Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies.

The possible interrelations between human leukocyte antigen (HLA)-DQ, non-HLA single-nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34-year-old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high-risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison P=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison P=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison P=0.049) and IA-2 autoantibody-negative (comparison P=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison P=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens.

Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years.

AIMS: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D. METHODS: T1D children (n=260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined. RESULTS: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR=1.35 (1.09, 1.67), p=0.006); similarly for ZnT8WA (OR=1.39 (1.09, 1.77), p=0.008) and ZnT8QA (OR=1.55 (1.06, 2.26) p=0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders. CONCLUSIONS: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis.

The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies.

The single nucleotide polymorphism 1858C>T in the PTPN22 gene is associated with type 1 diabetes (T1D) in several populations. Earlier reports have suggested that the association may be modified by human leukocyte antigen (HLA), as well as by islet autoantibodies. In a large case-control study of Swedish incident T1D patients and controls, 0-34 years of age, we tested whether the odds ratio (OR) measure of association was dependent on HLA or autoantibodies against the islet autoantigens glutamic acid decarboxylase 65 kDa autoantibodies (GADA), insulin, islet antigen-2, or islet cell. The association between the carrier status of 1858C>T allele in PTPN22 (PTPN22(CT+TT)) and T1D was modified by HLA. In addition, in GADA-positive T1D, the OR was 2.83 (2.00, 3.99), whereas in GADA-negative T1D, the OR was 1.41 (0.98, 2.04) (P for comparison=0.007). The OR of association between PTPN22(CT+TT) and GADA-positive T1D declined with increasing HLA-risk category from 6.12 to 1.54 (P=0.003); no such change was detected in GADA-negative T1D (P=0.722) (P for comparison=0.001). However, the absolute difference in risk between PTPN22(CC) and PTPN22(CT+TT) subjects with high-risk HLA was five times higher than that for subjects with low-risk HLA. We hypothesize that the altered T-cell function because of the PTPN22(1858C>T) polymorphism is exclusively associated with GADA-positive T1D at diagnosis.

Islet cell autoantibody levels after the diagnosis of young adult diabetic patients.

AIMS: The aim was to determine the course of islet cell antibodies [glutamate decarboxylase (GADA), tyrosine phosphatase-like islet antigen 2 (IA-2A) and islet cell (ICA)] after the diagnosis of the diabetic patient. METHODS: The Diabetes Incidence Study in Sweden (DISS) attempted to prospectively enrol all newly diagnosed diabetic patients aged 15-34 years during 1992 and 1993. C-peptide and autoantibody levels were determined from venous blood samples at diagnosis and again at yearly intervals for 6 years. RESULTS: After the first year, the odds of remaining GADA positive decreased by 9% per year [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85-0.96] while the mean GADA index remained unchanged ( = 0.8, P = 0.37). There was no change in the percentage of subjects testing IA-2A positive after the first year ( = 0.1, P = 0.75). However, the mean index decreased 0.04 per year (95% CI: 0.03-0.05)-a 7.9% decline (95% CI: 5.4-10.4%). The odds of a subject testing positive for ICA decreased by 24% per year (OR = 0.76, 95% CI = 0.70-0.82). The mean ICA levels decreased 0.75 per year (95% CI: 0.66-0.84)-a 16.4% decline (95% CI: 14.1-18.6%). The rate of change in titres for all three autoantibodies was independent of gender, human leucocyte antigen genotype and C-peptide status. CONCLUSIONS: GADA levels remained high while ICA levels declined. In contrast to a previous study, we found that the proportion of IA-2A subjects remaining positive did not decrease after the first year, while the average index decreased slightly.

No excess of early onset cancer in family members of Wilms tumor patients.

BACKGROUND: Wilms tumor is one of the few pediatric cancers with well-defined familial and genetic components. The authors assessed the risk of early-onset cancers in first- and second-degree relatives of patients enrolled by the National Wilms Tumor Study Group. METHODS: Using a stratified sampling scheme that targeted 530 families of patients who were believed a priori to have a genetic contribution to their disease, the authors conducted interviews regarding cancer occurrence in 4258 family members from 296 families of patients with Wilms tumor. Reports of malignant neoplasms that occurred before 55 years of age were confirmed by review of medical records wherever possible. A period of risk was defined for each family member based on calendar time and his or her relationship to the proband. RESULTS: Ninety-nine cancers were observed, whereas 126.8 were expected by applying standard cancer rates for age and calendar period to the 120,885 person-years at risk. The standardized incidence ratio (SIR) was O-E = 0.78 with 95% confidence interval (CI) of (0.64, 0.95). In subgroup analyses, the highest relative risks were observed for parents of the index case (O/E = 21/13.0 = 1.6, 95% CI = 1.0, 2.5) and for leukemia (O/E = 9/4.9 = 1.9, 95% CI= 0.85,3.5). CONCLUSIONS: The results of this study may provide reassurance to families of children who have had Wilms tumor. Potential sources of bias included the low (56%) rate of participation of targeted families. In general, the biases might have led to the underreporting of some cancers, especially in more distant relatives. The possibility of a slight excess of cancer in parents of Wilms tumor patients could not be excluded.

Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the treatment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

Stature loss following treatment for Wilms tumor.

BACKGROUND: The study was designed to estimate reduction in adult stature induced by megavoltage radiation therapy (RT) of the spine in children treated for Wilms tumor and to ascertain whether the dose reduction in successive National Wilms Tumor Study Group (NWTSG) trials has mitigated late effects of RT in these children. PROCEDURE: Effects of RT dose, age at treatment, and chemotherapy on stature of 2,778 children with Wilms or another solid tumor of the kidney were analyzed using statistical models accounting for the dependence of height on gender and advancing age. Model predictions were validated by descriptive analysis of heights measured at 17 to 18 years of age for 205 patients. RESULTS: Radiation-induced reductions below normal height depended on dose, portal size, and age at treatment and were not augmented by doxorubicin or cyclophosphamide. Younger children were more strongly affected. Predicted height deficit at age 18 years was 1.8 cm for a child treated with 10 Gy to the flank at age 4 years. Observed height deficits at age 1 7 to 18 years were 4.1 cm for 57 patients who received 15-24 Gy at a mean age of 55 months and zero for 16 children who received RT doses under 15 Gy at a mean age of 83 months. CONCLUSIONS: Reduction in stature following RT to the pediatric spine is dose- and age-dependent, persists into adulthood, and is not exacerbated by doxorubicin or cyclophosphamide. Average height deficits observed at maturity for children receiving doses currently recommended by the NWTSG are clinically nonsignificant.

Intravascular extension of Wilms tumor.

OBJECTIVE: To define the incidence and manifestations of and optimal therapy for children with intravascular extension of Wilms tumor. METHODS: Children on a collaborative study of Wilms tumor who had intravascular extension into the inferior vena cava (IVC) or atrium were identified. Surgical checklists and surgical and pathology reports were reviewed. RESULTS: One hundred sixty-five of 2,731 patients had intravascular extension of Wilms tumor. The level of extension was IVC in 134 and atrium in 31. Sixty-nine had received preoperative therapy (55 with IVC extension and 14 with atrial extension) for a median of 8 weeks. Complications during preoperative chemotherapy were seen in five patients (tumor embolism and tumor progression in one each, and three with adult respiratory distress syndrome, one of which was fatal). The intravascular extension of the tumor regressed in 39 of 49 children with comparable pre- and posttherapy radiographic studies, including 7 of 12 in whom the tumor regressed from an atrial location, thus obviating the need for cardiopulmonary bypass. Surgical complications occurred in 36.7% of the children in the atrial group and 17.2% in the IVC group. The frequency of surgical complications was 26% in the primary resection group versus 13.2% in children with preoperative therapy. When all the complications of therapy were considered, including those that occurred during the interval of preoperative chemotherapy (one of the five also had a surgical complication), the incidence of complications among those receiving preoperative therapy was not statistically different from the incidence among those who underwent primary resection. The difference in 3-year relapse-free survival (76.9% for 165 patients with intravascular extension, 80.3% for 1,622 patients with no extension) was not statistically significant whether or not it was adjusted for stage and histology. CONCLUSIONS: Preoperative treatment of these children may facilitate resection by decreasing the extent of the tumor thrombus, but the overall frequency of complications is similar in both groups.

Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group.

PURPOSE: We determined the frequency of and risk factors for congestive heart failure following treatment for Wilms' tumor that included doxorubicin. PATIENTS AND METHODS: Flow sheets and medical records were reviewed to identify cases of congestive heart failure in a cohort of patients treated on National Wilms' Tumor Studies (NWTS)-1, -2, -3, and -4. The frequency of congestive heart failure was estimated using the Kaplan-Meier method. A case-control study was conducted to determine the relationship among cumulative doxorubicin dose, site(s), total dose of abdominal and thoracic irradiation, sex, and the frequency of congestive heart failure. RESULTS: The cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin and 17.4% at 20 years after diagnosis among those treated with doxorubicin for their first or subsequent relapse of Wilms' tumor. The relative risk (RR) of congestive heart failure was increased in females (RR = 4.5; P =.004) and by cumulative doxorubicin dose (RR = 3.3/100 mg/m(2); P <.001), lung irradiation (RR = 1.6/10 Gy; P =.037), and left abdominal irradiation (RR = 1.8/10 Gy; P =.013). CONCLUSION: We conclude that congestive heart failure is a risk of treatment with doxorubicin for Wilms' tumor. Additional follow-up of those children treated on NWTS-4 will be necessary to determine if the decrease in dose to 150 mg/m(2) significantly reduces this risk.

Surgical complications after primary nephrectomy for Wilms' tumor: report from the National Wilms' Tumor Study Group.

BACKGROUND: Surgical complications are a recognized morbidity of the treatment of patients with Wilms tumor. This study examines the incidence of surgical complications in the most recently completed study from the National Wilms' Tumor Study Group (NWTSG). STUDY DESIGN: The fourth National Wilms' Tumor Study (NWTS-4) enrolled 3,335 patients from August 1986 to August 1994. A random sample of 534 patients was selected from 2,290 eligible patients randomized to treatment regimens or enrolled in the followed category and treated according to NWXTSG protocol. The patient records received at the NWTSG Data and Statistical Center were analyzed for surgical complications (intraoperative and postoperative). RESULTS: Sixty-eight patients (12.7%) experienced 76 complications. Intestinal obstruction was the most common complication (5.1% of patients), followed by extensive hemorrhage (1.9%), wound infection (1.9%), and vascular injury (1.5%). The incidence of surgical complications in NWTS-4 was significantly lower than NWTS-3 (12.7% versus 19.8%, p < 0.001). There has been a marked decrease in the risk of extensive intraoperative bleeding and major intraoperative complications. Factors previously shown to be associated with an increased risk for surgical complications, together with indicators of type of hospital and surgeon specialty, were analyzed by multiple logistic regression analysis. Intravascular extension into the inferior vena cava (IVC), the atrium, or both (p = 0.02; odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2, 11.8), and nephrectomy performed through a flank or paramedian incision (p = 0.02; OR 5.3, 95% CI 1.3, 22) were both associated with increased risk of complications. Tumor diameter greater than or equal to 10cm was also associated with an increased risk of surgical complications (p = 0.05; OR 2.0, 95% CI 1.0, 3.9). The risk of complications was higher if the nephrectomy was performed by a general surgeon (OR 9.0, 95% CI 1.3, 65; p = 0.03) rather than a pediatric surgeon (reference group, OR 1.0) or pediatric urologist (OR 0.7, 95% CI 0.3, 1.8). CONCLUSIONS: The incidence of surgical complications in NWTSG patients undergoing primary nephrectomy has significantly decreased over the past decade. But surgical morbidity should not be overlooked. It is important that surgeons treating young children with solid tumors are aware of their role and the potential risks encountered in removal of the primary tumor. This study found that surgical specialists who primarily treat children can perform these operations with lower surgical morbidity.

Clinical presentation of rhabdoid tumors of the kidney.

PURPOSE: We designed this study to differentiate the clinical presentation, particularly the incidence of hematuria, of a rhabdoid tumor of the kidney (RTK), a rare but highly malignant tumor, from a Wilms tumor. PATIENTS AND METHODS: We reviewed patient flow charts from the National Wilms Tumor Study Group and queried participating hospitals to obtain additional information regarding presenting symptoms and laboratory data for fifty patients. Patient ages ranged from 2 days to 3.5 years with a mean of 11 months. We documented the presence of gross and microscopic hematuria, fever, and hypercalcemia. RESULTS: Whereas 75% of children with rhabdoid tumor of the kidney (RTK) had stage III (44%), IV (27%), or V (4%) tumors, 67% of children with Wilms tumors had stage I (41%) or II (26%) tumors. Either gross or microscopic hematuria was present in 84.4% (27/32) of the patients with RTK. Gross hematuria was present in 59% (22/37) of children with RTK compared with 18% previously reported with Wilms tumor. Microscopic hematuria was present in 76% (22/29) of children with RTK compared with 24% previously reported with Wilms tumor. Fever was found in 44% (16/36) of children with RTK, compared with 22% of children previously reported with Wilms tumor. Hypercalcemia was seen 26% (6/23) of children with RTK. CONCLUSION: Although diagnosis of any renal mass still must be confirmed with histopathologic features, a distinct clinical presentation with fever, hematuria, a young age, and high-tumor stage at presentation suggests the diagnosis of RTK.

Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group.

PURPOSE: This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. PATIENTS AND METHODS: The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. RESULTS: Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. CONCLUSIONS: The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.

What does a single determination of malaria parasite density mean? A longitudinal survey in Mali.

Temporal variations of blood parasite density were evaluated in a longitudinal study of young, asymptomatic men in a village with endemic malaria in Mali (West Africa). Our main intention was to challenge the value of a single measure of parasite density for the diagnosis of malaria, and to define the level of endemicity in any given area. Parasitaemia and body temperature were recorded three times a day in the wet season (in 39 subjects on 12 days) and in the dry season (in 41 subjects on 13 days). Two thousand nine hundred and fifty seven blood smears (98.5% of the expected number) were examined for malaria parasites. We often found 100-fold or greater variations in parasite density within a 6-hour period during individual follow-up. All infected subjects had frequent negative smears. Although fever was most likely to occur in subjects with a maximum parasite density exceeding 10000 parasites/mm3 (P = 0.009), there was no clear relationship between the timing of these two events. Examples of individual profiles for parasite density and fever are presented. These variations (probably due to a 'sequestration-release' mechanism, which remains to be elucidated) lead us to expect a substantial impact on measurements of endemicity when only a single sample is taken. In this study, the percentage of infected individuals varied between 28.9% and 57.9% during the dry season and between 27.5% and 70.7% during the wet season. The highest rates were observed at midday, and there were significant differences between days. Thus, high parasite density sometimes associated with fever can no longer be considered as the gold standard in the diagnosis of malaria. Other approaches, such as decision-making processes involving clinical, biological and ecological variables must be developed, especially in highly endemic areas where Plasmodium infection is the rule rather than the exception and the possible causes of fever are numerous.

Renal failure in the Denys-Drash and Wilms' tumor-aniridia syndromes.

Nearly 6000 patients enrolled in four clinical trials of the National Wilms' Tumor Study Group during 1969-1995 were followed until death or for a median of 11.0 years of survival for the onset of renal failure (RF). Thirteen of 22 patients with Denys-Drash syndrome and 10 of 46 patients with the Wilms' tumor aniridia syndrome developed RF. The cumulative risks of RF at 20 years from Wilms' tumor diagnosis were 62% and 38%, respectively. Only 21 cases of RF were observed among 5358 patients with unilateral disease who did not have characteristic congenital genitourinary anomalies, and their risk was <1%. Although other explanations cannot be completely excluded, the high rate of RF in patients with the aniridia syndrome challenges the view that nephropathy is associated uniquely with missense mutations in the WT1 gene. It suggests the possibility of a further gradation in the spectrum of phenotypes associated with different WT1 mutations. Patients with Wilms' tumor and aniridia or genitourinary abnormalities should be followed closely throughout life for signs of nephropathy or RF.

Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the National Wilms Tumor Study Group.

PURPOSE: Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for developing Wilms' tumor (WT). We reviewed the National Wilms Tumor Study Group (NWTSG) records to assess clinical characteristics and outcome of patients with WT and BWS. METHODS: In the NWTSG, treating clinicians were asked to report, for each enrolled patient, whether the patient had BWS. Between 1980 and 1995, 4,669 patients were treated on two consecutive NWTSG protocols (NWTS 3 and NWTS 4). We retrospectively reviewed the clinical characteristics and treatment outcomes of BWS patients compared with patients with WT without BWS. RESULTS: Fifty-three children enrolled onto NWTS 3 and 4 were reported to have BWS. BWS patients were more likely to present with lower-stage tumors (P =.0001), with more than half (27 of 53) presenting with stage I disease. The overall treatment outcomes for the BWS patients were nearly identical to those without BWS, with overall survival at 4 years from diagnosis at 89% and 90%, respectively. Overall, 21% of the patients with BWS had bilateral disease, either at diagnosis (nine of 53) or as metachronous contralateral recurrence (two of 53). BWS patients enrolled onto NWTS 4 had smaller tumors than those enrolled onto NWTS 3 (P =.02), a trend not seen in the non-BWS patients. CONCLUSION: Like children without BWS, children with BWS and WT have an excellent prognosis with modern treatment regimens. There is a high risk of bilateral disease, and increasingly smaller tumors are being detected. This suggests that a national trial assessing the role of ultrasound screening followed by nephron-sparing surgery for some patients may be appropriate.

Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center.

We reviewed 351 cases of clear cell sarcoma of the kidney (CCSK), including 182 cases entered on National Wilms Tumor Study Group (NWTSG) trials 1-4 for which clinical follow-up information was available. Tumors were restaged using NWTS 5 criteria. Mean age at diagnosis in the NWTS group was 36 months with a range of 2 months to 14 years. The male to female ratio was 2:1. Typical gross features included large size (mean diameter 11.3 cm), a mucoid texture, foci of necrosis, and prominent cyst formation. Nine major histologic patterns were identified (classic, myxoid, sclerosing, cellular, epithelioid, palisading, spindle, storiform, and anaplastic); virtually all tumors contained multiple patterns that blended with one another. Immunohistochemical stains were performed on 45 cases; only vimentin was consistently immunoreactive. Consistently negative results with other antibodies helped exclude other tumors in the differential diagnosis; all CCSKs were cytokeratin-negative, including epithelioid tumors that mimicked Wilms tumor, and MIC2-negative, including cellular tumors that mimicked primitive neuroectodermal tumor. The p53 gene product was rarely overexpressed in non-anaplastic CCSKs, but strikingly overexpressed in two of three anaplastic CCSKs. Overall survival was 69%. Multivariate analysis revealed four independent prognostic factors for survival: treatment with doxorubicin, stage, age at diagnosis, and tumor necrosis. Of note, stage 1 patients had a remarkable 98% survival rate. No other histologic or clinical variable independently correlated with survival.

Nuclear morphometry and prognosis in favorable histology Wilms' tumor: A prospective reevaluation.

PURPOSE: This study was designed to evaluate the ability of a previously published nuclear morphometry discriminant function to predict disease-free survival in patients with Wilms' tumor. PATIENTS AND METHODS: We identified 218 patients with stage I-IV Wilms' tumor of favorable histology who were entered onto the National Wilms' Tumor Study (NWTS) between January 1, 1990 and April 15, 1994. The nuclear morphometry score was calculated for each patient as follows: MV(f) = (0.02 x AGE) + (1.17 x SNRF) + (90.6 x LEFD) - 94, with AGE denoting age at diagnosis in months, SNRF the skewness of the nuclear roundness factor, and LEFD the lowest value of nuclear ellipticity as measured by the feret diameter method. Relative risks of relapse were estimated for the total score and for each of its components. Sensitivity and specificity were determined for the criterion of "MV(f) is greater than -0.35" as a predictor of relapse. RESULTS: By contrast with previously published results, neither the SNRF nor the LEFD made any contribution to the prediction of disease-free survival. Sensitivity and specificity of the criterion of "MV(f) is greater than -0.35" were 71% and 56%, respectively. CONCLUSION: Re-evaluation of a published nuclear morphometry score showed that it did not predict disease-free survival in patients with Wilms' tumor. The earlier study very likely overestimated the predictive power of nuclear morphometry by using the same data set both to develop the score and to evaluate its properties. Because of the huge number of combinations of nuclear morphometry measurements that may enter into the multivariate discriminant function, use of appropriate statistical methods is essential to estimate accurately the sensitivity and specificity.

High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms' tumor.

Telomerase is a reverse transcriptase that maintains chromosome ends, compensating for the progressive loss of DNA that occurs during replication. High telomerase enzyme activity is an unfavorable prognostic feature for several types of cancers. We investigated whether telomerase level predicts outcome for patients with the pediatric renal malignancy Wilms' tumor. In a case-cohort study of 78 patients with favorable histology Wilms' tumor, we compared tumor telomerase levels in patients with and without eventual recurrence. Three measures of telomerase were used: (a) telomerase enzyme activity; (b) expression of hTR, the RNA component of telomerase; and (c) mRNA expression of hTERT, the gene that encodes the catalytic component of the enzyme. Of the evaluable samples, 81% had detectable telomerase activity, 97% had detectable hTERT transcript, and 100% had detectable hTR. Weak correlations were observed between telomerase activity and hTR level (r = 0.34, P = 0.02) and between telomerase activity and hTERT mRNA level (r = 0.32, P = 0.04). Of the variables assessed, only hTERT mRNA expression correlated with outcome. The median hTERT mRNA level in tumors with recurrence was higher than that in tumors without recurrence (1.42 versus 0.97 units, P = 0.023, Wilcoxon). Univariate analysis of hTERT mRNA level as a continuous variable suggested that each unit increase in hTERT mRNA level increased the risk of recurrence (RR) by a factor of 1.66 [95% confidence interval (CI), 1.2-2.3; P < 0.005]. Compared with tumors with hTERT mRNA levels of 0-1 units, tumors with hTERT mRNA levels of 1-2 units had a RR of 2.72 (95% CI, 0.91-8.13; P = 0.074), and tumors with hTERT mRNA levels >2 units had a RR of 6.40 (95% CI, 1.49-27.67, P = 0.013). Multivariate analysis of hTERT mRNA level as a predictor of recurrence, adjusted for tumor stage and age at diagnosis, revealed a RR of 1.48 (95% CI, 0.9-2.6; P = 0.16). Measurement of hTERT mRNA level may, therefore, enable clinicians to identify a population of patients at high risk for recurrence and to adjust their therapy accordingly. A larger study will be necessary to determine whether hTERT expression is an independent prognostic indicator. Further biological investigation is warranted to discern whether the link between high hTERT expression and unfavorable prognosis is causative or correlative.