Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer.

BACKGROUND: Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed. PATIENTS AND METHODS: This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined. RESULTS: In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes. CONCLUSIONS: Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.

Demonstration of wavelength-scan-free action spectroscopy in pump/probe measurement with supercontinuum pump light.

We devise and introduce the principle of wavelength-scan-free spectroscopy for the pump light in pump/probe measurement (action spectroscopy) using supercontinuum light; we demonstrate its implementation by measuring transmission spectra. We use the supercontinuum light noise as a code in order to discriminate wavelength. We extract the stimulation at the desired wavelength by correlating the noise at that wavelength observed separately and the observed total stimulation carried by the probe light. The wavelength-scan-free spectroscopy is enabled with a simultaneous procedure for multiple wavelengths.

Fluorescence anisotropy in indole under two-photon excitation in the spectral range 385-510 nm.

This paper presents the detailed study of two-photon excited fluorescence in indole dissolved in propylene glycol produced by two-photon absorption from the molecular ground state to several high lying excited states. The experimental method involved excitation with linearly and circularly polarized femtosecond pulses and time-resolved detection of the polarized fluorescence decay. The fluorescence intensity, anisotropy, excited state lifetime, and rotation diffusion time as function of the excitation light wavelength in the spectral range 385-510 nm were determined in experiment. The theoretical fit of the experimental results obtained demonstrated the contributions of six highly excited molecular states of different symmetry to the two-photon absorption intensity and fluorescence anisotropy. An intense two-photon absorption peak was observed experimentally in the spectral range 385-480 nm and explained as contributions from four high lying electronic excited states. The temporal dependence of fluorescence intensity in indole was satisfactory characterized by a single excited state lifetime τf and a single rotational diffusion time τrot. As shown, the excited state lifetime τf depends on the excitation light wavelength, which was explained by taking into account nonradiative relaxation transitions in the molecular vibronic excited states. The rotation diffusion time τrot was found to be equal to τrot = 0.9 ± 0.5 ns and practically independent of the excitation wavelength. The determined molecular anisotropy changed substantially in the spectral area 385-480 nm taking positive and negative values, and the anisotropies referring to linearly and circularly polarized excitation light changed almost in opposite phases with each other. The experimental results obtained were interpreted using ab initio molecular structure computations and a model based on the Frank-Condon approximation and taking into account vibronic absorption bands.

Outcomes of fulvestrant therapy among japanese women with advanced breast cancer: a retrospective multicenter cohort study (JBCRG-C06; Safari).

PURPOSE: This retrospective study evaluated the effect of clinical background and treatment line on time to treatment failure (TTF) in advanced/metastatic breast cancer (AMBC) patients receiving F500 in Japan (UMIN 000015168). METHODS: Patients who commenced F500 treatment were registered at 16 sites in Japan. Correlations between baseline clinicopathological factors, treatment line, and TTF were investigated by Kaplan-Meier analysis. TTF data were analyzed using univariate analysis and multivariate analysis with a Cox proportional hazards model. RESULTS: Data for 1072 patients were available; 1031 patients (96.2%) were evaluable for efficacy. F500 was administered as first-line treatment in 2.0%, second-line in 22.7%, third-line in 26.7%, and ≥fourth-line in 48.6% patients. Median TTF was 5.4 months. Multivariate analysis found that earlier F500 use (first and second vs. third vs. ≥fourth line; hazard ratio (HR) = 0.80, 95% confidence interval (CI) 0.74-0.86; P < 0.001), longer period from AMBC diagnosis to F500 use (≥3 vs. <3 years; HR 0.60, 95% CI 0.51-0.70; P < 0.001), and no prior palliative chemotherapy administered for unresectable or metastatic breast cancer (no vs. yes; HR 0.69, 95% CI 0.60-0.80; P < 0.001) were associated with significantly longer TTF. Among 691 patients, where information on histologic/nuclear grade was available, a low grade was also associated with a longer TTF, but this finding was not maintained among patients with recurrent breast cancer (N = 558). Among women with recurrent breast cancer, a longer DFI between a patient's initial breast cancer diagnosis and their recurrence was associated with a longer TTF on F500 therapy. CONCLUSIONS: Our study showed that treatment period of F500 was longer when used in earlier-line treatment. For patients on F500, TTF was also longer for patients who had not received prior palliative chemotherapy and for those who had a longer period from their AMBC diagnosis to F500 use.

Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

Lack of contact transmission of recombinant Marek's disease virus type 1 expressing the fusion protein of Newcastle disease virus.

To clarify the level of excretion of a recombinant Marek's disease virus type 1 (rMDV1) that confers good protection in chickens against both Marek's and Newcastle diseases, even in the presence of maternal antibodies, contact transmission tests were conducted. Naïve chickens kept in the same cage or room with chickens inoculated with rMDV1 did not produce antibodies against MDV1 or the fusion protein of Newcastle disease virus. Moreover, the rMDV1 was not isolated from the dander of chickens inoculated with rMDV1. Even under the stressful conditions of forced molting and a high temperature environment, rMDV1 was not isolated from the dander of inoculated birds. The viral DNA, however, was detected from the dander of chickens inoculated with rMDV1 as well as a commercial vaccine. These findings indicate that dander from chickens inoculated with rMDV1 includes viral DNA, but does not contain infectious virus.

Genetic alterations in the human Tcf-4 gene in Japanese patients with sporadic gastrointestinal cancers with microsatellite instability.

Disruption of the APC/beta-catenin/Tcf pathway has been proposed as an important step in the development of cancer. The Tcf-4 transcription factor gene was reported to be one of the targets of microsatellite instability (MSI) in colorectal cancers in with MSI. We carried out a sequencing analysis of the Tcf-4 gene in 41 Japanese patients with gastrointestinal tumors with MSI as well as in cancer cell lines. Three of 21 (14.3%) colorectal tumors with MSI contained a mutant Tcf-4 gene encoding 1-bp deletion in an (A)9 repeat, leading to carboxyl terminal truncation of Tcf-4 protein. No Tcf-4 mutations were detected in 20 gastric tumors with MSI, or in gastric cancer cell lines. Additionally, we found a novel transcript of the Tcf-4 gene which contained a segment of 73 bp in front of the (A)9 repeat of the Tcf-4 coding sequence. Sequencing analysis revealed that the inserted fragment was 60% homologous to that of exon IXA of the Tcf-1 gene. It is of interest that this insertion resulted in truncation of Tcf-4, similar to the 1-bp deletion in the (A)9 repeat. Therefore, in part of the Japanese colorectal tumors with MSI, frameshift mutations in Tcf-4 may be of functional significance. Functional alterations in the Tcf-4 signaling network in gastrointestinal tumorigenesis require further investigations.

Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis.

OBJECTIVE: Natural cytotoxicity, mediated by natural killer (NK) cells, has been believed to play an important role in inhibiting experimental tumor metastasis, and diminished NK cell activities leads to a high incidence of tumor occurrence. Despite convincing evidence from experimental studies, the role of NK cells in the immunological surveillance against cancer in human is poorly defined. METHODS: The present study was based on a retrospective analysis of data on 156 patients with gastric cancer, who were surgically treated in the Department of Surgery II, Kyushu University Hospital from 1993 to 1996. All patients were examined for NK cell activity based on a peripheral blood sampling done preoperatively. RESULTS: Significant association between NK cell activity and clinicopathological parameters including tumor size, lymphatic involvement, vascular involvement, and lymph node metastases was evident. When comparing the two groups according to NK cell activity, tumors with low NK cell activity tend to have lymphatic involvement. The 5-yr survival rates were 94.6% and 72.3% for those with NK cell activity > 25% lysis and < or = 25% lysis, respectively, the value being statistically significant (p < 0.05). The independent risk factors for prognosis examined by logistic regression analysis were lymphatic involvement. NK cell activity, depth of tumor invasion, and lymph node dissection. CONCLUSIONS: These current data showed that NK cell activity may be related to tumor volume and dissemination. Measurement of preoperative NK cell activity may be pertinent for the prognosis of patients with gastric cancer and for follow-up clinical management.

Gastric cancer with high telomerase activity shows rapid development and invasiveness.

Telomerase activity was reported to be activated in most immortal cells and cancers. As the clinical significance of telomerase activity in human gastric cancer is controversial, we investigated this activity using a telomeric repeat amplification protocol. The telomerase activity was tentatively defined by strength of activity as follows: 3+, observed with 0.06 microg of protein; 2+, observed with 0.6 microg of protein; 1+, observed with 6 microg of protein; 0, not observed under these three conditions. Telomerase activity was detected in 35 of 39 (89.7%) gastric cancer specimens. Tumors with high telomerase activities (2+/3+) tended to have a deeper invasion, lymphatic and vascular invasion, lymph node metastasis, liver metastasis, and peritoneal dissemination, as compared to findings in case of low telomerase activities (-/1+). Thus, telomerase activity of gastric cancer tissue may reflect the malignant potential of the tumor and intensive postoperative care might be required for such patients.

Heparanase gene expression and metastatic potential in human gastric cancer.

BACKGROUND: Heparanase has been reported to play an important role in tumor progression and metastasis. We examined the relationship between heparanase mRNA expression and biological factors regarding invasion and metastasis of human gastric cancer. MATERIALS AND METHODS: In 63 human gastric carcinomas, 42 adjacent normal gastric tissues and four gastric cancer cell lines, heparanase mRNA expression was evaluated using reverse transcription PCR (RT-PCR). Total RNA obtained from human peripheral blood (PB) leucocyte and placenta were used as positive controls. The relationship between heparanase mRNA expression and various clinicopathological factors were analyzed. RESULTS: The heparanase mRNA expression evaluated with RT-PCR revealed that 31 out of 63 gastric cancer tissues (49%), 11 out of 42 normal gastric tissues (26%) and 4 gastric cancer cell lines were positive. The positive rate in cancer tissues was significantly higher than that in normal tissues (p<0.05). In the heparanase mRNA-positive cancer tissues, venous invasion was frequent (p<0.05) and the histological differential grade was significantly poorer than in negative cases (p<0.01). CONCLUSION: We propose that heparanase mRNA expression is involved in invasion and development of human gastric cancer and detection of this expression may be a factor related to metastasis and prognosis of such patients.

Differential growth inhibition by 5-fluorouracil in human colorectal carcinoma cell lines.

The effects of 5-fluorouracil (5-FU) on cell growth were investigated using a primary culture of human fibroblasts, MRC-5, and three established human colon cancer cell lines, DLD-1, LoVo and SW620. Detailed flow cytometric analyses revealed differential growth inhibition among these cell lines including three modes of cell growth modulation: (a) loss or accumulation of S phase cells; (b) G2/M block; and (c) G1-S arrest. From analyses on the amount of 5-FU incorporated into cellular RNA and the activity of thymidylate synthase (TS), suppression of TS and depletion of dTTP, a possible consequence of the former, was considered to be the major action of 5-FU in these cells. Differences in the cellular responses to the nucleotide pool imbalance appeared to make the cell growth modulation diverse. Loss of S phase cells and G1-S phase arrest were evident in p53 wild-type cells, MRC-5 and LoVo. Cells proficient in DNA mismatch repair, SW620 and MRC-5, showed marked modulations in S-G2/M progression. These findings suggest that multiple factors, including p53 and DNA mismatch repair, participate in diverse cell growth modulations in cells treated with 5-FU. Cellular resistance to 5-FU correlated well with a loss of modulations in S-G2/M progression, rather than with a defect of G1-S arrest, which suggests the significance of DNA mismatch repair as a factor affecting the sensitivity of cells to 5-FU.

Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma.

BACKGROUND: Hematogenous metastasis occurs when cancer cells released from the primary site enter blood vessels and are transported to distant organs, where they attach and proliferate. Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. METHODS: We analyzed data on 1184 Japanese adult men and women with gastric cancer with respect to the relation between vascular invasion and the potential for tumor angiogenesis and metastasis. All these patients were treated from 1976 to 1995 in the Department of Surgery II, Kyushu University. In 300 patients, the expression of vascular endothelial growth factor (VEGF) and p53 protein in tumor tissues was examined by using an immunohistochemical staining method or Northern blotting or both. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. RESULTS: Vascular invasion was evident in 254 patients (21.5%), and in these patients lymphatic invasion was more frequent and the rate of lymph node metastasis was higher in relation to the extent of vascular invasion. The positive findings were directly related to the depth of invasion and the presence of lymph node and liver metastasis. Tumor invasive and metastatic rates increased in relation to the extent of vascular invasion. Expressions of VEGF and p53 protein were higher and microvessel density was more prominent in tumor tissues in relation to the extent of vascular invasion. A close relation between VEGF and p53 protein expressions was also noted in tumors that showed vascular invasion. The expression of VEGF is one of the independent risk factors for vascular invasion. The postoperative outcome was poorer in patients with vascular invasion in relation to the extent of vascular invasion. CONCLUSIONS: Our findings show that gastric cancers with characteristics of vascular invasion have greater intratumoral angiogenesis and that VEGF and p53 overexpression is associated with intratumoral angiogenesis and metastases to distant organs.

Frequency of microsatellite instability inBreast cancer determined by high-resolution fluorescent microsatellite analysis.

In breast cancer, the rates of positivity for microsatellite instability (MSI), vary greatly in the literature. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 75 patients with sporadic breast cancer. In this system, several devices were prepared to improve reproducibility of polymerase chain reaction products, migration accuracy of electrophoresis, and characteristics of the detection system. Precise and objective analyses of microsatellite alterations are made feasible using HRFMA. Seven of the 75 cases were judged to be positive for MSI, the rate of positivity being 9. 3%. This rate is relatively low compared to the data in the literature. All the microsatellite changes observed in this system can be classified into two types: type A with relatively small changes in microsatellite sequences observed in limited loci and type B with drastic and widely dispersed changes. The former was thought to be connected to abnormal activity in DNA mismatch repair (MMR). Among the 7 cases, 6 (8.0%) had type A alterations, which means that the tumors may have an abnormal MMR activity. Application of precise and objective systems for microsatellite analysis is expected to be clinically useful to detect patients at high risk for cancers.

Diminished expression of ING1 mRNA and the correlation with p53 expression in breast cancers.

p33(ING1) is a novel candidate tumor suppressor and its overexpression induces growth arrest or apoptosis in different cell lines. These functions of p33(ING1) depend largely on the activity of p53, and p53-dependent activation of the transcription from the p21/WAF1 promoter also requires p33(ING1). We examined the expression of ING1 mRNA in breast cancer cell lines and clinical breast cancer tissues, using quantitative RT-PCR and real time TaqMan technology. In breast cancer cell lines, ING1 mRNA was expressed at almost the same level. However, in a comparison between the cancer and matched normal tissues, a significant decrease in ING1 mRNA expression was found in 17 of 24 (70.8%) breast cancer tissues. We also examined the correlation between ING1 mRNA expression and p53 expression. There was a significant decrease of ING1 mRNA in nine of 15 tumors negative for p53 immunostaining, most of which were considered to have wild type p53. In these tumors, p53 may not function in case of a decreased expression of p33(ING1), and the lack of cell cycle regulation may correlate with the carcinogenesis and tumor progression.

Development of an effective polyvalent vaccine against both Marek's and Newcastle diseases based on recombinant Marek's disease virus type 1 in commercial chickens with maternal antibodies.

An earlier report (M. Sakaguchi et al., Vaccine 16:472-479, 1998) showed that recombinant Marek's disease virus type 1 (rMDV1) expressing the fusion (F) protein of Newcastle disease virus (NDV-F) under the control of the simian virus 40 late promoter [rMDV1-US10L(F)] protected specific pathogen-free chickens from NDV challenge, but not commercial chickens with maternal antibodies against NDV and MDV1. In the present study, we constructed an improved polyvalent vaccine based on MDV1 against MDV and NDV in commercial chickens with maternal antibodies. The study can be summarized as follows. (i) We constructed rMDV1 expressing NDV-F under the control of the MDV1 glycoprotein B (gB) promoter [rMDV1-US10P(F)]. (ii) Much less NDV-F protein was expressed in cells infected with rMDV1-US10P(F) than in those infected with rMDV1-US10L(F). (iii) The antibody response against NDV-F and MDV1 antigens of commercial chickens vaccinated with rMDV1-US10P(F) was much stronger and faster than with rMDV1-US10L(F), and a high level of antibody against NDV-F persisted for over 80 weeks postvaccination. (iv) rMDV1-US10P(F) was readily reisolated from the vaccinated chickens, and the recovered viruses were found to express NDV-F. (v) Vaccination of commercial chickens having maternal antibodies to rMDV1-US10P(F) completely protected them from NDV challenge. (vi) rMDV1-US10P(F) offered the same degree of protection against very virulent MDV1 as the parental MDV1 and commercial vaccines. These results indicate that rMDV1-US10P(F) is an effective and stable polyvalent vaccine against both Marek's and Newcastle diseases even in the presence of maternal antibodies.

Overexpression of the heat shock protein HSP70 family and p53 protein and prognosis for patients with gastric cancer.

The cell synthesis of heat shock proteins is increased by a variety of environmental and pathophysiological stressful conditions. The 70-kD heat shock protein family (HSP70 family) which constitutively expresses hsc70 and heat-inducible hsp70 is thought to be involved in protein-protein interactions, including oncogene products. We investigated the HSP70 family expression and biological behavior of gastric cancer, and its relation to p53 overexpression. Expressions of HSP70 and p53 in 164 primary gastric tumors were determined immunohistochemically. Exploratory data were analyzed on a set of 164 primary gastric cancers, and we constructed in prognostic significance of the HSP70 expression level and the relation to p53 overexpression. Expression of HSP70 (hsc70 and hsp70) were detected in nuclei and/or cytoplasm of cancer cells. Western blotting analysis showed that hsc70 and hsp70 were both expressed in five gastric cancer cell lines. Immunohistochemically stained positive cells of HSP70 varied from 0 (very weak) to 100%, in each case. The median level of positive cell rate was 19.0%. A HSP70 expression of over 19.0% was related to the differentiated tissue type of gastric cancer, but not to other clinicopathological factors. There was no difference in survival rates in subjects with higher and lower groups of HSP70 expression. HSP70 expression was also not related to p53 overexpression in the nuclei and p53 overexpression-related poorer prognosis. Our findings show that the expression of HSP70 is not associated with tumor advance-related characteristics or with the prognosis of gastric cancer. Measurements of HSP70 expression do not appear to be a useful prognostic marker.

Postoperative outcome and sites of recurrence in patients following curative resection of gastric cancer.

BACKGROUND: Recurrence occurs in a variety of forms and in different organs after 'curative resection' of gastric cancer. This study investigated the postoperative prognosis for each type of recurrence. METHODS: From 1969 to 1988, 939 patients with gastric cancer underwent curative resection; data on 130 of 207 patients who died with recurrence were analysed. Attention was focused on the site of recurrence and the postoperative outcome. RESULTS: Haematogenous recurrence was evident in 54 per cent (70 of 130 patients), peritoneal recurrence in 43 per cent (56 of 130), lymph node recurrence in 12 per cent (16 of 130) and local recurrence in 22 per cent (29 of 130). Thirty-three patients (25 per cent) had recurrences at multiple sites. Peritoneal and local recurrences were related to infiltrative growth, in contrast to haematogenous and lymphatic recurrences. There were no statistical differences in survival time among each type of recurrence and survival was not related to the number of sites of recurrence. Survival did not depend on factors of sex, age, tumour location, tumour size, depth of invasion, tissue differentiation, histological growth pattern, lymphatic and vascular involvement, lymph node metastasis and extent of lymph node dissection. CONCLUSION: The clinicopathological characteristics of gastric cancer determine the type of recurrence, although the clinical outcome is the same for each type of tumour and is not related to the number of sites of recurrence.

Application of quantitative RT-PCR using "TaqMan" technology to evaluate the expression of CK 18 mRNA in various cell lines.

Reverse transcriptase polymerase chain reaction (RT-PCR) is often used for sensitive detection of micrometastasis in peripheral blood, lymph nodes and bone marrow. While the utility of this method has been documented, it also has limitations in the detection of micrometastasis. The mRNA of target genes can be detected in healthy donors or in samples used for negative control, therefore the non-quantitativeness of conventional RT-PCR has been called into question. We analyzed the expression level of cytokeratin (CK) 18 mRNA in established esophageal and gastrointestinal carcinoma cell lines and non-epithelial cells, using quantitative RT-PCR, based on real time 'TaqMan TM' technology. CK 18 mRNA is more highly expressed in carcinoma cells than in non-epithelial cells. However, the expression level in non-epithelial cells was easily detected using conventional RT-PCR and agarose gel electrophoresis. In an analysis of CK 18 mRNA expression in peripheral venous blood in 13 healthy volunteers, we found that CK 18 mRNA was much less expressed than in cancer cell lines. However, the expression in all samples was at a level which was also detected using conventional RT-PCR. It would thus seem that not only qualitative, but also quantitative analysis, of the target mRNA is important to detect micrometastasis. Quantitative RT-PCR methods will make comparisons of the possible differences in expression levels of the target gene. For clinical applications, much further study is needed.

Recurrences and relation to tumor growth potential and local immune response in node-negative advanced gastric cancer.

Biological characteristics and the prognosis for subjects with node-negative advanced gastric cancer have been given little attention in related literature. We analyzed data on 112 patients with serosally invasive gastric cancer who were lymph node metastasis-negative; all had been surgically treated in the Department of Surgery II, Kyushu University Hospital, between 1970 and 1992. Recurrences and relation to the growth potential of the tumor and local immune response were examined. Thirty patients died with a recurrence of the gastric cancer, and in these patients, the tumor was larger, the whole stomach was more frequently involved and infiltrative growth was more common, compared to findings in patients who were recurrence-free. Peritoneal recurrence was evident in half the number of patients and the 5-year survival rate was 74. 5%. Tumor growth potential was evaluated, based on the level of proliferating cell nuclear antigen (PCNA) of the primary tumor and on dendritic cell infiltration into the tumor, determined as a level of local immune function of the host. Higher growth potential and lower immune levels were more frequent in patients with recurrences. Multivariate analysis revealed that tumor size and PCNA labeling index were significant prognostic factors for node-negative gastric cancers. In a subset of advanced gastric cancers, there was no apparent distinct lymph node metastasis and the prognosis was better. However, cancer cells with a higher growth potential and a lower immune response in the host can biologically amplify and mainly infiltrate the gastric wall, extend to the serosa and disseminate transserosally into the peritoneum.

Prognostic value of p53 protein expression for patients with gastric cancer--a multivariate analysis.

Mutations in the p53 gene, one of the most common genetic alterations in human cancer, are implicated in tumorigenesis and tumour progression. Although p53 protein expression appears to be correlated to prognosis in patients with malignancy, its prognostic role in gastric cancer has remained controversial. We examined the clinical significance of p53 overexpression in 427 patients with gastric cancer, using multivariate analysis. Tumour sections of gastric cancer tissues from these 427 Japanese patients were stained immunohistochemically with monoclonal antibody PAb1801. The presence of p53 expression was statistically compared with clinicopathological features and post-operative survival, using univariate and multivariate analyses. p53 expression was detected in 38.6% (165 out of 427) of these gastric cancers and immunoreactivity was not observed in normal mucosa adjacent to the tumour. A higher rate of p53 detection was observed among large tumours and in those with a prominent depth of invasion, lymphatic and vascular invasion and lymph node involvement. Prognosis was significantly worse for patients with p53-positive-staining tumours. The 5-year survival rate was 62.5% for patients with p53-negative tumours and 43.3% for those with positive malignancies. p53 expression was a significant prognostic factor for node-positive gastric cancers in subjects undergoing treatment with curative resection, as assessed by Cox regression analysis. Thus, the expression of p53 was closely related to the potential for tumour advance and a poorer post-operative prognosis for patients with gastric cancer.