PKC delta mediates ionizing radiation-induced activation of c-Jun NH(2)-terminal kinase through MKK7 in human thyroid cells.

The thyroid gland is one of the most sensitive organs in ionizing radiation (IR)-induced carcinogenesis. To determine, therefore, the specific cascade of IR-induced signal transduction in human thyroid cells, we investigated the functional role of protein kinase C (PKC), especially its interlocking activation of c-Jun NH(2)-terminal kinase (JNK) pathway. In the present study, using adenovirus expression vectors for diverse dominant-negative (DN) types of PKC isoforms (alpha, beta2, delta, epsilon and zeta) expressed in primary cultured human thyroid cells, only DN/PKC delta suppressed IR-induced JNK activation. In addition, Rottlerin, a PKC delta specific inhibitor, inhibited IR-induced JNK activation. IR-induced activation of transcription factor AP-1, downstream target of JNK, was also attenuated by DN/PKC delta. To examine the involvement of upstream kinases of JNK, we performed immune-complex kinase assays of mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. IR activated MKK7 but not MKK4, and this activation was inhibited by Rottlerin. Furthermore, IR-induced JNK activation was suppressed by overexpression of kinase-deficient MKK7. Our results indicate that IR selectively activates the cascade of PKC delta-MKK7-JNK-AP-1 in human thyroid cells, suggesting a not apoptotic but radio-resistant role of PKC delta in human thyroid cells following IR.

Differences in 20q13.2 copy number between colorectal cancers with and without liver metastasis.

Frequent gains of 20q have been identified recently in many neoplasias, including breast, bladder, ovarian, pancreatic, and colon cancers. A high level of 20q13.2 amplification is associated with poor prognosis in breast cancer. We investigated the copy number of the 20q13.2 region including the ZNF217 oncogene in 17 nonmetastatic colorectal cancers (CRCs), 18 primary CRC tumors with liver metastasis, and 18 metastatic lesions by two-color fluorescence in situ hybridization to evaluate the significance of an increased copy number of 20q13.2 in CRC, especially in those cases with liver metastasis. The frequency of increased relative copy number of the 20q13.2 region was higher in primary and liver metastatic lesions of CRC than in CRC lesions without liver metastasis. In particular, a high-level increase (>3.0-fold) in the relative copy number of 20q13.2 was observed in 2 of 18 (11%) primary CRC lesions with liver metastasis, 7 of 18 (39%) liver metastatic lesions, and in none of the cases of primary CRC without liver metastasis. The absolute and relative copy number of chromosome 20q13.2 was higher in CRCs with metastasis than in CRCs without metastasis. The percentage of cells with high-level 20q13.2 amplification was also higher in both lesions with metastasis per specimen than without metastasis. Our results suggest that the level of 20q13.2 amplification correlates with the metastatic potential and tumor progression of CRC. The results also suggest that 20q13.2 amplification with ZNF217 is associated with increased metastatic potential.

Clinical and pathological significance of numerical aberrations of chromosomes 11 and 17 in colorectal neoplasms.

Numerical chromosome aberrations by interphase cytogenetic analysis have been reported in a few samples of colorectal neoplasms. No studies have defined a distinct relationship between these aberrations and clinicopathological features. To investigate the chromosome aberrations as a marker of invasiveness or prognosis, we conducted an interphase cytogenetic study using fluorescence in situ hybridization and examined 142 colorectal neoplasms consisting of 15 adenomas and 127 cancers. The target chromosomes were chromosomes 11 and 17. We also evaluated the nuclear DNA content as detected by flow cytometry, analyzed the relationship between the frequency of aneusomy and clinicopathological features, and examined the survival rate in these patients. The loss of chromosome 11 was observed in 31% of adenomas, whereas in cancers DNA aneuploidy was observed in 63% of cases, a gain of chromosome 17 was observed in 63% of cases, and a gain of chromosome 11 was observed in 42% of cases. Numerical chromosome aberrations in diploid DNA were also observed. Increased depth of invasion (>/=T3) and advanced Dukes' stage (>/=B) of malignant tumors were associated with a higher frequency of a gain of chromosome 11 (P < 0.01 and P < 0.05, respectively). Increased depth of invasion (>/=T2) in cancers was associated with a higher frequency of a gain of chromosome 17 (P < 0.05). Multivariate analysis of postoperative survival showed that a loss or gain of chromosome 11 was independently associated with a poor prognosis (P < 0.05). Numerical chromosome aberrations appear prior to the alteration of nuclear DNA content as detected by flow cytometry and influence the progression of colorectal cancers. Aneusomy of chromosome 11 is associated with poor postoperative prognosis of primary colorectal cancers.

Therapeutic usefulness of wild-type p53 gene introduction in a p53-null anaplastic thyroid carcinoma cell line.

Anaplastic thyroid carcinomas very often harbor the mutations in the tumor suppressor gene p53. We have previously shown that wild-type (wt) p53 gene introduction led to cell growth arrest, but not apoptosis, in p53-null anaplastic thyroid carcinoma cells. The present studies were designed to evaluate other therapeutic effects of wt-p53 gene introduction on p53-null thyroid carcinoma cells, as chemo- and radiosensitization and inhibition of angiogenesis have also been described recently as additional therapeutic advantages of wt-p53 gene introduction in tumor cells with p53 mutations. A p53-null anaplastic thyroid carcinoma cell line, FRO, and a FRO subline stably expressing a temperature-sensitive (ts) mutant of p53 (p53Val138), tsFRO, were used. ts-p53 functions as mutant and wt at nonpermissive (37 C) and permissive (32 C) temperatures, respectively. tsFRO showed a prolonged cell doubling time compared to parental FRO when cultured at 32 C, but the cell growth rate was similar between FRO and tsFRO at 37 C. The cytotoxic and clonogenic assays demonstrated that although the sensitivity to three different anticancer agents (cisplatin, 5-fluorocytosine, and doxorubicin) was unaltered, radiosensitivity was enhanced in tsFRO compared to FRO at 32 C. Unexpectedly, in studies on angiogenesis, expression levels of vascular endothelial growth factor (an angiogenic factor) messenger ribonucleic acid were similar between FRO and tsFRO, and thrombospondin-1 (an antiangiogenic factor) messenger ribonucleic acid and protein levels were about 2.5-fold lower in tsFRO than FRO at 32 C, although any difference could not be detected in their ability to inhibit in vitro angiogenesis with the culture medium conditioned by tsFRO and FRO at 32 C. These results suggest that p53-defective thyroid carcinomas may benefit from the combination of p53 gene therapy and radiotherapy. However, further study will be necessary to clarify the pathological significance of thrombospondin-1 in angiogenesis and thyroid tumor growth.

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.

Twenty-four-hour canine lung preservation using UW solution.

The left lungs of 14 mongrel dogs were isolated, preserved, and then reperfused for 120 min. Three groups of lungs were investigated: group 1, nonpreserved lungs (control n = 5); group 2, lungs were flushed with UW solution and cold-stored (4-6 degrees C) in the same flush solution for 24 hr (n = 4); and group 3, lungs flushed and cold-stored with modified Euro-Collins' solution for 24 hr (n = 5). Airway pressure (AWP), static lung compliance (Cst), and pulmonary vascular resistance (PVR) 120 min after reperfusion were significantly higher in group 3 compared with the lungs in group 1 and group 2. AWP was 18.7 +/- 3.9 in group 1, 21.1 +/- 3.8 in group 2, and 33.8 +/- 9.2 ml/cmH2O (mean +/- SD) in group 3 (P less than 0.05). Cst was 14.0 +/- 3.5, 10.8 +/- 1.5, and 6.2 +/- 1.2 ml/cmH2O, respectively (P less than 0.01). Pulmonary vascular resistance was 125 +/- 16, 120 +/- 42, and 410 +/- 108 mmHg/L/min (P less than 0.05). We conclude that UW solution is useful for hypothermic canine lung preservation.

Twenty-four-hour preservation in gamma-hydroxybutyrate improves lung function in a canine single-lung allotransplantation.

BACKGROUND: We investigated the effect of gamma-hydroxybutyrate (GHB) when added to the low-potassium University of Wisconsin (LPUW) solution used for the preservation of canine lung for 24 hr. We also examined the effect of pretreatment of donor and recipient dogs with GHB on lung function after transplantation. METHODS: Two groups were investigated. In the LPUW group, donor lungs were flushed with LPUW solution without GHB. In the GHB group, donor and recipient dogs were pretreated with GHB, and donor lungs were flushed with LPUW containing GHB. RESULTS: Posttransplant graft function was best in the GHB group. At 1 hr after reperfusion, PaO2 in the GHB group (475.7+/-96.2 mmHg) was significantly higher than in the LPUW group (188.3+/-102.7 mmHg, P<0.05). Furthermore, the use of GHB resulted in a significant increase in lung compliance (28.3+/-6.5 ml/cm H2O) compared with LPUW group (21.5+/-2.8 ml/cm H2O). CONCLUSIONS: Our results suggest that GHB is potentially useful for functional improvement of hypothermically preserved canine lung allografts after reperfusion.

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.

Increased expression of sialyl Le(x) antigen in non-polypoid growth type of colorectal carcinoma.

Colorectal carcinoma can be morphologically divided into two different categories, namely polypoid growth (PG-type) and non-polypoid growth (NPG-type). To ascertain whether the expression of sialyl Le(x) antigen correlates with biologically and clinically important differences, an immunohistochemical assay was performed in 30 PG-type and 119 NPG-type cancers. In contrast to PG-type, the characteristics of the NPG-type include (1) an increased expression of sialyl Le(x); (2) a high rate of lymph node metastasis; (3) a high proportion of moderately differentiated adenocarcinoma cells; (4) young age of onset. It is concluded that differences in sialyl Le(x) expression between the PG-type and NPG-type cancers may be at least partly responsible for different tumor progression behavior.

Influence of suture on bronchial anastomosis in growing puppies.

A comparison study of synthetic nonabsorbable suture (nylon or Prolene) with absorbable suture (Dexon-S or Vicryl) for bronchoplasty was performed in growing puppies. The experiments (n = 15) were followed up for 185 to 381 days (average 323.8 days). Bronchoscopic and bronchographic studies were done at intervals. No stenosis was observed in the group receiving absorbable suture (n = 8), and the anastomoses grew proportionately with the proximal and distal bronchi. In the group receiving nonabsorbable suture (n = 7), variable stenoses developed; two moderate and two severe stenoses were observed during the early healing stage by bronchoscopic examination. In the sequential bronchograms, an increase of stenosis was noted in two dogs. The results suggest that absorbable suture is superior to nonabsorbable suture in pediatric bronchoplasty.

Preoperative steroid therapy inhibits cytokine production in the lung parenchyma in asthmatic patients.

OBJECTIVES: During or after surgery, asthma attacks due to airway hyperresponsiveness (AHR) are likely to occur in patients with bronchial asthma. Preoperative administration of corticosteroid for prevention of perioperative asthma attacks is useful. We examined the mechanism of prevention of perioperative asthma attacks by the preoperative administration of corticosteroid in vitro. DESIGN: Five patients with asthma were treated with 20 mg of prednisolone orally for 2 preoperative days and 80 mg of methylprednisolone IV immediately before and after surgery. In another five patients without asthma, no steroids were administered. A noncarcinomatous part of the resected tissue from each patient with lung cancer was passively sensitized with the serum of an atopic patient. In the patients without asthma, the tissue was treated with or without dexamethasone, and then mite antigen was added. MEASUREMENTS: The culture supernatant and lung tissue were recovered, and the supernatant was assayed for histamine, leukotriene E(4) (LTE(4)), interleukin (IL)-5, and tumor necrosis factor (TNF)-alpha. Degranulation of mast cells was measured by tryptase staining of the lung tissue, and the expression of messenger RNA (mRNA) of IL-5 and TNF-alpha was determined by the reverse transcriptase-polymerase chain reaction method. RESULTS: While preoperative administration of corticosteroid did not suppress the release of histamine and LTE(4) from the lungs of asthmatic patients, it completely suppressed IL-5 and TNF-alpha production at the mRNA level. The same results were obtained in lung tissues of nonasthmatic patients treated in vitro with dexamethasone. CONCLUSIONS: Our results suggest that corticosteroid treatment reduces AHR and prevents perioperative attacks of asthma primarily by suppressing the production of inflammatory cytokines.

Improved bronchial healing in canine left lung reimplantation using omental pedicle wrap.

Bronchial complications are a major problem following lung transplantation. Ischemia of the donor bronchus is an important underlying cause of these complications. We have previously demonstrated the ability of an omental pedicle flap to revascularize the donor bronchus as early as 4 days following canine left lung reimplantation. In the present study, omental pedicle wraps markedly improved the healing of the bronchial anastomoses 23 days following canine left lung reimplantation. In dogs in which omentum was used (n = 6), the bronchial mucosal appearance was more normal and the degree of bronchostenosis was significantly less when compared with dogs without omental flaps (n = 10). These experiments suggest that the use of omental pedicle flaps may significantly reduce bronchial complications following lung transplantation.

A comparison between cyclosporin A and methylprednisolone plus azathioprine on bronchial healing following canine lung autotransplantation.

The effects of two low-dose immunosuppressive therapies upon the healing of the bronchial anastomosis and skin wounds following lung autotransplantation were evaluated. Autotransplantation was performed in three groups of dogs: Group 1 (nine dogs) received no immunosuppression, Group 2 (seven dogs) received postoperative immunosuppression with methylprednisolone (2 mg/kg) and azathioprine (1.5 mg/kg), and Group 3 (four dogs) received postoperative immunosuppression with cyclosporin A (20 mg/kg/day). Skin incisions 7 cm in length were made in the dorsal region of each dog. Dogs were put to death 23 days postoperatively, and the breaking strength of the bronchial anastomoses and skin wounds was evaluated with the Instron Universal Testing Machine, with a cross-head speed of 0.5 cm/min. Bronchial breaking strengths were similar in Groups 1 and 3 and significantly higher than in Group 2 (p less than 0.001). Skin breaking strengths were similar in Groups 1 and 3 and significantly higher than in Group 2 (p less than 0.001). Scanning electron microscopic (SEM) studies of both skin and bronchial wounds showed normal formation of collagen bundles in Groups 1 and 3 but a disorganized pattern in Group 2. Our results suggest that low-dose immunosuppression with methylprednisolone and azathioprine significantly affects wound healing and breaking strength of both bronchial anastomoses and healed skin incisions following canine lung autotransplantation. Immunosuppression with cyclosporin A had no adverse effect on either bronchial or skin healing.

Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation.

The effect of low-dose immunosuppressive therapy upon the healing of the bronchial anastomosis and skin wound following lung autotransplantation was evaluated. Autotransplantation was performed in two groups of dogs: Group 1 (15 dogs) received no immunosuppression and Group 2 (13 dogs) received postoperative immunosuppression with methylprednisolone (2 mg/kg) and azathioprine (1.5 mg/kg). Two to four skin incisions 7 cm in length were made in the dorsal region of each dog. Dogs were put to death at 4, 9, 16, and 23 days postoperatively and the bronchial anastomoses and skin wounds were evaluated by breaking strength measurements. Bronchus and skin breaking strength increased with time in both groups. Bronchus breaking strength was similar in the two groups at day 4 and day 9. However, by day 23 bronchus breaking strength was significantly higher in Group 1 (p less than 0.001). Skin breaking strength was significantly higher in Group 1 on days 9 and 16 (p less than 0.005) and on day 23 (p less than 0.001). Our results suggest that low-dose methylprednisolone and azathioprine significantly affect the breaking strength of both bronchial anastomoses and healing skin incisions following canine lung autotransplantation.

DNA stemline heterogeneity of non-small cell lung carcinomas and differences in DNA ploidy between carcinomas and metastatic nodes.

Nuclear DNA contents were measured using a flow cytometry technique in non-small cell lung carcinomas and differences in ploidy patterns were compared between primary lung carcinomas and metastatic lymph nodes. Negative node lung cancer revealed diploidy in 82.6% of the 224 non-small cell lung cancers, in contrast with 19.5% in positive node lung cancer. In multi-stemline cells, a high incidence of nodal involvement was seen when compared with single stemline cells. The more the DNA indices increased, the more the lymph nodes were seen to be extensively involved. Furthermore, intratumoral heterogeneity was evaluated in terms of n-categories. In conclusion, it is suggested that nodal metastasis may be caused by tumor cells with high DNA indices in lung carcinomas, in particular for multi-stemline cells.

Prognostic impact of cathepsin B and matrix metalloproteinase-9 in pulmonary adenocarcinomas by immunohistochemical study.

The expression of Cathepsin B (CB) and matrix metalloproteinase-9 (MMP-9) in extirpated tissues of adenocarcinomas in non-small cell lung cancer from 90 cases was investigated immunohistologically, and the correlations between the extent of the expression and the clinicopathological features were assessed for investigating the process of tumor metastasis. It is important to reveal the mechanisms of destruction of the basal membrane and infiltration of tumor cells at the primary lesion. Sections were obtained from 10%-formalin-fixed and paraffin-embedded tissues. They were reacted with an anti-human CB polyclonal antibody or an anti-human MMP-9 polyclonal antibody. Of 90 patients, 58 (64.4%) and 39 (48.3) cases were found to be positive for CB and MMP-9 expression, respectively. A significantly higher extent of the CB expression was observed in the tissues of patients who showed postoperative recurrence of the tumor (P = 0.013). Especially, a similar observation was obtained among early cases of T1N0 (P = 0.023). In contrast, no such tendency was demonstrated in the expression profile of MMP-9. Furthermore, the enzyme expressions were compared among different types of metastases. Patients with higher extents of CB expression tended to show significantly higher rates of hematogenous and intrapulmonary metastases (P = 0.023 and P = 0.010, respectively). However, there was no significant correlation between MMP-9 expression and the prognostic factor of the patients. Therefore, we suggested that evaluation of CB expression in the tumor tissue might be useful as a postoperative prognostic factor of pulmonary adenocarcinoma. Especially, early cancer of T1N0 cases showing higher expression of CB may need postoperative adjuvant chemotherapy.

Prolonged survival of rat cardiac allograft with proinflammatory cytokine inhibitor.

BACKGROUND: Proinflammatory cytokines, such as tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1), play important roles in acute allograft rejection. FR167653 is an inhibitor of these cytokines that acts through inhibition of the mitogen-activated protein kinase p38 pathway. We examined the effect of FR167653 on allograft rejection. METHODS: We used Brown-Norway and Lewis rats as donors and recipients, respectively. We performed heterotopic cardiac transplantation. The control group consisted of untreated rats. In the experimental groups, recipients were intraperitoneally injected with FR167653 just after operation, followed by daily injection of the drug from Day 1 to 10. We divided 20 rats into 5 groups, which received varying doses of FR167653, ranging from 75 to 300 mg/kg/day. RESULTS: In the control group, the mean graft survival was 6.8 +/- 0.3 days. FR167653 at 150 mg/kg/day significantly prolonged the survival period (up to 12.1 +/- 1.5 days, p = 0.002). Histologically, FR167653 markedly suppressed cellular infiltration on Day 5 post-transplantation. The serum level of TNF-alpha in the control group was persistently elevated from 9.3 +/- 3.9 pg/ml to 11.3 +/- 3.8 pg/ml, whereas FR167653 significantly suppressed the level to <1.4 +/- 1.4 pg/ml. CONCLUSIONS: FR167653 prolonged rat cardiac allograft survival by suppressing the action of proinflammatory cytokines.

Expression of proliferating cell nuclear antigen in bronchial epithelium after lung transplantation in the rat.

BACKGROUND: The normal, mature airway epithelium in experimental animals has a very slow cell turnover and minimal proliferation. The aim of this study was to investigate the expression of proliferating cell nuclear antigen (PCNA) as an index of bronchial cell proliferation in the Brown Norway to Lewis rat pulmonary allograft model with or without immunosuppression. METHODS: Brown Norway left lungs were transplanted into Lewis recipients. Some recipients were treated with a high dose of cyclosporine and FK506. Lewis-to-Lewis donor-recipient combination was performed as a control. Lungs were excised on postoperative days 3 and 5. Routinely processed, paraffin-embedded sections were prepared and stained by PCNA. Counts of PCNA-positive cells in the perivascular cellular infiltrate and bronchial surface epithelium were compared with the histologic grade of rejection. RESULTS: The PCNA index (percent of nuclei immunostaining for PCNA) in bronchial surface epithelium was significantly higher in allografts (21.0% +/- 3.1% at 3 days, 31.4% +/- 9.8 % at 5 days, p < 0.05) than in isografts (5.4% +/- 3.0% at 3 days, 4.7% +/- 4.6% at 5 days). The PCNA index was also greater in the perivascular infiltrates of rejecting lungs (23.9% +/- 3.7% at 3 days, 29.1% +/- 6.6% at 5 days). However, in the cyclosporine- and FK506-treated groups, the PCNA index in bronchial surface epithelium was suppressed to less than 5% at 3 and 5 days. Even at 50 days after transplantation, PCNA-positive cells were rare in bronchial epithelium of FK506-treated grafts. CONCLUSIONS: Bronchial epithelium in isografts has a relatively low rate of proliferation. In rejection, allografts have a very rapid cell turnover and proliferation. Proliferating epithelium may be a consequence of immune events or it may contribute to the pathogenesis of those events.

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.

Expression of ABH/Lewis-related antigens as prognostic factors in patients with breast cancer.

PURPOSE: The prognostic value of altered blood group factor and Lewis-related carbohydrate antigen expression in breast cancers has not been fully determined. METHODS: To this end, breast carcinoma samples from 87 radical mastectomy patients with primary cancer were analyzed by immunohistochemistry for the ABH factors, Le(a), sialyl Le(a), Le(x), and sialyl Le(x). RESULTS: It was found that ABH, Le(a), sialyl Le(a), Le(x), and sialyl Le(x) antigens were expressed in 25 (21.8%), 26 (22.6%), 26 (22.6%), 36 (31.3%), and 37 specimens (32.2%), respectively. Tumors with lymph node metastasis expressed Le(x) or sialyl Le(x) antigens more frequently than those without lymph node metastasis ( P=0.0020 or P=0.039, respectively). The survival time of patient s after surgery was significantly shorter for those whose tumors expressed Le(x) or sialyl Le(x) than for those without Le(x)- or sialyl Le(x)-positive tumors ( P=0.0028 and P=0.0029, respectively). Cox's multiple regression analysis revealed that sialyl Le(x) expression was an independent prognostic factor for patient survival regardless of primary tumor (T factor) and lymph node (N factor) status (hazards ratio, 3.80). CONCLUSIONS: Thus, expression of sialyl Le(x) antigen in tumor cells is associated with poor prognosis in patients with breast cancer and must be considered in the design of future therapeutic trials.