Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.

TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 µmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 µmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors.

Histophilus somni Stimulates Expression of Antiviral Proteins and Inhibits BRSV Replication in Bovine Respiratory Epithelial Cells.

Our previous studies showed that bovine respiratory syncytial virus (BRSV) followed by Histophilus somni causes more severe bovine respiratory disease and a more permeable alveolar barrier in vitro than either agent alone. However, microarray analysis revealed the treatment of bovine alveolar type 2 (BAT2) epithelial cells with H. somni concentrated culture supernatant (CCS) stimulated up-regulation of four antiviral protein genes as compared with BRSV infection or dual treatment. This suggested that inhibition of viral infection, rather than synergy, may occur if the bacterial infection occurred before the viral infection. Viperin (or radical S-adenosyl methionine domain containing 2--RSAD2) and ISG15 (IFN-stimulated gene 15--ubiquitin-like modifier) were most up-regulated. CCS dose and time course for up-regulation of viperin protein levels were determined in treated bovine turbinate (BT) upper respiratory cells and BAT2 lower respiratory cells by Western blotting. Treatment of BAT2 cells with H. somni culture supernatant before BRSV infection dramatically reduced viral replication as determined by qRT PCR, supporting the hypothesis that the bacterial infection may inhibit viral infection. Studies of the role of the two known H. somni cytotoxins showed that viperin protein expression was induced by endotoxin (lipooligosaccharide) but not by IbpA, which mediates alveolar permeability and H. somni invasion. A naturally occurring IbpA negative asymptomatic carrier strain of H. somni (129Pt) does not cause BAT2 cell retraction or permeability of alveolar cell monolayers, so lacks virulence in vitro. To investigate initial steps of pathogenesis, we showed that strain 129Pt attached to BT cells and induced a strong viperin response in vitro. Thus colonization of the bovine upper respiratory tract with an asymptomatic carrier strain lacking virulence may decrease viral infection and the subsequent enhancement of bacterial respiratory infection in vivo.

Successful treatment of severe refractory lupus hepatitis with mycophenolate mofetil.

Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis.

Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.

Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.

p27 deregulation by Skp2 overexpression induced by the JAK2V617 mutation.

Janus kinase 2 (JAK2) V617F mutation has been regarded as the major cause of myeloproliferative disorders (MPD). However, the mechanisms of abnormal cell growth by JAK2V617F have not been elucidated. In this study, cell cycle regulatory protein expression was analyzed using JAK2V617F-Ba/F3 and mock-Ba/F3. JAK2V617F-Ba/F3, but not mock-Ba/F3, showed IL-3 independent cell growth and constitutive STATs activation. Deregulation of p27(Kip1), the cell cycle regulator at the G1 to S transition, was observed in JAK2V617F-Ba/F3 but not in mock-control. p27(Kip1) deregulation was not due to p27(Kip1) mRNA level but due to high Skp2 expression, a subunit of ubiquitin E3 ligase, through the STAT binding in the Skp2 promoter. Like JAK2V617F overexpression, constitutively active STAT5 or STAT3 induced aberrant p27(Kip1) expression of Ba/F3 cells. Similar findings were observed in BCR/ABL-transfected Ba/F3. Our results elucidate the regulatory mechanism by which JAK2V617F modulates Skp2 gene expression through the STAT transcription factors.

Platelet-derived endothelial cell growth factor expression is an independent prognostic factor in colorectal cancer patients after curative surgery.

AIMS: Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor that undergoes increased expression in colorectal carcinomas, but its prognostic value is a topic of debate. The aim of this study is to clarify the prognostic value of PD-ECGF expression in colorectal carcinomas. METHODS: PD-ECGF expression was measured by enzyme-linked immunosorbent assay in frozen materials from 134 colorectal cancer patients who had received curative resections. Patients were divided into high expression and low expression groups based upon selected cut-off value. Correlations among PD-ECGF expression, clinicopathologic features, and disease-free interval were studied by univariate and multivariate analysis. To evaluate the origin of PD-ECGF, serial sections of the 134 tumours were stained for PD-ECGF and CD68. RESULTS: PD-ECGF expression in the normal mucosa was 34.4+/-15.5 (Units/mg protein) and the cut-off value was 65.4 (mean+2SD). There were no significant correlations between clinicopathological features and PD-ECGF expression. The disease-free interval for the high PD-ECGF expression group was significantly longer than that of the low expression group (P=0.05). A multivariate Cox's regression analysis revealed that high PD-ECGF expression is an independent factor for better outcome. In immunohistochemical study, almost all tumour cells were negative for PD-ECGF, but stromal macrophages were predominantly positive for PD-ECGF. CONCLUSIONS: The PD-ECGF expression originated from stromal macrophages was a predictor for favorable outcome after curative resections for colorectal cancer.

Chromosomal imbalances associated with acquired resistance to fluoropyrimidines in human colorectal cancer cells.

The chromosomal aberrations underlying the development of resistance to fluoropyrimidines have not yet been identified. To characterise the genomic changes that induce the development of resistance to fluoropyrimidines, we used comparative genomic hybridisation (CGH) to analyse and compare the parent DLD-1 human colorectal cancer cell line and two cell lines, DLD-1/5-FU and DLD-1/FdUrd, which were resistant to 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), respectively. Both resistant cell lines showed a genetic aberration derived from the parental cell line DLD-1. Losses of 3p and 3q were also detected as additional genetic changes in the two resistant cell lines. Both resistant cell lines showed decreased orotate phosphoribosyltransferase (OPRT) activity, which is associated with the activity of the uridine monophosphate (UMP) synthase gene (3q13). These results suggested that the loss of 3q might be a genetic change responsible for the decreased OPRT activity and fluoropyrimidine cytotoxic response in cancer cells. Amplification of 18p11.2-p11.3 containing the thymidine synthase (TS) gene (18p11.32) was observed only in the DLD-1/FdUrd-resistant cell line, which overexpresses TS. These findings suggested that 18p amplification represents a genetic change associated with the overexpression of the TS protein. Our results indicate that chromosomal aberrations identified by CGH could explain, at least in part, acquired fluoropyrimidine resistance.

Prognostic significance of the null genotype of glutathione S-transferase-T1 in patients with acute myeloid leukemia: increased early death after chemotherapy.

We investigated the prognostic significance of genetic polymorphism in glutathione-S transferase mu 1 (GSTM1), glutathione-S transferase theta 1 (GSTT1), NAD(P)H:quinone oxidoreductase (NQO1) and myeloperoxidase (MPO), the products of which are associated with drug metabolism as well as with detoxication, in 193 patients with de novo acute myeloid leukemia (AML) other than M3. Of the patients, 64.2% were either homozygous or heterozygous for GSTT1 (GSTT1(+)), while 35.8% showed homozygous deletions of GSTT1 (GSTT1(-)). The GSTT1(-) group had a worse prognosis than the GSTT1(+) group (P = 0.04), whereas other genotypes did not affect the outcome. Multivariate analysis revealed that GSTT1(-) was an independent prognostic factor for overall survival (relative risk: 1.53; P = 0.026) but not for disease-free survival of 140 patients who achieved complete remission (CR). The rate of early death after the initiation of chemotherapy was higher in the GSTT1(-) group than the GSTT1(+) group (within 45 days after initial chemotherapy, P = 0.073; within 120 days, P = 0.028), whereas CR rates and relapse frequencies were similar. The null genotype of GSTT1 might be associated with increased toxicity after chemotherapy.

Effect of 6-hydroxydopamine on host resistance against Listeria monocytogenes infection.

Recent studies have shown that immunocompetent cells bear receptors of neuropeptides and neurotransmitters and that these ligands play roles in the immune response. In this study, the role of the sympathetic nervous system in host resistance against Listeria monocytogenes infection was investigated in mice pretreated with 6-hydroxydopamine (6-OHDA), which destroys sympathetic nerve termini. The norepinephrine contents of the plasma and spleens were significantly lower in 6-OHDA-treated mice than in vehicle-treated mice. The 50% lethal dose of L. monocytogenes was about 20 times higher for 6-OHDA-treated mice than for vehicle-treated mice. Chemical sympathectomy by 6-OHDA upregulated interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) production in enriched dendritic cell cultures and gamma interferon (IFN-gamma) and TNF-alpha production in spleen cell cultures, whereas chemical sympathectomy had no apparent effect on phagocytic activities, listericidal activities, and nitric oxide production in peritoneal exudate cells and splenic macrophages. Augmentation of host resistance against L. monocytogenes infection by 6-OHDA was abrogated in IFN-gamma(-/-) or TNF-alpha(-/-) mice, suggesting that upregulation of IFN-gamma, IL-12, and TNF-alpha production may be involved in 6-OHDA-mediated augmentation of antilisterial resistance. Furthermore, adoptive transfer of spleen cells immune to L. monocytogenes from 6-OHDA-treated mice resulted in untreated naive recipients that had a high level of resistance against L. monocytogenes infection. These results suggest that the sympathetic nervous system may modulate host resistance against L. monocytogenes infection through regulation of production of IFN-gamma, IL-12, and TNF-alpha, which are critical in antilisterial resistance.

Instability of chromosome 17 and the p53 locus in non-familial colorectal cancer with multiple primary malignancies.

Recently, two different mechanisms of genetic instability have been demonstrated in the carcinogenesis of colorectal cancer. Microsatellite instability is an important genetic event for carcinogenesis in hereditary non-polyposis colorectal cancer, proximal colon cancer, and multiple colorectal carcinoma. To examine the association among chromosomal instability and multiple primary malignancies (MPM) in colorectal cancer, fluorescence in situ hybridization using a chromosome 17-specific probe, p53 cosmid probe, and/or an alpha satellite DNA probe was performed in 184 patients with colorectal cancer. The proportion of aneusomy 17 in MPM was significantly higher than that of single cancers (SC) (46.1+/-8.0% and 39.0+/-10.3%, respectively; p<0.01). Multiple numerical aberrations of chromosome 17 in MPM occurred more often than those of SC (64.3% and 22.9%, respectively; p<0.01). The mean frequency of p53 deletion was also higher in MPM (70.4+/-16.7%) compared with SC (53.4+/-18.1%, p<0.05). The frequency of chromosome 17 translocation was significantly greater in tumors with MPM (4/6; 67%) than in SC (3/23; 13%, p<0.05). The frequency of p53 locus translocation was also significantly greater in tumors with MPM (4/6; 67%) than in SC (0/23; 0%, p<0.01). These results suggested that numerical and structural aberrations of chromosome 17 and the p53 locus are important genetic events associated with carcinogenesis in non-familial colorectal cancer with MPM.

Completion pneumonectomy for recurrent or second primary lung cancer.

OBJECTIVE: We studied 8 patients undergoing completion pneumonectomy for recurrent or second primary lung cancer. METHODS: Subjects were men who averaged 62 years of age. Of these 6 had p-stage I, and 2 p-stage II disease at initial operation. At the second operation, we diagnosed 3 with second primary lung cancer and 5 with recurrent lung cancer. We predicted postoperative pulmonary function by calculating the predicted forced expiratory volume in 1.0 second (FEV1.0) from residual numbers of subsegments after completion pneumonectomy. All predicted FEV1.0 in our 8 cases ranged from 544 to 926 (773 +/- 144) ml/m2. RESULTS: Six patients experienced postoperative complications and morbidity was 75%. One patient undergoing completion sleeve pneumonectomy after radiation therapy for local carina recurrence died on 7th postoperative day due to anastomotic dehiscence and pneumonia. Overall operative mortality was 12.5% (1/8). Four remain alive and actuarial 5-year survival was 37.5%. CONCLUSIONS: Careful consideration is needed in determining operative indications for completion pneumonectomy for patients after radiation therapy. Patients with recurrent squamous cell carcinoma who have p-stage I disease at initial operation and those with second primary lung cancer and p-stage I or II disease can expect relatively a long-term survival, and we concluded that completion pneumonectomy could be conducted in these cases with a satisfactory prognosis.

Evaluation of metastatic potential of gastric tumors by staining for proliferating cell nuclear antigen and chromosome 17 numerical aberrations.

BACKGROUND: Aberrations in chromosome 17 are important in carcinogenesis. We recently reported that numerical aberrations in chromosome 17 were associated with tumor progression in gastric cancer. The aim of this study was to determine the biological characteristics of gastric tumor cells with chromosome 17 numerical aberrations. METHODS: Gastric tumor sections (n = 105) and metastatic lymph nodes (n = 16) were stained simultaneously for PCNA (proliferating cell nuclear antigen) and chromosome 17 centromere. Cancers were classified as follows: Group 1: PCNA(+) and numerical chromosomal aberration(+); Group 2: PCNA(-) and numerical chromosomal aberration(+); Group 3: PCNA(+) and numerical chromosomal aberration(-); and Group 4: PCNA(-) and numerical chromosomal aberration(-). RESULTS: The frequency of Group 1 cells correlated with lymphatic invasion (P < .0001), lymph node metastasis (P < .0001), and venous invasion (P < .01). The frequency of these cells in gastric lesions was lower than in metastatic lymph nodes (P < .01). Logistic regression analysis identified the depth of invasion followed by the frequency of Group 1 cells were two of the most significant independent factors that could predict lymph node metastasis and lymphatic invasion. CONCLUSIONS: The frequency of gastric tumor cells positive for PCNA and chromosome 17 numerical aberrations may be an indicator of the metastatic potential of gastric cancers.

Organ infectivity of Toxoplasma gondii in interferon-gamma knockout mice.

To determine the influence of interferon (IFN)-gamma on the organ infectivity and on the genetic susceptibility of susceptible (C57BL/6) and resistant (BALB/c) strains after peroral infection with cysts of Toxoplasma gondii. IFN-gamma knockout (KO) mice in C57BL/6 and BALB/c backgrounds were utilized. The kinetics of the changes in T. gondii abundance were evaluated with a quantitative competitive polymerase chain reaction assay in various organs at different times after peroral infection. In IFN-gamma KO mice, a T. gondii-specific gene, SAG1, was detected in all organs examined, and the protozoan proliferated much more actively than in wild-type mice. The abundance of T. gondii was much higher in mesenteric lymph nodes and the heart than in other organs. In contrast, in the nervous system organs and kidneys, only a weakly detectable reaction was observed. Toxoplasma gondii grew at a more rapid rate in the organs of IFN-gamma KO C57BL/6 mice than in the organs of IFN-gamma KO BALB/c mice during the course of infection. Destruction of the IFN-gamma gene showed remarkable effects on the infectivity in both susceptible and resistant mice.

Comparison of the expression of ABH/Lewis-related antigens in polypoid and non-polypoid growth types of colorectal carcinoma.

BACKGROUND AND AIMS: Colorectal tumors can be classified based on their growth pattern into the polypoid growth-type (PG-type) and non-polypoid growth-type (NPG-type). To ascertain whether there is any relationship between the expression of particular blood group-related antigens (A, B, H, Lewis (Le)a, sialyl Le(a), Le(x), sialyl Le(x)) in a colorectal tumor, and a tumor having polypoid or non-polypoid growth, we examined 78 PG-type and NPG-type colorectal cancers. METHODS: Fourteen PG-type and 64 NPG-type colorectal carcinomas were subjected to immunohistochemical analyses by using monoclonal antibodies against A, B, H, Le(a), sialyl Le(a), Le(x) and sialyl Le(x). RESULTS: The patients with NPG-type carcinomas had a significantly younger age of onset, significantly smaller maximal tumor diameter, significantly higher rate of lymph node metastasis and significantly worse prognosis than those with PG-type carcinomas. Among the 32 tumors of patients with blood type A or AB, isoantigen A was expressed in a significantly larger percentage of NPG-type carcinomas than PG-type carcinomas (95.8 vs 62.5%, respectively; P=0.014). Among all 78 tumors, sialyl Le(x) antigen was expressed in a significantly larger percentage of NPG-type than PG-type carcinomas (90.6 vs 64.3%, respectively; P=0.010). Multivariate analysis using the logistic regression model revealed that isoantigen A and sialyl Le(x) expression were independent predictive risk factors for the development of NPG-type colorectal carcinoma. CONCLUSIONS: These data suggest that the expression of isoantigen A and sialyl Le(x) in a colorectal carcinoma partially determines whether the tumor will have polypoid or non-polypoid growth.

Hematological characteristics of rats spontaneously developing eosinophilia.

Hematological and genetic characteristics of newly found eosinophilic rats were studied. Hematologically, high blood eosinophil counts started at 6 weeks of age. Almost all 10-week-old rats had eosinophilia with individual counts above 500/microliter and 5 to 100 times the normal level. Proliferating eosinophils had normal morphology. An increase in lymphocyte counts was observed at 5 weeks of age, one week earlier than the onset of eosinophilosis. In bone marrow, proliferation of eosinophils was also observed at 8 weeks of age and thereafter progressed, suggesting a role in the pathogenesis of eosinophilia in this rat. The results of genetic cross experiments revealed the disease to be hereditary. The spontaneously eosinophilic rat therefore warrants attention as a model for studying the underlying mechanisms of human and animal eosinophilia.

Expression of Lewis(a), sialyl Lewis(a), Lewis(x) and sialyl Lewis(x) antigens as prognostic factors in patients with colorectal cancer.

BACKGROUND: Altered expression of blood group-related carbohydrate antigens such as sialyl Lewis (Le)(x) antigen in tumours is associated with tumour progression behaviour and subsequent prognosis. However, the prognostic value of the expression of Le-related antigens in colorectal tumours remains unclear. PURPOSE: To clarify the prognostic value of Le(a), sialyl Le(a), Le(x) and sialyl Le(x) expression in colorectal carcinomas as prognostic factors after surgery. PATIENTS AND METHODS: Colorectal carcinoma samples from 101 patients with primary colorectal carcinoma who underwent surgical resection were subject to immunohistochemical analyses for Lea, sialyl Lea, Lex and sialyl Le(x) expression with the respective monoclonal antibodies. RESULTS: Le(a), sialyl Le(a), Le(x) and sialyl Le(x) were expressed in 69 (68.3%), 73 (72.3%), 66 (65.4%) and 76 (75.3%) carcinomas, respectively. The patients with sialyl Lex-expressing tumours had more advanced cancer than those with nonsialyl Lex-expressing tumours (P=0.0029). The survival time after surgery of patients with Le(x)- or sialyl Le(x)-expressing tumours was significantly shorter than the survival time of those with non-Le(x)- or nonsialyl Le(x)-expressing tumours, respectively (P=0.023 and P=0. 0001, respectively). Cox's regression analysis revealed that Le(x) and sialyl Le(x) expression, separate from stage and histological type, were prognostic variables for patient survival (hazard ratio [HR] for sialyl Le(x)-positive expression to sialyl L(x)-negative expression 2.90; HR for Le(x)-positive expression to Le(x)-negative expression 12.76 in stage I/IV, 0.63 in stage II and 1.69 in stage III). CONCLUSIONS: Le(x) expression and sialyl Le(x) expression in colorectal carcinomas are each associated with poor prognosis. These variables should be considered in the design of future trials.

Difference in prognostic value between sialyl Lewis(a) and sialyl lewis(x) antigens in blood samples obtained from the drainage veins of the colorectal tumors.

Subtraction values, (i.e. values obtained by subtracting the serum titer of sialyl Lewis(a) (CA19-9) and sialyl Lewis(x) (SLX) antigens in peripheral venous blood from the serum titer of the same antigen in the tumor's drainage venous blood) were determined in order to clarify whether or not such values for these specific antigens (d-CA19-9 and d-SLX) are prognostic factors after resection for colorectal cancer. The blood samples were obtained from 144 colorectal cancer patients during surgical excisions of the tumors. Univariate and multivariate analyses revealed that d-SLX level was an independent prognostic factor, separate from stage, while d-CA19-9 level did not have any additional prognostic value. In conclusion, a high d-SLX level is a predictor of poor outcome after surgery.

The relationship between circulating sialyl Tn antigen and polypoid or nonpolypoid growth characteristics in colorectal cancer.

Recent studies delineated two different patterns of tumor growth in colorectal carcinoma characterized as polypoid and nonpolypoid (PG-type and NPG-type, respectively). We quantified serum sialyl Lewis (Le)a (CA19-9), sialyl Lex (SLX), sialyl Tn (STN), and carcinoembryonic antigen (CEA) in 269 colorectal cancer patients to establish whether their levels correlated with any biological or clinical differences between PG-type and NPG-type cancer. Patients were divided into high and low antigen groups (higher or lower than a selected diagnostic-based cut-off value) and compared. Statistical testing was by univariate and multivariate (logistic regression) analyses. Forty-seven (17.5%) patients with PG-type and 222 (82.5%) with NPG-type cancer were studied. In contrast to NPG-type, the characteristics of the PG-type cancers included a low rate of lymph node metastasis and a high serum STN level. In contrast to a low STN level, a high STN level was independently related to the presence of distant metastasis in patients with PG-type cancer, and also to the presence of distant metastasis and large-sized tumor in patients with NPG-type cancer. These data suggest that differences in STN levels in the serum of patients with PG-type or NPG-type colorectal carcinomas may be at least partly responsible for different tumor progression behavior.

Different expression of sialyl Tn antigen between polypoid and nonpolypoid growth types of advanced colorectal carcinoma.

Colorectal tumors can be classified based on their growth pattern into the polypoid growth type (PG-type) and nonpolypoid growth type (NPG-type). We examined sialyl Tn antigen expression in advanced colorectal carcinomas that were classified as PG-type and NPG-type cancers in order to ascertain whether or not such expression correlates with other biologically and clinically important differences. A total of 94 advanced colorectal carcinomas were examined for sialyl Tn antigen expression, which was immunohistochemically detected by the monoclonal antibody TKH2. Univariate and multivariate analyses using logistic regression models were performed. Forty carcinomas (42.6%) were negative and 54 (57.5%) were positive for sialyl Tn antigen. Eighteen carcinomas (19.2%) were of PG type and 76 (80.8%) of NPG type. NPG-type cancers had a higher proportion of positive lymph node metastasis than PG-type cancers. Furthermore, sialyl Tn antigen was less often detected in NPG-type cancers (39 of 76; 51.3%) than in PG-type cancers (15 of 18; 83.3%; p = 0.0167). Multivariate analysis showed that two variables, lymph node metastasis and sialyl Tn antigen expression in carcinoma, were independently related to tumor growth patterns, that is NPG type and PG type. These data suggest that the difference in sialyl Tn antigen expression between two kinds of tumor growth patterns of advanced colorectal carcinomas, PG type and NPG type, may reflect different biological behaviors during tumor progression.

Expression of blood group antigens A, B and H in carcinoma tissue correlates with a poor prognosis for colorectal cancer patients.

The deletion of blood group ABH isoantigens on tumor tissues has been reported to be an adverse prognostic marker for patients with various solid tumors. In the present study, we evaluated the prognostic value of altered expression of ABH isoantigens in colorectal carcinomas. Using monoclonal antibodies, the expression of A, B, and H antigens was assessed by immunohistochemistry on paraffin-embedded carcinoma samples from 82 patients who had undergone surgery for colorectal cancer. ABH isoantigens were found to be deleted in 36 carcinomas (43.9%) and expressed in 46 (56.1%). Univariate and multivariate analysis using a logistic regression model revealed that N factor (lymph node metastasis) and blood group type were independently related to the expression of ABH isoantigens. In contrast to previous reports on other cancers, patients whose colorectal carcinomas express ABH isoantigens had a poorer prognosis than those whose carcinomas showed deletion of ABH isoantigens (P = 0.0008). The expression of ABH isoantigens was an independent prognostic variable, in addition to T (depth of tumor invasion), N, and M (distant metastasis) factors, as shown by means of Cox regression analysis. In conclusion, the expression of ABH isoantigens in carcinoma tissue is an important poor prognostic factor in patients with colorectal cancer. This variable needs to be considered in the design of future trials of therapy.