IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model.

The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers.

[Therapeutic strategy for hepatic metastasis of primary colon cancer].

PURPOSE: To analyze the clinical results of treatments for hepatic metastasis of primary colon cancer for an evaluation of treatment strategies. MATERIALS AND METHODS: Two hundred and twenty-five patients with only hepatic metastasis of primary colon cancer (synchronous tumors, 164 patients: metachronous tumors, 61 patients) between 1983 and 1999 were studied. Of these 225 patients, 68 patients (synchronous tumors, 39 patients: metachronous tumors, 29 patients) were treated with curative resection. These 225 patients were categorized into group A (chemotherapy only), group B (hepatic arterial infusion only), group C (curative resection + hepatic arterial infusion), and group D (curative resection only). The therapeutic results were compared. RESULTS: The five-year survival rate and five-year recurrence-free rate of 68 patients with curative resection were 40.6% and 31.0%. By therapeutic modality, the five-year survival rate and five-year recurrence-free rate of the 36 patients of group C were 40.7% and 29.5%, and those of the 32 patients of group D were 43.4% and 33.0%, respectively. No significant difference was found between these two groups. However, in the patients with synchronous tumors, the five-year survival rate and five-year recurrence-free rate of group C and group D were 65.7, 49.6% and 13.8, 15.9%, respectively. The results of group C were significantly better than those of group D. Recurrence was found in 36 patients (52.2%). Among these patients, 25 (36.8%) recurred within one year from the end of treatment(s). Twenty-one patients (32.4) had the recurrence in the residual liver, and 14 (17.6%) had metastasis to the lung. In group B, in which curative resection was impossible, the one-year and two-year survival rates in the patients with synchronous tumors were good in comparison with those of group A. Herein we report two cases in which hepatic arterial infusion was effective. CONCLUSION: It is important to set aggressive resection and hepatic infusion as a fundamental treatment policy, and to perform not only hepatic infusion but to combine other treatments with consideration of the next recurrence.

[Significance of radical recurrent tumor resection for recurrent gastric cancer as assessed by prognosis].

To evaluate the relationship between radical surgery of recurrent tumor and prognosis in cases of recurrent gastric cancer, we analyzed data on 202 patients with relapsed gastric cancer, focusing on surgical recurrent tumor removal. In our series, 18 of the 202 patients underwent radical recurrent tumor resection. Resected tumors were located in the ovarium (n = 4), colorectum (n = 3), liver (n = 3), lymph node (n = 2), locoregional stoma (n = 2), and peritoneum, adrenal gland, brain, and lung (n = 1 each). No surgery-related mortality occurred. One patient remains alive over 5 years after hepatectomy without recurrence, and 17 died within 3 years: 7 patients from primary recurrence and 10 from multiple modes of recurrence. Median survival after recurrence (MSTAR) in the 18 radical surgery patients was 14 months, against 5 months in those treated palliatively (p = 0.0001). MSTAR for the ovary and the liver were 30 months and 15 months in the radical surgery cases, and 2.5 months for the ovary and 5 months for the liver in the palliative cases. Significant differences were thus seen between radical and palliative cases in the ovary (p = 0.010) and in the liver (p = 0.036). Median survival after gastrectomy was 45 months in the radical surgery cases, and 28 months in the palliative cases (p = 0.024). In postoperative gastric cancer follow-up, early detection of recurrence and radical surgery may well benefit patients with relapse, especially in the liver and ovary, in terms of survival.

Should scirrhous gastric carcinoma be treated surgically? Clinical experiences with 233 cases and a retrospective analysis of prognosticators.

BACKGROUND/AIMS: The prognosis of patients with scirrhous gastric carcinoma has been poorest. METHODOLOGY: To clarify the role of surgical treatment, 233 patients with a primary scirrhous gastric carcinoma were retrospectively analyzed. RESULTS: Of the 233 patients, 182 underwent surgical resection, while the other 51 did not. The median survival time of those with unresectable tumors was 88.0 +/- 15.3 days and that of those who underwent resection was 380.0 +/- 41.8 days. In the 182 patients who underwent resection, multivariate analysis revealed four significant factors; lymphatic invasion, serosal invasion, curability, and lymph node dissection. Of these, curability was the most significant. The median survival time of patients whose tumor were curatively resected was 727.0 +/- 116.3 days, significantly longer than 272 +/- 34.9 days for those whose resection ended noncuratively. In 65 patients whose tumor was curatively resected, subset analyses of factors by multivariate analyses revealed an absence of serosal invasion as the single significant prognosticator. The 5-year survival rate was 55.6% in patients with scirrhous cancer without serosal invasion. CONCLUSIONS: For patients with scirrhous gastric carcinoma, palliative resection should not be attempted for poor outcome. However, if curative resection seems feasible, radical surgery would be justified, especially for tumors without serosal exposure.

[Significance of laparoscopy for response assessment of chemotherapy in gastric cancer].

UNLABELLED: We performed laparoscopy before and after chemotherapy in two patients with relapsed and advanced gastric cancer, whose major metastatic sites had been diagnosed as being in the peritoneum. A change in tumor responses when assessed by laparoscopy was found. Case 1: A 63-year-old man presented with an umbilical metastasis and suspected peritoneal metastases after gastrectomy. Laparoscopy revealed peritoneal metastases before chemotherapy. After one course of chemotherapy the umbilical tumor disappeared (CR). Laparoscopy after two courses of chemotherapy revealed increasing peritoneal metastases (PD). The overall response was PD. Case 2: A 67-year-old woman was referred to our hospital with a diagnosis of type 4 gastric cancer. Staging laparoscopy revealed massive lymph node metastases and the patient was positive in peritoneal washing cytology. After four courses of chemotherapy, the primary tumor and the metastatic lymph nodes had decreased in size (PR). In contrast, laparoscopy revealed increasing peritoneal metastases (PD). The overall response was PD. CONCLUSION: In patients with peritoneal and other modes of metastasis, tumor response to chemotherapy may be misjudged by conventional imaging alone. Intraperitoneal examination by laparoscopy provides accurate information, including the tumor response to chemotherapy.

Expression of peptide transporter following intestinal transplantation in the rat.

BACKGROUND: The absorptive function of the intestinal graft is one of the most important factors for successful intestinal transplantation. To clarify whether the intestinal H(+)/peptide cotransporter (PEPT1) was expressed in the transplanted intestine, we examined the expression of PEPT1 in an experimental model of rat small intestinal transplantation in comparison with expression of Na(+)/glucose cotransporter (SGLT1). MATERIALS AND METHODS: Heterotopic intestinal transplantation was performed in allogeneic and syngeneic rat strain combinations. An additional group of allogeneic recipients was treated with tacrolimus (1 mg/kg) prior to transplantation, then daily for 7 days. Intestinal grafts were examined for histopathology and PEPT1 and SGLT1 expression. RESULTS: In the isografts, the levels of messenger RNA (mRNA) encoding both transporters were not changed, while the amount of SGLT1 protein was decreased and that of PEPT1 protein was increased. In the allografts, mRNA level and protein amount of both transporters and the amount of villin protein were decreased, and microscopic examination revealed histopathological features of rejection on day 7. Tacrolimus treatment ameliorated the histopathological features and prevented the decrease in villin protein expression. However, the decreases in PEPT1 and SGLT1 expression (both mRNA and protein) were partially prevented by tacrolimus treatment. CONCLUSION: This study indicated that the expression of transporters should be determined to evaluate intestinal graft function in addition to histopathological examination of the mucosa and that the levels of mRNA encoding intestinal nutrient transporters in biopsy specimens may be useful for evaluating the intestinal graft function for intestinal transplant patients.

Intratumoral concentrations of tissue inhibitor of matrix metalloproteinase 1 in patients with gastric carcinoma a new biomartker for invasion and its impact on survival.

BACKGROUND: Previously, the authors clarified that the plasma concentration of tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) in patients with gastric carcinoma was a significant predictor of tumor invasiveness and metastasis. METHODS: To further clarify the clinical significance of TIMP-1, the authors used an enzyme-linked immunoassay to assess TIMP-1 protein concentrations in samples of tumor tissue from 86 patients who underwent primary resection for gastric carcinoma. Concentrations in samples of normal gastric mucosa from 73 of these patients also were assessed. RESULTS: Tissue TIMP-1 concentrations were significantly greater in gastric tumors than in normal gastric mucosa and were associated significantly with a variety of pathologic factors, including macroscopic type, depth of tumor invasion in the gastric wall, presence of lymphatic vessel invasion, pattern of tumor infiltration into the surrounding tissue, and disease stage. Significantly greater TIMP-1 concentrations were found in tumors that were exposed to the serosal surface compared with tumors that were limited to the submucosal layer. TIMP-1 protein was significantly greater in tumors with lymphatic vessel invasion, an infiltrative pattern into the surrounding tissue (INF-gamma), and in tumors from patients with Stage III disease. Survival was significantly poorer in patients with TIMP-1 concentrations > or = 10.0 ng/mg total protein. When patients were stratified by disease stage, survival was significantly different in patients with Stage III disease. Multivariate analysis demonstrated that intratumoral concentrations of TIMP-1 were the most significant independent factor for survival. CONCLUSIONS: These findings suggest that the intratumoral concentration of TIMP-1 protein may be a good indicator of tumor aggressiveness and can serve as a significant independent predictor of survival in patients with gastric carcinoma.

Clinicopathologic differences between early gastric remnant cancer and early primary gastric cancer in the upper third of the stomach.

BACKGROUND/AIMS: This study was designed to clarify the clinicopathologic characteristics and survival in early gastric remnant cancer and compare with early primary cancer in the upper third of the stomach. METHODOLOGY: Twenty-five patients with early gastric remnant cancer, who underwent resection at Kanagawa Cancer Center and First Department of Surgery, Yokohama City University between 1974 and 1996 were evaluated in this study. Various clinicopathologic characteristics, such as age, sex, symptoms, size of tumor, depth of invasion, lymph node metastasis, cell differentiation, and survival were investigated and early gastric remnant cancer was compared with early primary cancer in the upper third of the stomach. RESULTS: According to the macroscopic type, protruded type such as I or II type accounted for a great majority in early gastric remnant cancer, while II c depressed type was common in early primary cancer in the upper third of the stomach, comprising 64.2% of all cases. Pathological examination disclosed that well-differentiated carcinoma and mucosal carcinoma were more frequently observed in early gastric remnant cancer than in early primary cancer in the upper-third of the stomach. The 5-year survival rate was 83.5% for early primary cancer in the upper-third of the stomach. In contrast, no patients experienced recurrence after operation for early gastric remnant cancer. CONCLUSIONS: From the view point of clinicopathological evaluation, gastric remnant cancer is a special from of gastric cancer. A follow-up program is important in order to detect early gastric remnant cancer. A low incidence of lymph node metastasis suggests that endoscopic mucosal resection of the tumor or limited operation could be performed under strict indication.

One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells.

Members of the small Maf family of transcription factors play important roles in hematopoiesis. Using transgenic assays, we discovered a tissue-specific enhancer 3' to the mafK gene. This enhancer directs mafK transcription in hematopoietic as well as in developing cardiac muscle cells, and was thus designated the hematopoietic and cardiac enhancer of mafK (HCEK). Only two of four GATA consensus motifs identified within HCEK contributed to enhancer activity, and both of these sites were required for both cardiac and hematopoietic transcriptional activation. The expression profile of MafK significantly overlapped that of GATA-1 in hematopoietic cells and of GATA-4/-6 in cardiac tissues. Each of these GATA factors bound with high specificity to both of the critical GATA sites in HCEK. Hence, the mafK gene is regulated by different GATA proteins in the hematopoietic and cardiac compartments through the same two GATA-binding sites in HCEK. These data provide the first in vivo demonstration that distinct members of a related transcription factor family activate the tissue-specific expression of a single target gene using the same cis-regulatory element.

Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element.

The mammalian transcription activator Nrf2 plays critical roles in executing oxidative stress response by binding to the regulatory DNA sequence Maf recognition element. Bach2 is an Nrf2-related transcription repressor and a tissue-specific partner of the Maf oncoprotein family. We show here how Bach2 is regulated by an oxidative stress-sensitive conditional nuclear export. In cultured cells, Bach2 was localized in cytoplasm through its C-terminal evolutionarily conserved cytoplasmic localization signal (CLS). The CLS directed leptomycin B-sensitive nuclear export of reporter proteins, suggesting its dependence on the nuclear exporter Crm1/exportin 1. However, the CLS sequence does not bear a resemblance to the leucine-rich class of nuclear export signal, and mutagenesis analysis indicated that a stretch of nonhydrophobic amino acids is essential for its activity. Oxidative stressors aborted the CLS activity and induced nuclear accumulation of Bach2. Whereas oxidative stress is known to activate MARE-dependent transcription, overexpression of Bach2 in cultured cells silenced the inducibility of MARE. The results suggest that Bach2 mediates nucleocytoplasmic communication to couple oxidative stress and transcription repression in mammalian cells.

Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer.

Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been reported to be related to disease progression in patients with gastric cancer. However, the prognostic significance of plasma TIMP-1 concentrations has not been clarified. Concentrations of TIMP-1 protein were measured by enzyme-linked immuno-sorbent assay in plasma samples of 147 preoperative patients who subsequently underwent gastric resection, and prognosis was compared. The cut-off value of plasma TIMP-1 concentrations was defined as 112.5 ng/ml, referring to the TIMP-1 levels in patients with intramucosal gastric cancer. Twenty-nine out of 147 patients had higher plasma TIMP-1 levels than the cut off value. When the patients were divided into those with elevated values and those with normal TIMP-1, such parameters as age, serosal invasion, metastases to lymph nodes, peritoneum, and liver, lymphatic invasion, curability, and stage were significantly different between the two. By univariate analysis of the factors affecting survival, macroscopic type, histology, serosal invasion, metastasis to lymph node, peritoneum, and liver, vessel invasions, curability, and plasma TIMP-1 were significant. However, multivariate analysis revealed that TIMP-1 was the only significant factor. In patients with gastric cancer, plasma TIMP-1 seem to be an independent and most powerful prognosticator for the survival.

Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma.

We examined plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 54 patients with gastric carcinoma. Postoperative survival was significantly poorer in patients with plasma VEGF levels more than 10.0 pg/ml at the time of surgery. By an univariate analysis of the factors affecting survival, serosal invasion, lymph node metastasis, peritoneal dissemination, lymphatic vessel invasion, curability, and VEGF proteins were significant. By a multivariate analysis only VEGF levels and curability remained significant. Patients with recurrent disease, including liver metastasis, had significantly higher plasma VEGF concentrations than those with resectable primary tumors. VEGF, not bFGF, may serve as an independent prognosticator and a sensitive indicator for liver recurrence in patients with gastric carcinoma.

Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice.

Prior studies exploring the mechanisms controlling erythroid gene regulation implicated MARE (Maf recognition element) cis-elements as crucial to the transcriptional activity of many erythroid genes. Numerous transcription factors can elicit responses through MAREs, including not only the AP-1 family proteins, but also a growing list of factors composed of Cap-N-Collar (CNC)-small Maf heterodimers. While these factors can activate transcription from MAREs in co-transfection assays, mouse germline mutations in cnc genes tested to date have failed to reveal primary erythroid phenotypes. Here we report that after combining the mafK and mafG targeted null alleles, mutant animals display several synthetic phenotypes, including erythroid deficiencies. First, compound homozygous small maf gene mutants survive embryogenesis, but die postnatally. Secondly, compound mutant animals develop severe neurological disorders. Thirdly, they exhibit an exacerbated mafG deficiency in megakaryopoiesis, specifically in proplatelet formation, resulting in profound thrombocytopenia. Finally, the compound mutant animals develop severe anemia accompanied by abnormal erythrocyte morphology and membrane protein composition. These data provide direct evidence that the small Maf transcription factors play an important regulatory role in erythropoiesis.

Angiogenesis inhibitor, TNP-470, suppresses growth of peritoneal disseminating foci.

BACKGROUND/AIMS: Angiogenesis is critical not only for growth of primary tumors but also for cells established at distant organs. We investigated the effects of angiogenesis inhibitor, TNP-470, on the establishment and growth of intraperitoneally inoculated human gastric cancer cell line, MKN-45, and survival of nude mice with this tumor. METHODOLOGY: Human gastric cancer cell line, MKN-45, were injected into the peritoneal cavity of an ICR nude mouse and a model of peritoneal dissemination was developed. TNP-470 was injected subcutaneously every other day from day 1 until sacrifice or death. The effects of TNP-470 on MKN-45 cells were also examined in vitro. RESULTS: Although the number of disseminated foci was not significantly different, the maximum size was significantly smaller in a TNP-treated group than those of a control. Survival time was significantly longer in a TNP-treated group. TNP-470 demonstrated no growth inhibition of MKN45 cells in vitro. CONCLUSIONS: Those results suggested that anti-angiogenic agent, TNP-470, might be effective in treating peritoneal dissemination of gastric cancer by inhibiting growth of the seeded tumor cells on the peritoneum.

Neoadjuvant chemotherapy with a combination of irinotecan and cisplatin in advanced gastric cancer--a case report.

We report a case of advanced gastric carcinoma successfully treated with a combination of irinotecan and cisplatin as neoadjuvant chemotherapy. The patient, a 78-year-old man, had type 2 gastric cancer, which had metastasized to the paraaortic lymph nodes. He was treated with irinotecan, 70 mg on day 1 and day 15, and cisplatin, 80 mg on day 1. The course was repeated every 4 weeks. Two courses of treatment resulted in a marked reduction of both the primary tumor and lymph nodes. Subsequently, the patient underwent curative surgery consisting of total gastrectomy, splenectomy, and D3 lymph node dissection. No surgical complications were observed. On microscopic examination, only a few tumor cells were detected in the granulation tissues of the resected stomach and in the lymph nodes. This would be the first case to demonstrate the effectiveness and the safety of irinotecan and cisplatin used in the neoadjuvant setting for treatment of advanced gastric carcinoma.

Is gastric carcinoma different between Japan and the United States?

BACKGROUND: Analyses of surgical results for gastric carcinoma often lead to the conclusion that gastric carcinoma occurring in Japan is different from that diagnosed in the U.S. METHODS: To elucidate factors that might explain the differences in surgical results between the two countries, the authors compared data from a cancer center and a university hospital in Japan and a specialist cancer hospital in the U.S (Memorial Sloan-Kettering Cancer Center [MSKCC]). RESULTS: The mean age and body mass index were significantly greater in patients in the U.S. The N category appeared to be determined less accurately at MSKCC compared with the Japanese centers. The occurrence of early gastric carcinoma was not confined to Japanese patients because 20% of U.S. patients who underwent surgery were determined to have early stage disease. However, mucosal (in situ) carcinoma was detected rarely, and the proportion of advanced stage disease was greater in the U.S. Lesions in the upper gastric body, including the gastroesophageal junction, occurred in > 50% of cases at MSKCC but in only 20% of cases at the Japanese centers (P < 0.001). D2 lymph node dissection was possible with low morbidity and minimum mortality (31% and 3%, respectively, at MSKCC). The 5-year survival rates, stratified by tumor location and T category, revealed more similar results between Japan and the U.S. than had been reported previously. The marked difference between Japanese and American institutions only was observed for T1 and T2 tumors occurring in the lower gastric body and for T3 tumors occurring in the middle and upper third of the stomach. CONCLUSIONS: Based on the findings of the current study, it would appear that the more favorable outcome noted for gastric carcinoma patients in Japan primarily is explained by the differences in tumor location, a greater frequency of early stage disease, and more accurate staging compared with gastric carcinoma patients in the U.S. Results of gastric carcinoma treatment comparable to those obtained in Japan can be obtained in Western centers.

Positive or negative MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins.

The small Maf transcription factor proteins bind to Maf Recognition Elements (MAREs) by dimerizing with CNC proteins or themselves. We undertook experiments to clarify the functional relationship between the small Mafs and their partners in vivo. Embryos expressing abundant transgene-derived MafK died of severe anemia, while lines expressing lower levels of small Maf lived to adulthood. Megakaryocytes from the latter overexpressing lines exhibited reduced proplatelet formation and MARE-dependent transcription, phenocopying mafG null mutant mice. When the mafG null mutants were bred to small Maf-overexpressing transgenic animals, both loss- and gain-of-function phenotypes were reversed. These results provide direct in vivo evidence that transcriptional regulation through MARE elements hinges on an exquisitely sensitive balance of activating CNC molecules and their small Maf partners.

The effects of intraoperative glucose infusion on portal blood insulin concentration and hepatic mitochondrial redox state during surgery: comparison of short-term and continuous infusions.

The relationships between the blood glucose level, portal blood immunoreactive insulin (IRI) concentration, ketogenesis, and hepatic mitochondrial redox state associated with intraoperative glucose administration were evaluated in patients undergoing total gastrectomy. A total of 26 patients were randomly allocated to two groups according to the type of infusion given; group 1 was given a short-term glucose infusion of 25 g in 30 min and group 2 was given a continuous glucose infusion of 10 g/h. The blood glucose concentration peaked 30 min after the glucose infusion was commenced, then decreased in group 1, despite a continuous rise in group 2. A temporary but significantly higher blood glucose level was observed in group 1 than in group 2, 30 and 60 min after the infusion was commenced. The portal blood IRI concentrations and arterial ketone body ratio (AKBR) continued to increase and the blood ketone body concentrations continued to decline after the start of the glucose infusion in both groups; however, after 60 and 120 min, the portal blood IRI and AKBR levels were significantly higher, and the blood ketone body levels significantly lower in group 1 than in group 2. These findings suggest that intraoperative glucose administration is beneficial for insulin secretion, ketogenesis, and the hepatic mitochondrial redox state, and that short-term infusion is superior to continuous infusion.

[Distribution of lymphocytes to tumor tissue and regional lymph nodes in patients with gastric cancer--the effects of oral administration of OK-432].

We attempted to clarify the accumulation of radiolabeled lymphocytes to tumors and regional lymph nodes in patients with gastric carcinoma. The effects of oral administration of OK-432 were also studied. Five patients with gastric cancer and one who underwent endoscopic mucosal resection, were entered in the study. Prior to the tracer study in 3 patients with gastric cancer, 5 KE of OK-432 was administered for 2 days. Peripheral mononuclear cells were separated and labeled with [111] In-tropolone. After the resection of stomach, tumor tissue, normal gastric mucosa, regional lymph nodes, and non-regional lymph nodes were dissected and radioactivity was measured by a gamma-counter. Accumulation of lymphocytes to the tumor tissue and n1 lymph node station was more than two times that in the normal gastric mucosa and ten times that in non-regional lymph nodes. Accumulation of lymphocytes to the n2 station was strongly enhanced by oral administration of OK-432.

Tissue inhibitor of matrix metalloproteinase-1 in the plasma of patients with gastric carcinoma. A possible marker for serosal invasion and metastasis.

BACKGROUND: Expression of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in tumor tissue from patients with gastric carcinoma has been reported to be related to disease progression. However, to the authors' knowledge the clinical significance of plasma TIMP-1 concentrations in these patients has not been clarified. METHODS: Concentrations of TIMP-1 protein were examined by enzyme-linked immunoadsorbent assay in plasma samples from 149 patients who underwent resection of their primary tumors and from 18 patients with nonresected or recurrent disease. RESULTS: In the 149 patients whose primary tumors were resected, plasma TIMP-1 concentration was associated significantly with a variety of pathologic factors including macroscopic type, depth of invasion, lymph node and peritoneal metastases, vessel invasion, pattern of tumor infiltration into surround ing tissue, and disease stage. Plasma TIMP-1 concentration was significantly higher in patients with serosal invasion, lymph node metastasis, peritoneal dissemination, or liver metastasis than in those without these factors. Neither carcinoembryonic antigen (CEA) nor CA 19-9 concentrations appeared to be related to these measures of disease progression. In the 18 patients with nonresected or recurrent disease, TIMP-1, CEA, and CA 19-9 were similarly sensitive in predicting peritoneal, liver, and lymph node metastases. The combination of these three factors was able to detect 73.3% of patients with peritoneal metastasis, 83.3% of patients with liver metastasis, and 88.9% of patients with disease recurrence. CONCLUSIONS: In patients with gastric carcinoma, plasma concentration of TIMP-1 appears to correlate with both serosal invasion and metastasis.