Effectiveness and outcomes of surgery for cerebral metastases.

INTRODUCTION: The main treatment modalities for single brain metastases are whole brain radiotherapy (WBRT), surgery and stereotactic radiosurgery. Current guidelines recommend complete surgical excision for single cerebral metastases and two randomised controlled trials (RCT) have also found survival benefit of surgery. However, a more recent RCT and a Cochrane review have challenged the effectiveness of surgery for cerebral metastases. This study aims to assess the effectiveness of surgery for cerebral metastases in current practice. MATERIALS AND METHODS: A retrospective review was performed for a single surgeon series of consecutive patients undergoing primary surgery for cerebral metastases between June 2005 and April 2010. The main outcome measure was the survival time after surgery. RESULTS: One hundred and twenty three patients (61 males, 62 females) were identified with a mean age of 58.4 years. Eighty three patients (67%) were under 65 years. The overall 30-day mortality rate was 2.4%. The overall median survival was 10 months. There were 26 (21%) breast cancers with median survival of 13.5 months, 32 (26%) NSCLC with 8.3 months, 24 (19%) melanomas with 6.7 months, 13 (11%) colorectal cancers with 6.4 months, and 11 (9%) renal cell cancers with 13.6 months. The differences were not significant (p > 0.05). However, when the breast cancer group was compared to the NSCLC group, the difference was significant (p = 0.005). The median survival differences were not significant (p > 0.05) with regard to the RPA class, the site (supratentorial or infratentorial) and the number of metastases (single or two). CONCLUSIONS: Median survival in this cohort was identical to those in the two RCTs that showed survival benefits from surgery. This was significantly longer than that (5.6 months) in the single series demonstrating no benefit. Therefore, our results support the previous evidence of improved outcomes with surgery.

Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour.

The insulin-like growth factor-II (IGF2) and H19 genes are imprinted in mouse and human, with expression of the paternal IGF2 and maternal H19 alleles. IGF2 undergoes loss of imprinting (LOI) in most Wilms' tumours (WT). We now show that: (i) LOI of IGF2 is associated with a 80-fold down regulation of H19 expression; (ii) these changes are associated with alterations in parental-origin-specific, tissue-independent sites of DNA methylation in the H19 promoter; and (iii) loss of heterozygosity is also associated with loss of H19 expression. Thus, imprinting of a large domain of the maternal chromosome results in a reversal to a paternal epigenotype. These data also suggest an epigenetic mechanism for inactivation of H19 as a tumour suppressor gene.

Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations.

The genetics of Wilms' tumour (WT), a paediatric malignancy of the kidney, is complex. Inactivation of the tumour suppressor gene, WT1, is associated with tumour aetiology in approximately 10-15% of WTs. Chromosome 17p changes have been noted in cytogenetic studies of WTs, prompting us to screen 140 WTs for p53 mutations. When histopathology reports were available, p53 mutations were present in eight of eleven anaplastic WTs, a tumour subtype associated with poor prognosis. Amplification of MDM2, a gene whose product binds and sequesters p53, was excluded. Our results indicate that p53 alterations provide a molecular marker for anaplastic WTs.

Magneto-optical stokes polarimetry and nanostructured magnetic materials.

Stokes parameters fully characterize the polarization state of light in an experimentally accessible manner. Photoelastic modulator (PEM) based Stokes polarimetry offers a very high sensitivity which is particularly suitable for the investigation of the magneto-optical properties of nanostructured magnetic materials. In this paper, we shall describe a robust methodology recently developed by us that utilizes a dual PEM setup. As an example of its application, we report on the magneto-optical characteristics of focused Ga ion beam patterned Fe films. We have investigated Ga ion irradiation of single-layer polycrystalline Fe films deposited on Si3N4 substrates, which allows us to study the effects of ion implantation with minimum added complications. Complemented by structural and other characterization techniques, the absolute measurement of magneto-optical effects through the determination of Stokes parameters has enabled us to effectively separate the various contributions from film thinning due to sputtering, structural modifications and compositional changes caused by Ga incorporation. A comparison is also made between the magneto-optical behavior of patterned thin films and that of anodic aluminum oxide embedded magnetic nanowire arrays.

Patient experience and satisfaction with awake craniotomy for brain tumours.

Awake craniotomy is increasingly used to facilitate safe maximal resection of brain tumours. Very little published data is available to determine patient experiences and satisfaction. This knowledge may lead to improvement in technique and enhance future patient care. In 2006, we began to use conscious sedation ('full awake technique') for craniotomies for tumour resection. A questionnaire designed with reference to Royal College of Surgeons (RCS) guidelines was sent out to 60 consecutive patients. Four areas of care were explored. These included the out-patient consultation with the neurosurgeon, anaesthetic consultation, operation and the post-operative period. Fourty-five responses were received. Ninety-three percent of the patients in our study felt involved sufficiently in the decision for awake surgery and felt they were given enough information when seen in the surgical consultation. However, only 64% of patients received written information in advance of their surgical date. Ninety-one percent of patients were confident that they would be looked after during surgery following their anaesthetic consultation. Eighty-seven percent of patients felt at ease during surgery. Twenty-four percent experienced some discomfort during surgery, some of which was related to positioning of the patient rather than surgical technique. Fifty-six percent of our patients reported no post-operative pain. Eighty-four percent of patients were happy with timing of their discharge. Eighty percent felt well supported post-discharge. This study demonstrates high levels of patient satisfaction and provides surgeons with useful data for consenting patients. We identified no difference in levels of patient satisfaction comparing day-case patients with those admitted. We identified areas for improvement including provision of written information, enhancing post-discharge support and allowing more time for anaesthetic discussion before surgery.

Anthropomorphic measurements and event-free survival in patients with favorable histology Wilms tumor: a report from the Children's Oncology Group.

PURPOSE: We retrospectively examined the effect of body weight and body mass index (BMI) on event-free survival (EFS) of children with Wilms tumor treated on National Wilms Tumor Study-5 (NWTS-5). PATIENTS AND METHODS: Eligible study participants: stages I-IV favorable histology Wilms tumor with immediate nephrectomy; height and weight recorded at diagnosis, and loss of heterozygosity for chromosomes 1p and 16q assessed. RESULTS: A total of 1,532 patients were included in the analysis. The median follow-up was 4.9 years. 493 patients were less than 2 years of age and 1039 were 2 years of age or older. In both age groups there were more patients than expected with a weight or body mass index (BMI) less than the 10 per thousand or greater than the 90 per thousand. There was no relationship of weight-for-age or BMI-for-age and EFS in univariate analyses (P = 0.28, log-rank test for both comparisons). A Cox proportional hazards model, stratified by risk/treatment groups, showed that, among patients less than 2 years of age, low or high weight-for-age was not predictive of EFS (P = 0.16). Similarly, a Cox proportional hazards model, stratified by risk/treatment groups, showed that among patients greater than 2 years of age, low or high body mass index for age was not predictive of EFS (P = 0.58). CONCLUSIONS: There was no evidence that anthropomorphic data obtained at diagnosis for patients with favorable histology stages I-IV Wilms tumor was predictive for EFS in the setting of current treatment regimens. There were more patients with lower or higher weight/BMI than expected.

A comparison of two models of follow-up care for adult survivors of childhood cancer.

PURPOSE: Few studies have compared follow-up-care models for adult survivors of childhood cancer (ASCCs), though choice of model could impact medical test adherence, and health-related quality of life (QOL). This study compared two follow-up-care models, cancer-center-based versus community-based, for ASCCs in Alberta, Canada, to determine which model would demonstrate greater ASCC adherence to guideline-recommended medical screening tests for late effects, QOL, physical symptoms, and adherence to yearly follow-up. METHODS: ASCC discharged to a community model (over 15 years) and those with comparable birth years (1973-1993) currently followed in a cancer center model were recruited via direct contact or multimedia campaign. Chart review identified chemotherapeutic and radiation exposures, and required medical late effect screening tests. ASCCs also completed questionnaires assessing QOL, physical symptoms, and follow-up behavior. RESULTS: One hundred fifty-six survivors participated (community (n = 86); cancer center (n = 70)). Primary analysis indicated that cancer center ASCCs guideline-recommended total test adherence percentage (Mdn = 85.4%) was significantly higher than the community model (Mdn = 29.2%, U = 3996.50, p < 0.0001). There was no significant difference in QOL for cancer center ASCCs (M = 83.85, SD = 20.55 versus M = 77.50, SD = 23.94; t (154) = 1.77, p = 0.078) compared to community-based ASCCs. Cancer center-based ASCCs endorsed from 0.4-7.1% fewer physical symptom clusters, and higher adherence to follow-up behavior in comparisons using effect sizes without p values. CONCLUSION: This study highlights the cancer center model's superiority for adherence to exposure-based medical late effect screening guidelines, cancer-specific follow-up behaviors, and the reporting of fewer physical complaints in ASCCs. IMPLICATIONS FOR CANCER SURVIVORS: ASCCs followed in a cancer center model likely benefit from earlier late-effects detection and opportunities for early intervention.

Modulation of platelet-derived growth factor receptor function in BP3T3, a chemically transformed BALB/c-3T3 cell line.

BP3T3, a clonal benzo(a)pyrene-transformed BALB/c-3T3 cell, has been shown to be conditionally responsive to platelet-derived growth factor (PDGF)-stimulated DNA synthesis. PDGF stimulates DNA synthesis in BP3T3 cell cultures maintained in 0.5% platelet-poor plasma, but pretreatment with 10% serum or 10 micrograms/ml insulin inhibits PDGF-modulated DNA synthesis. BALB/c-3T3 cells remain mitogenically responsive irrespective of pretreatment with serum or insulin. The present study demonstrates that pretreatment with serum or insulin inhibits BP3T3 cell DNA synthesis by affecting receptor function. Insulin and serum, however, act through different mechanisms. Pretreatment with serum for 3 or more days down-modulated the BP3T3 cell PDGF receptor, resulting in both inhibition of PDGF binding and inhibition of PDGF-stimulated receptor autophosphorylation. In contrast, treatment of nontransformed BALB/c-3T3 cells with serum for 3 or more days did not down-modulate the PDGF receptor. Pretreatment of BP3T3 cells with insulin did not inhibit PDGF binding to BP3T3 cells but did inhibit PDGF-stimulatable tyrosine-specific receptor autophosphorylation. This effect was minimal to nonexistent in BALB/c-3T3 cell cultures. It appears likely that pretreatment of BP3T3 cells with insulin either inhibits the tyrosine kinase activity of the PDGF receptor or activates receptor dephosphorylation.

Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome.

We have prospectively analyzed Wilms' tumors from 232 patients registered on the National Wilms' Tumor Study for loss of heterozygosity (LOH) on chromosomes 11p, 16q, and 1p. These chromosomal aberrations were found in 70 (33%), 35 (17%), and 21 (12%) of the informative cases, respectively. LOH for two of these regions occurred in only 25 cases, and only one tumor harbored LOH at all three sites. There was no statistically significant association between LOH at any of the three regions and either the stage or histological classification of the tumor. Patients with tumor-specific LOH for chromosome 16q had relapse rates 3.3 times higher (P = 0.01) and mortality rates 12 times higher (P < 0.01) than patients without LOH for chromosome 16q. These differences remained when adjusted for histology or for stage. Patients with LOH for chromosome 1p had relapse and mortality rates three times higher than those for patients without LOH for chromosome 1p, but these results were not statistically significant. In contrast, LOH for chromosome 11p had no effect on measures of outcome. These molecular markers may serve to further stratify Wilms' tumor patients into biologically favorable and unfavorable subgroups, allowing continued use of the clinical trial mechanism in the study of Wilms' tumor.

Increased birth weights of National Wilms' Tumor Study patients suggest a growth factor excess.

An analysis of over 1800 patients with Wilms' tumor revealed significantly higher birth weights than newborns in the general United States population. The highest birth weights were found not only in patients diagnosed with the Beckwith-Wiedemann syndrome (mean, 3.78 kg), as had been expected, but also in those with hemihypertrophy (3.80 kg) or perilobar nephrogenic rests (3.56 kg) in addition to their Wilms' tumor. The birth weights of Wilms' tumor patients with intralobar nephrogenic rests (3.43 on average kg) and of those without associated anomalies (3.45 kg) were slightly but still significantly higher on average than national birthweights (overall mean, 3.35 kg) adjusted for gender, race, and year of birth in each subgroup. Birth weights of children with aniridia and Wilms' tumor (2.99 kg) were lower than the national mean. Among more than 3000 patients with Wilms' tumor, heights and weights at diagnosis were significantly higher for the subgroups of patients with Beckwith-Wiedemann syndrome or hemihypertrophy, and height was lower for those with aniridia or characteristic genitourinary anomalies, when compared to other patients with Wilms' tumor. These data suggest prenatal effects of growth factors on the development of Wilms' tumors, or vice versa, and provide further epidemiological support for heterogeneity in the pathogenesis of Wilms' tumors associated with perilobar nephrogenic rests versus intralobar nephrogenic rests.

ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.

Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.

Identification of novel regions of deletion in familial Wilms' tumor by comparative genomic hybridization.

Wilms' tumor, an embryonic renal neoplasm diagnosed primarily in young children, can occur in either a noninheritable (sporadic) or a familial form, with the latter presenting earlier and more often at bilateral sites. Although familial Wilms' tumor is thought to develop through inherited and acquired mutational inactivation of the two alleles of predisposing tumor suppressor genes, only a small percentage of cases can be accounted for by mutations affecting the WT1 gene or linkage to the Beckwith-Weidemann syndrome of the BWS region on the short arm of chromosome 11. To find chromosomal regions that might contain genes important in the development of this disease, we used comparative genomic hybridization to analyze tumor specimens from familial cases for chromosomal regions that were consistently lost. Although inherited lesions of tumor suppressors are most often inactivating point mutations, accompanying somatic lesions in the malignant clones are often chromosomal deletions; therefore, consensus regions of loss in familial tumors are likely to harbor genes linked to familial predisposition. There were extensive genomic aberrations among the eight familial cases studied, with an average of 6.5 changes/tumor (range, 0-22). The most consistent findings with likely biological relevance were deletions of chromosomes 4 (consensus, 4q21-qter), 9 (consensus, 9p21-pter), 20p, and 3 (consensus, 3q12-q21). These regions have not been previously implicated in Wilms' tumor and may harbor novel genes that could aid attempts to understand the familial predisposition as well as the development and progression of these tumors.

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.

A third Wilms' tumor locus on chromosome 16q.

Loss of heterozygosity studies have been used to identify chromosomal regions which are frequently deleted and thus indicate areas which may harbor tumor suppressor genes. As a result, both the WT1 gene located in chromosome 11p13 and an unidentified gene(s) within chromosome 11p15 have been implicated in Wilms' tumorigenesis. Cytogenetic and linkage studies suggest that additional non-chromosome 11 sites are involved in Wilms' tumor. Because these sites may also involve loss of heterozygosity, loci on 33 autosomal arms were screened for allele loss in a series of Wilms' tumors. We found that in addition to loss on chromosome 11p (11 of 25 informative tumors) there was significant loss on chromosome 16q (9 of 45 informative tumors), while the total frequency of allele loss excluding these loci was low (9 of 426 total informative loci). These data indicate that losses of both chromosome 11p and 16q alleles are nonrandom events and suggest that 16q is the location of a third tumor suppressor gene underlying Wilms' tumorigenesis. The parental origin of the lost chromosome 16q allele was determined in eight sporadic tumors. Alleles of paternal and of maternal origin were each lost in four sporadic tumors indicating that, unlike chromosome 11p, alleles of either parental origin are lost on 16q.

Genomic imbalances pinpoint potential oncogenes and tumor suppressors in Wilms tumors.

BACKGROUND: Wilms tumor (WT) has a not completely elucidated pathogenesis. DNA copy number alterations (CNAs) are common in cancer, and often define key pathogenic events. The aim of this work was to investigate CNAs in order to disclose new candidate genes for Wilms tumorigenesis. RESULTS: Array-CGH of 50 primary WTs without pre-chemotherapy revealed a few recurrent CNAs not previously reported, such as 7q and 20q gains, and 7p loss. Genomic amplifications were exclusively detected in 3 cases of WTs that later relapsed, which also exhibited an increased frequency of gains affecting a 16.2 Mb 1q21.1-q23.2 region, losses at 11p, 11q distal, and 16q, and WT1 deletions. Conversely, aneuploidies of chromosomes 13 and 19 were found only in WTs without further relapse. The 1q21.1-q23.2 gain associated with WT relapse harbours genes such as CHD1L, CRABP2, GJA8, MEX3A and MLLT11 that were found to be over-expressed in WTs. In addition, down-regulation of genes encompassed by focal deletions highlighted new potential tumor suppressors such as CNKSR1, MAN1C1, PAQR7 (1p36), TWIST1, SOSTDC1 (7p14.1-p12.2), BBOX and FIBIN (11p13), and PLCG2 (16q). CONCLUSION: This study confirmed the presence of CNAs previously related to WT and characterized new CNAs found only in few cases. The later were found in higher frequency in relapsed cases, suggesting that they could be associated with WT progression.

Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms' tumor.

Wilms' tumor (WT) is an embryonal renal malignancy, which overexpresses insulin-like growth factor II (IGF-II), a fetal mitogen. Relaxation of parental imprinting of IGF2, the gene encoding IGF-II, is found in Wilms' tumors, suggesting an important role for IGF2 dosage in tumorigenesis. The IGF2R gene encodes a nonmitogenic receptor which targets IGF-II to the lysosomes for degradation and, therefore, inhibits the mitogenic function of IGF-II. The human IGF2R is imprinted in a proportion of normal individuals. To test the hypothesis that IGF2R imprinting predisposes to Wilms' tumor through the effect of decreased IGF2R dosage on IGF-II inactivation, we examined IGF2R imprinting in Wilms' tumors. Two transcribed CA repeat polymorphisms were used to distinguish the two alleles in the RT-PCR product. We observed that in 7/16 of Wilms' tumor patients, the paternal IGF2R was markedly but not completely repressed in both tumor and normal kidney. In one additional case, IGF2R was likewise imprinted in the tumor but not in the normal kidney. A similar imprinting was observed in fetal tissues and placenta prior to 20 weeks fetal age but not in term placenta or postnatal blood cells, indicating abnormal persistence of a fetal pattern in the kidneys of Wilms' patients. Genetic analysis showed association of the imprinting with a cis-acting locus. The high frequency of aberrant persistence of IGF2R imprinting in the kidneys of Wilms' tumor patients, which may be an embryonic feature, suggests that it is a predisposing factor in tumorigenesis. This is in accordance with evidence that IGF2R is a tumour suppressor in other types of malignancies.

Prognostic factors for children with recurrent Wilms' tumor: results from the Second and Third National Wilms' Tumor Study.

The characteristics of 367 stage I-IV National Wilms' Tumor Study (NWTS) children who relapsed after initial treatment for unilateral disease in the second and third NWTS trials (NWTS-2 and -3) were analyzed to identify features predictive of survival. Although modifications in initial therapy resulted in a lower rate of first relapse in these two studies compared with NWTS-1, all previously identified prognostic factors after relapse remained statistically significant predictors of survival. Tumor histology, length of initial remission, initial therapy with two v three drugs, and site of relapse each were independently predictive of postrelapse survival. The 3-year postrelapse survival for all 367 patients was 30% +/- 3%; however, subgroups classified by these prognostic factors were identified that had 3-year postrelapse survival rates of greater than 40%. These subgroups included patients who had tumors of favorable histology (FH) that recurred (1) only in the lungs, (2) in the abdomen when radiotherapy (RT) was not initially given, or (3) that were originally stage I, (4) that were originally treated with only two drugs, or (5) that recurred 12 months or more after diagnosis. These results were achieved with the use of standard treatments, ie, surgery, RT, and chemotherapy using dactinomycin (AMD), vincristine (VCR), and Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH). It is suggested that patients in these groups might be managed with aggressive use of conventional therapies until newer chemotherapeutic agents and drug combinations are shown to be more effective. Patients with adverse prognostic features at relapse have a poor survival expectancy with standard measures. Salvage attempts for these patients are better based on experimental approaches.

Constitutional WT1 mutations in Wilms' tumor patients.

PURPOSE: Patients with Wilms' tumors (WT) who carry constitutional mutations in the WT1 gene have been described in case reports and small case series. We sought to determine the frequency of constitutional WT1 mutations in a larger cohort, and to identify clinical manifestations associated with the risk for carrying a WT1 mutation. METHODS: We collected clinical data and blood samples from 201 patients with a history of WT. Southern blot analysis, single-strand conformation polymorphism (SSCP) analysis, and direct DNA sequencing were performed on DNA isolated from peripheral-blood lymphocytes from each patient. Odds ratios (ORs) for the carriage of a germline mutation of the WT1 gene were calculated for patients who had specific clinical risk factors compared with those who did not. RESULTS: Of 201 patients with WT in the cohort, eight patients were carriers of mutations in the WT1 gene. Six of the eight mutations were protein-truncating nonsense mutations. None of 56 patients with isolated unilateral WT was a carrier. The OR of carrying a WT1 mutation was elevated for patients with genitourinary anomalies (OR19.3; P < .002). Seven of 28 boys with WT with cryptorchidism carried WT1 mutations. No increased risk was observed for patients with nephrogenic rests, bilateral tumors, history of secondary cancers, or family history of WT. CONCLUSION: Germline WT1 mutations in patients with WT are associated with genitourinary anomalies, especially cryptorchidism and/or hypospadias. Patients with WT and no genitourinary anomalies are at low risk for carrying a WT1 mutation. Constitutional WT1 mutations that encode truncated WT1 proteins may predispose to the development of cryptorchidism, hypospadias, and WTs.

Treatment of children with stages II to IV anaplastic Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the combination of vincristine, dactinomycin, and doxorubicin with (regimen J) or without (regimen DD-RT) cyclophosphamide on the relapse-free survival of children with stages II to IV Wilms' tumor and focal or diffuse anaplasia. PATIENTS AND METHODS: We reviewed the clinical courses of all randomized patients from National Wilms' Tumor Study (NWTS)-3 and NWTS-4 with stages II to IV anaplastic Wilms' tumor, and determined the 4-year relapse-free survival rate separately for those with focal or diffuse anaplasia. Anaplasia was evaluated using newly developed topographic definitions for focal and diffuse anaplasia. RESULTS: The 4-year relapse-free survival rate for five children with focal anaplasia who received regimen DD-RT was 80.0%, compared with 100.0% for eight children who received regimen J (P = .68). The 4-year relapse-free survival rate for 29 children with diffuse anaplasia treated with regimen DD-RT was 27.2%, compared with 54.8% for 30 children treated with regimen J (P = .02). CONCLUSION: We conclude that children with focal anaplasia have an excellent prognosis when treated with vincristine, doxorubicin, and dactinomycin. The addition of cyclophosphamide to the three-drug treatment regimen improved the 4-year relapse-free survival rate of children with stage II to IV diffuse anaplasia. This result suggests that further intensification of the treatment regimen for children with diffuse anaplasia may result in an additional improvement in prognosis.

Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of the administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS: Between August 6, 1986 and September 1, 1994, 905 previously untreated children aged younger than 16 years with stage II favorable histology (FH) WT (low-risk [LR]), stages III to IV FH WT, or stages I to IV clear-cell sarcoma of the kidney (high-risk[HR]) were randomized after the completion of 6 months of chemotherapy to discontinue (short) or continue for 9 additional months (long) treatment with chemotherapy regimens that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either divided-dose (STD) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: The 4-year relapse-free survival (RFS) rates after the second randomization for LR patients were 83.7% for the 190 patients treated with short and 88.2% for the 187 patients treated with long chemotherapy (P = .11). The 4-year RFS rates after the second randomization for HR FH patients were 89.7% for the 256 patients treated with short and 88.8% for the 246 patients treated with long chemotherapy (P = .87). The charge for treatment with the short PI treatment regimens for all children with stages I through IV FH WT was approximately one half of that with the long STD treatment regimens. CONCLUSION: The short administration schedule for the treatment of children with WT is no less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.