Factors related to long-term renal transplant function in children.

Short-term renal allograft survival in children has improved. It is therefore important to determine the factors leading to long-term graft function. To this end, we evaluated patients in the NAPTRCS registry who were <12 years old when they received their renal transplant between 1987 and 1993. Children with 10 years of post-transplant follow-up were compared to those in whom the transplant failed within 10 years. Children with a failed transplant within 10 years of the surgery tended to be older, female, and non-Caucasian; they also manifested obstructive uropathy less often and had focal segmental glomerulosclerosis more often, and they received more deceased donor kidneys. Children with a failed renal transplant had fewer HLA donor and recipient matches, received pre-transplant dialysis compared to a preemptive transplant, required dialysis in the first week post-transplant, and required more antihypertensives the first month post-transplant. Allograft function was examined at 10 years. Patients with continued allograft function and a serum creatinine

Recombinant growth hormone use pretransplant and risk for post-transplant lymphoproliferative disease--a report of the NAPRTCS.

rhGH, widely used to optimize linear growth in children with ESRD, also modulates B-cell precursor development and may be associated with malignancy development. To determine if rhGH use in children was associated with higher risk of PTLD, we analyzed retrospectively collected data on children with CRI, on dialysis or with renal transplants in a large multi-center registry of children with ESRD. Of the 194 LPD patients currently listed in the registry, 41 were previously enrolled in the CRI registry and 18/41 (43.9%) used rhGH during their period with CRI. Among CRI patients who later received a transplant, rates of PTLD post-transplant were significantly higher among rhGH users (18/407 or 4.4%) compared to patients who never used rhGH during their CRI follow-up and received a transplant (23/1240 or 1.9%, p = 0.009). After adjusting for the confounders of recipient age (at CRI and at transplant) and transplant era, the use of rhGH pretransplant was associated with a borderline higher risk for PTLD (odds ratio 1.88, 95% CI = 1.00-3.55, p = 0.05). In contrast, use of rhGH during dialysis or post-transplant only was not associated with a higher risk for PTLD. Continued monitoring is recommended.

BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry.

BACKGROUND AND OBJECTIVES: There is limited information regarding BK virus nephropathy in pediatric kidney transplantation. The objective of this study was to evaluate cases of BK virus nephropathy in the North American Pediatric Renal Trials and Collaborative Studies database. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a questionnaire that was sent to North American Pediatric Renal Trials and Collaborative Studies centers, we assessed the incidence, risk factors, clinical features, and outcomes of BK virus nephropathy in pediatric renal transplant recipients who received a transplant between 2000 and 2004. RESULTS: BK virus nephropathy was reported in 25 (4.6%) of 542 patients at a median onset of 10.1 mo after transplantation. The median age was 11 yr. All patients who were tested reported BK viruria, and 19 (91%) of 21 who had plasma tested reported BK viremia. Treatment of BK virus nephropathy included reduction of immunosuppression (84%), cidofovir (24%), leflunomide (8%), and intravenous Ig (20%). Simultaneous rejection treatment was reported in four (16%). The median creatinine was 2.0 mg/dl at a mean follow-up of 24 mo. There were six (24%) graft failures in the patients with BK virus nephropathy at a mean of 24 mo after diagnosis. Rejection occurred in eight (32%) after diagnosis. Multivariate analysis showed that use of polyclonal induction therapy and zero HLA DR mismatch were associated with the development of BK virus nephropathy. CONCLUSIONS: This first multicenter, retrospective, cohort study of BK virus nephropathy in pediatric renal transplant recipients found a BK virus nephropathy incidence of 4.6% and identified polyclonal induction and zero HLA DR mismatch as significant risk factors for BK virus nephropathy.

Racial differences in graft survival: a report from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS).

Multiple studies have documented racial differences in graft survival in kidney transplant recipients. Although several studies in adult kidney transplant recipients have evaluated risk factors that might predispose to these differences, studies in pediatric patients are lacking. This study retrospectively analyzed data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) to identify racial differences in kidney transplant outcomes and evaluate factors that might contribute to those differences. The study was restricted to the first NAPRTCS registry-reported kidney transplant for pediatric patients (age < or =21 yr) whose race was reported as either black or white. Univariate graft survival analyses were performed using the log rank statistic. Relative hazard rates for the effect of race on graft failure were determined using proportional hazards models. Multivariate analyses were restricted to patients with >30 d of graft survival and were adjusted for initial diagnosis, donor source, presence of delayed graft function, era of transplantation, estimated GFR at 30 d after transplantation, and number of days hospitalized in the first month after transplantation. Graft survival was significantly lower in black transplant recipients at 3 yr (70.9 versus 83.3%) and 5 yr (59.9 versus 77.7%). After controlling for confounding factors, black recipients continued to have a higher risk for graft failure than white recipients (adjusted hazard rate 1.65; 95% confidence interval 1.46 to 1.86). Significant racial differences in kidney transplant outcomes exist among pediatric patients even after controlling for confounding factors.

Anemia and growth status in pediatric patients receiving maintenance dialysis after a failed renal transplant course: an NAPRTCS report.

We conducted a retrospective review of the North American Renal Transplant Cooperative Study (NAPRTCS) Registry transplant and dialysis arms to assess anemia and growth patterns in children who returned to dialysis after a failed renal transplant from January 1, 1992 to February 3, 2004. Of the 1807 potential study subjects, 1451 had transplant removal data (TxIn vs. TxOut) available for analysis. Four hundred and twenty-one of 1451 patients (29%) had a transplant nephrectomy at the time of entry into the NAPRTCS Registry Dialysis arm. Anemia rates steadily decreased from 72.2% at 30 days after dialysis initiation to 59.5% at 12 months after dialysis initiation. Factors associated with anemia at 30 days after dialysis initiation included hemodialysis, lack of Epo use, and patients who comprised earlier study era cohorts. At one yr after return to dialysis, earlier study cohort era was the only factor associated with anemia status. Patients did not demonstrate significant improvement in height SDS over the course of the study (-2.17 at day 30 to -2.32 at 24 months). The high anemia, poor growth, and low recombinant human growth hormone utilization rates in a group of patients followed longitudinally as they transition from renal transplant to dialysis should cause the pediatric nephrology community to reassess the processes in place to provide optimal care to pediatric end-stage renal disease patients.

Outcomes of dialysis initiated during the neonatal period for treatment of end-stage renal disease: a North American Pediatric Renal Trials and Collaborative Studies special analysis.

OBJECTIVE: We sought to determine the outcomes of initiating long-term dialysis of neonates and children aged > 1 to 24 months with end-stage renal disease. PATIENTS AND METHODS: By querying the North American Pediatric Renal Trials and Collaborative Studies database, we obtained information on 193 neonates (< or = 1 month of age) and 505 children (> 1-24 months of age) with a presumptive diagnosis of end-stage renal disease who initiated long-term dialysis. Dialysis characteristics and likelihood of hospitalization were compared using the chi2 test, and duration of hospitalization was compared using the Wilcoxon 2-sample test. Product limit methods were implemented, and the log rank test was used to compare time-to-event analyses. Multivariate analyses were performed using Cox proportional hazards models. RESULTS: Neonates with end-stage renal disease were more likely to receive peritoneal dialysis versus hemodialysis than older children with end-stage renal disease. Moreover, neonates who initiated dialysis during the first month of life were just as likely to terminate dialysis as were the older children. Rates of renal transplantation were significantly lower in the neonates compared with the older children, but neonates were more likely to recover function of the native kidney. Although neonates were more often hospitalized, their overall risk of mortality was similar to that observed in older children. CONCLUSIONS: Neonates with a presumptive diagnosis of end-stage renal disease may initiate long-term dialysis during the first month of life with outcomes comparable to those of patients who initiate dialysis later in infancy.

Feasibility of performing chemoprevention trials in women at elevated risk of ovarian carcinoma: initial examination of celecoxib as a chemopreventive agent.

BACKGROUND: A pilot study was undertaken to determine the feasibility of examining a COX-2 inhibitor (Celecoxib) as a chemopreventive agent in women at increased risk of ovarian cancer undergoing risk reducing salpingoophorectomy. METHODS: Women at elevated inherited risk of ovarian carcinoma pursuing risk reducing salpingoophorectomy were eligible for this trial. Ten patients were assigned to a control group while 10 patients were administered Celecoxib (400 mg/day) for 3 months prior to surgery. Demographic data at enrollment was collected. Serum, urine, peritoneal fluid, and resected tissues were obtained for correlative laboratory study. Evaluation of serum VEGF alterations was examined using an ELISA-based assay. RESULTS: Enrollment of patients was completed in 16 months. Of 29 eligible patients, 20 enrolled onto the study. One patient from each group did not complete surgical intervention. No significant differences were observed in the enrollment characteristics between the groups. No occult cases of ovarian cancer were identified and no differences in the presence of follicular cyst, hemorrhagic cysts, or inclusion cysts were noted on initial pathologic review. While the mean serum VEGF levels obtained following the administration of a COX-2 inhibitor were lower than the pre-administration in 5 of 6 patients, statistical significance in this difference was not observed (P = 0.359). However, this is most likely due to the small number of serum samples available. CONCLUSION: These results would suggest that chemoprevention trials in ovarian cancer will be eagerly embraced by this patient population.

Obesity and renal transplant outcome: a report of the North American Pediatric Renal Transplant Cooperative Study.

OBJECTIVE: Obesity is increasing in the end-stage renal disease population. Studies that have evaluated the effect of obesity on transplant outcomes in adults have yielded varying results. This issue has received little attention in the pediatric population. METHODS: We performed a retrospective study of the effect of obesity on pediatric renal transplant outcomes using the North American Pediatric Renal Transplant Cooperative Study database. Registry data from 1987 through 2002 on 6658 children aged 2 to 17 years were analyzed. Obesity was defined by a BMI >95th percentile for age. RESULTS: Overall, 9.7% were obese with an increase noted in recent years (12.4% after 1995 vs 8% before 1995). Obese children were significantly younger and shorter and had been on dialysis for a longer time than nonobese children. There was no significant difference in the overall patient and allograft survival between the 2 groups. However, obese children aged 6 to 12 years had higher risk for death than nonobese patients (adjusted relative risk: 3.65 for living donor; adjusted relative risk: 2.94 for cadaver), and death was more likely as a result of cardiopulmonary disease (27% in obese vs 17% in nonobese). Overall, graft loss as a result of thrombosis was more common in obese as compared with nonobese (19% vs 10%). CONCLUSIONS: Obesity is an increasing problem in children who present for transplantation and may have an adverse effect on allograft and patient survival.

Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer.

PURPOSE: The Krüppel-like transcription factor KLF4/GKLF induces both malignant transformation and a slow-growth phenotype in vitro. Although KLF4 expression is increased in most cases of breast cancer, it was unknown whether these cases represent a distinct subtype with a different clinical outcome. EXPERIMENTAL DESIGN: We examined expression of KLF4 by immunostaining 146 cases of human primary infiltrating ductal carcinoma of the breast. Staining patterns were correlated with clinical outcome and with established prognostic factors. RESULTS: Subcellular localization exhibited case-to-case variation. Tumors with high nuclear staining and low cytoplasmic staining were termed type 1. For patients with early-stage disease (i.e., stage I or IIA), type 1 staining was associated with eventual death because of breast cancer (hazard ratio, 2.8; 95% confidence interval, 1.23-6.58; P = 0.011). The association was stronger in patients with early-stage cancer and small primary tumors (i.e., < or =2.0 cm in diameter; hazard ratio, 4.3; 95% confidence interval, 1.75-10.62; P < 0.001). For patients with early-stage disease, multivariate analysis indicated that type 1 staining was independently associated with outcome (adjusted hazard ratio 2.6; 95% confidence interval, 1.10-6.05; P = 0.029). Type 1 staining was also associated with high histological grade (P = 0.032), increased expression of Ki67 (P = 0.016), and reduced expression of BCL2 (P = 0.032). In vitro, KLF4 was localized within the nucleus of transformed RK3E epithelial cells, consistent with a nuclear function of this transcription factor during induction of malignant transformation. CONCLUSIONS: The results suggest that localization of KLF4 in the nucleus of breast cancer cells is a prognostic factor and identify KLF4 as a marker of an aggressive phenotype in early-stage infiltrating ductal carcinoma.

Glandular cell atypia on Papanicolaou smears: interobserver variability in the diagnosis and prediction of cell of origin.

BACKGROUND: The 2001 Bethesda System recommended qualification of atypical glandular cells (AGC) to indicate the site of origin and separated endocervical adenocarcinoma in situ (AIS) from "AGC favor neoplastic" as a specific diagnostic category. To the authors' knowledge, the literature evaluating the reproducibility of Papanicolaou (Pap) smear diagnosis of glandular cell abnormalities with emphasis on the cell of origin is limited. The aim of the current study was to investigate whether a variety of benign to neoplastic glandular lesions can be reliably classified on Pap smear with regard to diagnosis and cell of origin. METHODS: Twenty-three conventional Pap smears (CPS) with glandular cellular changes varying from benign to adenocarcinoma (ACA) were reviewed by six observers. They were asked to categorize each smear according to cell of origin (endocervical vs. endometrial) and diagnosis (benign, AGC, or ACA). Kappa statistics were used to evaluate interobserver agreement and correlation of interobserver agreement with experience. RESULTS: There was no consensus among observers for both the origin of the cells and the diagnosis. Interobserver agreement for site was poor (kappa < 0.4) especially in the AGC category. Unanimous agreement for site was reached for 7 of 23 smears (30%). Two of five endocervical AIS were classified as endometrial and another two were classified as benign by four observers. Interobserver agreement was poor in all diagnostic categories (kappa < 0.4) and showed slight correlation with level of experience. Unanimous agreement for diagnosis was reached for only 2 smears (9%). Three of 11 (27%) smears demonstrating preneoplastic/neoplastic processes were diagnosed as benign by 3 observers. Three (25%) benign CPS were diagnosed as ACA by 2 observers. Accurate prediction of the final histologic diagnosis by observers varied from 30% to 87% and did not correlate closely with experience. CONCLUSIONS: Cytologic diagnosis of glandular lesions by CPS was problematic and suffered from significant interobserver subjectivity.

Expression of CEA, Tag-72, and Lewis-Y antigen in primary and metastatic lesions of ovarian carcinoma.

Ovarian carcinoma has a high mortality rate, because most ovarian carcinomas are detected at a late stage. Traditional therapies, such as surgical debulking and chemotherapy, have not been successful in improving the long-term survival of these patients. Alternative therapies targeting various biomarkers, such as carcinoembryonic antigen (CEA), Tag-72, and Lewis-Y antigen, have been developed to treat patients with advanced ovarian cancers. To ensure that therapies targeting these biomarkers are effective, it is imperative to determine whether there is any differential expression of these targeted biomarkers between primary and metastatic ovarian carcinomas. In the present study, primary and metastatic lesions from 68 and 58 patients, respectively, including primary and matched metastatic lesions from 31 patients, were evaluated for cytoplasmic and membranous expression of CEA (clone Col-1), Tag-72 (clone CC-49), and Lewis-Y antigen (clone BR-96) by immunohistochemistry. No significant differences were observed with cytoplasmic and membranous expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) in the primary and metastatic, matched and unmatched lesions (Wilcoxon signed-rank test). Although there was no statistically significant difference in the scores of CEA (Col-1) between primary and metastatic lesions, 5 of 11 (45%) cases with positive staining with CEA (Col-1) demonstrated discordant results between primary and metastatic lesions. There was a moderate positive correlation of the cytoplasmic and membranous expression of Tag-72 (CC-49), as well as cytoplasmic expression of BR-96 between primary and metastatic ovarian carcinomas. There was a weak negative correlation between the membranous expression of CEA (Col-1) and that of Lewis-Y antigen (BR-96); however, the difference was not statistically significant. No correlation was observed with other combinations of biomarkers. Our findings suggest that samples from either primary or metastatic ovarian carcinomas can be used for the evaluation of the expression of Tag-72 (CC-49) and Lewis-Y antigen (BR-96) to identify targets for novel therapies in patients with disseminated ovarian carcinomas. CEA (Col-1), due to its low expression and variation in phenotypic expression between primary and metastatic lesions, should be evaluated carefully in metastatic lesions before targeting the CEA antigen with CEA (Col-1)-like antibodies.

Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial.

OBJECTIVE: To determine the impact of the rapid diagnosis of influenza on physician decision-making and patient management, including laboratory tests and radiographs ordered, patient charges associated with these tests, antibiotics/antivirals prescribed, and length of time to patient discharge from the emergency department. METHODS: Patients aged 2 months to 21 years presenting to an urban children's teaching hospital emergency department were screened for fever and cough, coryza, myalgias, headache, and/or malaise. After obtaining informed consent, patients were randomized to 1 of 2 groups: 1) physician receives (physician aware of) the rapid influenza test result; or 2) physician does not receive (physician unaware of) the result. For patients in the physician aware group, nasopharyngeal swabs were obtained, immediately tested with the FluOIA test for influenza A and B, and the result was placed on the chart before patient evaluation by the attending physician. For the physician unaware group, nasopharyngeal swabs were obtained, stored according to manufacturer's directions, and tested within 24 hours. Results for the physician unaware group were not disclosed to the treating physicians at any time. The 2 resultant influenza-positive groups (aware and unaware) were compared for laboratory and radiograph studies and their associated patient charges, antibiotic/antiviral prescriptions, and length of stay in the emergency department. RESULTS: A total of 418 patients were enrolled, and 391 completed the study. Of these, 202 tested positive for influenza. Comparison of the 96 influenza-positive patients whose physician was aware of the result with the 106 influenza-positive patients whose physician was unaware of the result revealed significant reductions among the former group in: 1) numbers of complete blood counts, blood cultures, urinalyses, urine cultures, and chest radiographs performed; 2) charges associated with these tests; 3) antibiotics prescribed; and 4) length of stay in the emergency department. The number of influenza-positive patients who received prescriptions for antiviral drugs was significantly higher among those whose physician was aware of the result. CONCLUSIONS: Physician awareness of a rapid diagnosis of influenza in the pediatric emergency department significantly reduced the number of laboratory tests and radiographs ordered and their associated charges, decreased antibiotic use, increased antiviral use, and decreased length of time to discharge.

Pancreatic acinar cell metaplasia in autoimmune gastritis.

OBJECTIVE: To determine the frequency and significance of pancreatic acinar cells in the gastric oxyntic mucosa. DESIGN: One hundred gastric oxyntic mucosal biopsy specimens from patients with chronic active gastritis (n = 30), multifocal atrophic gastritis (n = 15), autoimmune gastritis (n = 18), and normal gastric oxyntic mucosa (n = 37) were evaluated for the presence of pancreatic acinar cells. Formalin-fixed, paraffin-embedded tissues were stained with hematoxylin-eosin, and those positive for pancreatic acinar cells were immunostained with antibodies against trypsin and pancreatic amylase. RESULTS: Eleven (11%) of 100 oxyntic mucosal tissue samples contained pancreatic acinar cells. These samples came from 9 of the 18 (50%) specimens of autoimmune gastritis, 1 of the 15 (6.6%) specimens of multifocal atrophic gastritis, and 1 of the 37 (2.7%) specimens of normal oxyntic mucosa. None of the samples with chronic active gastritis contained pancreatic acinar cells. CONCLUSIONS: Pancreatic acinar cells were found in the oxyntic mucosa of patients with autoimmune gastritis significantly more frequently (P <.001) than in individuals with multifocal atrophic gastritis, normal oxyntic mucosa, or chronic active gastritis. Our study supports a metaplastic origin for pancreatic acinar cells in the oxyntic mucosa. Furthermore, detection of pancreatic acinar cells in the oxyntic mucosa of patients with gastritis strongly suggests an autoimmune pathogenesis.

Microvessel density and vascular endothelial growth factor expression in infiltrating lobular mammary carcinoma.

Angiogenesis is an important prognostic factor in infiltrating ductal carcinoma (IDC). Vascular endothelial growth factor (VEGF) stimulates angiogenesis in vivo. VEGF expression has been correlated with high vascularity in IDC. However, little is known about the prognostic significance of microvessel density (MVD) and its correlation with the expression of VEGF in infiltrating lobular carcinoma (ILC). We analyzed tumor samples from 51 patients with primary classic ILC to determine the relationship between tumoral MVD and VEGF expression. Cases of pleomorphic lobular carcinoma and tubulolobular carcinoma were excluded. Five-micron thick sections obtained from formalin-fixed, paraffin-embedded tissue blocks were immunostained with antibodies to factor VIII-related antigen (Dako, Carpenteria, CA) and VEGF (Calbiochem, Boston, MA). The former was used for MVD analysis. The vessel counts from the three most vascular fields (x200 magnification) were recorded and the highest of the vessel counts of the three fields was designated as the MVD. The intensity of VEGF staining and the proportion of cells staining were scored. Both the vessel counts and the scoring of VEGF staining were evaluated by two independent pathologists. The Student's t-test and Wilcoxon rank sum test were used to compare mean MVD and VEGF scores according to various clinical and pathologic features. All significance tests were two-sided with an alpha-level of 0.05. There was good correlation between the MVD of each observer (correlation coefficient 0.775, p < 0.001). There was no correlation of MVD or VEGF score with the size or stage of the tumor. In addition, the MVD or VEGF score was not significantly different between axillary lymph node-positive cases and node-negative cases, between patients with recurrence and those without, and between patients who survived and those who died of disease. There was, however, a weak negative correlation between the MVD and VEGF expression (Spearman correlation coefficient -0.08). Neither MVD or VEGF immunoscore were associated with tumor recurrence or vital status in patients with ILC. The absence of a statistically significant positive correlation between MVD and VEGF expression suggests that other factors may play a more important role in the angiogenesis of ILC.

Interobserver variability in assessing adequacy of the squamous component in conventional cervicovaginal smears.

We compared the interobserver reproducibility of estimating the adequacy of the squamous component of conventional Papanicolaou (Pap) smears using traditional and newly proposed criteria. Forty conventional Pap smears with varying degrees of squamous cellularity were reviewed by 13 observers who evaluated adequacy (satisfactory vs unsatisfactory) based on the traditional criterion of estimating 10% slide coverage. After being introduced to the new criterion and the reference images, the observers reevaluated adequacy on the same set of smears, using the new criterion and the reference images. With the original criterion of 10% slide coverage, 15 smears had a unanimous designation; the overall kappa value was 0.49 (P < .001). With the newly proposed adequacy criterion and reference images, 17 smears had a unanimous designation; the overall kappa value was 0.60 (P < .001). The difference in the kappa correlation coefficients was statistically significant (P = .007). While traditional and newly proposed criteria resulted in fair interobserver agreement, it seemed that the newly proposed criterion, along with the use of reference images, for evaluating adequacy of the squamous component of conventional Pap smears results in better interobserver reproducibility.

Survey of physician knowledge about hemochromatosis.

PURPOSE: To survey physicians about knowledge of hemochromatosis. METHODS: A questionnaire was faxed to American physicians. RESULTS: A total of 2,563 evaluable responses were obtained. There were > or = 70% correct responses about at-risk population, associated abnormalities, and population screening. There were 32% and 53% correct answers about diagnosis and treatment, respectively. A total of 8.0% and 4.9% reported asking > 75% of patients about family history of hemochromatosis and iron overload, respectively. Less than 25% requested HFE mutation analysis in the previous year. Correct answers were associated with academic practice, internal medicine specialty, and medical school graduation within 10 years. CONCLUSION: Many physicians have inadequate knowledge about hemochromatosis diagnosis and treatment.

Interobserver variability: comparison between liquid-based and conventional preparations in gynecologic cytology.

BACKGROUND: Studies have shown that the ThinPrep Papanicolaou test (TP) increases the detection of epithelial cell abnormalities compared with the conventional preparation. Little is known about the interobserver variability of reporting gynecologic cytology results using the TP preparation and its comparison with results obtained using the conventional method. METHODS: To compare the interobserver variability between the TP method and the conventional method for reporting the diagnoses of gynecologic cytology, 20 pairs of conventional and TP slides (total, 40 slides) that were prepared from split samples were evaluated blindly by 19 cytotechnologists from three different laboratories. Each reviewer was asked to categorize each slide into the following five categories: within normal limits, benign cellular changes, atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL). For both conventional and TP preparations, interobserver variability was analyzed using Spearman rank correlation coefficients. The mean correlation coefficients (weak, 0.0-0.4; fair, 0.4-0.7; and strong, 0.7-1.0) between the TP method and the conventional method were then compared. RESULTS: The overall interobserver agreement as well as interobserver agreement within each laboratory was good for both TP and conventional preparations. Based on the set of conventional cervical smears, only one slide that was diagnosed as HSIL had unanimous agreement; whereas, based on the set of TP slides, three slides, including two diagnosed as HSIL and one diagnosed as LSIL, had a unanimous diagnosis. The difference in the interobserver agreement between TP and conventional methods, based on comparing their mean +/- standard deviation correlation coefficients (TP method, 0.84 +/- 0.081; conventional method, 0.82 +/- 0.105; P < 0.001), was statistically significant. CONCLUSIONS: Interobserver agreement in reporting gynecologic cytology using the TP method is good, particularly for squamous intraepithelial lesions, and appears to be superior to the conventional method.

Hormone receptors and proliferation in breast carcinomas of equivalent histologic grades in pre- and postmenopausal women.

Breast cancers in younger, premenopausal women are more likely to exhibit an adverse prognostic profile (including negative steroid hormone receptors and a high rate of cellular proliferation) and poor outcome than breast cancers in postmenopausal women. It has been hypothesized that this adverse prognostic profile is a result of the higher histologic grade of breast cancers in pre- compared with post-menopausal women. To assess the association of expression of steroid hormone receptors and indicators of proliferation while controlling for histologic grade, we identified 100 infiltrating ductal carcinomas from premenopausal women 45 years of age or younger and 100 from postmenopausal women 65 years of age or older. The carcinomas were selected so that the histologic grades (low versus high) were distributed equally between the 2 groups. Estrogen receptors (ER), progesterone receptors (PR), p27(Kip1) and Ki-67 (to measure rate of proliferation) were assessed by immunohistochemistry and compared between groups. Clinical information and survival data were also analyzed. ER content was lower and proliferation was higher in carcinomas in premenopausal women (p = 0.048 and p = 0.005, respectively). By univariate analysis, p27(Kip1) and PR were not different between the groups; however, in multivariate analysis, p27(Kip1) was higher in postmenopausal women, but only in a subgroup with highly proliferative carcinomas. Overall survival was similar in the pre- and postmenopausal women. Furthermore, low p27(Kip1) and African-American ethnicity predicted a poorer overall survival in the premenopausal, but not in the postmenopausal, women in our study. After controlling for histologic grade, a lower expression of ER and a higher proliferative index were detected in breast carcinomas in premenopausal women. Therefore, some prognostic indicators, such as ER and proliferative rate, may be more closely associated with menopausal status than histologic grade. Our data also suggest that some prognostic factors are not equally effective as predictors of survival in pre- and postmenopausal women.

Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines: preclinical evaluation of NSAIDs as chemopreventive agents.

PURPOSE: Nonsteroidal anti-inflammatory agents may inhibit carcinogenesis in specific tissues including the colon, breast, and pancreas, and, hence, may prove to be effective chemopreventive agents. The purpose of this study was to investigate the cellular effects of acetylsalicylic acid (ASA), acetaminophen, and a COX-2 inhibitor (NS-398) on the growth of cell lines of human ovarian cancer in vitro. EXPERIMENTAL DESIGN: SK-OV-3, Caov-3, and NIH:OVCAR-3 ovarian carcinoma cell lines were treated with ASA (10(-6) M-10(-2) M), acetaminophen (10(-6) M-10(-2) M), and a COX-2 inhibitor (10(-6) M-10(-4) M) for 96 h. The number of viable cells was determined using a tetrazolium conversion assay. Immunohistochemical assessment was performed for alterations in expression of Ki-67, erbB-2, COX enzyme, and apoptosis in primary ovarian cancer cells using terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay. RESULTS: A decrease in cell number compared with controls was observed for all of the cell lines treated with ASA, acetaminophen, and COX-2 inhibitor by cell count and tetrazolium conversion assay. A significant decrease in Ki-67 compared with controls in the OVCAR-3 (P = 0.005) and SK-OV-3 (P = 0.007) cell lines after treatment with the COX-2 inhibitor was observed. We observed a decrease in mitotic activity compared with controls in each cell line after treatment with the COX-2 inhibitor. Apoptosis was observed in primary ovarian cancer cell culture treated with COX-2 inhibitor. CONCLUSION: Our results suggest additional study for the use of nonsteroidal anti-inflammatory agents, specifically COX-2 inhibitors, as a strategy of chemoprevention for ovarian cancer.

Molecular staging of colorectal cancer in African-American and Caucasian patients using phenotypic expression of p53, Bcl-2, MUC-1 AND p27(kip-1).

The gold standard for clinical outcome of most cancers has been the clinical and pathologic staging of the tumors after surgery. For colorectal cancer (CRC), nodal involvement at the time the primary tumor is resected has been the most reliable indicator of clinical outcome; however, recently, combinations of molecular markers have been reported to be equivalent to pathologic or clinical staging in predicting clinical outcome. In addition, molecular markers can be used in conjunction with clinical or pathologic staging to provide a stronger indicator of clinical outcome than staging alone. We propose that "molecular staging" be added to pathologic staging to aid in predicting clinical outcome and making therapeutic decisions for colorectal cancers, especially stage II and III CRCs. We have reported that the clinical usefulness of most molecular markers varies with the ethnic group of the patients and the anatomic location of CRCs; this complicates the evaluation of prognostic biomarkers and requires much larger numbers of cases to be evaluated. Nevertheless, nuclear accumulation of p53 (p53(nac)) and phenotypic expression of Bcl-2, MUC-1 and p27(kip-1) may be molecular markers approaching acceptance for use in molecular staging of specific subgroups of colorectal cancers.