Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer.

Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.

Vascular invasion in non-small cell lung carcinoma.

AIMS: To determine if there is any correlation between vascular invasion and prognosis in non-small cell carcinoma of the lung; and to look specifically at invasion of vascular channels by tumour cells. METHODS: Eighty seven patients undergoing lobectomy or pneumonectomy for adenocarcinoma or squamous carcinoma were followed up for five years. The histological sections were studied for evidence of vascular invasion using an elastic van Gieson stain. The incidence of intimal fibrosis in arteries and veins was noted and the proportion with vascular invasion evaluated using a scoring system. The presence or absence of lymphatic permeation and tumour necrosis were noted. Survival data were analysed using the log rank test. RESULTS: The overall five year survival was 32%. There were 64 squamous cell carcinomas and 23 adenocarcinomas. Vascular invasion was seen in 77% of patients and lymphatic invasion in 44%. Neither the presence nor absence nor the proportion of blood vessels showing vascular invasion showed any relation to prognosis. Intimal fibrosis and tumour necrosis were unrelated to prognosis. Patients with lymphatic permeation had recurrence and died earlier than those without. CONCLUSION: The presence of arterial or venous invasion by adenocarcinoma or squamous carcinoma of the lung was unrelated to survival; lymphatic permeation was associated with poor prognosis. The two common non-small cell lung cancers behaved differently from other solid tumours, where vascular invasion was a significant factor in determination of prognosis. The presence of intimal fibrosis was unrelated to prognosis.

Campylobacter pylori: clinical, histological, and serological studies.

The presence of Campylobacter pylori, histologically diagnosed gastritis, and antibodies to C pylori were determined in a series of 113 patients undergoing endoscopy. Paired biopsy specimens from the fundus, body, and antrum were collected from 59 patients and from the antrum of 54 patients. The presence of C pylori was confirmed by either culture or silver stain in 30 of 59, 31 of 59, and 54 of 103 biopsy specimens from the fundus, body, and antrum, respectively. Of the specimens which contained C pylori 20 of 30 (66%) from the fundus, 25 of 31 (80%) from the body, and 54 (100%) from the antrum showed gastritis. C pylori and gastritis were shown in seven of nine (78.1%) of patients with gastric ulcers and in nine of 11 (82%) of patients with duodenal ulcers. Using an enzyme linked immunosorbent assay (ELISA) technique to detect IgG antibody to C pylori, all patients with histologically diagnosed gastritis and organisms present had titres of greater than or equal to 640; eight of 39 (21%) of patients without gastritis and without organisms gave similar titres. Hence the presence of C pylori was associated with gastritis and with raised titres of IgG antibody.

Prognostic significance of cyclin D1 gene (CCND1) polymorphism in epithelial ovarian cancer.

We have investigated the influence of CCND1 genotype on clinical outcome in 138 women with epithelial ovarian cancer. CCND1 genotypes were identified from peripheral blood DNA by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Patient CCND1 genotypes were compared with clinical details including FIGO tumor stage, residual tumor volume, tumor histology and differentiation, response to chemotherapy, progression free interval, and survival. We observed no association between patient CCND1 genotypes and tumor characteristics or response to chemotherapy. There was no significant difference in overall survival and progression free interval (PFI) among women with different CCND1 genotypes. However, analysis of data from patients who responded to postoperative chemotherapy revealed that women with CCND1 AA genotype were associated with early disease progression (P = 0.020, HR 4.58, 95% CI 1.27-16.48) and reduced survival (P = 0.026, HR 4.48, 95% CI 1.19-16.79) compared with those with CCND1 AG and GG genotypes. These data show that CCND1 genotype does not influence overall prognosis in a cohort of epithelial ovarian cancer patients, however, it is associated with disease progression in a subgroup of patients following initial response to chemotherapy.

Polyarthritis, rash and lymphadenopathy: case reports of two patients with angioimmunoblastic lymphadenopathy presenting to a rheumatology clinic.

Two patients presented with a symmetrical inflammatory polyarthropathy. Both patients fulfilled the diagnostic criteria for angioimmunoblastic lymphadenopathy. We present the two case histories and review the current literature. Although an uncommon disease, the diagnosis of angioimmunoblastic lymphadenopathy should be considered in a patient presenting with polyarthritis and skin rash.

Echocardiographic diagnosis of multiple congenital aneurysms of the sinus of Valsalva.

Aortic regurgitation developed in a 56 year old man with severe nephrotic syndrome. Cross sectional echocardiography showed bilateral aneurysms of the sinus of Valsalva and a bicuspid aortic valve. He died of intercurrent pneumonia. Postmortem examination confirmed the presence of the congenital aneurysms.

Spindle cell stromal tumour of the rectum treated by restorative resection.

Stromal tumours of the rectum and anal canal are rare, representing 0.02-0.03% of malignant neoplasms in the region. Current advice in their management is treatment by abdomino-perineal resection. We report a case of malignant spindle cell stromal tumour in which adequate clearance was obtained whilst preserving the anal sphincter, using a posterior parasacral approach.

Glomus tumor of the lip. A case report and immunohistochemical study.

A rare glomus tumor of the lip is reported and--with nineteen glomus tumors from other sites--examined immunohistochemically with both monoclonal and polyclonal antibodies. In every case, the glomus cells showed strong reactivity with antivimentin, and factor VIII-related antigen was consistently identified in the endothelial cells but not in the glomus cells. Antiblood group A antigen was located in endothelial cells in nine cases; of these nine, five also showed focal staining in glomus cells. In no case was there reactivity with antibodies to common leukocyte antigen or cytokeratin proteins. These results support the hypothesis of Tajima et al. that the glomus cell is transitional--between smooth muscle and vascular endothelium--being essentially a modified, smooth muscle cell with some endothelial cell properties.

Naloxone and mortality in the gerbil stroke model.

Endorphins and narcotics have been implicated in the exacerbation of neurologic deficits after stroke. To test the theory that narcotic antagonists might offer an improvement in neurologic sequelae following stroke, we administered various doses of naloxone intraperitoneally to 50 adult gerbils 45 minutes after carotid artery transsection. Low-dose naloxone therapy (1.0 to 2.5 mg/kg) was more effective in preventing death than either control (sterile saline) or high-dose naloxone (10 mg/kg). A naloxone dose of 1.0 or 2.5 mg/kg offered a significant improvement in mortality over both the control and the high-dose therapy (P = .026). It appears that an appropriate dose of naloxone (1.0 to 2.5 mg/kg), given early enough to alter outcome, offers an improved survival in the gerbil stroke model. This finding obviously has significant implications for the use of narcotic antagonists in human beings with stroke.

Epithelial ovarian cancer: influence of polymorphism at the glutathione S-transferase GSTM1 and GSTT1 loci on p53 expression.

The importance of polymorphism in the glutathione S-transferase GSTM1, GSTT1 and, cytochrome P450, CYP2D6 loci in the pathogenesis of epithelial ovarian cancer has been assessed in two studies; firstly, a case-control study designed to determine the influence of these genes on susceptibility to this cancer, and secondly, the putative role of these genes in the protection of host cell DNA has been studied by comparing p53 expression in patients with different GSTM1, GSTT1 and CYP2D6 genotypes. The frequencies of GSTM1, GSTT1 and CYP2D6 genotypes in 84 cases and 325 controls were not different. Immunohistochemistry was used to detect p53 expression in 63 of these tumours. Expression was found in 23 tumours. Of the patients demonstrating immunopositivity, 20 (87%) were GSTM1 null. The frequency distributions of GSTM1 genotypes in p53-positive and -negative samples were significantly different (P = 0.002) and those for GSTT1 genotypes approached significance (exact P = 0.057). The proportion of patients with both GSTM1 null and GSTT1 null was also significantly greater in the immunopositive (4/22) than in the immunonegative group (1/40) (P = 0.0493). Single-strand conformational polymorphism (SSCP) analysis was used to detect mutations in the 23 tumour samples demonstrating p53 positivity. A shift in electrophoretic mobility of amplified fragments was found in 11 patients (exons 5, 6, 7 and 8) and these exons were sequenced. In eight samples a mutation was found. No SCCP variants were identified in the other 12 immunopositive patients. Sequencing of exons 4-9 of p53 from these tumours resulted in the detection of mutations in two patients (exons 5 and 7). Thus, in 23 patients who demonstrated immunopositivity, p53 mutations were found in nine patients with GSTM1 null (90.0%). In the 13 patients in whom no mutations were identified, 11 were GSTM1 null (84.6%). The data show that overexpression of p53 is associated with the GSTM1 null genotype. We propose the data are compatible with the view that GSTM1 and GSTT1 are critical in the detoxification of the products of oxidative stress produced during the repair of the ovarian epithelium. Thus, failure to detoxify products of this stress may result in damage to various genes in the host cell, including to p53, resulting in persistent expression of mutant protein. In other patients, oxidative stress effects damage to various genes, but not including p53, resulting in overexpression of wild-type p53.

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells.

The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCND1 was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.