Correlation of recurrence rates and times with posttreatment human papillomavirus status in patients treated with loop electrosurgical excision procedure conization for cervical squamous intraepithelial lesions.

The aim of the present study was to assess recurrence rates and times in patients with squamous intraepithelial lesion (SIL) of the uterine cervix treated with loop electrosurgical excision procedure (LEEP) conization, in order to define categories of patients who have a different risk of recurrence and who need a different surveillance protocol. This study was carried out on 119 consecutive patients who underwent LEEP. All patients were followed up with cervical smear and colposcopy after 3, 6, and 12 months in the first-year posttreatment, and every 6-12 months afterwards. Human papillomavirus (HPV) testing was performed at the time of LEEP and repeated 3-6 months later. The histologic examination of LEEP specimens revealed stage IA1 squamous cell cervical cancer in 4 (3.4%) cases, high-grade SIL in 75 (63%) cases, and low-grade SIL in 40 (33.6%) cases. The four patients with stage IA1 cervical cancer were not included in the further analyses. Disease recurred in none of the 50 patients with negative posttreatment HPV testing, in 4 (9.3%) of the 43 patients with positive posttreatment HPV testing and negative surgical margins, and in 8 (36.4%) of 22 patients with positive posttreatment HPV testing and positive margins. The combined evaluation of surgical margin status and posttreatment HPV testing could allow to subdivide patients treated with LEEP into categories at different risk of recurrence, requiring new tailored surveillance procedures.

HPV testing and Pap test: role for a combined approach in a non-screened population.

The aim of the present study was to test the polymerase chain reaction (PCR) as a tool to identify human papillomavirus (HPV) in routine cytological samples scraped from the uterine cervix. Moreover, attention has been focused on the correlation between HPV types and early intraepithelial lesions. The study involved 586 women who had undergone conventional Pap test. Analysis of HPV infection was performed by PCR and HPV typing by dot blot. In a group of 78 cases histologically diagnosed as high-grade squamous intraepithelial lesions (HSILs), the cytological diagnosis was correct in 92.3% and the HPV test was positive in 89.8% of cases; combined positivity at Pap and/or HPV tests raised this figure to 99.0%. In a group of 67 cases histologically diagnosed as low-grade squamous intraepithelial lesions (LSILs), the cytological diagnosis was correct in 73.1% and the PCR-based HPV test was positive in 64.2%; combined positivity at Pap and/or HPV tests raised this figure to 91.0%. This study confirms the limitations of screening programs based on Pap test only. Our results suggest, in fact, that adding the HPV test to primary screening could increase the yield of preinvasive cervical lesions.

The defective transforming phenotype of c-Jun Ala(63/73) is rescued by mutation of the C-terminal phosphorylation site.

Cotransfection of primary rat embryo fibroblasts (REF) with c-Jun and activated Ras leads to oncogenic transformation and this process requires the phosphorylation of the N-terminal domain of c-Jun. Ras augments this phosphorylation and, consequently activates the c-Jun transactivation property of TRE (TPA Responsive Element)-dependent promoters. To analyse the role of the c-Jun C-terminal phosphorylation site in oncogenic cooperation we tested the activities of N-terminal c-Jun Ala(63/73) (named Nt), C-terminal c-Jun Ala(234/242/246/252) (named Ct) and (Nt+Ct)-with both mutations-non-phosphorylatable c-Jun mutants. In cooperation with Ras, the Ct mutant and wt c-Jun display similar oncogenic properties whereas the Nt form was defective in transforming REF cells. Unexpectedly, the Nt+Ct mutant exhibited identical oncogenic properties to wt c-Jun, demonstrating that the Ct mutation rescues in cis the Nt mutation. The transcriptional activity and the capacity to bind the c-Jun coactivator CREB Binding Protein (CBP) were enhanced by Ras for the wt and Ct proteins but not for the Nt mutant. Interestingly, the Nt+Ct mutant presents identical transactivation and CBP binding activities to wt c-Jun. Therefore the rescue in cis of the defective Nt mutation by the Ct mutation seems to be due to the recovery of CBP binding. Our results revealed that the process of oncogenic cooperation can occur between Ras and the Nt+Ct non-phosphorylatable c-Jun protein.

Clinical ability of Heidelberg retinal tomograph examination to detect glaucomatous visual field changes.

PURPOSE: To determine the agreement between Heidelberg Retinal Tomograph (HRT; Heidelberg Instruments, Heidelberg, Germany) and visual field examinations in differentiating normal from glaucomatous eyes and to evaluate the sensitivity and specificity of HRT optic disc examination in detecting eyes with glaucomatous damage. STUDY DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred fifty-nine patients, for a total of 359 eyes (55 normal, 209 with ocular hypertension [OHT], and 95 with primary open-angle glaucoma). INTERVENTION: Optic disc imaging by HRT, using a 10 degrees angle view; a mean of three repeated images were analyzed using version 2.01 software. The optic disc was classified as "normal/glaucomatous" on the basis of multivariate discriminant analysis and cumulative frequency distribution (ranked-segment distribution curves). The visual field was examined using the DS 30 II program (Humphrey perimeter, Zeiss Humphrey System, Dublin, CA), with a glaucomatous visual field being defined on the basis of an abnormal glaucoma hemifield test and a statistically significant corrected pattern standard deviation less than 4 dB. MAIN OUTCOME MEASURES: Agreement between HRT and visual field examinations calculated by means of the kappa statistic and the sensitivity and specificity of HRT examination. RESULTS: The agreement between the visual field-based and HRT definition of glaucoma was fair to poor, with a kappa statistic of between 0.48 and 0.28. The sensitivity and specificity of the HRT examination were, respectively, 80% and 65%, according to Mikelberg's analysis, and, respectively, 31% to 53% and 90% to 92%, according to the analysis based on cumulative curves of normality. CONCLUSIONS: In a broad clinical setting including normal, OHT, and glaucoma patients, the HRT and visual field tests have fair to poor agreement in detecting glaucoma. The HRT demonstrated a lack of specificity when using Mikelberg's multivariate discriminant analysis and a lack of sensitivity when using cumulative frequency distribution (ranked-segment distribution) curves. These values did not change when normal or OHT patients were excluded from the analysis. In the clinical setting, caution should be used when interpreting HRT results on the basis of multivariate discriminant analysis or cumulative frequency distribution curves.

Is proper methodology associated with the use of a clinically relevant outcome measure? The case of randomized clinical trials on medical treatment of open-angle glaucoma.

OBJECTIVE: The aim of this study was to assess critically the published literature concerning medical treatment of primary open-angle glaucoma (POAG), and to see whether trial methodologic quality was related to a clinically relevant outcome measure. METHODS: We identified and reviewed the methodologic quality of 102 published randomized clinical trials (RCTs) on treatment of POAG using an explicit protocol and explored the association between selected aspects of design and conduct and the studies' clinical relevance. RESULTS: Our analysis revealed serious methodologic problems with the trials reviewed. Areas of major concern were: use of unsatisfactory or unspecified methods of randomization (89% of the trials reported no information), exclusion of some patients from the analysis (53% of the studies), failure to provide evidence of having estimated the number of patients needed to detect a prespecified treatment difference (96% failed to provide such an estimate), and incomplete description of patient characteristics (in 39% of the RCTs information on this item was insufficient). Within this generally unsatisfactory picture we found, however, that those studies adopting a double-masked design and those not excluding patients after randomization followed patients for longer periods of time and assessed treatment effectiveness using a clinically relevant outcome (that is, visual field changes) compared to other studies. CONCLUSIONS: For clinicians to make use of the results of clinical trials, future studies must be adequately designed and conducted. In particular, proper method of randomization, masking of the observers, and inclusion of all randomized patients in the analysis must be used. Of perhaps even greater importance is the need for trials to measure clinically relevant outcomes.

Randomized clinical trials on medical treatment of glaucoma. Are they appropriate to guide clinical practice?

A systematic quantitative and qualitative overview of published randomized clinical trials was undertaken to assess the yield of medical treatment on the outcome of patients with primary open angle glaucoma. Reports of 102 randomized clinical trials were published between 1975 and 1991, totalling about 5000 patients. Only 16% (16/102) of the trials were, however, properly designed (ie, comparing an active treatment with a placebo-treated or untreated control group) to answer the question of whether any medical treatment can effectively cure patients with primary open angle glaucoma. Pooled analysis showed a moderate yet statistically significant reduction in mean intraocular pressure (-4.9 mm Hg; 95% confidence interval [CI], -7.3 to -2.5 mm Hg); however, data on long-term visual field changes were available in only three randomized clinical trials, and their statistical combination failed to show a significant protective effect of active treatment (odds ratio, 0.75; 95% CI, 0.42 to 1.35). All of the remaining 86 randomized clinical trials looked at the effectiveness of one drug vs another in lowering intraocular pressure and were thus of no use in the overview. Practicing ophthalmologists should be aware that the effectiveness of pressure-lowering agents in the treatment of primary open angle glaucoma is still to be determined and that the vast majority of published trials are not appropriate to guide clinical practice. It is urgent to plan trials with end-point and follow-up duration that is fully relevant for the health of patients.