Localization of N-myc downstream-regulated gene 1 in gastric cancer tissue.

BACKGROUND AND AIM: N-myc downstream-regulated gene 1 is detected in normal tissue but is down-regulated in cancer tissue. Furthermore, research has suggested that co-expression with p53 is necessary for induction of p53-mediated apoptosis. This study sought to investigate the clinicopathological significance of N-myc downstream-regulated gene 1 and p53 expression in gastric cancer tissue. PATIENTS AND METHODS: Immunohistochemical detection of N-myc downstream-regulated gene 1 and p53 was performed with tissue samples from 96 cases of gastric cancer, and the relationship between expression profiles of proteins and clinicopathological characteristics was statistically analysed. RESULTS: Positive staining of N-myc downstream-regulated gene 1 was observed in the cytoplasm (22 of 96 cases, 22.9%) and/or nucleus (29 of 96 cases, 30.2%) of cancer cells. In 15 cases (15.6%), both cytoplasm-positive cells and nucleus-positive cells were observed in the cancerous region. The nuclear localization of N-myc downstream-regulated gene 1 was frequently observed in the region of cancerous invasion and was significantly related to lymph node metastasis. In addition, accumulation of p53 protein in the nucleus of cancer cells significantly coincided with the nuclear localization of N-myc downstream-regulated gene 1. CONCLUSIONS: Localization of N-myc downstream-regulated gene 1 and its significant correlation with p53 expression may play an important role in cancer progression.

A single institutional non-randomized retrospective comparison between definitive chemoradiotherapy and radical surgery in 82 Japanese patients with resectable esophageal squamous cell carcinoma.

This retrospective study was conducted to compare the treatment results between radical surgery and definitive chemoradiotherapy for resectable squamous cell carcinoma of the esophagus. Between June 2000 and May 2005, 82 consecutive patients were selected for this study in which 33 were treated with chemoradiotherapy and 49 with surgery. The patients in the chemoradiotherapy (CRT) group received 2-4 cycles of 5-fluorouracil (1000 mg/m(2)/day, day 1-4, continuous) combined with cisplatin (75 mg/m(2), day 1, bolus) plus 50.4 Gy of radiation, while those in the surgery group were treated by an esophagectomy with radical node dissection. Eighteen surgical patients received postoperative chemotherapy. The baseline clinical TNM stage was similar between the two groups. With a median follow-up period of 36 months (range: 23-84 months) with 47 survivors (57%), the 3-year overall survival rates (P = 0.22) and disease-free survival rates (P = 0.16) were 48% and 44% in the chemoradiotherapy group versus 65% and 59% in the surgery group, and lacked statistical significance. This non-randomized study on patients with resectable squamous cell carcinoma of the esophagus showed that chemoradiotherapy could result in survival comparable with conventional surgery in spite of selection bias of patients. There is a trend toward improved survival with surgery versus definitive CRT.

A seasonal variation in the onset of postoperative adhesive small bowel obstruction is related to changes in the climate.

BACKGROUND: Postoperative small bowel obstruction following abdominal procedures is more common in patients who have undergone laparotomy. However, little is known about the influence of climate on the incidence of postoperative small bowel obstruction. METHODS: To evaluate whether seasonal climatic variations are a risk factor for postoperative small bowel obstruction, hospital-based, retrospective case series was designed from medical records of 230 patients suffering from postoperative small bowel obstruction admitted to the Tokyo University Branch Hospital. Detailed analysis of weather charts from the Japanese Meteorological Agency and review of medical records for selected patients who were diagnosed with postoperative small bowel obstruction. The obstruction was diagnosed by abdominal X-ray imaging, clinical examination, and patient interviews. RESULTS: A total of 233 patients diagnosed with postoperative small bowel obstruction were identified. Analysis of the medical records of these 233 patients revealed that the variables associated with an increased risk of postoperative small bowel obstruction included low ambient temperatures of 5-10 degrees C, an increase in air humidity by 40-50% and air pressure of 1010-1015 hPa. CONCLUSION: The typical winter weather in Tokyo is characterised by low temperatures, low humidity and moderate air pressure. These winter climate conditions could be correlated with an increased incidence of postoperative small bowel obstruction in Tokyo during our period.

Association of histochemical expression of Maackia amurensis leukoagglutinin-positive glycoconjugates with behaviour of human gastric cancer.

AIMS: To investigate the relationship between sialylation of glycoconjugates and clinicopathological characteristics of gastric cancer. METHODS AND RESULTS: Sialylation of glycoconjugates was examined histochemically in 71 gastric cancers using Maackia amurensis leukoagglutinin (MAL), a lectin that recognizes the trisaccharide sequence NeuAc alpha 2,3Gal beta 1,4GlcNAc/Glc. Positive staining with MAL was observed in the tumour region of all of the samples, but the populations of MAL-positive tumour cells in the tumour region varied among the samples. In the corresponding non-cancerous regions, however, no positive staining was observed. Calculating the percentage of MAL-positive tumour cells as part of the total tumour cells with respect to the MAL-staining index (MI) allowed the gastric cancer to be classified into two distinct groups: high and low levels of MI, with a cut-off level of 40% of MI. Furthermore, statistical analyses using the MI level and clinicopathological characteristics of the tumour indicated that a high MI level in gastric tumour tissues is related to a poorer prognosis. CONCLUSIONS: The appearance of MAL-positive glycoconjugates in gastric tumour cells is associated with the behaviour of gastric cancer.

Lymph node metastasis and preoperative diagnosis of depth of invasion in early gastric cancer.

BACKGROUND: No reports have, to date, focused on the relationship between preoperative determination of the depth of invasion and lymph node metastasis. The present study, under the leadership of the Japanese Gastric Cancer Association, was designed to form a basis for decision making in limited treatment for early gastric cancer (EGC). METHODS: From eight major hospitals in Japan, 2672 gastric cancers whose preoperative depth of invasion was mucosal(M-cancer), and 6209 EGCs, consisting of 3584 mucosal(m-) and 2625 submucosal(sm-) cancers, were collected by questionnaire. All registered patients underwent gastrectomy with D1 or more extensive lymphadenectomy between 1985 and 1998. RESULTS: The accuracy of preoperative diagnosis of depth of invasion of M-cancers was 80.2% (2144/2672). However, of the total of 2432 M-cancers in which no nodal involvement was observed intraoperatively (N0), histological examination of the resected specimens confirmed that lymph node metastasis was absent in 2353 (96.8%). The frequencies of lymph node metastasis in early gastric, m-, and sm-cancers were 8.9%, 2.5%, and 17.6%, respectively. Node involvement was associated with a higher frequency of undifferentiated than differentiated histology, as well as with greater tumor size. The incidences of lymph node metastasis in m-cancers with a diameter of less than 4 cm, and in sm-cancers with a diameter below 1 cm were 1.3% (37/2837) and 4.9% (4/82), respectively. These metastases rarely extended beyond the first tier. CONCLUSION: N0 and M-cancers, m-cancers less than 4 cm in diameter, and sm-cancers no larger than 1 cm in diameter may be appropriate indications for limited surgery.

A novel isoform of human fibroblast growth factor 8 is induced by androgens and associated with progression of esophageal carcinoma.

Human esophageal carcinomas occur more frequently in males, suggesting that androgens may play a role in the regulation of gene expression associated with malignant transformation. We previously established an androgen-sensitive squamous cell carcinoma line, KSE-1, from a male patient with esophageal cancer; recently a novel isoform of human fibroblast growth factor 8 (FGF8f, isoform FGF8b) was identified and expressed following androgen stimulation of KSE-1 cells. The predicted amino acid sequence of FGF8f contained an additional 29 amino acids when compared to FGF8b. Flutamide, an androgen antagonist, inhibited both FGF8b and FGF8f transcription in a dose-dependent manner. Tissue analysis from tumors revealed FGF8b expression in 24 of 41 male, but in 0 of 9 female esophageal carcinomas (58.5%), and none in adjacent normal esophageal mucosa. In addition, FGF8f was detected in 9 of 24 FGF8b-positive tumors (37.5%), and this observation was significantly associated with a poor prognosis (P < 0.001). Our observations suggest that androgenic exposure will induce FGF isoforms in tumor cells, and expression of these growth factors is associated with the prevalence and prognosis of esophageal carcinoma in males.

Outcome of patients with non-Hodgkin's lymphoma of the stomach after gastrectomy: clinicopathologic study and reclassification according to the revised European-American lymphoma classification.

BACKGROUND: The best treatment for patients with non-Hodgkin's lymphoma (NHL) of the stomach is still uncertain. The revised European-American lymphoma (REAL) classification has helped to define new, potentially more appropriate classification schemes for gastric lymphomas. METHODS: Fifty-one resected gastric lymphomas were reclassified according to the REAL classification, and the efficacy of multimodal treatment was examined retrospectively. The principal treatment plan consisted of: (1) surgical resection of the stomach with lymph node dissection, followed by (2) systemic chemotherapy, mainly using the cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) regimen. RESULTS: According to the Ann Arbor classification, 27 patients had stage IE, 19 had stage IIE, and 5 had stage IV NHL. Using the REAL classification, we diagnosed diffuse large B-cell lymphoma (DLBL) in 23 patients, marginal zone B-cell (low-grade mucosa-associated lymphoid tissue [MALT]-type) lymphoma in 22, follicle center lymphoma in 4, mantle cell lymphoma in 1, and peripheral T-cell lymphoma in 1 patient. Nine of the 51 patients relapsed, and 8 patients with DLBL died of cancer. Survival rates at 5 years after surgery were 96.0% for stage IE, 83.3% for stage IIE, and 87.0% for all patients. Univariate analysis indicated that the tumor histology (according to the REAL classification), depth of invasion, degree of nodal involvement, Ann Arbor staging, and chemotherapy had an impact on patient outcome (P = 0.0018; P = 0.0002; P = 0.0308; P = 0.0016, and P = 0.0118, respectively). CONCLUSIONS: These data reveal that gastric NHL, especially of the low-grade MALT-type, often remains localized and has a good prognosis after surgery. The REAL classification was useful for classifying new categories of NHL, including the MALT-type, in the clinical setting, and for determining the optimal treatment modality for gastric NHL.

Prognostic impact of tissue inhibitor of matrix metalloproteinase-1 in esophageal carcinoma.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the activity of matrix metalloproteinase, which may play an important role in carcinoma invasion and metastasis. TIMP-1 is thus considered to inhibit carcinoma invasion and metastasis. However, TIMP-1 possesses another important function, cell growth promotion. The clinical significance of TIMP-1 expression has not been fully determined in esophageal carcinoma. We thus examined the expression of TIMP-1 mRNA in tumor (T) and corresponding normal (N) tissues of 85 esophageal carcinoma cases by RT-PCR. The T:N ratio of TIMP-1 mRNA expression in each case was evaluated semi-quantitatively with adjustment by an internal control gene. The mean T:N ratio was 2.0 (range 0.2-6.5). When comparing high-expression cases (T:N > 2.0, n = 37) with low-expression cases (T:N < or = 2.0, n = 48), the former showed a significantly higher frequency of lymph vessel invasion, vascular vessel invasion, lymph node metastasis and advanced-stage disease. The former cases showed a poorer prognosis than the latter. Multivariate analysis disclosed that TIMP-1 expression status was an independent determining factor for prognosis. Our findings suggest that TIMP-1 expression correlates with tumor extension of esophageal carcinoma and might, if validated, prove useful as a novel prognostic marker for esophageal carcinoma.

Adrenalectomy for solitary adrenal metastasis from colorectal carcinoma.

A 60-year-old man underwent anterior resection for advanced rectal carcinoma. Seven years and 2 months later, right lower pneumonectomy was performed for a metastatic lung tumor. Two years and 2 months thereafter, left adrenalectomy was performed for solitary adrenal metastasis. The patient remained disease-free for 10 months postoperatively, until multiple lung metastases appeared. The patient is alive and well, under mild chemotherapy with oral doxifluridine, 3 years and 5 months after left adrenalectomy. We conclude that patients with solitary adrenal metastasis may benefit from surgical resection and that resection could be considered as a therapy for solitary adrenal metastasis from colorectal carcinoma.

Telomere shortening with aging in human liver.

Progressive telomere shortening with aging was studied in the normal liver tissue of 94 human subjects aged between 0 and 101 years old to determine the rate of telomere loss in 1 year. Telomere length demonstrated accelerated shortening with reduction of 55 base pairs (bp) per year. The mean telomere length in five neonates was 12.9 +/- 2.6 kilobase pairs (kbp), and that in one centenarian was 8.3 kbp. Mean telomere lengths by age group were 13.2 +/- 2.0 kbp (< or = 8 years; 10 subjects), 7.8 +/- 1.9 kbp (40-79 years; 29 subjects), and 7.5 +/- 2.0 kbp (> or = 80 years; 53 subjects), with reduction thus appearing to show slowing on the attainment of middle age. The difference of mean telomere lengths for two groups with or without advanced malignancies of other than liver origin was not significant in the older two groups. Despite the slow turnover of liver tissue, the overall reduction rate of telomere length decrease in 1 year was almost the same as that of digestive tract mucosa, with its very rapid renewal.

Influence of multimodality therapy on the cellular immunity of patients with esophageal cancer.

BACKGROUND: Cancer patients have often been reported to have impaired immune function, and the effect of treatment modalities, such as surgery, irradiation, and chemotherapy, in depressing patients' immunity has also been reported. In this investigation, the effect of treatment on the cellular immunity of esophageal cancer patients was evaluated. METHODS: Immunological parameters, such as natural killer (NK) activity and lymphocyte subsets in peripheral blood, were measured in 32 esophageal cancer patients on 5 occasions (on the day of admission, 2 days before surgery, and 1 week, 1 month, and 2 months after surgery). RESULTS: NK activity was greatly impaired shortly after the operation, and the percentages of lymphocytes as a whole, and CD8+, CD16+, and CD57+ lymphocytes were significantly decreased, on the other hand, a postoperative increase in the CD4+/CD8+ ratio was observed. No significant depression of immune function by postoperative irradiation was observed. CONCLUSIONS: The results of this study suggest that cellular immunity, especially cytotoxicity, shortly after esophagectomy may be greatly impaired by the surgical stress of esophagectomy and an added effect of chemotherapy.

Correlation of telomere lengths in normal and cancers tissue in the large bowel.

The hypothesis that telomeres in colorectal cancer cells exhibit age-related shortening, as in normal cells of the colorectal epithelium, was tested with samples of non-cancerous mucosa and cancer tissue from 124 patients (aged 29-97 years). Shortening with aging could be demonstrated for both normal and cancer tissues; regression analysis showed rates for length reduction of 44 and 50 base pair/year, respectively. Straight, essentially parallel, lines were obtained for the two cases, normal tissue values being about 2 kilobase pairs (kbp) higher, with a significant correlation between data at the individual patient level.

Autopsy findings in patients with esophageal carcinoma: comparison between resection and nonresection groups.

The prognosis of patients with esophageal cancer is poor, despite attempts at aggressive multimodality treatment. To yield some important information that could help to improve operative methods and multimodality treatments, we compared autopsy findings such as the extent of local and metastatic spread of cancer in resection (n = 33) and nonresection (n = 38) groups of patients who had had esophageal cancer. Residual or recurrent esophageal cancer was identifiable in 71.9% of patients in the resection group and 94.4% of patients in the nonresection group. Local residual cancer was identified much less frequently in the former group than in the latter (21.2% vs. 94.4%) (P < 0.0001). The most frequent mode of metastasis was hematogenous, occurring in 51.5% of the resection cases and 63.9% of the nonresection cases. Lymph-node metastasis was also observed frequently, being present in 51.5% of resection cases and 58.3% of nonresection cases. Serosal dissemination of cancer was found in 36.4% of resection cases and 25.0% of nonresection cases. The low incidence of localized disease suggests that esophagectomy, even though palliative in some cases, is effective as a treatment for esophageal cancer. The high incidence of lymph-node and hematogenous metastasis after esophagectomy implies that more extensive lymph-node dissection and stronger adjuvant chemotherapy might be required.

Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma.

Matrix metalloproteinases (MMP) play an important role in tumor cell invasion and metastasis. We examined the expression of MMPs in hepatocellular carcinoma (HCC) to determine whether they may help indicate the progression of HCC and patient outcome. The expression of MMP-1, -2, -7, -9, and MT1-MMP were determined in 37 pairs of HCC and adjacent non-tumor tissue specimens by semiquantitative reverse transcription polymerase chain reaction (RT-PCR). The tumor to non-tumor (T/N) ratios for mRNA expression of each MMP were compared with the clinicopathological findings and two-year disease-free survival rates. Immunohistochemical analysis for MMP-1 and -9 was performed in 30 specimens. MMP-1 and -9 expression was significantly higher in tumor tissue than in non-tumor tissue (p=0.001 and 0.0078, respectively). By contrast, the expression of MMP-2 and -7 was significantly lower in tumor tissue than in non-tumor tissue (p=0. 003 and 0.03, respectively). A higher MMP-9 T/N ratio was significantly associated with small HCCs (/=20 ng/ml) (p=0.013 and 0.028, respectively). Immunohistochemical analysis suggested that well differentiated HCC showed stronger immunoreactivity for MMP-9 than moderately differentiated HCC. MMP T/N ratio was not significantly associated with the disease-free survival rates. Overexpression of MMP-9 mRNA (T/N ratio >/=2) may be associated with the progression of small HCC (

A dominant negative mutation of transforming growth factor-beta receptor type II gene in microsatellite stable oesophageal carcinoma.

Recent investigations revealed microsatellite instability in colon cancers are associated with mutations of the transforming growth factor-beta receptor type II gene (TGF-beta RII) that encodes a transmembrane protein containing an intracellular serine/threonine kinase domain. Activation of TGF-beta receptor type I (RI) and RII by TGF-beta induces nuclear translocation of Smad proteins including Smad2 and Smad4 that have been originally identified as tumour suppressor genes. We have previously reported six cases with microsatellite instability in 32 oesophageal carcinomas. In this study, we analysed genetic mutations of TGF-beta RII, Smad2 and Smad4 in these oesophageal carcinoma tissues and established 16 cell lines. No genetic mutation was detected in any tissues or cell lines except one tissue sample of microsatellite stable oesophageal carcinoma, that is, a mis-sense mutation of glutamic acid to glutamine at codon 526 (E526Q) in the TGF-beta RII serine/threonine kinase domain. Interestingly, the mutant TGF-beta RII E526Q can completely inhibit TGF-beta-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-beta RII that is not associated with microsatellite instability might make a dominant negative effect on TGF-beta signal transduction in oesophageal carcinoma.

L-myc restriction fragment length polymorphism in Japanese patients with esophageal cancer.

L-myc polymorphism is a representative genetic trait related to an individual's susceptibility to several cancers. However, there have been no reports concerning the association between esophageal cancer and L-myc polymorphism. To analyze the distribution of polymorphism in Japanese patients with esophageal cancer, a molecular genotyping method using a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used. Based on an analysis of 65 Japanese patients with esophageal cancer and 107 healthy control subjects, a significant difference was observed in either the distribution of genotypes (P=0.012) or of allele frequencies between the two groups (P=0.004). The relative risk of esophageal cancer for genotypes including the shorter allele was 2.9 compared to the longer allele homozygote. Furthermore, the patients with S-allele had a tendency for poor prognosis among those with three genotypes. A significant difference between the distribution of genotypes and the incidence of lymph node metastasis was found based on the clinicopathological features of the cancers. These results suggest that L-myc polymorphism may be implicated as a genetic trait affecting an individual's susceptibility to esophageal cancer, at least among Japanese patients.

Assessment of gastric carcinoma risk associated with Helicobacter pylori may vary depending on the antigen used: CagA specific enzyme-linked immunoadsorbent assay (ELISA) versus commercially available H. pylori ELISAs.

BACKGROUND: Previous epidemiologic studies produced inconsistent results when examining the relation between Helicobacter pylori infection and the risk of gastric carcinoma by measuring various anti-H. pylori antibodies. This study investigated the increased risk of cancer by examining different antibodies, including the specific anti-CagA antibody and antibodies from two commercially available kits. METHODS: An ELISA for the detection of serum anti-CagA was established using a recombinant CagA protein that the authors previously reported. Serum anti-CagA titer was determined for 80 patients with gastric carcinoma and 80 gender- and age-matched controls. Two anti-H. pylori antibodies from the commercially available kits HEL-p (Amrad, Kew Vic, Australia) and HM-CAP (Enteric Product Inc., Westbury, NY) were also evaluated. RESULTS: Anti-CagA seropositivity differed significantly between gastric carcinoma patients and controls (92.5% vs. 55.0%; P = 0. 0001), showing an odds ratio of 10.4 (95% confidence interval [CI]: 4.23-29.74). The difference was less prominent for the seropositivity of HEL-p (77.5% vs. 58.8%; P = 0.0139; odds ratio: 2. 38; 95% CI: 1.20-4.82) and insignificant for that of HM-CAP (65.0% vs. 57.5%; P = 0.4325; odds ratio: 1.30; 95% CI: 0.68-2.49). CONCLUSIONS: The current study revealed that the antibody assay system used could be one important factor in the assessment of gastric carcinoma risk for patients with H. pylori.

alpha6 integrin expression in esophageal carcinoma.

One of the genes that the authors have isolated by a differential display of hepatocellular carcinoma compared to adjacent liver is the alpha6 integrin. alpha6 integrin is the major adhesion receptor for laminin and is suggested to be involved in tumor cell invasion and metastasis. To our knowledge, however, there are no reports on alpha6 integrin expression in esophageal carcinoma. We thus conducted a study to determine its clinicopathologic significance in human esophageal carcinoma. The tumor/normal (T/N) ratio of alpha6 integrin expression was calculated by Northern hybridization in 45 cases of esophageal carcinoma. In selected cases the expression of the alpha6 integrin variants A and B was also investigated by reverse transcriptase-polymerase chain reaction, and immunostaining for alpha6 integrin was performed. The expression levels of alpha6 integrin mRNA in the tumor tissue were greater than those of the corresponding normal tissue in 39 of 45 cases (87%). The overexpression of alpha6 integrin was also recognized by immunostaining. Fifteen cases with a high T/N ratio demonstrated a deeper invasion into the esophageal wall than the 30 cases with a low T/N ratio. Although there was no significant difference, the 15 cases with a high T/N ratio had a tendency for a worse prognosis. The ratio of the two variants (alpha6A/alpha6B) did not show any relationship to survival. The findings imply that alpha6 integrin is overexpressed in human esophageal carcinomas and that alpha6 integrin may play an important role in esophageal tumor invasion.