Correlation between COX-2 and APC expression in left versus right-sided human colon cancer.

BACKGROUND: Because of clinicopathologic and genetic differences between left-sided colorectal cancer (LSCRC) and right-sided colon cancer (RSCC), cyclooxygenase-2(COX-2) and adenomatous polyposis coli (APC) expression may be of clinical relevance. MATERIALS AND METHODS: Clinicopathologic information for 72 primary colon tumors, 44 left and 28 right, from 72 patients (34 F, 38 M) were analyzed. COX-2 and wild-type APC (W-APC) immunohistochemical expressions were determined for each case. The data were analyzed using the Chi-square test and exact binomial confidence intervals. RESULTS: Overall, 31 out of 44 (70%) LSCRC were W-COX-2 positive vs. 13 out of 28 (46%) RSCC (p-value=0.042). When evaluated independently of the anatomic location, COX-2 expression showed a borderline statistical correlation with the lack of W-APC protein (p-value=0.054). When considering location of tumors, the inverse correlation between COX-2 and W-APC expression became statistically significant (p-value=0.024). CONCLUSION: We report a strong inverse correlation between COX-2 and W-APC expression, with COX-2 being more frequently as expressed in LSCRC. These data may be useful to stratify colorectal cancer patients into right- and left-sided and COX-2 expressor and non-expressor subsets, when evaluating COX-2 inhibitor and other targeted therapies in colon cancer.

Complications of hepatic artery infusion: a review of 4580 reported cases.

PURPOSE: The resurgence of hepatic artery infusion (HAI) for the treatment of colorectal liver metastases has been dampened by concern over its complications. We have reviewed the incidence and frequency of complications associated with HAI and discussed the factors associated with these complications. METHODS: A PUBMED search was conducted from 1950-2001 using various combinations of these keywords: hepatic arterial infusion, colorectal carcinoma, complications, and trials. The main inclusion criterion was the reporting of HAI complications. The main exclusion criterion was duplicated patients. Extracted data included chemotherapeutic agents, catheter technique, drug toxicities, and catheter related complications. Relative risks and 95% confidence intervals were calculated. RESULTS: We reviewed 437 articles/abstracts and included 101 studies. 4580 patients with 4582 toxicities and complications were reported. The mortality rate was 1%. The most common toxicities were: GI symptoms 22%, chemical hepatitis 19%, and bone marrow toxicity 8%. 5-fluorouracil (5-FU) HAI had statistically significant risk for GI symptoms and bone marrow toxicity. Floxuridine (FUDR) HAI had statistically significant risk for chemical hepatitis, sclerosing cholangitis, and biliary toxicity. The most common catheter complications were: hepatic artery occlusion 6%, catheter thrombosis 5%, and catheter displacement 7%. CONCLUSIONS: This literature review of the complications of HAI confirms a low mortality associated with HAI. Sclerosing cholangitis and chemical hepatitis are associated with the use of FUDR, while the use of 5-FU is associated with bone marrow toxicity. Our observations support the development of hepatic cytoprotective agents and other effective anti-tumor agents to improve the results and morbidity of HAI for colorectal liver metastases.

Vitamin E succinate promotes breast cancer tumor dormancy.

BACKGROUND: Vitamin E succinate (VES) is the most potent antitumor analogue of vitamin E. Despite many reports of VES's antitumor activity in vitro, there is little information about its antitumor effects in vivo. MATERIALS AND METHODS: We investigated the effect of VES on the growth of human breast cancer cells in vitro and in vivo. RESULTS: VES decreased cell viability in MDA-MB-231 and MCF-7 human breast cancer cells. Although VES increased apoptosis in MDA-MB-231 cells, it had no effect on apoptosis in MCF-7 cells. The inhibitory effect of VES on cell growth was specific for the intact molecule because a markedly reduced effect was noted when either vitamin E or succinic acid was administered alone. VES inhibited the growth of MDA-MB-231 cells in nude mice. Also, VES was found to inhibit vascular endothelial growth factor (VEGF) gene expression in MDA-MB-231 cells. CONCLUSIONS: VES inhibits the growth of breast cancer cells in vitro and in vivo. This is the first report of VES inhibition of established tumor growth in vivo. The mechanism of VES's in vivo effects may involve inhibition of tumor angiogenesis since VES inhibits VEGF gene expression.

Sentinel node biopsy for staging of aggressive digital papillary adenocarcinoma.

BACKGROUND: Aggressive digital papillary adenocarcinoma is a rare malignancy with a propensity for metastases and recurrence. The role of lymph node staging in this tumor is poorly defined. We describe the use of sentinel lymph node mapping and biopsy in staging this tumor. OBJECTIVE: To describe and discuss the use of lymphatic mapping in staging aggressive digital papillary adenocarcinoma. METHODS: Sentinel lymph node mapping and biopsy was performed after excision of an aggressive digital papillary adenocarcinoma of the toe. RESULTS: Metastatic tumor cells were absent in sentinel lymph nodes by hematoxylin and eosin staining and immunocytochemistry analysis. CONCLUSION: We describe the first reported case of staging lymph nodes in a patient with aggressive digital papillary adenocarcinoma utilizing sentinel lymph node mapping and biopsy.

Dose-dependent protection by lipoic acid against cisplatin-induced nephrotoxicity in rats: antioxidant defense system.

This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.

Effect of cisplatin on the expression of glutathione-S-transferase in the cochlea of the rat.

Glutathione-S-transferase (GST) has been found to conjugate glutathione (GSH) to diverse electrophiles and play a major role in the detoxification of alkylating and platinating agents. However, there is little information regarding the pattern of GST expression in the cochlea. Although cisplatin is ototoxic, its effect on GST in the cochlea is unknown. In the present study we investigated the pattern of GST expression in control and cisplatin-treated cochleas by using the laboratory rat as animal model. Sixteen mature rats were randomly assigned to control or cisplatin groups. After treatment, cochleas were procured and tissues stained by immunohistochemical methods to detect the presence of GST. Optical density measurements were determined to gauge intensity of GST immunostaining. Strong positive GST immunostaining was demonstrated in all cochleas, with the most intense staining found in the spiral ligament and the least in Reissner's membrane. Mean optic density scores were lower for cisplatin-treated cochleas than for control cochleas in all areas analyzed. These findings showed that GST is expressed throughout the rat cochlea, with cisplatin treatment causing its decreased expression.

MnSOD expression is increased in metastatic gastric cancer.

BACKGROUND: Manganese superoxide dismutase (MnSOD) catalyzes the scavenging of superoxide radicals in order to protect cells from the damage caused by reactive oxygen species. Previous studies implicate MnSOD in cancer progression, but its role in gastric cancer metastasis is poorly understood. MATERIALS AND METHODS: To determine whether MnSOD expression correlates with gastric cancer metastasis, we compared immunostaining for MnSOD in the primary tumors of gastric cancer patients with (n = 15) and without (n = 9) nodal metastases. These patients were matched for risk factors associated with gastric cancer metastasis, such as tumor site, depth, and grade. MnSOD expression was scored positive (increased) if MnSOD staining of tumor cells was more intense than MnSOD staining in corresponding normal gastric epithelial cells. Statistical analyses were via chi(2) test and Fisher's exact test. RESULTS: MnSOD expression was increased in 14 of the 15 (93%) metastatic tumors, compared to only 4 of the 9 (44%) nonmetastatic tumors (P = 0.015). There was no significant difference in staining when the two groups were compared based on tumor grade (P = 0.70) or depth of tumor cell invasion (T stage) (P = 0.22). CONCLUSIONS: MnSOD expression is upregulated in the primary tumors of gastric cancer patients with lymph node metastases. This finding supports an involvement of MnSOD and possibly the reactive oxygen status of the gastric tumor microenvironment in gastric cancer metastasis.

Angiogenesis correlates with metastasis in melanoma.

BACKGROUND: Angiogenesis has been correlated with melanoma progression, but its role in melanoma metastasis is unclear. METHODS: To determine whether angiogenesis correlates with the presence of melanoma metastases, we compared the number of microvessels in the primary melanomas of 12 patients presenting with metastases to those of 13 patients without metastases. Patient groups were matched for gender, age, tumor depth, and histological type and anatomical location of the primary melanoma. Microvessels were stained with factor VIII antibody and counted. RESULTS: Microvessel counts were significantly greater for the metastatic than the nonmetastatic melanomas (51.63+/-14.95 vs. 24.86+/-8.415; P < .0001). One hundred percent of the metastatic melanomas had a mean microvessel count of > or = 37, whereas only 8% of the nonmetastatic melanomas had a mean microvessel count of > or = 37 (sensitivity = 1.00, specificity = .92). Interestingly, patients with lymph node metastases had significantly lower microvessel counts than did patients with distant metastases (42.00+/-3.482 vs. 58.50+/-16.40; P < .05), and significantly higher microvessel counts than did patients without metastases (42.00+/-3.482 vs. 24.86+/-8.415; P < .001). CONCLUSIONS: An increased number of microvessels in the primary tumors of patients with melanoma correlates with the simultaneous presence of metastases. This suggests that angiogenesis may be important in the process of melanoma metastasis.

Differential gene expression in experimental hepatocellular carcinoma induced by woodchuck hepatitis B virus.

Hepatitis B virus infection is closely linked to hepatocellular carcinoma (HCC), the pathological mechanism of hepatocarcinogenesis by this virus is not well understood. In order to gain further insight into the molecular mechanism of HCC, we constructed and screened a subtracted c-DNA library which was specific to HCC cells of a woodchuck infected with woodchuck hepatitis B virus. Among eight clones that were isolated based on their differential expressions, we determined nucleotide sequences of two genes whose expressions were most significantly stimulated in HCC. Our results indicate that these two genes appear to be woodchuck counterpart genes of hemopexin (HPX) and alpha-1 acid glycoprotein (AGP), suggesting that the expression of HPX and AGP genes are strongly augmented in tumor cells partly due to transcriptional regulation.

Isolation and functional analysis of a Kluyveromyces lactis RAP1 homologue.

Saccharomyces cerevisiae RAP1 (Sc RAP1) is an essential protein which interacts with diverse genetic loci within the cell. RAP1 binds site-specifically to the consensus sequence, 5'-AYCYRTRCAYYW (UASRPG, where R = A or G, W = A or T, Y = C or T). In Kluyveromyces lactis (Kl) ribosomal protein-encoding genes (rp) retain functional RAP1-binding elements, suggesting the presence of a RAP1-like factor. Kl extracts display an activity capable of specifically binding to rp fragments bearing UASRPG. We subsequently isolated the Kl RAP1-encoding gene by homology to a subfragment which encodes the N terminus of the DNA-binding domain of Sc RAP1. The predicted amino acid (aa) sequence of Kl RAP1 indicates it is smaller than Sc RAP1 (666 vs. 827 aa) with the N terminus being truncated. The DNA-binding domain is virtually identical between the two RAP1 proteins, while the RIF1 domain is moderately conserved. The region between these two domains and the N-termini are highly divergent. Two potential UASRPG were identified in the 5' flanking region, suggesting an autoregulatory role for RAP1. Despite the similarities between the two proteins, KI RAP1 is unable to complement Sc rap1ts mutants, suggesting that domains essential for function in Sc are absent from the Kl protein.

Distribution of estrogen receptor in ductal carcinoma in situ of the breast.

BACKGROUND: Long-term antiestrogen therapy has been suggested as a possible treatment alternative for ductal carcinoma in situ (DCIS) of the breast. However, very little information is available on the distribution of estrogen receptor (ER) and treatment success with antiestrogen for such lesions. METHODS: Thirty-two formalin-fixed tissue specimens of DCIS from 32 female patients aged 38 to 71 years were evaluated for the presence of ER by an immunoperoxidase technique. Antigenic sites for ER were exposed by treating the tissue sections with deoxyribonuclease followed by peroxidase-antiperoxidase staining with monoclonal antibody against ER. Parallel negative controls were run with negative control monoclonal antibody and normal rat serum. The quality control for positive staining was performed with tissue sections from specimens with known ER detected by the radioreceptor method. RESULTS: Eighteen (60%) of the 32 lesions were positive for ER. In 7 of the 18 lesions less than 25% of cells stained positive for ER and in 4 of the 18 more than 50% of cells stained positive for ER. CONCLUSIONS: The incidence of ER in DCIS is similar to the incidence of ER in invasive carcinoma, leading to the speculation that ER-positive invasive carcinoma originates from an ER-positive precursor lesion. Because only 60% of the cases have detectable ER and approximately 70% of positively stained ERs are expected to be functional (as in invasive carcinoma), it appears that approximately 42% of the patient population with DCIS will benefit from antiestrogen therapy.

Successful treatment of acute humoral rejection in a heart transplant patient.

Eight months after undergoing orthotopic heart transplantation, a patient had hypotension and biventricular heart failure. Endomyocardial biopsy specimens showed a modest cellular infiltrate, predominantly of plasma cells, and progressive myocyte injury, suggesting a humoral rejection process. The patient was treated with Minnesota antilymphoblast globulin and aggressively with plasmapheresis, resulting in evidence of myocyte repair, improved hemodynamics, and long-term survival.

Estrogen receptors in ductal carcinoma in situ of breast.

A number of investigators have suggested treatment of precursor lesions for invasive breast cancer such as ductal carcinoma in situ with antiestrogen. However, very little information is available on the incidence of estrogen receptor in such lesions and the probability of treatment success. Fourteen formalin-fixed tissue specimens of intraductal carcinoma in situ from 14 female patients aged 40 to 66 years were evaluated for the presence of estrogen receptor by immunoperoxidase technique using estrogen receptor antibody. Eight of the 14 lesions (57%) were positive for estrogen receptor. The incidence of estrogen receptor in intraductal carcinoma in situ is very similar to that of invasive carcinoma of breast, leading to the speculation that ER-positive invasive carcinoma originates from ER-positive precursor lesions. Since only 70 per cent of positive receptor lesions are expected to respond to antiestrogens, it appears that only 40 per cent of patients with ductal carcinoma in situ of breast will benefit from endocrine therapy.

Arteriovenous fistula between the hepatic artery and the hepatic vein.

A patient is presented with multiple vascular anomalies in the branches of the celiac axis as well as in the portal vein and its branches. Apparently, unique in the literature is the presence of a large arteriovenous fistula between the hepatic artery and one of the hepatic veins. The anomalies are presumed to be congenital in origin.