National Wilms Tumor Study Research Articles

Outcome of Children with Wilms' Tumor in Developing Countries.

Wilms’ tumor is the most common kidney tumor of childhood. The outcome of this malignant tumor has improved due to the improvement of therapeutic strategies. The most important factor in determining the prognosis of these patients is the histopathology subtype of the tumor; unfavorable histopathology is seen in only 11.5% of the patients, which accounts for 52% of deaths. Therefore, the aim of this study was to determine the outcome of children with Wilms’ tumor referred to our hospital over a period of 10 years. This is a retrospective cohort study, and the target population included all patients with Wilms’ tumor referred to Ali Asghar Hospital and were treated according to the National Wilms tumor study 4 (NWTS-4) protocol. All patients’ data were extracted from the medical records of the department. Overall survival and event-free survival (EFS) were analyzed by the Kaplan Mayer method in the SPSS software, version 23. Fifty-two patients (24 male and 28 female patients) with Wilms’ tumor were included. The mean age of the subjects was 40 months. The most common stage among boys and girls was stage II (23.08% and 28.85%, respectively). Our findings revealed that the overall five-year survival of patients was 87±5%; this figure was determined as 100% for boys and 76.8% ± 1.6 for girls (P = 0.018). Our findings show a dramatic improvement in the outcome of children with Wilms’s tumor, and our results are comparable with other results from developed countries. Gender may be an independent prognostic factor of children with Wilms’ tumor.

Is radiotherapy required in first-line treatment of stage I diffuse anaplastic Wilms tumor? A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG.

As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy. Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28weeks without local irradiation. One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%. Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.

Bilateral Wilms tumor with neonatal onset and the importance of prenatal diagnosis

Wilms tumor (WT) occurs in 1:10.000 live births and affects mainly the unilateral kidney. The National Wilms Tumor Study Group registered 6832 patients with WT from 1969 to January 1993, out of whom only 11 patients (0.16%) were newborns. Since 1969, 14 cases of prenatal diagnosis of WT have been reported in literature, two of which were bilateral WT. Currently, the patients’ survival rate is greater than 90%, owing to a combination of surgery, chemotherapy, and radiotherapy for high-risk patients. We report a case of bilateral WT, undiagnosed during the prenatal period due to the incomplete evaluation of the abdomen with ultrasonography. The newborn was vaginally delivered at 40 weeks’ gestational age with a good perinatal adaptation. Suddenly, during the night the newborn showed respiratory distress, bradycardia and then respiratory arrest. For this reason, he was ventilated, intubated and subjected to conventional mechanical ventilation. Despite the normal cardiac ultrasonography, the health care providers suspected a cyanotic congenital heart disease with duct dependency. After a gradual resumption of the oximetry and blood pressure, the infant was transported by the neonatal emergency transport system to the Cardiac Pediatric Surgery Department of a level III hospital. There, the clinical condition became extremely serious and the infant died of asystole. During autopsy, two large tumoral masses were found in both kidneys, also the characterization of the tumors was done through histological exam, which confirmed the diagnosis of WT. A prenatal diagnosis of WT is very important because the families can take advantage of prenatal counseling to understand the risks of continuing the pregnancy and to evaluate the need for abortion, while health care providers can prepare to face a difficult delivery. The review of the literature suggests that prenatal diagnosis of bilateral WT is possible. During prenatal age, the complete assessment of the abdomen with ultrasonography and Eco-Color-Doppler can reveal kidney anomalies and raise suspicion of diseases with urinary malformations.

Augmentation of Therapy for Combined Loss of Heterozygosity 1p and 16q in Favorable Histology Wilms Tumor: A Children's Oncology Group AREN0532 and AREN0533 Study Report.

In National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy. Patients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies. LOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%). Augmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Factors responsible for stage III disease in patients with Wilms tumor enrolled in the JWiTS-2 study.

Treatment is more intensive for stage III Wilms tumor (WT) than for stages I and II non-metastatic WTs. Various factors including tumor spillage, unresectability, and lymph node metastasis are responsible for stage III disease. The present study aimed to not identify clinical factors associated with the features of stage III WT to establish new treatment strategies. Of 166 patients with non-metastatic WT enrolled in the Japan Wilms Tumor Study (JWiTS)-2, 51 patients had stage III disease. The treatment protocol for JWiTS-2 was essentially the same as that in the National Wilms Tumor study (NWTS)-5. Local hospitals were surveyed to collect details of clinical findings related to stage III disease, and data regarding 45 (88%) patients were obtained. Nine patients with massive tumors underwent preoperative chemotherapy. Biopsy was performed in 6. Reduction in the tumor size was achieved in 8 of the 9 cases. Nephrectomy was finally performed in all of them. Thirty-six patients underwent primary nephrectomy. The reason for the stage III disease was lymph node metastasis (n = 9, 25%), tumor spillage (n = 20, 56%), and tumor extension/incomplete resection (n = 17, 47%). Some patients had more than one of these factors. Most patients were treated with the DD-4A regimen, and 43 (95.6%) of the 45 patients received abdominal radiation therapy. Tumors recurred in three patients (local, 1; metastasis, 2), and two patients died. Overall and relapse-free survival rates were 95.2% and 90.8%, respectively. The prognosis of stage III WT was good. In the next stage, the doses of chemotherapy and radiotherapy should be reduced to avoid late effects. The high rate of tumor spillage after primary resection suggests that preoperative chemotherapy should be started instead of aggressive tumor resection in the large tumor cases with surgical risks.

Treatment of stage I anaplastic Wilms' tumour: a report from the Children's Oncology Group AREN0321 study

BackgroundIn the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients. Patients and methodsTumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m2) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1–5 and AREN0321 with respect to treatment regimens. ResultsEighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1–5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3–100] vs. 77.5% [95% CI: 67.6–87.4]) but not by flank radiation (p = 0.15). ConclusionsTreatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation.

Conversion of computational human phantoms into DICOM-RT for normal tissue dose assessment in radiotherapy patients

Radiotherapy (RT) treatment planning systems (TPS) are designed for the fast calculation of dose to the tumor bed and nearby organs at risk using x-ray computed tomography (CT) images. However, CT images for a patient are typically available for only a small portion of the body, and in some cases, such as for retrospective epidemiological studies, no images may be available at all. When dose to organs that lie out-of-scan must be estimated, a convenient alternative for the unknown patient anatomy is to use a matching whole-body computational phantom as a surrogate. The purpose of the current work is to connect such computational phantoms to commercial RT TPS for retrospective organ dose estimation. A custom software with graphical user interface (GUI), called the DICOM-RT Generator, was developed in MATLAB to convert voxel computational phantoms into the digital imaging and communications in medicine radiotherapy (DICOM-RT) format, compatible with commercial TPS. DICOM CT image sets for the phantoms are created via a density-to-Hounsfield unit (HU) conversion curve. Accompanying structure sets containing the organ contours are automatically generated by tracing binary masks of user-specified organs on each phantom CT slice. The software was tested on a library of body size-dependent phantoms, the International Commission on Radiological Protection reference phantoms, and a canine voxel phantom, taking only a few minutes per conversion. The resulting DICOM-RT files were tested on several commercial TPS. As an example application, a library of converted phantoms was used to estimate organ doses for members of the National Wilms Tumor Study (NWTS) cohort. The converted phantom library, in DICOM format, and a standalone MATLAB-compiled executable of the DICOM-RT Generator are available for others to use for research purposes (http://ncidose.cancer.gov).

Management of Wilms tumor with intravenous thrombus in children: a single center experience

BackgroundWilms tumor tends to grow into vena cava, even invade atrium, which increased operating difficulty and frequency of surgical complications.MethodsForty-two patients of Wilms tumor with intravenous thrombus were retrospective studied. The diagnosis and therapy were discussed according to the medical records and interrelated literatures.ResultsForty-two children with thrombus were diagnosed by computed tomography and 41 cases by ultrasound simultaneously. 36 children had received preoperative chemotherapy. Surgical resection was performed in all patients. Cardiopulmonary bypass was used for the removal of the intra-atrial thrombus in 5 patients. There were no surgical complications occurred. The patients received chemotherapy and radiotherapy according to clinical staging by National Wilms’ Tumor Study (NWTS)-4 or NWTS-5. 34 patients were successfully followed up, 32 patients survive at present, including one who has been followed up more than 20 years since operation.ConclusionStandardized sequential treatment, including preoperative chemotherapy and radiotherapy, nephrectomy combining resection of thrombus, postoperative adjuvant therapy, is the mainstay of treatment of Wilms tumor with intravenous thrombus.

SOX21-AS1 is associated with clinical stage and regulates cell proliferation in nephroblastoma.

LncRNA SOX21 antisense RNA 1 (SOX21-AS1) dysregulated in many types of human cancer, and functioned as tumor suppressor or promoter depending on tumor types. However, there was no report about the role of SOX21-AS1 in nephroblastoma. In the present study, we first found that SOX21-AS1 expression was elevated in nephroblastoma tissues and cell lines compared with adjacent normal tissues and normal human embryonic kidney cell line, respectively. Moreover, we observed nephroblastoma patients with large tumor size, advanced National Wilms Tumor Study (NWTS) stage or unfavorable histopathological type, and patients that had higher SOX21-AS1 expression levels than nephroblastoma patients with small tumor size, early NWTS stage or favorable histopathological type. The in vitro studies suggested that knockdown of SOX21-AS1 suppressed nephroblastoma cell proliferation and colony formation, and induced cell-cycle arrest through up-regulating p57 expression. In conclusion, our study suggests that SOX21-AS1 functions as oncogenic lncRNA in nephroblastoma, which may provide a novel insight for nephroblastoma carcinogenesis.

Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients With Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group.

The use of computed tomography (CT) for routine surveillance to detect recurrence in patients with Wilms tumor (WT) has increased in recent years. The utility of CT, despite increased risk and cost, to improve outcome for these patients is unknown. We conducted a retrospective analysis with patients enrolled in the fifth National Wilms Tumor Study (NWTS-5) to determine if surveillance with CT correlates with improved overall survival (OS) after recurrence compared with chest x-ray (CXR) and abdominal ultrasound (US). Overall, 281 patients with recurrent unilateral favorable-histology WT were reviewed to assess how WT recurrence was detected: sign/symptoms (SS), surveillance imaging (SI) with CT scan, or SI with CXR/US. The estimated 5-year OS rate after relapse was 67% (95% CI, 61% to 72%). Twenty-five percent of recurrences were detected with SS; 48.5%, with CXR/US; and 26.5%, with CT. Patients with SS had a 5-year OS rate of 59% (95% CI, 46% to 72%) compared with 70% (95% CI, 63% to 77%; P = .23) for those detected by SI. Recurrences detected by CT had a shorter median time from diagnosis to recurrence (0.60 years) compared with SS (0.91 years) or CXR/US (0.86 years; P = .003). For recurrences detected by SI, more tumor foci at relapse ( P < .001) and size of the largest focus greater than 2 cm ( P = .02) were associated with inferior OS. However, there was no difference in OS after relapse when recurrence was detected by CT versus CXR/US (5-year OS rate, 65% v 73%; P = .20). In patients with favorable-histology WT, elimination of CT scans from surveillance programs is unlikely to compromise survival but would result in substantial reduction in radiation exposure and health care costs.

Impact of cyclophosphamide and etoposide on outcome of clear cell sarcoma of the kidney treated on the National Wilms Tumor Study-5 (NWTS-5).

To improve the event-free survival (EFS) and overall survival (OS) for patients with clear cell sarcoma of the kidney (CCSK) by incorporating cyclophosphamide and etoposide into treatment on National Wilms Tumor Study (NWTS)-5. Patients less than 16 years of age with a centrally confirmed pathological diagnosis of CCSK were eligible for treatment on this prospective single-arm study conducted between August 1995 and June 2002. Staging consisted of CT scans of chest, abdomen, pelvis, bone scan, skeletal survey, and CT or MRI of the head. Treatment consisted of vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide for 24weeks and radiation to sites of disease. One hundred eight eligible patients were enrolled on study (69% males, 63% Caucasian), with a median age of 22 months. Stage distribution was as follows: stage I, 12; II, 44; III, 45; IV, 7. Median follow-up was 9.7 years. Five-year EFS and OS were 79% (95% CI: 71%-88%) and 90% (95% CI: 84%-96%). Five-year EFS for stage I-IV was 100%, 88%, 73%, and 29%, respectively. Twenty of the 23 disease-related events occurred within three years of initial treatment. The most common site of recurrence was brain (12/23). The outcome for patients with CCSK treated on NWTS-5 was similar to NWTS-4 and accomplished over a shorter treatment duration. Stage was highly predictive of outcome. Brain metastases occurred more frequently than on NWTS-4. Regimen I showed more benefit for patients with stage I and II disease as compared with higher stages of disease where new therapies are needed.

Outcome of Wilms tumor patients with bone metastasis enrolled on National Wilms Tumor Studies 1-5: A report from the Children's Oncology Group.

Wilms tumor (WT) is the most common renal tumor in children. We describe the outcomes for patients with WT that metastasized to bone (WTBM) to assist in decision making for these uncommon patients. We retrospectively reviewed the research records of patients identified with WTBM from the National Wilms Tumor Study (NWTS 1-5) database. We then related overall survival (OS) to histology, chemotherapy, radiation therapy to bone, location of metastasis, and when bone metastasis presented. Thirty-eight of 8609 patients enrolled on NWTS 1-5 (0.44%) developed bone metastasis. Bone metastasis most commonly first occurred at progression or relapse (29/38, 76%). Five of thirty-eight survived (13%) with the 5-year OS following presentation of bone metastasis of 14.3% (95% CI: 2.7-25.8%). The primary cause of death was tumor (29/33, 88%). Of those who died, the median survival time was 10.9 months (range 0.49-61.4). Four of nine (44%) patients presenting at diagnosis and 3% (1/29) of patients presenting in progression or relapse survived (P=0.0075). Nineteen percent (5/26) of patients with favorable histology and 0% (0/12) with anaplastic histology survived (P=0.16). Of the five survivors, median follow-up was 14 years (range 6.7-23.8). Radiation to metastatic bone sites was recorded in three of five survivors. No consistent chemotherapeutic approach appeared to be associated with disease outcome. Bone metastasis is rare in patients with WT, occurring more commonly in progression or relapse than at initial diagnosis. Patients with WTBM have poor prognosis. We could not identify a consistent chemotherapeutic strategy associated with survival.

Feasibility and accuracy of UF/NCI phantoms and Monte Carlo retrospective dosimetry in children treated on National Wilms Tumor Study protocols.

This pilot study was done to determine the feasibility and accuracy of University of Florida/National Cancer Institute (UF/NCI) phantoms and Monte Carlo (MC) retrospective dosimetry and had two aims: (1) to determine the anatomic accuracy of UF/NCI phantoms by comparing 3D organ doses in National Wilms Tumor Study (NWTS) patient-matched UF/NCI phantoms to organ doses in corresponding patient-matched CT scans and (2) to compare infield and out-of-field organ dosimetry using two dosimetry methods-standard radiation therapy (RT) treatment planning systems (TPS) and MC dosimetry in these two anatomic models. Twenty NWTS patient-matched Digital Imaging and Communications in Medicine (DICOM) files of UF/NCI phantoms and CT scans were imported into the Pinnacle RT TPS. The NWTS RT fields (whole abdomen, flank, whole lung, or a combination) and RT doses (10-45Gy) were reconstructed in both models. Both TPS and MC dose calculations were performed. For aim 1, the mean doses to the heart, kidney, thyroid gland, testes, and ovaries using TPS and MC in both models were statistically compared. For aim 2, the TPS and MC dosimetry for these organs in both models were statistically compared. For aim 1, there was no significant difference between phantom and CT scan dosimetry for any of the organs using either TPS or MC dosimetry. For aim 2, there was a significant difference between TPS and MC dosimetry for both CT scan and phantoms for all organs. Although the doses for infield organs were similar for both TPS and MC, the doses for near-field and out-of-field organs were consistently higher for 90% to 100% of MC doses; however, the absolute dose difference was small (<1Gy). This pilot study has demonstrated that the patient-matched UF/NCI phantoms together with MC dosimetry is an accurate model for performing retrospective 3D dosimetry in large-scale epidemiology studies such as the NWTS.

Outcome Of Wilms Tumors Among Children At Single Center In A Developing Country

Objective: To determine the outcome of wilms tumors among children in our center and compare the results of treatment on the basis of management proposed by the National Wilms tumor study board (NWTS) and the Societe international D’oncologie pediatrique (SIOP) Patients and methods:- This study includes 49 children who presented to the Aga Khan University Hospital(AKUH) with wilms tumors from January 1988 to December 2015 (aged 0-16 years). Patients were further divided according to the treatment strategies they received i.e NWTS and SIOP. Data was analyzed using SPSS 10. Results:-.A total of 49 patients (57%male and 43% female) were included in the study. Majority of the cases (56%) were between 1-5 years. The tumors mostly presented on the right side (65%).The diagnostic work up of the patients mainly involved CT imaging (69%).35% of children in the SIOP group presented with stage 3 diseases whereas in the NWTS group 42% presented with stage 1 disease. In the SIOP group 4 (14%) patients had disease reoccurrence and 2 (7%) patients died. In the NWTS group 2(10%) patients had disease reoccurrence and 1 (5%) patient expired. A 5 year survival rate of both groups was calculated to be more than 80%. Mean follow up in SIOP group was 119 months and In NWTS group was 114 months. Conclusions:- Wilms tumors are curable in the majority of the patients even with limited resource as in our country. The NWTS and SIOP treatment approaches are almost equally effective at our center however adherence to a single treatment is mandatory for effective treatments.

Timing of Radiation Therapy in Pediatric Wilms Tumor: A Report From the National Cancer Database

Todetermine, using the National Cancer Database (NCDB), the impact of the surgery to radiation therapy interval (SRI) on survival in contemporary patients with Wilms tumor (WT). The NCDB was queried for patients aged ≤25years diagnosed from 2004 to 2013 with unilateral WT who underwent definitive surgery and radiation therapy. The SRI was calculated for each patient. A stratified analysis was performed based on presence of metastasis using logistic regression to calculate risk factors for prolonged SRI, with a focus on the recommended SRI according to recent Children's Oncology Group trials (by day 14) and National Wilms Tumor Study-5 (by day 9). Cox regression was performed to assess the association of SRI with overall survival. A total of 1488 patients were included; 32.1% had metastasis at diagnosis. Among both metastatic and nonmetastatic groups, older patients were more likely to have prolonged SRI. For those without metastasis, SRI > 14days was associated with increased risk of mortality (hazard ratio 2.13, P = .013). Analyzing SRI as a continuous variable also demonstrated an increased risk of death with longer SRI (hazard ratio 1.04 per day, P=.006) in this group. In contrast, among patients with metastasis, no significant association between SRI and mortality was found. Early initiation of radiation therapy remains a critical component of multimodal treatment for patients with nonmetastatic WT. For nonmetastatic patients, SRI ≤ 14days correlates with improved overall survival. However, no such association was noted for patients with metastases. These results may inform the development of future WT trials.

Metanephric adenofibroma in a child with impaired renal function

A 5-year-old girl presented with a history of bilateral reflux nephropathy and a left kidney mass, suspicious of Wilms tumor on imaging studies. She underwent radical nephrectomy according to the National Wilms Tumor Study protocol. The pathology report was consistent with metanephric adenofibroma (MAF), for which radical nephrectomy was considered curative. MAF is a benign, uncommon tumor, which is frequently confused with Wilms tumor on diagnostic imaging; histopathologic studies reveal the diagnosis. The diagnostic and management approach to MAF is discussed.

Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group Study AREN0532.

Background The National Wilms Tumor Study (NWTS) approach to treating stage III favorable-histology Wilms tumor (FHWT) is Regimen DD4A (vincristine, dactinomycin, and doxorubicin) and radiation therapy. Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.

A Ten Year Retrospective Audit of the Clinic-pathological Management and Treatment Outcomes of Patient’s with Nephroblastoma (Wilms Tumor) at Kenyatta National Hospital

<b>Background and aims: </b>Treatment of Nephroblastoma (Wilms’ tumor) in children is one of medicine's success stories. Due to improvements in surgical techniques, drug therapies, and radiation, 85 to 90 percent of children with Wilms tumor who receive state-of-the-art treatment are cured. While this is true for developed countries the outcomes of nephroblastoma (Wilms’ tumor, WT) in our hospital and other developing countries are notably below those in these countries. There are continuous reviews and updates of clinical pathologic features, treatment designs, and treatment outcomes every 2 or 3 years, in the developed countries. However, in resource poor countries, such frequent reviews and updates are presently not affordable but, nevertheless, efforts should be made to undertake them every 5 or so years, to improve patient management and treatment outcomes. The objectives of this study were to review the clinical presentation and management of children with Wilms tumor and the factors influencing the outcome at Kenyatta National Referral and Teaching Hospital (KNH). This was a retrospective descriptive cross-sectional study. Analysis of the data was carried out using the statistical package for the social sciences (SPSS) software. The findings of the study will form a basis for revision of treatment design for patients diagnosed with Nephroblastoma at KNH, and by extension, other tertiary public health care facilities in Kenya. <b>Patients and methods: </b>The records of 140 WT patients, aged less than 16 years, who were treated in Kenyatta National Hospital, Kenya, during the period from January 1997 to December 2008 were reviewed. The management protocol followed the scheme of the US National Wilms Tumor Study Group (NSWTG). <b>Results: </b>Thirteen cases (38.2%) were diagnosed as stage I, 4 (11.8%) as stage II, 13 (38.2%) as stage III and 2 (5.9%) as stage IV. Eight cases had bilateral disease (stage V). Four-year overall survival (OS) and event free survival (EFS) rates were xx% and xx%, respectively. Univariate analysis by Log-rank test revealed statistically significant associations between OS and nodal status (p- value < 0.01), manifestation of gross hematuria (p-value 0.02), and tumor size of 10 centimeters or more (p-value 0.02). Multivariate analysis found only the nodal status to be independently associated with OS at a Hazard Ratio of 16.6 (p-value < 0.01). Eight of 13 stage I cases and 6/13 stage III cases had relapsed, with two-year post-relapse survival of 42.8%. Significantly poorer outcome was found in cases with early relapse within 200 days after enrollment (p-value 0.02). <b>Conclusion: </b>Childhood Wilms’ tumor presents late in our setting with its consequent management challenges. The need to educate the populace and the primary healthcare providers on the benefits of early diagnosis and treatment of this condition cannot be overemphasized. Large tumor size and gross hematuria were associated with risk of a poorer outcome.

Outcome of patients with intracranial relapse enrolled on national Wilms Tumor Study Group clinical trials.

The occurrence of brain metastases (at diagnosis or at relapse) in patients with Wilms tumor is very rare. We retrospectively reviewed the clinical characteristics of patients with Wilms tumor and relapse to the brain enrolled on the National Wilms Tumor Studies (NWTSs) 1-5. Intracranial relapse was documented in 47 patients (0.5%). Of the 45 patients with adequate data, 26 (58%) patients were male. Thirty-eight (84%) patients had favorable histology Wilms tumor. In 30 patients (67%), the appearance of intracranial disease was preceded by relapse at another site. Ten patients did not have any disease-directed therapy. Surgical resection was attempted in 15 patients; gross total resection was achieved in 11 patients. Twenty-nine patients received brain irradiation; the median dose was 3,000 cGy (range 1,080-4,000 cGy). Twenty-seven patients received chemotherapy. The 5-year overall survival from the time of intracranial relapse was 28.7% (95% confidence interval: 14.4-43.1%). Nine patients (all favorable histology Wilms tumor) were alive with a median follow-up from brain relapse of 140 months (range 35-381 months). All nine survivors received radiation therapy, eight received chemotherapy, and four underwent surgery (two gross total resection, two partial resection). The overall survival after brain metastases of the NWTS-5 patients was significantly higher than the overall survival of the NWTS 1-4 patients (P value = 0.029, log-rank test). Patients with Wilms tumor recurrence involving the brain may have durable survival, particularly those treated in recent years. Multimodality therapy including radiation and chemotherapy should be considered for these patients.

Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group.

To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582-91. ©2016 AACR.