ovarian tumor was detected, and left oophorectomy with paraaortic and intrapelvic lymph node dissection was performed. Poorly differentiated adenocarcinoma from the stomach was confirmed in both left ovary and paraaortic lymph nodes. Chemoradiation therapy was performed for the bone metastasis in lumbar vertebra, which was detected in month 4 after the oophorectomy, and partial response was achieved. As of June 2003, no other malignant lesion has been detected.

Lateral lymph node dissection is technique for reducing local recurrence rate after resection of rectal cancer. In this study, we will report a decade experience for lateral lymph node dissection of rectal cancer in 491 cases. Lateral lymph node metastases occurred in 15.4% of rectal cancer which was below peritoneal reflection and through muscularis propria into non-peritoneal. It is a problem that it has never been well designed study of lateral lymph node dissection for rectal cancer. On the other hand, TME has also contributed reducing local recurrence rate. But, distant margin for resection of rectal cancer is controversial.

The efficacy and safety of the oral fluoropyrimidine TS-1, which contains a dihydropyrimidine dehydrogenase (DPD) inhibitor, were examined in fifty-five patients with gastric cancer. The patients were divided into 28 with measurable cancer lesions (TUM group) and 27 without them (ADJ group). The total number of courses was 164 (mean: 5.9 courses) in the TUM group and 146 (mean; 5.4 courses) in the ADJ group. The response rate in the TUM group, excluding three patients who could not be evaluated because of incomplete administration, was 40% (CR: 4, PR: 6, NC: 6, PD: 9). Among responders, the mean number of courses to response was 2.2 and the median survival time (MST) was 21.7 months. In terms of safety, adverse reactions appeared in forty-five patients (82%) and the incidence was higher in the ADJ group. Major toxicities were leukopenia (38%), anorexia (27%), increased total bilirubin concentration (25%) and diarrhea (24%). Adverse reaction of grade 3 was found in only three patients (5.5%) and there were no drug-related deaths. In conclusion, TS-1 is safe and effective if attention is given to biweekly examinations for the development of adverse reactions.

Germline and somatic mutations of the hMSH2 gene were determined in a Japanese hereditary nonpolyposis colorectal cancer (HNPCC) family fulfilling the Amsterdam criteria. PCR-SSCP-sequencing of genomic DNA detected a somatic hMSH2 mutation of an A deletion at codon 227–229 in a duodenal carcinoma and a somatic hMSH2 mutation of an A insertion at codon 21 in a gastric carcinoma from affected family members, both carcinomas exhibiting high microsatellite instability. However, no germline hMSH2 mutation was detected by the PCR-SSCP-sequencing method. Genomic DNA was then analyzed by Southern blot hybridization using three hMSH2 cDNA probes (probe A involving exons 1–5, probe B involving exons 4–11 and probe C involving exons 9–16) after digestion by restriction enzymes, EcoRI, HindIII and NsiI. The NsiI digest of DNA from normal tissues of affected members exhibited an aberrant 8.6 kb restriction fragment, in addition to the normal 10.6 kb fragment, when hybridized to probes A and B. This suggested the presence of a heterozygous 2 kb genomic deletion encompassing exon 4, 5 or 6. RT-PCR-sequencing revealed that the deleted region encompassed exon 5. This novel genomic deletion of the hMSH2 gene was confirmed to be pathogenic, and the Southern hybridization pattern was applied to the pre-symptomatic diagnosis.

The chemotherapy at home is most different from the conventional chemotherapy because of the condition not to watch patients all the time. In order to avoid serious side effect it is necessary to administrate some drugs continuously or together. It is useful to use portable pump system. It is also important to educate patients about the chemotherapy at home and to establish the observation system against the trouble from the chemotherapy at home. As the chemotherapy at home is safe if we know the side effect well, this type of chemotherapy will become the one of main branch in the chemotherapy of colorectal cancer.

Hand-foot syndrome (HFS) is a rare adverse reaction to oral fluoropyrimidine TS-1, which contains the dihydropyrimidine dehydrogenase (DPD) inhibitor. We treated a recurrent gastric cancer patient with chronic renal failure who developed grade 2 HFS, grade 2 conjunctivitis and grade 3 stomatitis soon after TS-1 administration. Those symptoms improved with the administration of vitamin B6, topical emollient therapy, and so on. We thought that the continuous elevation of serum 5-FU concentration, due to the accumulation of DPD inhibitor from the renal dysfunction, led to the development of HFS, although the participation of 5-FU metabolites such as F-beta-alanine cannot be ruled out.

We analyzed the effectiveness and adverse effects of hepatic arterial infusion chemotherapy (HAI) for patients with liver metastasis of colorectal cancer in order to clarify the rules of HAI. We provided HAI to 72 patients after hepatic resection and to 119 patients with unresectable liver metastases. The preventive effect on hepatic recurrence was recognized in the group administered more than 15 g of 5-FU (total dose). The response rate of patients with unresectable metastases was 60.3%. Adverse effects were observed in 65.8% of the patients. It is important to establish a follow-up system in each hospital to treat the patients as soon as possible when patients develop an adverse reaction.

Background Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. We conducted a phase I/II study to assess the safety and efficacy of capecitabine plus Irinotecan (CPT) (XELIRI) plus BV in Japanese patients with metastatic colorectal cancer (mCRC). The results of phase I part were reported at the previous meeting, and then planned interim analysis of phase II was carried out. Methods Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1*6*28 were eligible for this study. This was a phase I study composed of two steps, and dose-limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m2 on day 1, and BV 5mg/kg on day 1 every 2 weeks. To evaluate the initial safety, 3–6 patients received XELIRI + BV (CPT 150 mg/m2) in step 1, and 6 patients received XELIRI + BV (CPT 180 mg/m2) in step 2. If DLT occurred in one patient in step 1, three patients would be newly added to step 1, and if in none of 3 or 1–2 of six patients, the step 2 would be started. If DLT occurred in less than or equal to two of six patients in step 2, phase II study would be proceeded, and if In more than two of six patients, phase II would be conducted at the recommended dose of step 1. Interim analysis of toxicity was planed at the end of second cycle in tenth patient in Phase II. Results In phase I, initial safety of nine patients was confirmed without occurrence of DLT. Recommended dose of CPT was determined as 180 mg/m2. Adverse events observed in interim analysis of early toxicity in phase II were: neutropenia in 6; nausea in 4; diarrhea in 6; alopecia in 5; albumin decreased in 6. One patient required a dose reduction due to grade 3 nausea and grade 3 fatigue during the initial cycle of therapy. Another patient discontinued treatment due to intestinal pneumonia considered as CPT-related. Conclusions In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI + BV was confirmed and recommended dose of CPT-11 was determined as 180 mg/m2. According to the interim analysis of safety of phase II study, safety in early cycle was demonstrated. Phase II study is now on-going.

Liver metastasis is the most common recurrence after curative surgery for colorectal cancer. Adjuvant chemotherapy such as hepatic arterial infusion or intensive systemic infusion may protect against metastatic tumor formation in the liver, but conversely have some adverse effects on patients. Therefore, the patients with a high risk of liver metastasis after curative resection should be selected for the chemotherapy. Portal blood samples of tumor drainage vein were obtained during operation from 148 colorectal cancer patients (Dukes' A: 41, B: 41, C: 33, D: 33) in our institutes from August 1998 to June 2001. Serum E-cadherin concentration (ng/ml) was estimated using an ELISA kit according to the manufacturer's instructions (Takara Shuzo Co.). After at least 6 months follow-up, each patient's status regarding recurrence was re-examined, as were the sites of any recurrences. Serum E-cadherin concentration in each Dukes' stage at the primary operation was as follows: A: 1,664.0, B: 1,974.6, C: 2,270.8, D: 3,123.1. In these follow-up periods, 21 patients developed metastatic tumor (liver: 13, extrahepatic: 8) and 95 did not. The average E-cadherin concentration in each group was as follows: liver: 3,585.6, extrahepatic: 2,261.8, no metastasis: 1,848.4 (p0.01 as shown in Figure 4). If the cut-off point is set at 3,000 ng/ml, liver metastasis can be predicted with sensitivity of 62.1%, specificity of 90.3%, and positive predictive value of 64.3%. High levels (3,000 ng/ml) of serum E-cadherin in portal blood may predict metachronous liver metastasis after curative surgery.

A 53-year-old woman who had been treated for rectal cancer was admitted to our hospital with edema, abdominal distension, and general fatigue. Abdominal CT showed multiple liver metastases and paraaortic lymph node metastases. After she was administered irinotecan by hepatic arterial infusion, the liver metastases decreased and paraaortic lymph node metastases were remarkably reduced in size.

The optimal interval for drug administration was examined for repeated intraperitoneal chemotherapy (IPC). The subjects were 31 patients who underwent curative surgical resection excluding P1 or CY1 factor, followed by IPC. IPC was carried out 180 times in total, and the intervals were divided into three groups: 2-week interval 45 times, 3-week interval 10 times and 4-week or greater interval 94 times. The optimal method of drug administration was evaluated from the therapeutic outcome and the development of adverse effects with each interval time. The cytology of ascites obtained via an i.p. port was examined before each drug administration, and those with a negative change (CY0) were judged as responders. The adverse effects in the patients receiving drugs at 2-week intervals were grade 1 or 2, although the incidence was high compared with other patients. All responders obtained a negative change in CY within six courses. At present, we conclude that it is reasonable for IPC to be carried out six times at 2-week intervals.

A 51-year-old man underwent partial hepatectomy in July 2000 for metastatic liver tumor after gastrectomy for gastric cancer. He received seven cycles of hepatic arterial infusion with mitomycin C 20 mg during induced hypertension with angiotensin II from October 2000 to April 2001. His body temperature sometimes rose above 38 degrees C in June and jaundice appeared in August 2001. Blood biochemistry tests showed an elevated value of alkaline phosphatase, gamma-glutamyl transpepsidase and total bilirubin. Based on an enhanced CT scan of the liver showing a low-density area along intrahepatic biliary tracts and hepatic arteriography showing stenosis of the proper hepatic artery, we diagnosed bile duct necrosis and hepatic necrosis. Bile duct necrosis is a serious complication in arterial infusion chemotherapy, and the infusion chemotherapy should be suspended or the dose should be reduced for patients with abnormalities shown by hepato-biliary function tests.

The purpose of the present study was to identity ways to prevent negative side effects in homechemotherapy. We conducted continuous hepatic arterial infusion chemotherapy (CHAI) in 122 cases of unresectable hepatic metastases from colorectal cancer. We continuously administered 5-FU at 250 mg/day for 7 days using a pump system. We also conducted systemic chemotherapy (FP therapy) in 145 cases of advanced or recurrent colorectal cancer in our outpatient clinic. Based on these experiences, we analyzed the problems of homeochemotherapy. The rate of negative side effects was 15.1% with CHAI. More than half were cases of abdominal pain. Because we had established an observation system for emergency cases, there were no fatal accidents. With FP therapy, about 40% of patients had gastrointestinal discomfort, but the rate of those with higher than grade 3 was low (1-2%). We conclude that it is very important to establish a hospital system to respond quickly to any negative effects of homeochemotherapy.

The treatment of patients with liver metastasis from colorectal cancer was evaluated. Although surgical resection was the most effective therapy and 5-year survival was 30%, more than two-thirds of the patients were judged unresectable at the beginning of the treatment. Those whose metastasis was judged to be unresectable received hepatic arterial infusion (HAI) of 5-FU therapy. In a comparison of the survival period, patients received more than 15 g of 5-FU were found to have a statistically significant longer survival than those who received less than 15 g. Even though the patients who revealed a PR or CR response with HAI did not survive more than 4 years, we began surgical resection in these patients after HAI therapy. As a result, the 5-year survival rate of patients whose metastasis was unresectable and who underwent surgical resection after successful HAI was 30% which was equal to the result of the patients judged resectable at the beginning of the treatment. Such treatment may become the fundamental treatment for unresectable liver metastasis in the near future.

611 Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrated the prolonged progression-free survival (PFS) with higher response rate (RR) in the OPUS study. To evaluate the clinical efficacy and safety of the cet plus mFOLFOX6, we conducted a multi-center phase II study of Japanese pts. Methods: In this trial, pts with KRAS wild type tumor and receiving no prior chemotherapy for mCRC were treated with cet (initial dose 400, and 250 mg/m2 weekly) followed by mFOLFOX6 (oxaliplatin 85mg/m2, l-leucovorin 200 mg/m2, fluorouracil, as 400mg/m2 intravenous bolus then 2,400mg/m246-hour continuous infusion). The treatment was repeated every 2 weeks. The primary endpoint was RR evaluated by the external review board according to RECIST v1.1. Secondary endpoints included PFS, OS, % chronological change at the base line and safety. Results: A total of 57 pts were enrolled from August 2010 to September 2011. The median age was 60 years, 65% of pts were male, and ECOG PS 0 was observed in 91% of pts. All pts had EGFR-expressing disease. The median treatment courses were 21 (cet) and 10 (FOLFOX). The RR was 66.7% (95%CI, 53.4 to 77.7). Complete remission was observed in 5 cases (9.3%). The median PFS was 11.1 months (95%CI, 8.0 to 14.7). The early tumor shrinkage (ETS; over 20% regression at 8 weeks) was observed in 80% of pts, and the PFS for pts with ETS was statistically significantly prolonged as compared with pts without ETS (median PFS, 11.5 vs. 3.7 months, respectively; p = 0.0002). The OS was not reached at the time of median follow-up (19.2 months). Grade 3 or worse adverse events were neutropenia (48.2%), leucopenia (22.2%), rash acneform (20.4%), and peripheral neuropathy (18.5%). Conclusions: The first-line cet+mFOLFOX6 has an acceptable safety profile and demonstrates advantages in response rate for pts with KRAS wild tumor. The first-line cet+mFOLFOX6 should be considered as one of the recommended treatment regimens for pts with KRAS wild tumor. Update survival data will be presented. Clinical trial information: UMIN000004197.

Purpose This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naive or chemo-resistant patients with advanced gastric cancer. Materials and methods All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of aged 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for the detection and HER2 expression for CTC. Results We detected more than or equal to 1 CTC/7.5 ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including six patients with HSR2-negative primary tumors. Twenty-one patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda + cisplatin; 15, weekly paclitaxel; 5). We detected more than or equal to 1 CTC/7.5 ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusion HER2 expression on CTC was associated with chemoresistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.

Introduction In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2010. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU patients (pts) were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese pts with mCRC. Methods Pts with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. Therapy consisted of capecitabine 800 mg/m2 bid on days1-15, CPT 200 mg/m2 on day 1, and BV 7.5mg/kg on day 1, q21 days. Primary endpoint was incidence of Dose limiting Toxicity (DLT) in phase I part and progression free survival (PFS) in phase II part. Results Total 34 pts (6 pts in phase I part, 28 pts in phase II part) were enrolled from May 2010 to June 2011. Baseline characteristics were median age of 60 years (range, 22-74); PS 0/1 (22/12 pts); male/female (24/10 pts), UGT1A1 wild/*6hetero/*28hetero (21/7/6 pts), prior treatments FOLFOX4+BV/mFOLFOX6+BV/XELOX+BV/others (1/15/10/8) and reasons for 2nd-line treatment progression disease/others (33/1 pts).DLT was not appeared in phase I part. The median PFS was 8.3 months (95%CI, 6.3-11.3). The best overall response rate was 18 %, and disease control rate was 88%. The most frequently related adverse event were neutropenia (any grade: 53%, grade3/4: 9%), diarrhea (any grade: 50%, grade 3/4: 9%), and hand-foot syndrome (any grade: 44%, grade 3/4: 0%). Conclusion This study suggested that XELIRI+BV regimen had shown well-tolerated and effective as 2nd-line treatment for mCRC in Japanese pts. This regimen seems to be appropriate for using for Oxaliplatin based regimen resistant.

e14070 Background: It has been reported that preoperative chemoradiation (preCRT) and extended surgery with lateral node dissection (LND) both decrease local recurrence compared with total mesorect...