[A Case of Advanced Neuroendocrine Cell Carcinoma of the Stomach Treated with S-1 and Cisplatin Chemotherapy].

A 69-year-old man presented to our hospital because of epigastric pain. A type 2 lesion was seen in the lesser curvature of the antrum of the stomach. A moderately differentiated adenocarcinoma(human epidermal growth factor receptor 2-negative) was diagnosed by biopsy. Abdominal computed tomography showed a mass shadow 52mm in diameter in the pyloric region invading the surrounding organs, but no evidence of distant metastasis. Chemotherapy with S-1 and cisplatin(SP therapy)was initiated because of a diagnosis of locally advanced gastric cancer. After 2 courses of chemotherapy, the tumor shrinkage rate was 70%, confirming that treatment was effective. However, severe skin disorders developed, precluding the continuation of chemotherapy. Staging laparoscopy showed no evidence of peritoneal dissemination, but invasion into the superior mesenteric vein was noted. The tumor was resected by pancreaticoduodenectomy with partial resection of the venous wall. Pathological examination of the resected specimens provided a definite diagnosis of neuroendocrine cell carcinoma. As of 1 year and 7 months after surgery, there has been no observation of metastasis or recurrence. SP therapy was suggested to be a useful regimen for preoperative chemotherapy in patients with locally advanced neuroendocrine cell carcinoma.

Involvement of NIPSNAP1, a neuropeptide nocistatin-interacting protein, in inflammatory pain.

BACKGROUND: Chronic pain associated with inflammation is an important clinical problem, and the underlying mechanisms remain poorly understood. 4-Nitrophenylphosphatase domain and nonneuronal SNAP25-like protein homolog (NIPSNAP) 1, an interacting protein with neuropeptide nocistatin, is implicated in the inhibition of tactile pain allodynia. Although nocistatin inhibits some inflammatory pain responses, whether NIPSNAP1 affects inflammatory pain appears to be unclear. Here, we examined the nociceptive behavioral response of NIPSNAP1-deficient mice and the expression of NIPSNAP1 following peripheral inflammation to determine the contribution of NIPSNAP1 to inflammatory pain. RESULTS: Nociceptive behavioral response increased in phase II of the formalin test, particularly during the later stage (26-50 min) in NIPSNAP1-deficient mice, although the response during phase I (0-15 min) was not significantly different between the deficient and wild-type mice. Moreover, phosphorylation of extracellular signal-related kinase was enhanced in the spinal dorsal horn of the deficient mice. The prolonged inflammatory pain induced by carrageenan and complete Freund's adjuvant was exacerbated in NIPSNAP1-deficient mice. NIPSNAP1 mRNA was expressed in small- and medium-sized neurons of the dorsal root ganglion and motor neurons of the spinal cord. In the formalin test, NIPSNAP1 mRNA was slightly increased in dorsal root ganglion but not in the spinal cord. In contrast, NIPSNAP1 mRNA levels in dorsal root ganglion were significantly decreased during 24-48 h after carrageenan injection. Prostaglandin E2, a major mediator of inflammation, stimulated NIPSNAP1 mRNA expression via the cAMP-protein kinase A signaling pathway in isolated dorsal root ganglion cells. CONCLUSIONS: These results suggest that changes in NIPSNAP1 expression may contribute to the pathogenesis of inflammatory pain.

Evaluation of 64-Channel Contrast-Enhanced Multi-detector Row Computed Tomography for Preoperative N Staging in cT2-4 Gastric Carcinoma.

BACKGROUND: Preoperative N staging is essential for the best treatment planning in patients with gastric carcinoma. The aim of this study was to evaluate the accuracy of preoperative N staging using contrast-enhanced multi-detector row computed tomography (CE-MDCT) in patients with resectable cT2-4 gastric carcinoma. METHODS: A total of 218 patients who underwent a gastrectomy with D2 lymphadenectomy for previously untreated cT2-4 primary gastric carcinoma were studied. Preoperative N staging was performed according to the 7th (UICC) TNM Staging System using pre-specified criteria on a 64-channel CE-MDCT and was compared with postoperative pathologic N staging. RESULTS: In all 218 patients, a distal or total gastrectomy was performed. The overall accuracy of the preoperative N staging was 46.3% (101/218), with the proportion of over- and under-staging being 26.6% (58/218) and 27.1% (59/218), respectively. The sensitivity, specificity, and accuracy for lymph node metastasis (≥pN1) were 79.1% (106/134), 50.0% (42/84), and 67.9% (148/218), respectively. The sensitivity, specificity, and accuracy for multiple lymph node metastases (≥pN2) were 80.2% (73/91), 68.5% (87/127), and 73.4% (160/218), respectively. Multivariate analyses showed that macroscopic type 2 and ≥6 cm-sized tumors were associated with preoperative over-N staging, while macroscopic type 1/3 tumors were associated with under-N staging. CONCLUSION: Preoperative N staging with pinpoint accuracy is difficult. However, CE-MDCT offers a reasonably high sensitivity and specificity for ≥pN2 and may be useful for selecting candidates for neoadjuvant therapies. The macroscopic type and size of the primary tumor may affect the accuracy of preoperative N staging.

Feasibility of neoadjuvant S-1 and oxaliplatin followed by surgery for resectable advanced gastric adenocarcinoma.

PURPOSE: In Japan, the administration of S-1 following D2 gastrectomy is a standard treatment for stage II/III gastric cancer (GC). However, the survival of stage IIIB/IIIC GC remains unsatisfactory. To improve this, we conducted a multicenter phase II study to evaluate the safety and efficacy of a neoadjuvant S-1 and oxaliplatin regimen (SOX) followed by surgery targeted at stage III GC. METHODS: Oxaliplatin was administered intravenously (130 mg/m(2)) on day 1, and S-1 was administered orally (40 mg/m(2), twice a day) for 14 days followed by a seven-day rest period. After three cycles of therapy, D2 gastrectomy was performed. RESULTS: A total of 14 patients were enrolled and completed the protocol treatment. Grade 3/4 toxicities included thrombocytopenia (21.4 %), anorexia (14.3 %), and diarrhea (7.1 %). Seven patients (50 %) underwent total gastrectomy, and seven patients underwent distal gastrectomy. Grade 3/4 surgical complications included pancreatic fistula (21.4 %) and lung infection (7.1 %). The pathological response rate was 85.7 %. CONCLUSION: Although our data are limited and preliminary, neoadjuvant SOX followed by surgery can be performed safely with a high pathological response rate in patients with resectable advanced GC. Further investigation of this neoadjuvant approach is warranted.

Surgical treatment of non-early gastric remnant carcinoma developing after distal gastrectomy for gastric cancer.

BACKGROUND AND OBJECTIVES: The optimal surgical procedure for gastric remnant carcinoma (GRC) remains debatable. The aim of this study was to retrospectively evaluate the surgical treatments for T2-4 GRC developing after distal gastrectomy for gastric cancer. METHODS: Between 1970 and 2012, a total of 50 patients underwent R0 resection for T2-4 GRC. The clinicopathologic features, therapeutic methods, and follow-up data of these patients were reviewed. RESULTS: The tumor was located at a non-anastomotic site of the remnant stomach in 43 of the 50 patients. Total gastrectomy was performed in 48 patients and partial gastrectomy was in two patients. Lymph node metastasis was found in 19 patients. Major postoperative complications occurred in 16 patients. The overall 1-, 3-, and 5-year survival rates of the 50 patients were 90%, 66%, and 44%, respectively. Presence of small intestinal or esophageal infiltration and postoperative complications was independently associated with poorer survival. Dissection of the perigastric and splenic hilar/artery nodes was found to have potential therapeutic benefit. CONCLUSIONS: Surgical resection for T2-4 GRC developing after distal gastrectomy for gastric cancer can be invasive, but is feasible and effective. Total gastrectomy with splenectomy is one of the recommendable procedures for this disease.

Functional Advantages of Proximal Gastrectomy with Jejunal Interposition Over Total Gastrectomy with Roux-en-Y Esophagojejunostomy for Early Gastric Cancer.

BACKGROUND: The postoperative functional advantages of a proximal gastrectomy over a total gastrectomy remain debatable. The aim of this study was to evaluate the functional outcomes of a proximal gastrectomy with jejunal interposition (PG-JI), compared with those for a total gastrectomy with Roux-en-Y esophagojejunostomy (TG-RY), in patients with early gastric cancer. METHODS: Between 2007 and 2012, 65 patients underwent PG-JI and 117 underwent TG-RY for cT1 gastric cancer. Various parameters, including body weight, serum hemoglobin level, and interview-based symptoms, were prospectively evaluated in these patients. In patients who underwent PG-JI, the postoperative endoscopic findings were also assessed. RESULTS: All the surgeries were performed via a laparotomy alone. During a median postoperative follow-up of 42 months (range, 12-78 months), PG-JI offered significant reductions in body weight loss (12.5 ± 5.8 vs. 17.4 ± 6.4 %, P < 0.001), serum hemoglobin decline (7.0 ± 5.7 vs. 9.7 ± 5.4 %, P = 0.002), and dumping symptoms (11 % [7/65] vs. 30 % [35/117], P = 0.003), while being associated with similar incidences of anastomotic stricture (9 % [6/65] vs. 8 % [9/117], P = 0.781), small bowel obstruction (0 % [0/65] vs. 2 % [2/117], P = 0.538), stasis symptoms (51 % [33/65] vs. 44 % [51/117], P = 0.358), and reflux symptoms (34 % [22/65] vs. 23 % [27/117], P = 0.121), compared with TG-RY. Four cases of gastric remnant cancer and no cases of endoscopic reflux esophagitis were found after PG-JI. CONCLUSIONS: PG-JI has clear functional advantages over TG-RY, although it requires active surveillance for remnant gastric cancer.

HER2 expression in carcinomas of the true cardia (Siewert type II esophagogastric junction carcinoma).

OBJECTIVES: To evaluate the HER2 status in patients with Siewert type II esophagogastric junction carcinoma. BACKGROUND: Trastuzumab is now approved for use in the treatment of human epidermal growth factor receptor 2 (HER2)-positive unresectable metastatic gastric or esophagogastric junction (EGJ) carcinoma. Several studies have evaluated HER2 status in EGJ carcinoma, but none has addressed the implication of HER2 positivity in patients with Siewert type II EGJ carcinoma. METHODS: We retrospectively evaluated the frequency of HER2 positivity in a large single-center cohort of 208 patients with Siewert type II tumors. The relations between HER2 expression and the outcomes and other clinicopathologic features were examined. RESULTS: Overall, 18.2 % (38/208) of patients in our cohort had HER2-positive tumors. HER2 positivity was associated only with differentiated carcinomas. The 5-year overall survival (OS) rate was 58.7 %. The 5-year OS rates in the patient groups with HER2-negative and HER2-positive tumors were 61.2 and 48.5 %, respectively. There was no significant difference between the groups. Recurrence in the liver was observed in 23.7 % patients of the HER2-positive group and 7.6 % patients of the HER2-negative group. Multivariate analysis to identify the risk factors for liver recurrence revealed only HER2 positivity (p = 0.0155) as an independent predictive factor. CONCLUSIONS: HER2 positivity is a powerful predictor of liver recurrence in patients with Siewert type II EGJ carcinoma. Use of trastuzumab in combination with chemotherapy in an adjuvant setting can be a potentially useful therapeutic strategy to prevent hepatic recurrence in patients with resectable EGJ adenocarcinoma showing HER2 overexpression.

Identification of risk factors for esophagojejunal anastomotic leakage after gastric surgery.

BACKGROUND: Despite the development of the surgical technique and improvements in perioperative management, anastomotic leakage still occurs at esophagojejunal anastomoses after total or proximal gastrectomy. Anastomotic leakage is one of the major complications of concern, chiefly because it can lead to death. The objective of the present study was to identify the risk factors for esophagojejunal anastomotic leakage. METHODS: The study was based on retrospective analysis of the data of a total of 1,640 consecutive patients who underwent total, proximal, or completion gastrectomy, including esophagojejunal anastomosis, between 1999 and 2008. RESULTS: Thirty-five patients (2.1 %) developed anastomotic leakage. Univariate analysis revealed patient age, pulmonary insufficiency, lymph node dissection, combined resection of other organs, omental resection, operative time, blood loss, intraoperative blood transfusion, and postoperative creatinine level were the significant factors influencing anastomotic leakage. Multivariate analysis identified pulmonary insufficiency and the duration of the operation as the predictors of anastomotic leakage. CONCLUSIONS: To avoid leakage, surgeons should take care in creating the anastomosis in gastrectomy patients, particularly in cases of poor pulmonary function or when the procedure requires a longer operation.

Biliary Peritonitis Caused by Spontaneous Bile Duct Rupture in the Left Triangular Ligament of the Liver after Endoscopic Sphincterotomy for Choledocholithiasis.

Spontaneous bile duct rupture is a rare condition in adults, with only 70 cases reported. Increased bile duct wall pressure may lead to rupture and biliary peritonitis. In this patient, the bile duct ruptured in the hepatic left triangular ligament. A 91-year-old man underwent endoscopic retrograde cholangiopancreatography for choledocholithiasis and endoscopic retrograde biliary drainage (ERBD) placement. One week later, removal of the ERBD and common bile duct stones and an endoscopic sphincterotomy (EST) were performed. Four days later, the patient had abdominal pain, increased inflammatory reaction, and jaundice. Abdominal computed tomography showed ascites, bile duct dilatation and fluid collection under the liver (10 cm in diameter). Emergency surgery was performed to drain the fluid. On laparotomy, encapsulated biliary ascites was seen. To search for the site of the leak, after cholecystectomy, a tube (C-tube) was inserted into the common bile duct via cystic duct stump. Because of uncontrollable bleeding, after packing with surgical gauze, the operation was temporarily stopped. The next day, reoperation was performed. Intraoperative cholangiography with contrast dye revealed the perforation site in the left triangular ligament and a partial resection was performed. Bile excretion from the C-tube was subsequently observed, but the patient's jaundice did not improve. Although endoscopic retrograde cholangiopancreatography revealed that the EST site was normal, ERBD was placed again, and the jaundice gradually improved. Although EST was performed in this case, biliary peritonitis resulting from spontaneous bile duct rupture occurred. This case was very informative because biliary perforation may occur even after EST.

[Highly advanced gastric cancer that responded to neoadjuvant combination chemotherapy with docetaxel/CDDP/S-1 (DCS)].

A 60-year-old male was found to have advanced gastric cancer and multiple lymph node metastases. Since curative surgery was concluded to be unfeasible, we tried neoadjuvant chemotherapy with the aim of controlling the lymph node metastasis. S-1 (80 mg/m2) was administered orally for two weeks then followed by 2-week rest period. CDDP (60 mg/ m2) and docetaxel (40 mg/m2) were simultaneously administered on day 1. Two courses of treatment resulted in marked shrinkage of the primary lesion and a reduction in size of the lymph nodes. The results were evaluated as a clinical PR based on RECIST, and radical resection was considered possible. The patient experienced a grade 3 leukocytopenia and neutropenia as adverse events of the chemotherapy. Total gastrectomy, splenectomy, and D2 lymph node dissection were performed with curative intent, and the postoperative course was uneventful. Histological examination of the surgical specimens revealed almost complete disappearance of cancer cells in the primary lesion in the stomach and complete disappearance in the lymph nodes. Pathological efficacy was Grade 2. The patient experienced a grade 3 appetite loss, and the adjuvant chemotherapy (S-1 regimen) was discontinued. The patient died of peritoneal dissemination eight months after the operation. We concluded that DCS as neoadjuvant chemotherapy was a promising strategy for patients with highly advanced gastric cancer because of its rapid antitumor effect.

Intratumoral interferon-alpha gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation.

One of the major challenges in the treatment of solid cancers by allogenic hematopoietic stem cell transfer (alloHSCT) is the specific enhancement of antitumor immunity. Interferon (IFN) is a cytokine with pleiotropic biological functions including an immunomoduration, and our preclinical studies have shown that an intratumoral IFN-alpha gene transfer induced strong local tumor control and systemic tumor-specific immunity. In the present study, we examined whether the IFN-alpha gene transfer could enhance recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. First, when a mouse IFN-alpha adenovirus vector (Ad-mIFN) was injected into subcutaneous xenografts of syngeneic renal and colon cancer cells, tumor growth was significantly suppressed in a dose-dependent manner. A significant tumor cell death and infiltration of immune cells was recognized in the Ad-mIFN-injected tumors, and the dendritic cells isolated from the tumors showed a strong Th1-oriented response. The antitumor effect of Ad-mIFN was then examined in a murine model of minor histocompatibility antigen-mismatched alloHSCT. The intratumoral IFN-alpha gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors which did not receive the vector injection. A cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to IFN-alpha. Graft-versus-host disease was not exacerbated serologically or clinically in the mice treated with IFN-alpha. This combination strategy deserves evaluation in future clinical trials for human solid cancers.

Tumor initiating potential of side population cells in human gastric cancer.

Side population (SP) cells are a small subpopulation of cells with enriched source of gastric tumor-initiating cells (TICs) with stem-like cell property that are characterized by high efflux ability of Hoechst 33342 dye, reflecting high expression of several subtypes of the ATP-binding cassette transporter family that is characteristic of stem cells. The present study is the first to discover and characterize SP cells within gastric cancer (GC) tumors. In this study, human GC cell lines (MKN45, KATOIII, MKN74, MKN28 and MKN1) were analyzed using flow cytometry for SP cell isolation, and all GC cell lines showed a distinct fraction of SP cells, ranging from 0.02+/-0.001 to 1.93+/-0.16%. Among these cell lines, MKN45 cultures possessed the highest percentage of SP cells. Using MKN45 cells, we demonstrated stem cell-like characteristics of SP cells of the cell lines as a possible subpopulation with enriched TICs, as indicated by ABC transporter gene expression (MDR1 and BCPR1), chemo-resistance and tumorigenicity in vivo. In addition, we report the first identification and isolation of SP cells from clinical GC tissues as well as human GC cell lines. These SP cells demonstrate higher tumorigenicity in vivo than does the overall cell population in the parent tissue. In conclusion, we demonstrate that solid tumor tissue such as human GC contains TICs, with the existence of heterogeneity and distinct hierarchy in malignancy, suggesting the future possibility of a novel therapeutic tool targeting TICs for overcoming this malignant disease.

[A partial response to S-1 as second-line chemotherapy in a patient with unresectable pancreatic cancer].

A male in his fifties presented with a primary complaint of abdominal distension and appetite loss. CT revealed a primary pancreatic tumor with massive ascites. The patient was treated with gemcitabine as the first-line chemotherapy. Gemcitabine (1,000 mg/m2) was intravenously administered 3 times (on days 1, 8, 15) every 4 weeks (days 1-28) as 1 course. CT revealed the size of the primary tumor to decrease and no ascites were observed. A new abdominal lesion appeared after 11 courses of gemcitabine. The time to progression was 11 months after the first-line chemotherapy. The patient was then treated with S-1 as second-line chemotherapy. S-1 (80 mg/m2) was orally administered daily for 4 weeks (days 1- 28) every 6 weeks. CT thereafter revealed a partial response. The patient experienced no adverse events. The time to progression was 6 months after starting the second-line chemotherapy. Gemcitabine is the standard regimen for unresectable pancreatic cancer. However, the benefits of second-line chemotherapy remain unclear. S-1 has been reported to show a considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. S-1 is therefore considered to be promising as second-line chemotherapy for unresectable pancreatic cancer, due to the fact that a considerable survival benefit has been observed for patients with unresectable pancreatic cancer.

Allogeneic MHC gene transfer enhances an effective antitumor immunity in the early period of autologous hematopoietic stem cell transplantation.

PURPOSE: In autologous hematopoietic stem cell transplantation (HSCT), lymphopenia-induced homeostatic proliferation of T cells is driven by the recognition of self-antigens, and there is an opportunity to skew the T-cell repertoire during the T-cell recovery by engaging tumor-associated antigens, leading to a break of tolerance against tumors. However, the homeostatic proliferation-driven antitumor responses seem to decline rapidly in association with tumor growth. We hypothesized that a tumor-specific immune response induced by an immune gene therapy could enhance and sustain homeostatic proliferation-induced antitumor immunity. EXPERIMENTAL DESIGN: The antitumor effect of allogeneic MHC (alloMHC) gene transfer was examined at the early phase of the immune reconstitution after syngeneic HSCT. RESULTS: Syngeneic HSCT showed significant tumor growth inhibition of syngeneic colon cancer cells within a period of 30 days; however, the tumor then resumed rapid growth and the survival of the mice was not prolonged. In contrast, when the alloMHC plasmid was intratumorally injected at the early phase after syngeneic HSCT, the established tumors were markedly regressed and the survival of recipient mice was prolonged without significant toxicities, whereas no survival advantage was recognized in recipient mice injected with a control plasmid. This tumor suppression was evident even in the other tumors that were not injected with the alloMHC plasmid. The antitumor response was characterized by the development of tumor-specific T cell- and natural killer cell-mediated cytotoxicities. CONCLUSION: The results suggest the efficacy and safety of integrating intratumoral alloMHC gene transfer with an autologous HSCT for the treatment of solid cancers.

[A partial response to combined S-1 and CDDP chemotherapy enabling a curative resection in a patient with locally advanced duodenal cancer].

A 60-year-old male presented with a primary complaint of back pain. CT revealed a primary duodenal tumor with bulky lymph node metastases. Gastrofiberscopy revealed a primary duodenal tumor located the second portion. The patient was treated with combined chemotherapy using S-1 and CDDP to prior to performing a surgical curative resection. S-1 (80 mg/m2) was orally administered for 3 weeks (day 1-21), and CDDP (60 mg/m2) was simultaneously administered on day 8 every 5 weeks. The chemotherapy was repeated for 2 cycles. The patient experienced no adverse event. CT revealed a partial response after chemotherapy. The patient underwent a curative pancreaticoduodenectomy. The pathological efficacy was Grade 2. Adjuvant chemotherapy was provided using S-1 regimen because of its pathological efficacy and the absence of severe adverse events. Six months after the operation, the patient was doing well and showed no signs of recurrence of the cancer. This S-1/CDDP combination chemotherapy was therefore considered to be suitable as neo-adjuvant chemotherapy because it permitted the patient to subsequently undergo a curative resection, and thereby achieving a survival benefit for locally advanced duodenal cancer.

Allogeneic MHC gene transfer enhances antitumor activity of allogeneic hematopoietic stem cell transplantation without exacerbating graft-versus-host disease.

Enhancement of the specific antitumor activity of allogeneic hematopoietic stem cell transplantation (alloHSCT) against solid cancers is a major issue in the clinical oncology. In this study, we examined whether intratumoral allogeneic MHC (alloMHC) gene transfer can enhance the recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. In minor histocompatibility antigen-mismatched alloHSCT (DBA/2-->BALB/c: H-2(d)) recipients, alloMHC gene (H-2K(b)) was transduced directly into a s.c. tumor of CT26 colon cancer cells. Because CT26 cells have an aggressive tumorigenicity in syngeneic BALB/c mice, an H-2K(b) gene transfer provides only a limited antitumor effect after syngeneic (BALB/c-->BALB/c) HSCT. By contrast, the H-2K(b) gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors without gene transduction. In vitro cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to the H-2K(b) gene transfer. Graft-versus-host disease was not exacerbated serologically or clinically in the treated mice, demonstrating that alloMHC gene transfer enhances the antitumor effects of alloHSCT without exacerbating graft-versus-host disease. This combination strategy has important implications for the development of therapies for human solid cancers.

[A case with a single liver metastasis from pancreatic cancer surviving for 29 months].

We report a 62-year-old man with advanced pancreatic cancer who underwent pancreatoduodenectomy and was then found to have a single hepatic metastasis. Hepatic resection was performed after 19 months of systemic chemotherapy. The patient survived for 29 months after diagnosis of the hepatic metastasis without occurrence of further metastatic lesions. The patient was given a diagnosis of pancreatic head cancer and underwent pancreatoduodenectomy in September 2001. A single hepatic metastasis was found in July 2002. No local recurrence, lymph node metastasis, distant metastasis or peritoneal metastasis were noted on imaging studies. Chemotherapy with S-1 was performed. The hepatic metastasis remained single and there were no other metastatic lesions for 19 months. A metastasis was found in the right lung in May 2004. The patient died in December 2004 without local recurrence, lymph node metastasis or new hepatic metastasis.

Role of the MTT chemosensitivity test in the prognosis of gastric cancer patients after postoperative adjuvant chemotherapy.

The clinical usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) chemosensitivity test (MTT assay; MTTA) in the selection of anticancer drugs against advanced gastric cancer (AGC) was evaluated. MTTA is widely used to predict patient responses to particular drugs, allowing for the selection of appropriate chemotherapeutic drugs and the avoidance of ineffective chemotherapeutic drugs, thereby improving patient survival. Since 1989, we have accumulated MTTA efficacy data from AGC patients. In this study, the present clinical roles of MTTA and the data from 202 patients with stage III or IV gastric cancer analyzed for survival outcome following surgery, with or without postoperative chemotherapy, evaluated by MTTA, are discussed. The patients were divided into 3 groups; an adapted group found to be sensitive to chemotherapy by MTTA, a non-adapted group found to be insensitive to chemotherapy by MTTA and a group that received no chemotherapy. For stage III gastric cancer patients, the adapted group had a statistically better survival rate compared to the other groups, while for stage IV patients, there was no difference in survival rate between any of the groups. However, further classification of stage IV patients as to the presence or absence of peritoneal dissemination (P) showed that the adapted group with P showed better prognoses than the other groups with P. The analysis of data collected since 2000 revealed that the 11 patients in the taxane-adapted group, who received chemotherapeutic regimens that included taxanes and were found to be sensitive to taxanes by MTTA, demonstrated better survival than the taxane non-adapted group (n=11) (p=0.045). In conclusion, MTTA results predicted patient prognoses, based on the selection of appropriate chemotherapy.

Intraperitoneal injection of adenovirus expressing antisense K-ras RNA suppresses peritoneal dissemination of hamster syngeneic pancreatic cancer without systemic toxicity.

We examined the antitumor effect and safety of the adenovirus-mediated expression of antisense K-ras RNA in two peritoneal dissemination models of pancreatic cancer. First, we found that the infection of an adenovirus vector expressing antisense human K-ras RNA (AxCA-AS) induced significant apoptosis in vitro in human pancreatic cancer cells with K-ras mutation. Second, the intraperitoneal (ip) injection of AxCA-AS effectively suppressed the growth of human pancreatic cancer cells in the peritoneal cavity of nude mice. Third, in the hamster syngeneic peritoneal dissemination model, the ip injection of an adenovirus expressing antisense hamster K-ras RNA significantly suppressed the peritoneal growth of hamster pancreatic cancer cells, and no significant systemic toxicity was observed in the treated hamsters. This study suggests a feasibility of the development of a therapeutic strategy against pancreatic cancer based on the adenovirus-mediated transduction of an antisense K-ras construct.