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Angiogenesis contributes to numerous pathological conditions. Understanding the molecular mechanisms of angiogenesis will offer new therapeutic opportunities. Several experimental in vivo models that better represent the pathological conditions have been generated for this purpose in mice, but it is difficult to translate results from mouse to human blood vessels. To understand human vascular biology and translate findings into human research, we need human blood vessel models to replicate human vascular physiology. Here, we show that human tumor tissue transplantation into a cranial window enables engraftment of human blood vessels in mice. An in vivo imaging technique using two-photon microscopy allows continuous observation of human blood vessels until at least 49 days after tumor transplantation. These human blood vessels make connections with mouse blood vessels as shown by the finding that lectin injected into the mouse tail vein reaches the human blood vessels. Finally, this model revealed that formation and/or maintenance of human blood vessels depends on VEGFR2 signaling. This approach represents a useful tool to study molecular mechanisms of human blood vessel formation and to test effects of drugs that target human blood vessels in vivo to show proof of concept in a preclinical model.

A female in her late 50s experienced dyspnea and was transported by an ambulance. Her hemoglobin score was low, and CT imaging showed a giant tumor in her stomach. The tumor perforated her liver and invaded the abdominal wall and duodenum around the Treitz ligament. She required surgery because of the massive hemorrhage due to the tumor. Total gastrectomy with lateral segmentectomy of the liver and resection of the duodenum and the ileum around the Treitz ligament were performed. At 1.5 months after surgery, chemotherapy for malignant lymphoma was successfully initiated.

We report a long-term survival case treated by chemotherapy with new anticancer drugs such as S-1, CPT-11 and docetaxel after bilateral overiectomy for bilateral ovarian metastases of progressive gastric cancer. A 68-year-old female, who had undergone total gastrectomy with D2 lymphadenectomy for scirrhous gastric cancer of Stage IIIA, was admitted because of ovarian metastasis. Laparoscopic bilateral ovariectomy was performed for ovarian metastases of the gastric cancer (Krukenberg tumor) 6 months after gastrectomy. Seven months after gastrectomy, 11-course of S-1 treatment (80 mg/m2) for bilateral ovarian metastases of the gastric cancer was administered. CT scan revealed mediastinal lymphadenopathy 2 years and 5 months after gastrectomy. Then, the drug was changed to docetaxel (60 mg/m2). After 9-course of docetaxel treatment, the mediastinal lymphadenopathy disappeared. For a treatment of grade 3 neuropathy, a 12-course CPT-11 was started after gastrectomy 3 years and 6 months ago. CT scan and PET-CT showed no new metastasis in 4 years and 10 months after gastrectomy.

Purpose: Autonomic nerve preservation in a gastrectomy for gastric cancer improves the postoperative quality of life. We retrospectively examined the survival of patients treated by an autonomic nerve-preserving gastrectomy in comparison to the survival of the patients treated by a conventional gastrectomy., Methods: The survival of 385 patients treated by an autonomic nerve-preserving gastrectomy for clinical early gastric cancer (the ANP group) was compared with that of 285 patients treated by a conventional gastrectomy (non-ANP group)., Results: Among the ANP group, the numbers of patients with tumor invasion to the mucosa, submucosa, and muscularis propria were 210, 166, and 9, respectively, whereas the numbers of patients with lymph node metastasis grades of N0, N1, and N2 were 360, 21, and 4, respectively. The overall 5-year survival rate of the ANP group was 94.7%, which was superior to that of the non-ANP group (90.4%; P = 0.003). The 5-year survival rates of patients with lymph node metastasis were 94.9% and 91.8% in the ANP and non-ANP groups, respectively (P = 0.733). Only 3 patients in the ANP group died from gastric cancer., Conclusions: The survival of patients treated by an autonomic nerve-preserving gastrectomy was equivalent to that of patients treated by a conventional gastrectomy, thus suggesting that an autonomic nervepreserving gastrectomy could be a useful procedure for the treatment of early gastric cancer.

A 59-year-old man was admitted to our hospital for abdominal mass and found to have a gastric cancer with peritoneal dissemination. Three courses of neoadjuvant chemotherapy combined with S-1 and CDDP were performed. This chemotherapy showed a substantial reduction of the size of primary tumor and peritoneal dissemination by CT examination. Surgical resection consisted of distal gasterectomy and D2 lymph node dissection was performed, and an ip catheter was placed through the douglas pouch, and the catheter was attached to the subcutaneous portal delivery system for ip chemotherapy. Operative cytology of ascites proved positive and remnant neoplasm cells were identified in the peritoneum. The pathological stage was determined as T3 N2 H0 P1 CY1 M0, pStage IV. Following surgery, we selected the ip administration of paclitaxel at a dose of 100 mg per body. Finally, the peritoneal dissemination was re-grown. However, we continued the ip chemotherapy for twenty-five times on ambulant basis. Most gastric cancer patients with peritoneal dissemination die within a few months, and there is no standard treatment for peritoneal dissemination from gastric cancer. In conclusion, a condition of no progression has been achieved and maintained for more than three years by intraperitoneal administration of paclitaxel for patient with peritoneal dissemination due to advanced gastric cancer.

Background: The purpose of this study was to investigate the clinicopathological characteristics and frequency of lymph node metastasis to the splenic hilus in proximal gastric cancer and the effect of splenectomy., Patients and Methods: Three hundred and forty-nine patients undergoing total gastrectomy for primary proximal gastric cancer were included. Among these patients, lymph node metastasis to the splenic hilus was histologically assessed in 201 cases., Results: The incidence of lymph node metastasis to the splenic hilus was 31 cases (15.4%). No lymph node metastasis to the splenic hilus was detected in any T1 and T2 tumors located at the lesser curvature and anterior wall. No significant difference was observed between the survival rates of patients with and without splenectomy in each stage., Conclusion: Our findings indicated that gastrectomy with spleen preservation may be recommended at least in patients with T1 or T2 tumors located at the lesser curvature and anterior wall.

A 62-year-old female with epigastric pain was diagnosed with Type 4 gastric cancer upon detailed examination. Abdominal computed tomography(CT)revealed metastasis to the paraaortic lymph node and ascites at pelvis, and aspiration cytology of the ascites through vagina was positive(CY1). The clinical stage was determined as T4(panc) N1H0P0CY1M1(LYM), cStageIV. Three courses of neoadjuvant chemotherapy combined with paclitaxel and 5-fluorouracil( FT therapy)were performed. FT therapy showed a substantial reduction of the size of metastatic lymph nodes by sequentialCT examination, which was evaluated as partial response. Surgical resection consisted of total gastrectomy, and D2 lymph node dissection was performed. Operative cytology of ascites proved negative. The pathologic effect on primary lesion and metastatic lymph nodes was diagnosed as Grade 2. Although the prognosis of gastric cancer with carcinomatous peritonitis is poor, we here reported a patient with StageIV gastric cancer who markedly responded to FT therapy, which made surgical resection possible with the anticipation of extended survival. FT therapy may be a useful method for a patient with StageIVgastric cancer.

We report a case of advanced scirrhous gastric cancer treated by operation and chemotherapy for over four years. The patient was a 54-year-old female who had suffered from gastric cancer with esophageal invasion. She underwent total gastrectomy with D2 dissection. Operative findings revealed peritoneal dissemination, and it resulted in non-curative resection. After surgery, combination chemotherapy with low-dose CDDP administered intraperitoneally and S-1, combination chemotherapy with paclitaxel and 5-FU, and then combination chemotherapy with docetaxel and S-1 were sequentially performed. She also underwent palliative surgery for intestinal obstruction resulting from carcinomatous peritonitis. She achieved long survival with good quality of life (QOL) by multidisciplinary therapy of chemotherapy and surgical operation.

The patient was a 63-year-old male who came to our hospital with the chief complaints of dyspepsia and abdominal fullness. Endoscopic findings showed Type 3 gastric cancer with pyloric stenosis. CT examination revealed a large amount of peritoneal fluid, invasion to the pancreas, peritoneal dissemination and paraaortic lymph node metastasis. Intraperitoneal administration of weekly CDDP 10 mg/body was in vain, and combined chemotherapy of paclitaxel and 5-fluorouracil was carried out. Ascites was significantly reduced and oral intake became possible two courses after this regimen. The tumor decreased in size after 3 courses, and the tumor markers returned to within normal limits. The patient was then discharged, and followed as an outpatient thereafter. Endoscopic examination showed improvement in narrowing of the antrum. However,tumor invasion to pancreas, peritoneal dissemination and lymph node metastasis relapsed. He died one year and one month after the onset.

A 54-year-old male visited our hospital with the chief complaint of anorexia. Based on various tests, a diagnosis of scirrhous gastric carcinoma accompanied by bone metastasis and liver metastasis was made. As DIC developed following hospital admission, 5-FU and PTX therapy (5-FU at 600 mg/m(2), 24-hour continuous infusion, day 1-5 and PTX at 80 mg/m(2), iv, day 8, 15, 22) were administered. Although primary foci, bone metastasis, and liver metastasis were observed by image diagnostic procedures, recovery from DIC was achieved. 5-FU+PTX therapy is considered to be effective for DIC due to bone metastasis of gastric carcinoma.

Purpose: To evaluate the efficacy and toxicity of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 for patients with advanced or recurrent gastric cancer., Experimental Design: Patients with advanced or recurrent adenocarcinoma of the stomach and up to one previous chemotherapy regimen were treated with i.v. docetaxel 40 mg/m2 on day 1 and oral S-1 80 mg/m2/d on days 1 to 14 every 3 weeks., Results: Forty-eight patients (median age, 65 years; range, 25-75 years) received a total of 272 treatment cycles (median, 4; range, 1-17). No complete responses and 27 partial responses were observed for an overall response rate of 56.3% [95% confidence interval (95% CI), 38-66%]. Eighteen patients (37.5%) had stable disease and three patients (6.3%) had progressive disease as best response. The tumor control rate (complete response + partial response + stable disease) was 93.8% (95% CI, 83-98%). Median overall survival was 14.3 months (95% CI, 10.7-20.3 months) and median time to tumor progression was 7.3 months (95% CI, 4.3-10.0 months). The most common grade 3 to 4 hematologic toxicities were neutropenia (58.3%), leukopenia (41.7%), febrile neutropenia (8.3%), and anemia (8.3%). The most common grade 3 nonhematologic toxicities included anorexia (14.6%), stomatitis (8.3%), and nausea (6.3%). No grade 4 nonhematologic toxicities were reported and all treatment-related toxicities were resolved., Conclusion: Docetaxel/S-1 combination is highly active and well tolerated in advanced or recurrent gastric cancer. Further investigation in randomized studies is warranted.

A 29-year-old male underwent Cur B surgery including total gastrectomy, pancreaticoduodenectomy, transverse colectomy, and D 2 dissection for scirrhous gastric carcinoma accompanied by duodenal and pancreatic infiltration. Thereafter, the patient suffered from recurrence with development of ileus caused by carcinomatous peritonitis. Ileus tube was inserted, followed by conservative therapy without ingestion. But, as the symptoms aggravated without any alleviation, an emergency surgical procedure was conducted. As disseminated changes were observed in the entire region of the abdominal cavity of the epigastric region, ileus by-pass procedure and ileostomy were performed. Though ileus symptoms were improved, peroral intake was difficult,and the ileus tube had to be left in place. Thereafter, chemotherapy with combined use of paclitaxel and 5-FU was initiated, and peroral intake become possible. The Ileus tube could be removed after improvement of obstructive symptoms. The patient was treated at the outpatient clinic with nutritional help of HPN, but died 14 months after the recurrence.

We studied the significance of repeated intraperitoneal CDDP administration, as adjuvant chemotherapy, for the prevention of T3 and T4 gastric cancer. Fifty-two patients who had been operated as Curability B were divided into the following two groups, and the data on survival rate, median survival time and interval of "free of recurrence" were accumulated and analyzed. Group A consisted of nineteen patients treated with intraperitoneal CDDP administration and oral anticancer drugs. Group B were treated with systemic chemotherapy. Group A was superior to Group B in comparing the analyzed data. These results suggested that repeated intraperitoneal CDDP chemotherapy for the prevention of T3 and T4 advanced gastric cancer would improve survival rate.

We examined the significance of low-dose cisplatinum (CDDP) intraperitoneal administration for cases of peritoneal dissemination of gastric cancer. Sixty-eight cases of gastric cancer, diagnosed as P1 or CY1 in the gastrectomy operation that was carried out during the period between January 1994 and December 2001, were studied based on accumulated survival rate and mean survival time (MST). Ten milligram of CDDP was weekly administrated intraperitoneally through an infusion port. A two-week interval was taken after the eight-week administration. This group, the CDDP intraperitoneal administration group, was statistically superior both in the accumulated survival rate and MST. These results suggested that the low-dose CDDP intraperitoneal administration would contribute to improved prognosis of such gastric cancers as P1 or CY1.

We evaluated the significance of multimodality therapy for cases of liver metastases of gastric cancer. Accumulated survival rate and median survival time were analyzed for twenty cases of such gastric cancer. Survival rates of H1+H2 group and hepatic resection (HR) group were higher than that of H3 group and non-HR group. MST of HR group and hepatic arterial infusion (HAI) group were longer than that of non-HR group and non-HAI group. Survival rate of HAI group was higher than that of non-HAI group among eleven cases of HR group. On the other hand, survival rate of HR group was higher than that of non-HR group among eleven cases of HAI group. These results suggested that HAI chemotherapy after hepatic resection for gastric cancer patients with synchronous liver metastasis would improve prognosis.

Background: S-1, an oral fluorouracil antitumor drug, and docetaxel have both been identified as effective agents for the treatment of gastric cancer. The two drugs have incompletely overlapping principal toxicities, which constitute the rationale for evaluating the effects of a combination of S-1 and docetaxel in this phase I study. The aim of this phase I study was to determine the maximum-tolerated dose (MTD) and the recommended dose of docetaxel with a fixed dose of S-1 in patients with advanced or recurrent gastric cancer., Patients and Methods: The pharmacokinetics of both drugs were evaluated on Day 1 of treatment. Patients with a performance status (PS) of 0 to 2 received docetaxel at the starting dose of 40 mg/m2 by i.v. infusion over 1 hour on Day 1 and S-1 at the fill dose of 80 mg/m2 daily for two weeks every three weeks. Nine patients were treated with increasing dose levels of docetaxel as follows: (docetaxel/S-1, mg/m2): 40/80 (Level 1), 50/80 (Level 2) and 60/80 (Level 3) and all the cases were found to be assessable for drug safety, while 7 were assessable for response. Colony-stimulating factor (CSF) was not used in this study. The adverse effects of the treatment were analyzed according to NCI-CTC version 2, and the response was assessed according to the Japanese Classification of Gastric Cancer, 13th Ed., Results: The MTD was reached at the 50/80 mg/m2 dose level in three patients out of six, who experienced a dose-limiting toxicity (DLT). The DLTs were neutropenia and allergic reactions. No hematological or non-hematological adverse effects (nore severe than Grade 2) were observed in any of the Level 1 patients. However among the Level 2 patients, 50% developed neutropenia (more severe than Grade 2), 33% developed loss of appetite, 17% developed diarrhea, 33% developed stomatitis and 17% developed allergic reactions. On the other hand, partial response was achieved in 5 (71.4%) of the 7 patients with evaluable lesions. The pharmacokinetics of docetaxel were not altered as compared to that in the historical controls by the administration of S-1. These results indicate that the recommended doses of the two drugs in the combination therapy would be 40 mg/m2 for docetaxel and 80 mg/m2 for S-1., Conclusion: The drug combination showed a good safety profile, with neutropenia being a common but manageable adverse reaction. Moreover, the responses observed in the study suggest that the drug combination shows a high degree of efficacy in patients with advanced and or recurrent gastric cancer.

We attempted treating 5 patients with ascites from peritonitis carcinomatosa of gastric carcinoma using TS-1 as systemic chemotherapy, and repeated intraperitoneal injection of low-dose CDDP for the carcinomatous ascites. TS-1 was administered in the usual manner and repeated intraperitoneal injection of CDDP (10 mg/body) dissolved in physiological saline 20-500 ml was given with an implantable reservoir. In 3 patients, the carcinomatous ascites disappeared, and in 2 other patients they decreased remarkably. As a result, the QOL and PS of all patients were improved. Serum concentration of CDDP suggested that weekly repeated intraperitoneally injected CDDP not only has an effect on peritonitis carcinomatosa, but also functions as a modulator for 5-FU.

The patient was a seventy-seven-year old woman, who was diagnosed with advanced gastric cancer with stenosis of the esophagocardiac junction. Her cancer was diagnosed as Stage IV (T3N3H0P3M0). As there was no indication for surgery, radiation therapy (Linac electron beam, 1.8 Gy/day, total 50.4 Gy) was selected to improve the stenosis, after which she was able to eat food. Subjective complaints such as nausea and vomiting were also decreased, promoting her QOL. We conclude that radiation therapy treatment can be a treatment option for far advanced cardiac cancer.

Long-term survival is difficult after manifestation of distant lymph node metastasis following curative resection for advanced gastric cancer. Two patients who achieved long survival with linac therapy after curative treatment of gastric cancer, are reported. Case 1: 45 years old, male. Distal gastrectomy with D2 dissection was carried out for such gastric cancer as L.M, less.Post.Ant, fType 3, T2 (MP), fStage II, on July 13, 1994. As paraaortic lymph nodes metastases was observed with CT examination on October 12, 1995, irradiation therapy using linac was conducted, and CR was achieved. Though Virchow's lymph nodes metastases was followed that episode, PR was achieved with 4,750 cGy of linac therapy. Finally, however, the patient died with metastases to lung and bone on May 19, 2002. Case 2: 62 years old, male. Distal gastrectomy with D2 + No.8p and also No.16b1 interaorticocaval dissection was conducted for such advanced gastric cancers as M, less, fType 3, T3 (SE), fStage III B on June 7, 1995. Paraaortic lymph nodes metastases were observed through CT examination on October 12, 1995. Irradiation therapy using linac resulted in CR. Virchows lymph node metastasis, which appeared on December 12, 1997, was also treated with 5,000 cGy of linac, and CR was also achieved. The patient is surviving today without recurrence.

A patient with recurrent gastric cancer which infiltrated the pelvic muscle after the treatment of paraaortic lymph node and ovarian metastases was successfully managed by a novel oral anticancer drug, TS-1. TS-1 was administered at a dose of 80 mg/day. One course consisted of two repetitions of consecutive administration of TS-1 for 14 days and withdrawal of TS-1 for 14 days. Adverse reactions were mild and the patient did not request hospitalization after two courses had been completed. Subjective symptoms such as difficulty in walking improved after one week and a partial response was obtained after 2 weeks of treatment. At the end of 4 courses we could remove an indwelling pyelocatheter for the ureter stricture. As of 14 months after the beginning of administration of TS-1, the patient is being treated as an outpatient and has attained a better QOL than before.

Background: Jejunal pouch reconstruction after total gastrectomy has been demonstrated to ameliorate postgastrectomy symptoms, with the process of adaptation taking several months. In contrast to the short-term effects of pouch reconstruction, there are few reports about the long-term consequences (more than 2 years after surgery)., Methods: In this study, 22 patients with jejunal pouch (PRY group) and 12 patients without jejunal pouch (RY group) who survived for more than 2 years without any recurrence and were available for follow-up were compared. Patients in the two groups were compared 2 years after surgery in terms of postgastrectomy symptoms, and improvements in body weight and nutritional parameters., Results: Eating capacity at a single meal compared with that in the pre-illness state was significantly better in the PRY group than in the RY group. The total score on the gastrointestinal symptom rating scale (GSRS) in the PRY group was less than that in the RY group (3.17 vs 5.25). The GSRS score for reflux syndrome in the PRY group was significantly better than that in the RY group. Assessment according to Cuschieri's gradings revealed that the total score in the PRY group was lower than that in the RY group (2.73 vs 5.92). Among the various symptoms examined, the incidence of dietary restriction and that of heartburn were significantly lower in the PRY group., Conclusion: We conclude that, 2 years after total gastrectomy, the pouch reconstruction had alleviated postgastrectomy symptoms to a greater extent than simple Roux-en-Y reconstruction, but the effectiveness could be improved. The long-term effects of pouch reconstruction should be examined more precisely with an adequate and valid scoring system for determining quality of life.

Intercellular adhesion molecule-1 (ICAM-1), a molecule bound to the cell surface, is a ligand for leukocyte function antigen-1 (LFA-1), and the ICAM-1/LFA-1 system mediates various cell-cell interactions involved in immunity. Soluble ICAM-1 (sICAM-1) is a circulating substance and binds with LFA-1 of leukocytes, thus, making leukocytes less available for binding with cell surface ICAM-1 on target cells. The serum level of soluble ICAM-1 (sICAM-1) was found to be significantly elevated (p<0.01) in patients with early and advanced gastric cancer compared with healthy controls. Natural killer activity (NK activity) was assessed by measuring the cytotoxicity of peripheral blood mononuclear cells (PBMCs) for K562 cells. There was no significant difference in NK activity between gastric cancer patients and healthy controls when heat-inactivated fetal calf serum was used in assays. However, addition of patient serum significantly decreased (p<0.05) NK activity when the serum was from patients with advanced gastric cancer compared with healthy volunteers. Addition of anti-ICAM-1 monoclonal antibody 0 to 5.0 microg/ml caused little change in NK activity in healthy controls, but its addition at 10 microg/ml remarkably decreased NK-activity in gastric cancer patients, probably through antibody binding with ICAM-1 on target cells. In other experiments, liver metastasis was induced in mice by inoculation of colon 26 murine colon cancer cells. In vitro pretreatment of colon 26 cells with the anti-ICAM-1 monoclonal antibody significantly increased the number of metastatic nodules. These results suggest that both sICAM-1 and anti-ICAM-1 monoclonal antibody act as immunosuppressive factors by inhibiting the ICAM-1/LFA-1 system.

OK-432, a killed preparation of Streptococcus pyogenes, as well as Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum are all known biological response modifiers. To examine the immunomodulatory effects of OK-432, natural killer cell activity and cytokine production by peripheral blood mononuclear cells (PBMCs) were assessed in 32 patients with gastric cancer. Skin tests for Streptococcus pyogenes A-3Su (Su-PS) and BCG were performed in all patients. Other nutritional and immunological parameters were also determined. OK-432-treated PBMCs showed a significant increase of cytotoxicity against K562 cells (p < 0.01). Increased levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) were found in the supernatants of cultures treated with OK-432 in 29 (90.6%), 20 (62.5%), and 8 (25.0%) out of 32 patients, respectively. Natural killer cell activity, IFN-gamma production, and the Su-PS skin test were positively correlated (p < 0.01). In contrast, the BCG test and other markers were not correlated with natural killer cell activity and IFN-gamma production. These results suggest that the Su-PS skin test could predict OK-432-induced natural killer cell activity and IFN-gamma production in patients with gastric cancer, and was therefore useful to determine whether patients were responders to OK-432.

We previously reported that introduction of the wild-type p53 gene into human cancer cells with deleted p53 enhanced apoptosis induced by chemotherapy [Fujiwara et al. (1994) Cancer Res 54:2287]. This suggests that p53 status could be a potent determinant of the therapeutic efficacy of DNA-damaging cancer therapy. We analyzed 24 patients with gastric or colorectal cancer for p53 mutations and apoptotic changes in surgical specimens. Out of 11 patients with gastric cancer, 3 were treated with chemotherapeutic drugs before resection; 5 of 13 patients with colorectal cancer had 30 Gy radiation prior to surgery. p53 mutations were detected in 4 cases of gastric cancer (36.4%) and in 6 cases of colorectal cancer (46.2%) by immunohistochemical staining. The preoperative DNA-damaging therapies increased the number of apoptotic cells in wild-type-p53-expressing tumors; tumors with mutant p53, however, significantly showed fewer apoptotic cells compared with those expressing wild-type p53. The p53-inducible WAF1/CIP1 protein was immunohistochemically observed in wild-type-p53-containing tumors, whereas mutant-p53-expressing tumors expressed no detectable WAF1/CIP1. Taken together, we conclude that p53 mutations are associated with the poor response of chemotherapy and radiotherapy.