Large performance variation does not affect outcome in the Finnish cervical cancer screening programme.

OBJECTIVE: Cytology screening for prevention of cervical cancer can reduce incidence and mortality by more than 80% in settings with good organization and rigorous quality control. Audit studies are essential for reaching and maintaining a high quality of screening. The aim of this study was to evaluate variation in performance indicators by screening laboratory and assess the impact on the effectiveness of screening as indicated by cervical intraepithelial neoplasia grade 3 and above (CIN3+) rates after a negative screen. METHODS: Seven cytology screening laboratories operating during 1990-1999 with a total of 953 610 screening tests performed were included in the study. By linking screening and cancer register files, all cases of CIN3+ diagnosed in the screened population were identified. For 395 CIN3+ cases with a preceding negative screen and 787 controls, a re-evaluation of smears was undertaken to uncover false negative screening tests. Performance parameters and rates of CIN3+ after a negative screen were analysed for interlaboratory heterogeneity. RESULTS: The rates of follow-up recommendations and referrals varied by up to 3.6- (2.8-10.2%) and 4.0-fold (0.03-0.12%), respectively. CIN1, CIN2 and CIN3+ screen detection rates differed by up to 8.5- (0.02-0.17%), 5.4- (0.05-0.25%) and 3.3-fold (0.05-0.18%). False negative rates determined by re-evaluation showed up to 2.1-fold differences (29-62%). Rates of CIN3+ after a negative screen (0.023-0.048%) and as a proportion of total CIN3+ (15-31%) in the screened population were low and did not vary significantly. CONCLUSIONS: There were large variations in the sensitivity-specificity trade-off between laboratories, reflected in all performance indicators as well as in the test validity estimates of the re-evaluation phase, but not in screening effectiveness. Even though performance variations do not always have an impact on the effectiveness of screening, they lead to variations in cost, treatment and psychological burden, and should be addressed.

Recurrences after immediate reconstruction in breast cancer.

AIM: To determine the incidence of and reasons for recurrences after immediate breast reconstruction in breast cancer patients. MATERIAL AND METHODS: The data of 79 patients undergoing immediate breast reconstruction between 1998 and 2001 in Kuopio University Hospital were re-examined from both the local cancer register and the patient charts at the end of year 2003. RESULTS: There were five local recurrences (6.3%), one regional recurrence (1.2%), and three cases (3.8%) presented bone and/or visceral metastases. All recurrences except one (primary tumor noninvasive) appeared within the first two years after primary therapy. Young age and increasing size of the tumour were risk factors for distant or logoregional metastases. CONCLUSION: Immediate breast reconstruction is a safe procedure in breast cancer patients, but a multidisciplinary team is needed for careful patient selection.

Expression of retinoblastoma gene protein (Rb) in breast cancer as related to established prognostic factors and survival.

The expression of retinoblastoma gene product (Rb protein) was studied by immunohistochemical analysis of 205 cases of breast cancer. Rb protein was invariably expressed in non-neoblastic breast epithelium, in dysplastic and hyperblastic lesions adjacent to tumours, and none of the breast tumours was totally negative for Rb protein. According to the scoring system used, the expression of Rb protein was abnormal in 36.6% of cases. Abnormal expression of Rb protein was significantly related to grade (P < 0.00004), type (P = 0.0183), margin formation (P = 0.0116), DNA ploidy (P < 0.0002) and nuclear pleomorphism (P < 0.0001). Abnormal expression of Rb protein was related to high S phase fraction (P = 0.004), high mitotic index (P < 0.001) and high morphometric nuclear factor values (P < 0.01). The expression of Rb protein had no prognostic value in univariate or multivariate analysis. The results show that the tumour suppressor gene Rb participates in the growth regulation of breast cancer cells in vivo, but immunohistochemical assessment of the expression of Rb protein has no prognostic significance in clinical breast cancer over already established prognostic factors.

The important prognostic value of Ki-67 expression as determined by image analysis in breast cancer.

A series of 191 female breast carcinomas (with long-term follow-up) were analysed immunohistochemically (with a monoclonal MIB1 antibody) for Ki-67 (a proliferation marker) expression with special reference to well-established prognostic factors and patient survival. Expression of Ki-67 was directly related to the S-phase fraction (P < 0.0001), the volume-corrected mitotic index (P < 0.0001), histological grade (P < 0.0001), the apoptotic index (P < 0.0001), oestrogen and progesterose receptor content (P < 0.0001 for both) and p53 accumulation (P = 0.001). No correlation was found between Ki-67 expression and lymph node status (P = 0.25), metastasis at operation (n = 0.81) or tumour size (n = 0.38). The proliferation rate, as measured by image analysis of Ki-67 expression, predicted survival in the entire cohort (P = 0.001) and in axillary-lymph-node-negative (ANN) patients (P = 0.003). The difference in recurrence-free survival between the high- and low-expression groups was greatest in ANN tumours, 40% (P = 0.008). In axillary-lymph-node-positive tumours, the Ki-67 expression was not significantly related to recurrence-free survival (P = 0.723). The results of multivariate survival analysis showed that tumour size, axillary lymph node status, and mitotic index were independent prognostic factors in the entire series whereas, in ANN cases, tumour size and Ki-67 labelling were independent prognostic factors. These findings imply that Ki-67 expression could be an important prognostic determinant in breast cancer. Because of the evident loss of the predictive power of tumour size in the 1990s, the prognostic value of Ki-67 expression may even be accentuated in the currently diagnosed small breast carcinomas.

The surgical and oncological safety of immediate breast reconstruction.

AIM: The aim of our study was to (1) examine the incidence of surgical complications, (2) determine the incidence of loco-regional recurrences and (3) examine the safety of saving the nipple-areola-complex after immediate breast reconstructions in breast cancer. METHODS: Sixty-six immediate breast reconstructions were performed. Wide local excision (WLE), skin sparing mastectomy and subcutaneous mastectomy (SCM) were performed to 12, 20 and 34 patients, respectively. In all patients with WLE the reconstruction was performed with the latissimus dorsi (LD) miniflap. In other patients reconstructions were done with a free TRAM-flap (n=26) LD-flap (n=27) or with a prosthesis only (n=1). RESULTS: Major flap necrosis developed in four patients. Local recurrence rate was 8.3% in the group where nipple-areola-complex was removed and 7.1% in the group where nipple-areola-complex was saved. Metastases were found in 12.5 and 0%, respectively. CONCLUSION: SCM compared to skin sparing mastectomy may lead to an enhanced risk of immediate surgical complications, but does not threat the oncological safety. Saving the nipple-areola-complex in immediate breast reconstructions is possible in early breast cancer, if the tumour is not in the central part of the breast.

Expression of c-myc proteins in breast cancer as related to established prognostic factors and survival.

The expression of c-myc proteins was analysed immunohistochemically in a series of 206 breast carcinomas with special focus on established prognostic factors and patient survival. Nuclear expression of c-myc proteins was detected in 12% of carcinomas, and it was related to the lack of estrogen receptors (p = 0.05). Cytoplasmic expression of c-myc was present in 95% of the tumours. Expression of cytoplasmic c-myc at the invasive margin was related to tumour grade (p = 0.0013), low mitotic index (p = 0.0002) and low S phase fraction (p = 0.026), and weakly associated with distant metastasis at diagnosis (p = 0.06) and to a high proportion of intraductal growth (p = 0.08). Long recurrence-free survival of the patients was related to strong cytoplasmic expression of c-myc at the invasive margin in the entire series (p = 0.0049) and in axillary lymph node-negative (ANN) (p = 0.0028) tumours. Cytoplasmic c-myc expression in the central areas of the tumour predicted metastasis at diagnosis (p = 0.002), non-ductal type of growth (p = 0.018) and low mitotic index (p = 0.005). Expression of c-myc in the stroma was related to the lack of estrogen receptors (p = 0.02) and to high S phase fraction (p = 0.01). The results show that overexpression of c-myc is involved in a highly complex manner with the early stages of breast cancer development, but it shows hardly any independent prognostic value over standard prognostic factors in clinical disease.

WNT-4 mRNA expression in human adrenocortical tumors and cultured adrenal cells.

The members of the Wnt glycoprotein family are important in embryogenesis and adult tissue homeostasis, and deletion of WNT-4 gene in mice leads to improper development of many organs including the adrenals. The objective of this study was to investigate the expression of WNT-4 gene in human adrenals and adrenocortical tumors. The WNT-4 mRNA expression (analyzed by quantitative real-time RT-PCR) was significantly higher in Conn's adenomas (p<0.01) and lower in Cushing's adenomas, virilizing carcinomas and fetal adrenals (p<0.05) compared with normal adult adrenals. WNT-4 mRNA expression was clearly upregulated by ACTH and 8-bromo-cAMP (8-BrcAMP) in primary cultures of normal adult adrenocortical cells, but downregulated by 8-BrcAMP and 12- O-tetradecanoylphorbol-13-acetate (TPA) in human NCI-H295R adrenocortical carcinoma cells. Angiotensin II tended to increase WNT-4 mRNA expression at 24 hours and decreased it at 48 hours time point in both cell culture types. The abundant WNT-4 mRNA expression in Conn's adenomas and its hormonal regulation in adrenocortical cells suggest a role for WNT-4 in human adrenocortical function.

Ketoprofen 2.5% gel versus placebo gel in the treatment of acute soft tissue injuries.

A parallel, double-blind, placebo controlled and randomized study in a single center was done with ketoprofen 2.5% gel to treat acute soft tissue injuries. Patients applied the gel twice a day for seven days, corresponding to 250 mg of ketoprofen per day. Assessments were made on the third and seventh day by VAS, subjective evaluation and pain threshold algometry. The study group consisted of 29 patients and the control group 27 patients. Pain at rest was significantly relieved in the ketoprofen group, whereas in the placebo group the difference was not significant. In terms of side-effects, no difference between the groups was noticed. In both groups, local dermal irritation was found. Our results suggested that ketoprofen 2.5% gel was safe and superior to placebo in the treatment of soft tissue injuries.

Expression of p53 protein has no independent prognostic value in breast cancer.

A series of 392 female breast carcinomas was analysed immunohistochemically for expression of p53 protein with special emphasis on the role of p53 as an independent prognostic factor. Altogether, 54.8 per cent of the carcinomas expressed p53 protein, with the mean [standard error (SE)] fraction of positive nuclei being 17.1 per cent (1.2 per cent). Expression of p53 protein was independent of tumour metastasis at diagnosis, axillary lymph node status, tumour diameter, histological type, tubule formation, proportion of intraductal growth, margin formation, necrosis, DNA ploidy, and S-phase fraction. A high fraction of p53-positive nuclei was significantly related to patient age under 70 years, high grade, severe nuclear pleomorphism, dense infiltration of tumour by lymphocytes, high mitotic index, and high apoptotic index (for all, P < 0.05). Impaired survival probability in the entire cohort (P = 0.05) and in the axillary lymph node-positive (ANP) tumours (P = 0.015) was associated with a fraction of p53-positive nuclei less than 25 per cent, while in the axillary lymph node-negative (ANN) tumours, expression of p53 had no prognostic value. In multivariate analysis, independent prognostic predictors included axillary lymph node status, tumour diameter, and mitotic index. In the ANN tumours, tumour diameter, fraction of p53-positive nuclei, and tumour grade were independent prognostic factors, whereas in the ANP tumours, diameter and mitotic index were the two independent prognostic factors. The results suggest that abnormal expression of p53 protein is only a weak independent prognostic factor in female breast cancer.

Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis.

The expression of bcl-2 protein was analysed immunohistochemically in 202 female breast carcinomas. The intensity of bcl-2 expression was inversely related to tumour grade (P < 0.0001), tumor necrosis (P < 0.0001), mitotic index (P < 0.0001), oestrogen receptor content (P < 0.0001), progesterone receptor content (P = 0.0007), S-phase fraction (P = 0.00047), and apoptotic index (P = 0.087). A high fraction of bcl-2-positive cells was related to ductal or lobular type (P = 0.03) and slight nuclear pleomorphism (P = 0.03). Heterogeneous expression of bcl-2 protein was associated with high grade (P = 0.02), severe nuclear pleomorphism (P = 0.02), DNA aneuploidy (P = 0.018), high S-phase fraction (P = 0.05), and early metastasis (P = 0.03). Intense expression of bcl-2 protein was significantly related to favourable outcome in the entire cohort (P = 0.0013), as well as in axillary lymph node-negative (ANN) tumours (P = 0.0124). Long recurrence-free periods in the entire cohort (P = 0.037) and in ANN tumours (P = 0.08) were confined to cases with intense expression of bcl-2 protein. In multivariate analysis, bcl-2 expression had no independent prognostic value in the entire cohort or in axillary lymph node-negative breast carcinomas, whereas it was a weak independent prognostic factor in axillary lymph node-positive breast carcinomas.

The morphological, in situ effects of a self-reinforced bioabsorbable polylactide (SR-PLA 96) ureteric stent; an experimental study.

PURPOSE: The present study was done to evaluate the biocompatibility of a new biodegradable double helical spiral self-reinforced poly-L, D-lactide copolymer (L/D ratio 96/4, SR-PLA96) ureteric stent. MATERIALS AND METHODS: In sixteen dogs, the right ureter was cut transversally, sutured and stented with a 50 mm. long SR-PLA 96 stent. In eight dogs, left ureter was similarly operated and stented with a double-J pigtail stent (C-Flex, Cook Urological Inc.), while eight remaining ureters served as plain controls. Urine was analyzed for signs of infection. The dogs were terminated at 6, 12 and 24 weeks postoperatively and the ureters dissected to find persistent SR-PLA 96 particles or local ureteric changes. Histologic samples were taken at three levels of dissected ureters in contact with the stent. RESULTS: C-Flex and SR-PLA 96 materials were well tolerated. Both of these induced only minimal ureteral wall edema, epithelial hyperplasia, epithelial destruction and inflammatory cell reaction. In SR-PLA 96 stented ureters the tissue reaction subsided after the degradation of the device. CONCLUSIONS: SR-PLA 96 spiral stent is regarded highly compatible and SR-PLA 96 might be a suitable material for a partial ureteric stent. Biodegradation of a SR-PLA 96 stent makes stent removal unnecessary.

Application of a self-reinforced polyglycolic acid (SR-PGA) membrane to the closure of an abdominal fascial defect in rats.

The suitability of a polyglycolic acid (PGA) membrane to fascial closure was tested in 40 rats. To induce collagen synthesis, a fascial strip from the vastus lateralis muscle was applied to the peritoneal side of the PGA membrane. A midline laparotomy was performed, and the incision was covered with the membrane fixed at the edges. The animals were sacrificed at 3, 6, 12, and 28 weeks, at which time macroscopical, histological, and electron microscopical findings, as well as the results of breaking force tests were evaluated. Fascial augmentation had no effect on the results. Ventral hernias were observed in 37.5% of the cases, half of which were observed after 6 weeks postoperatively. In one case, intestinal adhesions to the membrane were found. Inflammatory reaction during the follow-up was moderate and lasted up to 12 weeks. Breaking force decreased up to 6 weeks, after which it slightly increased without reaching the breaking force level of the control animals.

p22/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis.

p21/WAF1 expression was studied in a series of 162 colorectal carcinoma patients and its relation to p53- and activator protein (AP)-2 expressions and to stage as well as survival was assessed. p21 expression was moderate or intense in 33% of the tumours, and 53% of the tumours had moderate or strong p53 staining intensity. Eighty-nine percent of the tumours showed a weak cytoplasmic AP-2 signal. As expected, p21 and p53 stainings were inversely related to each other (P < 0.001). There was a significant positive association between p21 and AP-2 expression levels (P= 0.01). p21 intensity and percentage were higher in Dukes' A and B stages (P< 0.001). The cancer-related survival and recurrence-free survival (RFS) rates were significantly lower among patients with a low signal for p21 (P< 0.001) and low p21 percentage in tumour epithelium (P < 0.001). High p53 staining intensity in tumour epithelium predicted poor survival (P = 0.01) and RFS (P = 0.003). In the multivariate analysis, p21 percentage distribution independently predicted cancer-related survival in all cases, and p21 expression intensity in T1-4/N0-3/M0 and T1-3/N0/M0 cases. p21 percentage distribution was an independent predictor of RFS in all and T1-3/N0/M0 cases. AP-2 staining did not reach any prognostic significance. These results suggest that the immunohistochemical detection of cyclin-dependent kinase inhibitor p21 could be used to predict more precisely the outcome of colorectal cancer patients.