The prognostic significance of epidermal growth factor receptor expression in patients with anal carcinoma.

The aim of the present retrospective study was to evaluate the prognostic significance of epidermal growth factor receptor (EGFR) expression in patients treated with radiotherapy or concomitant chemoradiotherapy for squamous cell anal cancer (SCAC)Patients and methods: A total of 17 patients with SCAC (clinical stages I-III) were studies. All patients were treated with radiotherapy (total dose range 40 - 68 Gy), 13 patients received concomitant chemotherapy (7 patients mitomycin/5-fluorouracil, 5 patients cisplatine/5-fluorouracil, 1 patient cisplatine weekly). EGFR expression in the pretreatment biopsieswas assessed with imunohistochemistry.Patients with EGFR expression had significantly shorter progression free survival (PFS) (p=0.0109; HR 9.38, 95% CI 1.75 - 50.35) and overall survival (OS) (p=0.0351; HR 7.11, 95% CI 1.4 - 36.13) than patients without expression EGFR. The 4-year PFS in patients with increased EGFR expression was only 28.57% (95% CI 17.07 - 62.04%) compared to 87.5% (95% CI 64.58 - 100%) in patients without EGFR expression. The 4-year OS in patients with increased EGFR expression was only 50.0% (95% CI 15.35 - 84.65%) compared to 87.5% (95% CI 64.58 - 100.0%) in patients without EGFR expression.Patients with expression EGFR had significantly shorter PFS and OS compared with patients without EGFR expression.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers.

PURPOSE OF REVIEW: In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. RECENT FINDINGS: The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. SUMMARY: Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

BD ProEx C immunostaining in extramammary Paget's disease and perineal melanoma.

The differential diagnosis of perineal biopsies can include squamous intraepithelial lesions, extramammary Paget's disease, and melanoma. Less frequently two of these lesions coexist. BD ProEx C is a recently developed immunoassay that targets expression of two genes shown to be associated with cervical cancer. Immunostaining for ProEx C has been validated in cervical cytology and positive staining has also been shown to be strongly associated with human papilloma virus (HPV)-induced cervical and anal intraepithelial neoplasia in biopsies. We observed positive staining for ProEx C in Paget cells in all of 26 cases of Paget's disease irrespective of tissue site (extramammary, mammary) and in melanoma cells in all of 12 cases of primary perineal melanoma with immunostaining in >50% of malignant cells in 73% of Paget disease cases and 43% of perineal melanoma cases. Positive staining was heterogeneous and exclusively nuclear in all cases. In situ hybridization was negative for low-risk and high-risk HPV subtypes in all Paget and melanoma cases that were tested. Currently neither of these lesions is known to be HPV related although according to the literature the possibility of a role for HPV in melanoma is still unsettled. Relevant literature is reviewed.

Glutathione S-transferase M1 genotypes and the risk of anal cancer: a population-based case-control study.

Some studies have reported an association of the GSTM1-null genotype with the risk of smoking-related cancers, such as lung, bladder, and colon cancer. Because the risk of anal cancer is strongly associated with a history of cigarette smoking, we examined whether the GSTM1-null genotype is a susceptibility marker for anal cancer. We obtained peripheral blood specimens from residents of western Washington who were diagnosed with squamous or transitional cell tumor of the anus between April 1991 and June 1994. Eligible for inclusion were persons 18-74 years of age, with either invasive or in situ lesions. Specimens were also obtained from controls identified via random-digit dialing of western Washington households. We determined GSTM1 genotypes of 71 cases and 360 controls by PCR using primer pair 5'-AACTCCCTGAAAAGCTAAAGC-3' and 5'-GTTGGGCTCAAATATACGGTGG-3'. The frequency of the GSTM1-null genotype in controls was approximately 57%; this differed little in relation to age, sex and smoking status. The incidence of anal cancer appeared to be reduced in persons with the GSTM1-null genotype; only 39.4% of cases had this genotype (age-adjusted odds ratio = 0.5, 95% confidence interval = 0.3-0.9). This inverse association was restricted to persons who had ever smoked cigarettes and was present in both women and men (and in the latter, in both those who had and did not have a male sexual partner). Our data strongly suggest that persons with the GSTM1-null genotype are not at increased risk of anal cancer, and may well be at a decreased risk.

CYP2D6 genotype and the incidence of anal and vulvar cancer.

The risks of anal and vulvar cancer are strongly related to cigarette smoking. Smokers are exposed to a substantial quantity of tobacco-specific nitrosamines, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK is present in the mucus of the female genital tract. The enzyme debrisoquine 4-hydroxylase (CYP2D6) activates NNK and is present in foreskin kerotinocytes and cervical epithelial cells. A polymorphism for the gene CYP2D6 exists, and persons who possess alleles that are associated with reduced levels of CYP2D6 activity might be expected to be at a relatively lower risk of cancers arising from NNK exposure. To test this hypothesis, we conducted a case-control study to examine the association of CYP2D6 genotype and the incidence of anal and vulvar cancer among cigarette smokers in western Washington State. We tested for 14 alleles (*1-*12, *14, and *17) among cases (25 men and 43 women with anal cancer, 64 women with vulvar cancer) and controls (30 men and 110 women). Contrary to the hypothesis, cases were not less likely than controls to have one (43.9 versus 40.7%) or two (6.8 versus 4.3%) inactivating alleles (*3, *4, *5, *6, *7, *8, *11, or *12). There was a suggestion that, if anything, the combined anal and vulvar cancer risk increased (rather than decreased) with an increasing number of CYP2D6 inactivation alleles: odds ratio = 1.2, 95% confidence interval = 0.7-2.0 with one inactivating allele; odds ratio = 1.8, 95% confidence interval = 0.6-5.4 with two inactivating alleles. These results provide no support for the hypothesis that cigarette smokers who carry the CYP2D6 alleles that result in a low activity phenotype have a decreased risk of anogenital cancer.

Role of a DT-diaphorase mutation in the response of anal canal carcinoma to radiation, 5-fluorouracil, and mitomycin C.

PURPOSE: To determine, retrospectively, the status of the bp 609 mutation in the DT-diaphorase gene in anal canal carcinoma patients who have undergone radical radiotherapy with concurrent 5-fluorouracil (5-FU) and mitomycin C (MMC), to determine the relationship of the mutant form of the gene to treatment outcomes. METHODS AND MATERIALS: Paraffin blocks of pretreatment tumor biopsies were obtained on 49 patients who underwent treatment with curative intent using radiation, infusional 5-FU and bolus MMC from January 1991 to December 1993. DNA was extracted and subjected to polymerase chain reaction (PCR) analysis using primers that encompassed the bp 609 C to T mutation. Restriction endonuclease cleavage with Hinf 1 and gel electrophoresis were used to determine the polymorphism status of each patient. RESULTS: DNA of 46 patients was successfully amplified. The 46 patients were distributed as follows: 26 (56.5%) C/C-homozygous wildtype, 18 (39%) T/C-heterozygous, and 2 (4.5%) T/T-homozygous mutant. Eleven of 46 patients had suffered treatment failure. The status of the bp 609 polymorphism in this group was 5 (45.5%) C/C, 5 (45.5%) C/T, and 1 (9%) T/T. CONCLUSION: In this series, there was not an overrepresentation of the mutant allele in patients with treatment failure, suggesting that the bp 609 alteration is not a strong determinant of treatment outcome.

20 alpha-hydroxysteroid dehydrogenase activity in canine spontaneous neoplasms.

20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD) activities in 57 neoplastic tissues surgically removed from dogs were measured. Forty-eight of 57 tumor samples were shown to possess 20 alpha-HSD activity. These tissues were histopathologically classified into 22 benign and 26 malignant tumors. Among these tumors, mixed tumor types demonstrated the higher 20 alpha-HSD activity than epithelial and non-epithelial types, and malignant tumors of each tissue type showed slightly but not significantly higher 20 alpha-HSD activities comparing with the corresponding benign ones. Comparing with the activity of normal tissues examined, the corresponding tumor tissues showed significantly higher 20 alpha-HSD activities. Thus, 20 alpha-HSD activity was found in neoplastic tissues at a considerable high rate and the activity seemed to be higher in pathologically malignant tumors.