Antepartum embolization in management of labor induction in placenta previa.

The authors present a case of a 29-year-old woman, gravid 2 para 1, who experienced complete placenta previa and underwent vaginal delivery, after performing antepartum uterine artery embolization and rivanol amniotic injection due to contraindication of obstetric surgery. In this case, treatment was successful despite thromboembolism. Hypercoagulability in pregnancy needs to be addressed.

Simvastatin-induced myopathy with concomitant use of cyclosporine: case report.

OBJECTIVE: Simvastatin has been shown to play an important role in reducing the risk of cardiovascular events caused by atherosclerosis. To promote the understanding of the potential toxicity of simvastatin and individualized treatment in genetic factors, we report a case of a renal transplant in a female patient who had developed acute myopathy after taking simvastatin. METHODS: By PCR restriction fragment length polymorphism (PCR-RFLP) and allele-specificity polymerase chain reaction (AS-PCR) and direct sequencing. The genotypes of CYP3AP1, CYP3A5, CYP3A4 and SLCO1B1 were analyzed. RESULTS AND DISCUSSION: The patient was identified to have mutant genotypes of CYP3AP1*3/*3 (-44G > A), CYP3A5*3/*3 (6986A > G) and wild genotype of CYP3A4*1/*1 and SLCO1B1*1/*1, which finally led to the elevation of her cyclosporine level except the SLCO1B1*1/*1 genotype and the acceleration of simvastatin-induced acute myopathy. CONCLUSION: Genetic factors have partly contributed to the development of simvastatin-induced myopathy with concomitant use of cyclosporine, and provided information on the adverse reactions of statins. What is different from other studies is that the SNP of SLCO1B1*5 does not take part in this adverse reaction.

Prediction of colorectal cancer relapse and survival via tissue RNA levels of matrix metalloproteinase-9.

PURPOSE: In this study, we investigated the association between matrix metalloproteinase (MMP)-9 RNA expression in primary colorectal cancer (CRC) and standard clinicopathologic variables and determined whether levels of MMP-9 RNA predict relapse and survival. PATIENTS AND METHODS: Tumor and paired normal mucosa specimens from 71 primary CRC patients following resections were assessed. RNA levels were determined via Northern blot hybridization and quantitated with laser densitometry. Results were expressed as tumor/normal mucosa (T/N) fold-increase calculated after normalizing for RNA loading using 28S expression. Statistical analysis was performed using the SAS statistical package procedure. Kaplan-Meier survival curves were compared with the two-sided log-rank test. RESULTS: The mean T/N MMP-9 RNA fold-increase was 9.4 +/- 1.0 (mean +/- SE) (P < .001). Overexpression of MMP-9 RNA correlated significantly with status of synchronous distant metastases (M stage) (P = .004) and Dukes' stage (P = .008). A T/N fold-increase of 5.0 was used to discriminate between high (> 5.0) and low (< or = 5.0) T/N MMP-9 expression. High T/N MMP-9 RNA expression was associated with a significantly shorter disease-free (P = .0001) and overall (P = .0002) survival duration. In univariate and multivariate analyses, T/N MMP-9 RNA level was found to be an independent prognostic factor for disease-free survival. CONCLUSION: This report provides the first evidence that increased MMP-9 RNA production in primary human CRC may be a powerful, independent predictor of recurrence and outcome.

p53 nuclear overexpression: an independent predictor of survival in lymph node--positive colorectal cancer patients.

PURPOSE: This study was performed to determine the prognostic significance of p53 gene overexpression in a homogeneous group of node-positive colorectal cancer patients. MATERIALS AND METHODS: Paraffin sections from the primary tumors in 107 colorectal cancer patients who had preoperative serum carcinoembryonic antigen (CEA) levels less than five were examined for the expression of p53 nuclear protein by immunohistochemical staining using the monoclonal antibody PAb 1801. The nuclear p53 overexpression was compared with clinicopathologic variables and follow-up data. RESULTS: Positive staining was not observed in normal colorectal mucosal cells. Specific p53 nuclear staining was detected in primary tumor from 50 patients (46.7%). p53 nuclear overexpression was not significantly correlated with patients' sex, age, tumor location, differentiation, T stage, N stage, and lymphatic and/or vascular vessel invasion. With a median follow-up of 61.7 months, 60% of the p53-positive patients have had disease recurrence, versus only 35% of the p53-negative group (P = .02). Forty-two percent of the p53-positive patients died of colorectal cancer compared with 21.1% of the p53-negative patients (P = .03). By multivariate analysis, p53 overexpression was found to be an independent predictor for disease-free and disease-specific survival. CONCLUSION: In node-positive colorectal cancer patients with low preoperative CEA levels, nuclear p53 overexpression as determined by immunohistochemistry on archived tissue is an independent predictor for prognosis.

Automated, multiplex assay for high-frequency microsatellite instability in colorectal cancer.

PURPOSE: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction. METHODS: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer. RESULTS: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P =.003), characteristic tumor morphology (0% v 64%; P =.006), and 5-year cancer survival rate (44% v 100%; P =.0003). CONCLUSION: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.

Elevated tissue inhibitor of metalloproteinase 1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases.

Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tumor invasion and metastases. The purpose of this study was to determine the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationships between TIMP-1 RNA expression and standard clinicopathological variables of CRC. Total cellular RNA, extracted from 56 CRC and 10 liver metastases, were examined by Northern blot hybridization. The mean/normal mucosa fold increase of TIMP-1 RNA was significantly elevated in both CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6). No relationship was noted between TIMP-1 expression and tumor size, location nor differentiation. Based on lymph node metastases status, significantly higher TIMP-1 RNA levels were found in CRC with metastases than in those without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04). Similarly, TIMP-1 RNA levels were higher in primary CRC with distant metastases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0. 04). In situ hybridization localized TIMP-1 mRNA predominantly in tumor stroma within spindle fibroblast-like cells rather than in cancer cells themselves. The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.

High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer.

Several genes have identified that play a role in colon cancer development. However, less is known about factors that increase the rate of progression of colon cancers to metastasis. One candidate is transforming growth factor beta 1 (TGF beta 1), which can enhance the aggressiveness of human colorectal cell lines in vitro and in vivo. The amount of TGF beta 1, TGF beta 2, and TGF beta 3 protein isoforms expressed in primary site colorectal cancers were measured to determine whether any correlation existed between protein levels and disease recurrence in a series of Memorial Sloan-Kettering Hospital patients who underwent potentially curative resections. Intense staining for TGF beta 1 correlated significantly (P < 0.0013; odds ratio, 18) with disease progression to metastasis and was independent of nodal status and the degree of differentiation of the primary tumor. Therefore, in this study, patients with high TGF beta 1 protein levels in their primary site colorectal cancer were 18 times more likely to experience recurrence of their disease than were patients whose tumors exhibited low levels of TGF beta 1. In this case-control study, patients whose cancer recurred and those remaining cancer free were age and sex matched. The disease recurred at a mean of 26.8 +/- 4.3 (SE) months, whereas the mean follow-up time in patients whose disease did not recur was over twice as long, 57.3 +/- 6.6 months. Ninety-four % of the patients in each group were node positive at the time of resection, with equal mean numbers of positive nodes per patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Metastatic and non-metastatic colorectal cancer (CRC) cells induce host metalloproteinase production in vivo.

Numerous studies have demonstrated the persistent localization of matrix metalloproteinase (MMP) expression to the interface between invading human colorectal cancer (CRC) cells and surrounding stroma supporting a role for MMPs in CRC invasion and metastasis. The present study sought to determine whether CRC cells of varying metastatic potential would have differential effects on host MMP release. Subcutaneous CRC tumors were generated in BALB/c nude mice using three CRC cell lines: SW480, SW620, and the highly metastatic SW620S5 clone. Representative samples from the subcutaneous CRC were then orthotopically implanted on the cecum of recipient nude mice. Subcutaneous and cecal tumors were analyzed for MMP expression via zymography, western blot, and RT-PCR. In vitro, none of the three cell lines expressed MMP-2 nor MMP-9. In contradistinction, the subcutaneous tumors expressed limited amounts of MMP-2 and MMP-9 while the cecal tumors expressed significant amounts of MMP-2 and MMP-9 as well as other smaller members of the MMP family. MMP-9 mRNA and protein was confirmed as host in origin by RT-PCR with mouse specific primers and a mouse MMP-9 molecular weight of 105 kDa as determined by zymography and western blot analysis. In situ hybridization also localized the mRNA for MMP-9 to the host stromal cells. In conclusion, CRC cells appear incapable of producing MMP-2 and MMP-9 in vitro but are capable of up-regulating host MMP production in vivo. Enhanced host MMP-9 production in metastatic CRC cell-derived subcutaneous and cecal tumors suggests that metastatic colon cells may acquire the expression of important MMP regulating factor(s) in vivo.

Cholecystectomy and colorectal cancer in China.

Colorectal cancer is a major public health problem in China: 79,800 new cases are estimated to occur each year, which ranks it among the five most common tumours in China. Although the association between cholecystectomy and colorectal cancer has been studied elsewhere, few studies have been conducted in the Chinese population, characterized by a lower fat intake, and low colorectal cancer incidence. We conducted this hospital-based case-control study to explore this association. The study included a total of 503 incident cases with pathologically diagnosed colorectal cancer in Drum Tower Hospital at Nanjing in China from 1965 to 1986, and 2188 healthy controls who had annual routine physical examinations at the same hospital. Diagnosis of cholelithiasis was confirmed by ultrasonography or X-ray cholecystography, and the information on cholecystectomy was obtained by checking medical charts for both cases and controls. The prevalence of cholelithiases was 5.8% for cases and 6.1% for controls (P > 0.05). Eight cases (1.6%) and 18 controls (0.8%) had a history of previous cholecystectomy. The period between cases' cholecystectomy and diagnosis of colorectal cancer ranged from 2.5 to 23 years, and the mean interval was 8.9 years. The crude odds ratio for patients having previous cholecystectomy is 1.95 (95% CI: 0.84-4.51) compared with controls. The odds ratio for female patients with previous cholecystectomy was 2.79 (95% CI: 1.03-7.59). When subsites were analysed, a significant association between right colon cancer and cholecystectomy was noted: the odds ratio was 6.2 (95% CI: 2.24-16.9), and that for females was even higher 8.61 (95% CI: 2.44-3.04) with statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity study of hepatic artery infusion chemotherapy with massive dose FUDR in rats.

Hepatic artery infusion (HAI) of fluoroudeoxyuridine (FUDR) has been shown to be effective in the treatment of liver metastases from colorectal cancer. However, local toxicity is the most serious limitation of this therapy. The aetiology of HAI toxicity remains unclear. To assess the HAI toxicity, forty-eight non-tumour-bearing, healthy BD-IX rats were randomized to control or treatment groups. The control group (n = 24) received heparinized saline alone (200 u heparin kg-1 day-1) and the treatment group (n = 24) received 6.7 mg FUDR kg-1 day-1 (equivalent to the human dose of 1.0 kg-1 day-1) via HAI for 28 days. Blood samples were collected for haematologic and biochemical analysis twice a week (on days 3 and 7). Toxicity was evaluated by determination of mortality, body weight, white blood cell (WBC) count, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin and blood urea nitrogen (BUN), and creatinine. No significant differences in WBC, SGOT, BUN and creatinine levels were found between the group receiving FUDR treatment and the control group. Significantly higher total bilirubin levels, mortality and body weight loss were found in the FUDR-treated group than in the control group. A multivariate analysis revealed that total bilirubin level was the only significant predictor of mortality in the FUDR treatment group. These results suggested that biliary tract damage seems to be the principal toxicity of HAI FUDR chemotherapy.

Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer.

Experimental in vitro and animal data support an important role for matrix metalloproteinases (MMPs) in cancer invasion and metastasis via proteolytic degradation of the extracellular matrix (ECM). Our previous data have shown that MMP-9 mRNA is localized to the interface between liver metastasis and normal liver tissue, indicating that MMP-9 may play an important role in liver metastasis formation. In the present study, we analysed the cellular enzymatic expression of MMP-9 in 18 human colorectal cancer (CRC) liver metastasis specimens by enzyme-linked immunosorbent assay (ELISA) and zymography. ELISA analysis reveals that the latent form of MMP-9 is present in both liver metastasis and paired adjacent normal liver tissue. The mean level of the latent form of MMP-9 is 580+/-270 ng per mg total tissue protein (mean+/-s.e.) in liver metastasis vs 220+/-90 in normal liver tissue. However, this difference is not significantly different (P = 0.26). Using gelatin zymography, the 92-kDa band representative of the latent form is present in both liver metastasis and normal liver tissue. However, the 82 kDa band, representative of the active form of MMP-9, was seen only in liver metastasis. This was confirmed by Western blot analysis. Our observation of the unique presence of the active form of MMP-9 within liver metastasis suggests that proMMP-9 activation may be a pivotal event during CRC liver metastasis formation.

Distinct pattern of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 mRNA expression in human colorectal cancer and liver metastases.

The matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are perceived as essential for tumour invasion and metastasis. In the present study, we compare the topographical pattern of MMP-9 and TIMP-1 expression in colorectal cancer and liver metastasis by in situ hybridisation. TIMP-1 mRNA was detected in all 26 colorectal cancers examined, while only 18 out of 26 (69.2%) were positive for MMP-9. Both MMP-9 and TIMP-1 mRNA were observed in all ten liver metastases but were absent in three adenomas and in all normal colonic mucosa and liver. There was no association between MMP-9 or TIMP-1 mRNA expression and degree of differentiation or size of Tumours. MMP-9 and TIMP-1 mRNA were similarly observed in the peritumour stroma cells rather than in tumour cells themselves. MMP-9 mRNA positive cells were round and identified as macrophages by immunostaining with an anti-macrophage antibody (KP1), while TIMP-1, mRNA was detected in spindle-shaped stromal cells. In liver metastases, MMP-9 localised within peritumour stroma or at the interface between the tumour stroma and normal liver, whereas TIMP-1 mRNA was located throughout the malignant tumour stroma. Our data demonstrate a distinct pattern of MMP-9 and TIMP-1 mRNA expression in colorectal cancer and liver metastases suggesting distinct cellular origins as well as separate patterns of regulation.

Colocalisation of matrix metalloproteinase-9-mRNA and protein in human colorectal cancer stromal cells.

The matrix metalloproteinases (MMPs) are perceived as essential for tumour invasion and metastases. The purpose of this study was to determine the expression and cellular localisation of the 92 kDa type IV collagenase (MMP-9) protein and mRNA in human colorectal cancer (CRC). In CRC and matched normal mucosa specimens from 26 CRC patients, Northern blot hybridisation and Western blot analyses provide convincing evidence that MMP-9 is expressed in greater quantities in CRC than in normal tissue. The MMP-9 tumour to normal mucosa fold-increase (T/N) was 9.7 +/- 7.1 (mean +/- s.d.) (P < 0.001) for RNA and 7.1 +/- 3.9 (P < 0.001) for protein. The sites of MMP-9 mRNA and protein synthesis were colocalised in tumour stroma by in situ hybridisation and immunohistochemistry in 26 CRC samples. Both MMP-9 mRNA and protein signals were strongest in the population of stromal cells concentrated at the tumour-stroma interface of an invading tumour. Furthermore, MMP-9-positive cells were identified as macrophages using an antimacrophage antibody (KP1) in serial sections from ten CRC samples. Given the persistent localisation of MMP-9-producing macrophages to the interphase between CRC and surrounding stroma, our observations suggest that MMP-9 production is controlled, in part, by tumour-stroma cell interactions. Further studies are needed to determine the in vivo regulation of MMP-9 production from infiltrating peritumour macrophages.

Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis.

Breakdown of basement membrane (BM) is believed to be an essential step for tumor invasion and metastases. We have previously demonstrated that matrix metalloproteinase-9 (MMP-9), the 92 kDa collagenase expression correlates with metastases in human colorectal cancer (CRC). This study explores the relationship between the 72 and 92 kDa type IV collagenase (MMP-2 and MMP-9) activities and pattern of type IV collagen expression during human colorectal tumorigenesis. Thirty-four CRC patients, including four synchronous adenomas and one synchronous liver metastases, were involved in this study. By immunohistochemical staining, type IV collagen expression was noted to be continuous in the BM of normal mucosa, adenoma and in two cases of carcinoma in situ. Limited or absent type IV collagen staining pattern was seen in 100 (19/19) and 23% (3/13) of CRC with and without metastases, respectively. By double immunostaining, MMP-9 protein expression was noted to localize within areas of limited type IV collagen staining. Similarly, type IV collagen staining was noted to be greatest in areas devoid of MMP-9 expression. Gelatin zymography detected both 92 and 72 kDa proenzyme forms in all CRC and normal mucosa extracts examined. The mean tumor/normal fold increases of the proMMP-2 and proMMP-9 enzyme forms were 1.6+/-0.1 (mean +/- SE) and 2.4+/-0.5 in adenomas, and 2.1+/-0.2 and 4.1+/-0.7 in CRC, respectively. The 62 and 82 kDa bands were present in 63 (12/19) and 74% (14/19) of CRC with metastases, compared with only 20 (3/15) and 33% (5/15) of CRC without metastases, respectively. These differences were significant (P = 0.045 and P = 0.030, respectively). Our results demonstrate that loss of BM type IV collagen along with elevations in MMP-2 and MMP-9 expression, especially the activated forms, occur during colorectal tumorigenesis. Our data suggest that control of type IV collagenase activation may be beneficial in preventing human colorectal tumor progression.

High level of Nm23-H1 gene expression is associated with local colorectal cancer progression not with metastases.

This study aimed to determine the expression of Nm23-H1 in colorectal cancer and liver metastases and to correlate Nm23-H1 expression with clinicopathological variables. Specimens from 59 primary colorectal cancers and five liver metastases were studied using Northern blot hybridisation. The mean +/- s.e. of tumour/normal (T/N) ratio of Nm23-H1 RNA expression was 4.3 +/- 0.4 (P < 0.001) and 5.1 +/- 0.90 (P < 0.01) for colorectal cancer and liver metastases respectively. No significant relationship was observed between the level of Nm23-H1 RNA and the patient's age, sex, tumour location, differentiation, presence of lymph node involvement or distant metastases. Nm23-H1 RNA level was 2.6 +/- 0.5 for tumour size less than 3.0 cm and 4.6 +/- 0.5 for those > or = 3.0 cm (P = 0.05). There appeared to be a trend between increasing relative Nm23-H1 RNA and bowel wall invasion, irrespective of metastatic status (T1 = 1.9 +/- 0.3, T2 = 4.1 +/- 0.6, T3 = 4.1 +/- 0.5 and T4 = 6.4 +/- 1.6). This difference was statistically significant when T1 was compared against > or = T2 lesions (P = 0.01). Western blot analysis reveals two Nm23H-1 bands (17.0 kDa and 18.5 kDa). In 16 colorectal patients, the T/N fold-increase in protein expression was 2.66 +/- 0.46 (P < 0.001) and 2.40 +/- 0.32 (P < 0.001) for the 17.0 and 18.5 kDa band respectively. Both Nm23-H1 RNA and protein levels in primary colorectal cancers do not appear to correlate with synchronous regional or distant metastases. Since Nm23-H1 RNA expression is associated with increasing tumour size and tumour local invasion, Nm23-H1 RNA expression may be associated with local disease progression.

Family history of cancer, body weight, and p53 nuclear overexpression in Duke's C colorectal cancer.

To examine the hypothesis that colorectal carcinomas with and without TP53 mutations may be characterised by aetiological heterogeneity, we analysed a group of 107 patients with primary Dukes' C colorectal cancer seen at the Memorial Sloan-Kettering Cancer Center (MSKCC) from 1986 to 1990. We assessed p53 overexpression using the monoclonal antibody PAb 1801, and identified 42 (39%) patients displaying p53-positive phenotype, defined as > or = 25% of positive cells. Patients with two or more first-degree relatives with cancer had an odds ratio (OR) of 2.9 (95% CI 1.0-8.3) for p53 overexpression in comparison with those without a family history of cancer (trend test, P = 0.11). A possible association between body weight and p53 overexpression was observed. The ORs were 1.9 for the second quartile, 1.9 for the third quartile and 3.4 for the highest quartile in comparison with the lowest quartile (trend test, P = 0.06). No association between occupational physical activity, smoking, drinking, parity and p53 overexpression was identified. The results suggest that p53 overexpression may be related to genetic predisposition to colorectal cancer, and p53-positive and p53-negative colorectal cancers may be controlled by different aetiological pathways.