This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Metzger, M. L. Articles by Dome, J. S. Search for Related Content PubMed PubMed Citation Articles by Metzger, M. L. Articles by Dome, J. S.

Current Therapy for Wilms’ Tumor

Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

Key Words. Pediatric cancer • Wilms’ tumor • Nephroblastoma • Therapy • SIOP • NWTS

Correspondence: Jeffrey S. Dome, M.D., Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105-2794, USA. Telephone: 901-495-2533; Fax: 901-495-3966; e-mail: jeff.dome{at}stjude.org

Received May 16, 2005; accepted for publication September 9, 2005.

	LEARNING OBJECTIVES

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
After completing this course, the reader will be able to:

1. Describe the clinical and biological prognostic factors for Wilms’ tumor.
   
2. Discuss the different treatment strategies and staging systems adopted in North America and Europe.
   
3. Explain the challenges and treatment approaches for anaplastic, bilateral, and recurrent Wilms’ tumor.
   

	ABSTRACT

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
Wilms’ tumor was the first solid malignancy in which the value of adjuvant chemotherapy was established. Multimodality treatment has resulted in a significant improvement in outcome from approximately 30% in the 1930s to more than 85% in the modern era. Although the National Wilms’ Tumor Study Group and the International Society of Pediatric Oncology differ philosophically regarding the merits of preoperative chemotherapy, outcomes of patients treated with either up-front nephrectomy or preoperative chemotherapy have been excellent. The goal of current clinical trials is to reduce therapy for children with low-risk tumors, thereby avoiding acute and long-term toxicities. At the same time, current clinical trials seek to augment therapy for patients with high-risk Wilms’ tumor, including those with bilateral, anaplastic, and recurrent favorable histology tumors.

	INTRODUCTION

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
In June 1877, at the General Infirmary at Leeds, England, Dr. Thomas Jessop (1837–1903) performed the first successful nephrectomy on a 2-year-old child with hematuria and a large malignant process arising from the left kidney [1]. It was not until 1899 that the surgeon Max Wilms (1867–1918) described seven children suffering from nephroblastoma in a monograph on "mixed tumors" [2]. It is now recognized that nephroblastoma, or Wilms’ tumor, is the most common renal malignancy of childhood. Developments in surgical techniques in the 20th century improved the prognosis for this previously lethal malignancy. However, it was the discovery of the tumor’s radiosensitivity and the introduction of active chemotherapy agents that drastically improved survival rates. Today, with an overall survival (OS) rate of 90%, new treatment protocols are shifting their primary objective from maximizing cure to maximizing cure with minimal treatment-related toxicities. In this review, we discuss the advances of Wilms’ tumor therapy and current treatment strategies in North America and Europe.

	PROGNOSTIC FACTORS

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
Treatment regimens for Wilms’ tumor are selected based on an individual’s risk of recurrence, which is defined by clinical, histological, and biological prognostic factors. In this section, we describe the main prognostic indicators for Wilms’ tumor. These indicators will provide a backdrop for our discussion of treatment strategies.

Tumor Stage
Staging criteria for Wilms’ tumor are based exclusively on the anatomic extent of the tumor, without consideration of genetic, biologic, or molecular markers [3]. Two major staging systems are currently used: a prechemotherapy/up-front, surgery-based system developed by the National Wilms’ Tumor Study Group (NWTSG) and a postchemotherapy-based system developed by the International Society of Pediatric Oncology (SIOP) (Table 1). Both staging systems have proven valuable in predicting outcomes. It is important to recognize, however, that the difference in surgical timing confounds stage-for-stage comparisons between the two systems.

Classic Wilms’ tumor is composed of three cell types—blastemal, stromal, and epithelial—which can be present in various proportions. Also present are heterologous epithelial or stromal components, which include mucinous or squamous epithelium, skeletal muscle, cartilage, osteoid tissue, and fat [11]. Histologic classification defined by the NWTSG and SIOP studies differs because the SIOP protocols use preoperative chemotherapy. Hence, the SIOP histologic classification reflects chemotherapy-induced changes, including "regressive" changes or cell differentiation. Whereas the NWTSG classifies Wilms’ tumors based on the presence or absence of anaplasia, the revised SIOP histologic classification divides Wilms’ tumors into three risk groups: (a) low risk (completely necrotic nephroblastoma or cystic partially differentiated nephroblastoma), (b) intermediate risk (regressive, epithelial, stromal, mixed, or focal anaplastic nephroblastoma), and (c) high risk (blastemal or diffuse anaplastic nephroblastoma) [12, 13].

Patient Age
Cooperative group studies have shown that increasing patient age is associated with increased risk of recurrence in nonmetastatic Wilms’ tumor [14–17]. A subgroup with an outstanding prognosis are patients less than 2 years of age with small (<550 g) stage I favorable histology tumors [18–20]. At the other end of the age spectrum, adults with Wilms’ tumor were previously found to have relatively unfavorable outcomes compared with their pediatric counterparts, with an event-free survival (EFS) rate of 20%–30% [21]. More recent studies, however, have indicated that the survival rate for adult Wilms’ tumor is similar to that for pediatric Wilms’ tumor, although toxicity of treatment is greater in adults [22, 23].

Biological Prognostic Factors
Several biological factors have recently been identified that may supplement stage and histology in assigning risk. One such factor is loss of heterozygosity (LOH) at chromosomes 1p and 16q. Studies in the 1990s showed that children with LOH at 16q had greater risks of relapse and mortality than did children without this change [24–26]. A similar finding applied to LOH at chromosome 1p [24, 25]. To corroborate these findings, the fifth National Wilms’ Tumor Study (NWTS-5) prospectively analyzed LOH in primary Wilms’ tumors. Tumor-specific LOH for both chromosomes 1p and 16q, identified in approximately 5% of patients with favorable histology Wilms’ tumor, was shown to correlate with a significantly increased risk of relapse and death [27]. Future Children’s Oncology Group (COG) clinical studies will augment therapy for patients with favorable histology Wilms’ tumor and LOH at 1p and 16q. Other promising prognostic markers are an increase in gene copy number or expression at chromosome 1q [28, 29] and telomerase expression level [30, 31]. Gene expression profiling also shows promise to identify new prognostic factors [32–34].

	TREATMENT OF WILMS’ TUMOR WITH FAVORABLE HISTOLOGIC FEATURES

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
Several cooperative groups and individual institutions have made important contributions to the optimization of Wilms’ tumor therapy. Because the NWTSG and SIOP studies have included the largest number of patients, this review focuses on their findings. Since the NWTSG and SIOP nephroblastoma studies began more than three decades ago, there has been a philosophical difference of opinions about the administration of preoperative chemotherapy. The NWTSG and its successor, the COG, advocate up-front resection of the primary tumor before chemotherapy is given. In contrast, SIOP recommends the administration of chemotherapy for 4 weeks before surgery. Both treatment approaches yield excellent clinical outcomes (Table 2), yet a fertile debate continues about the relative merits of each approach [35].

A study of the feasibility of partial nephrectomy in treating nonmetastatic, unilateral Wilms’ tumors found that only 4.7% of patients would be eligible for this procedure [39, 40]. Partial nephrectomy was allowed only if the tumor involved one pole and less than one third of the kidney, if the patient had a functioning kidney, if the collecting system or renal vein had no tumor involvement, and if clear margins existed between the tumor and surrounding structures. Because the rate of renal failure in patients with unilateral Wilms’ tumor is less than 1% [41], kidney-sparing resection is not generally recommended.

Nephrectomy without adjuvant therapy was suggested to be adequate treatment for a subset of patients with highly favorable clinical features in the 1970s [42]. Retrospective review of NWTS-4 found that age at diagnosis less than 24 months and tumor weight less than 550 g were correlated with the absence of relapse-associated variables previously described in patients with stage I favorable histology tumors [43, 44]. Based on these findings, NWTS-5 prospectively treated 75 children younger than 24 months with small (<550 g) stage I favorable histology tumors with nephrectomy only. The study closed early according to predefined stopping rules because the risk of relapse at 2 years was 13.5%; however, all patients were successfully salvaged with standard therapy [19]. In light of the high OS rate achieved, the COG is planning a study to re-evaluate the benefit of nephrectomy-only in this selected group of patients.

The NWTSG has recommended preoperative chemotherapy under certain circumstances, including the occurrence of Wilms’ tumor in a solitary kidney, bilateral Wilms’ tumor, tumor in a horseshoe kidney, tumor thrombus in the inferior vena cava above the level of the hepatic veins, and respiratory distress resulting from the presence of extensive metastatic tumor [45].

The role of chemotherapy in treating Wilms’ tumors is undisputed. The activity of dactinomycin and vincristine against Wilms’ tumor was shown in the 1950s and 1960s, and these drugs have served as the cornerstone of Wilms’ tumor therapy ever since [46, 47]. Doxorubicin was added to the Wilms’ tumor treatment armamentarium in the1970s [48]. Through successive NWTS trials, the combination, length, and mode of administration of these three drugs have been refined to optimize survival rates while minimizing acute and long-term toxicities. Radiation therapy, although still an important component of Wilms’ tumor therapy, is restricted to treatment of stage III or IV disease. The conclusions drawn from each of the five NWTS trials are summarized in Table 3.

Pros and Cons of the NWTSG and SIOP Approaches
The NWTSG and SIOP approaches to Wilms’ tumor treatment each have distinct advantages and disadvantages. The primary strength of the NWTSG approach is that up-front resection allows an accurate assessment of histologic diagnosis and tumor extent. Most patients treated on SIOP Wilms’ tumor studies do not undergo tumor biopsy before starting therapy. On SIOP 93-01, approximately 5% of lesions in patients treated with chemotherapy were ultimately shown not to be Wilms’ tumor and included 1.8% that were benign [12]. A research benefit of removing the tumor before chemotherapy is that it enables the collection of untreated tumor for biology studies and provides an unadulterated view of the tumor’s molecular biology. The primary strength of the SIOP approach is that preoperative chemotherapy usually reduces the tumor volume, thereby decreasing the likelihood of spillage and "downstaging" the tumor [11]. As a result, fewer patients received local irradiation on SIOP-9 than on NWTS-5, although slightly more of the SIOP-9 patients received anthracycline [35]. A second advantage of preoperative chemotherapy is that response to treatment may provide a valuable prognostic indicator [50, 51]. In the absence of a clear choice between up-front nephrectomy and preoperative chemotherapy, it is reasonable to base the timing of resection on factors such as tumor size, the patient’s clinical condition, and the experience of the surgeon.

Another difference between the NWTSG and SIOP studies is in the management of lung metastases. In the most recent NWTSG studies, computerized tomographic (CT) scan and chest x-ray were performed to determine the presence of lung metastases. If the two imaging modalities yielded discordant results (usually in the form of "CT-only" nodules), the disease stage was ultimately designated by the treating physician. Any patient deemed to have lung metastases was given whole-lung irradiation. The 2-year relapse-free survival estimate for patients with stage IV disease treated on NWTS-4 was 81% [52]. In the SIOP studies, only chest x-ray was used to evaluate lung metastasis. If lung metastases completely disappeared with chemotherapy (or were completely resected), patients did not receive lung irradiation. With this approach, SIOP reported a 4-year EFS rate of 83% [53]. In contrast, the first Wilms’ tumor study by the United Kingdom Children’s Cancer Study Group reported a survival rate of only 65% when radiation therapy was not given to patients with lung metastases [54]. This finding raises the question about the role of lung irradiation. Future COG trials will assess the necessity of lung irradiation for patients whose tumors have favorable biological and histological features and show rapid response to chemotherapy.

	TREATMENT OF ANAPLASTIC WILMS’ TUMOR

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
The first trial to place anaplastic Wilms’ tumor into a distinct treatment group was the third National Wilms’ Tumor Study (NWTS-3) (1979–1986). On this study and on NWTS-4 (1986–1994), patients received vincristine, dactinomycin, and doxorubicin for 15 months and were randomly assigned to receive or not receive cyclophosphamide [6]. Patients with stage II–IV diffuse anaplastic disease had a 4-year relapse-free survival estimate of 27 % when treated without cyclophosphamide and 55% when treated with cyclophosphamide (p = .02) [6]. On the basis of these results, NWTS-5 incorporated cyclophosphamide into the treatment plan for patients with stage II, III, or IV diffuse anaplasia. Such patients received abdominal irradiation and a novel chemotherapy regimen consisting of vincristine, doxorubicin, and cyclophosphamide alternating with cyclophosphamide and etoposide. Patients with stage II–IV focal anaplasia were treated with abdominal irradiation, vincristine, doxorubicin, and dactinomycin. The 4-year EFS estimates for patients with diffuse and focal anaplasia were 55.1% and 74.9%, respectively. Four-year EFS estimates for patients with stage II (n = 28), III (n = 51), and IV (n = 16) anaplasia who had undergone immediate nephrectomy were 82.1%, 68.3%, and 37.5%, respectively. OS estimates were similar to EFS estimates [55].

On NWTS-5, patients with stage I diffuse or focal anaplastic Wilms’ tumor were treated with vincristine and dactinomycin because earlier studies had shown good outcomes for this group [56]. However, preliminary analysis yielded unexpectedly low 4-year EFS and OS estimates of 69.5% and 82.6%, respectively [55]. Hence, future COG studies will add doxorubicin and irradiation to the therapeutic regimen for these patients.

	TREATMENT OF BILATERAL WILMS’ TUMOR

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
Synchronous bilateral Wilms’ tumors account for only 6% of all Wilms’ tumors but they pose the special challenge of establishing local tumor control while preserving renal function. The management of bilateral Wilms’ tumor has evolved from primary surgical extirpation to kidney-preserving resection after preoperative chemotherapy. Preoperative chemotherapy often results in significant reduction in tumor size, thereby facilitating subsequent renal salvage. Extended follow-up of patients with bilateral Wilms’ tumor who were enrolled on NWTS-2 and -3 showed no difference in survival rates between those treated initially with surgical resection and those treated with biopsy and preoperative chemotherapy [57]. On NWTS-4, the risk of local recurrence for patients who underwent kidney-sparing resection was 8.2% [58]. The NWTS-5 recommendation for the management of bilateral Wilms’ tumor includes initial biopsy and local staging followed by chemotherapy (according to abdominal stage and histologic features) and second-look surgery at week 5 [59]. If needed, additional chemotherapy or radiation therapy is given, but definitive surgery is recommended within 12 weeks of diagnosis to limit the risk of chemoresistant clonal expansion [3]. Failure of bilateral Wilms’ tumor to respond to preoperative chemotherapy is often due not to anaplasia but to persistence of mature elements with a skeletal muscle component. In patients with anaplastic tumors, complete surgical excision is warranted, and in such cases the NWTSG favors tumor resection with a margin of renal tissue rather than enucleation. Long-term survival rates for patients with synchronous bilateral Wilms’ tumors are approximately 70%–80% [57, 60, 61].

Metachronous bilateral Wilms’ tumor accounts for approximately 2% of all Wilms’ tumors. The NWTSG has reported lower survival rates for patients with metachronous rather than synchronous bilateral tumors [62,63]. A literature review by Paulino et al. showed that the OS rate for patients with metachronous bilateral Wilms’ tumor was 49.1% at 5 years and 47.2% at 10 years, and a second tumor developed at a median interval of 23.1 months [64]. Children in whom a contralateral tumor developed more than 18 months after the initial diagnosis had a better OS rate than did those in whom it developed less than 18 months after diagnosis (10-year OS rate, 55.2% versus 39.6%). Children younger than 12 months who have perilobar nephrogenic rests are at markedly increased risk of contralateral disease and require frequent and regular surveillance for several years [65].

	TREATMENT OF RECURRENT WILMS’ TUMOR

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
Before the mid-1980s, the long-term survival rate after recurrence of Wilms’ tumor barely reached 30% [66–70]. During this era, salvage therapy consisted of vincristine, dactinomycin, doxorubicin, radiation therapy, or surgery. Often, salvage therapy was identical to the primary therapy. In recent years, cyclophosphamide, ifosfamide, cisplatin, carboplatin, and etoposide were shown to be active against Wilms’ tumor [71– 83], and multiagent regimens containing these drugs, most notably the ICE combination (ifosfamide, carboplatin, and etoposide), have significantly improved postrelapse survival rates to the 50%–60% range [71, 84, 85]. Favorable prognostic factors after relapse include favorable histologic features, relapse occurring more than 12 months after the initial diagnosis, low stage (I or II) of primary disease, initial treatment with vincristine and dactinomycin only, few pulmonary nodules, and no previous irradiation of the tumor bed [67, 84]. Studies of relapsed Wilms’ tumor performed at St. Jude Children’s Research Hospital indicated that patients who undergo complete resection of the recurrent tumor have a greater chance of survival than do patients who undergo only a partial resection or no surgery at all [69, 84]. It is unclear whether surgical resection was therapeutic or whether the patients who underwent surgery had a lower disease burden. Another study from the NWTSG showed that although therapeutic resection of pulmonary nodules does not improve outcome, it may have a role in histological confirmation of recurrence [86].

An unresolved question regarding the treatment of recurrent Wilms’ tumor is the benefit of high-dose therapy with autologous stem cell rescue. Several groups have reported promising salvage rates resulting from the use of either single or tandem stem cell transplants (Table 6). It is unclear, however, whether outcomes of high-dose therapy are superior to those obtained with modern, multiagent chemotherapy regimens [71, 84, 85]. A large randomized study will be required to answer this question.

	FUTURE DIRECTIONS

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

	SUMMARY

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
The treatment of Wilms’ tumor is one of the great success stories in oncology. Modern treatment regimens yield OS rates of 90%, and this success has precipitated a shift in emphasis to reducing toxicity. Although North America and Europe have different philosophies on preoperative chemotherapy, the overriding message is that most patients with Wilms’ tumor survive long term, regardless of the sequence of therapeutic interventions. In spite of this success, there remain patients for whom current treatment is suboptimal, including those with anaplastic, bilateral, or recurrent disease with favorable histologic features. These "problematic" groups account for about 25% of patients who have Wilms’ tumor, and this high proportion underscores the need for a continued effort to develop novel treatment approaches.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
The authors indicated no potential conflicts of interest.

	ACKNOWLEDGMENT

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 
This work was supported by grants CA87903 and CA21765 from the National Institutes of Health, by the American Cancer Society, and by the American Lebanese Syrian Associated Charities (ALSAC). The authors thank Sharon Naron for her editorial assistance.

	REFERENCES

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

 

1. Willetts IE. Jessop and the Wilms’ tumor. J Pediatr Surg 2003;38:1496–1498.[CrossRef][Medline]
2. Wilms M. Die Mischgeschwülste der Niere. Georgi A, ed. Leipzig, Germany:1899.
3. Kalapurakal JA, Dome JS, Perlman EJ et al. Management of Wilms’ tumour: current practice and future goals. Lancet Oncol 2004;5:37–46.[CrossRef][Medline]
4. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms’ tumors: results from the First National Wilms’ Tumor Study. Cancer 1978;41:1937–1948.[CrossRef][Medline]
5. Faria P, Beckwith JB, Mishra K et al. Focal versus diffuse anaplasia in Wilms’ tumor–new definitions with prognostic significance: a report from the National Wilms’ Tumor Study Group. Am J Surg Pathol 1996;20:909–920.[CrossRef][Medline]
6. Green DM, Beckwith JB, Breslow NE et al. Treatment of children with stages II to IV anaplastic Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1994;12:2126–2131.[Abstract/Free Full Text]
7. Green DM, Breslow NE, Beckwith JB et al. Treatment of children with clear-cell sarcoma of the kidney: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1994;12:2132–2137.[Abstract/Free Full Text]
8. Haas JE, Palmer NF, Weinberg AG et al. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol 1981;12:646–657.[Medline]
9. Haas JE, Bonadio JF, Beckwith JB. Clear cell sarcoma of the kidney with emphasis on ultrastructural studies. Cancer 1984;54:2978–2987.[CrossRef][Medline]
10. Weeks DA, Beckwith JB, Mierau GW et al. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms’ Tumor Study Pathology Center. Am J Surg Pathol 1989;13:439–458.[Medline]
11. Beckwith JB. Wilms’ tumor and other renal tumors of childhood: a selective review from the National Wilms’ Tumor Study Pathology Center. Hum Pathol 1983;14:481–492.[Medline]
12. de Kraker J, Graf N, van Tinteren H et al. Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms’ tumour (SIOP 93-01 trial): a randomised controlled trial. Lancet 2004;364:1229–1235.[CrossRef][Medline]
13. Vujanic GM, Sandstedt B, Harms D et al. Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002;38:79–82.[CrossRef][Medline]
14. Breslow N, Churchill G, Beckwith JB et al. Prognosis for Wilms’ tumor patients with nonmetastatic disease at diagnosis–results of the second National Wilms’ Tumor Study. J Clin Oncol 1985;3:521–531.[Abstract]
15. Breslow N, Sharples K, Beckwith JB et al. Prognostic factors in nonmeta-static, favorable histology Wilms’ tumor. Results of the Third National Wilms’ Tumor Study. Cancer 1991;68:2345–2353.[CrossRef][Medline]
16. Breslow NE, Palmer NF, Hill LR et al. Wilms’ tumor: prognostic factors for patients without metastases at diagnosis: results of the National Wilms’ Tumor Study. Cancer 1978;41:1577–1589.[CrossRef][Medline]
17. Pritchard-Jones K, Kelsey A, Vujanic G et al. Older age is an adverse prognostic factor in stage I, favorable histology Wilms’ tumor treated with vincristine monochemotherapy: a study by the United Kingdom Children’s Cancer Study Group, Wilms’ Tumor Working Group. J Clin Oncol 2003;21:3269–3275.[Abstract/Free Full Text]
18. Green DM, Breslow NE, Beckwith JB et al. Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-histology Wilms’ tumors: a report from the National Wilms’ Tumor Study. J Clin Oncol 1993;11:91–95.[Abstract]
19. Green DM, Breslow NE, Beckwith JB et al. Treatment with nephrectomy only for small, stage I/favorable histology Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2001;19:3719–3724.[Abstract/Free Full Text]
20. Larsen E, Perez-Atayde A, Green DM et al. Surgery only for the treatment of patients with stage I (Cassady) Wilms’ tumor. Cancer 1990;66:264–266.[CrossRef][Medline]
21. Byrd RL, Evans AE, D’Angio GJ. Adult Wilms’ tumor: effect of combined therapy on survival. J Urol 1982;127:648–651.[Medline]
22. Arrigo S, Beckwith JB, Sharples K et al. Better survival after combined modality care for adults with Wilms’ tumor. A report from the National Wilms’ Tumor Study. Cancer 1990;66:827–830.[CrossRef][Medline]
23. Reinhard H, Aliani S, Ruebe C et al. Wilms’ tumor in adults: results of the Society of Pediatric Oncology (SIOP) 93-01/Society for Pediatric Oncology and Hematology (GPOH) Study. J Clin Oncol 2004;22:4500–4506.[Abstract/Free Full Text]
24. Grundy P, Telzerow P, Moksness J et al. Clinicopathologic correlates of loss of heterozygosity in Wilms’ tumor: a preliminary analysis. Med Pediatr Oncol 1996;27:429–433.[CrossRef][Medline]
25. Grundy PE, Telzerow PE, Breslow N et al. Loss of heterozygosity for chromosomes 16q and 1p in Wilms’ tumors predicts an adverse outcome. Cancer Res 1994;54:2331–2333.[Abstract/Free Full Text]
26. Grundy RG, Pritchard J, Scambler P et al. Loss of heterozygosity on chromosome 16 in sporadic Wilms’ tumour. Br J Cancer 1998;78:1181–1187.[Medline]
27. Grundy PE, Breslow N, Li S et al. Loss of Heterozygosity for Chromosomes 1p and 16q is an Adverse Prognostic Factor in Favorable Histology Wilms’ Tumor. A Report from the National Wilms’ Tumor Study Group. J Clin Oncol 2005;23:7312–7321.[Abstract/Free Full Text]
28. Hing S, Lu YJ, Summersgill B et al. Gain of 1q is associated with adverse outcome in favorable histology Wilms’ tumors. Am J Pathol 2001;158:393–398.[Abstract/Free Full Text]
29. Lu YJ, Hing S, Williams R et al. Chromosome 1q expression profiling and relapse in Wilms’ tumour. Lancet 2002;360:385–386.[CrossRef][Medline]
30. Dome JS, Bockhold CA, Li SM et al. High telomerase RNA expression is an adverse prognostic factor for favorable histology Wilms’ tumor. J Clin Oncol 2005 Sept 19 (epub ahead of print).
31. Dome JS, Chung S, Bergemann T et al. High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms’ tumor. Cancer Res 1999;59:4301–4307.[Abstract/Free Full Text]
32. Williams RD, Hing SN, Greer BT et al. Prognostic classification of relapsing favorable histology Wilms’ tumor using cDNA microarray expression profiling and support vector machines. Genes Chromosomes Cancer 2004;41:65–79.[CrossRef][Medline]
33. Li W, Kessler P, Yeger H et al. A gene expression signature for relapse of primary Wilms’ tumors. Cancer Res 2005;65:2592–2601.[Abstract/Free Full Text]
34. Takahashi M, Yang XJ, Lavery TT et al. Gene expression profiling of favorable histology Wilms’ tumors and its correlation with clinical features. Cancer Res 2002;62:6598–6605.[Abstract/Free Full Text]
35. D’Angio GJ. Pre- or post-operative treatment for Wilms’ tumor? Who, what, when, where, how, why–and which. Med Pediatr Oncol 2003;41:545–549.[CrossRef][Medline]
36. Ladd WE. Embryoma of the kidney (Wilms’ tumor). Ann Surg 1938;108:885–902.[CrossRef][Medline]
37. Shamberger RC, Guthrie KA, Ritchey ML et al. Surgery-related factors and local recurrence of Wilms’ tumor in National Wilms’ Tumor Study 4. Ann Surg 1999;229:292–297.[CrossRef][Medline]
38. Ritchey ML, Shamberger RC, Haase G et al. Surgical complications after primary nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. J Am Coll Surg 2001;192:63–68.[CrossRef][Medline]
39. Wilimas JA, Magill L, Parham DM et al. Is renal salvage feasible in unilateral Wilms’ tumor? Proposed computed tomographic criteria and their relation to surgicopathologic findings. Am J Pediatr Hematol Oncol 1990;12:164–167.[Medline]
40. Wilimas JA, Magill L, Parham DM et al. The potential for renal salvage in nonmetastatic unilateral Wilms’ tumor. Am J Pediatr Hematol Oncol 1991;13:342–344.[Medline]
41. Ritchey ML, Green DM, Thomas PR et al. Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 1996;26:75–80.[CrossRef][Medline]
42. Green DM, Jaffe N. The role of chemotherapy in the treatment of Wilms’ tumor. Cancer 1979;44:52–57.[CrossRef][Medline]
43. Green DM, Beckwith JB, Weeks DA et al. The relationship between microsubstaging variables, age at diagnosis, and tumor weight of children with stage I/favorable histology Wilms’ tumor. A report from the National Wilms’ Tumor study. Cancer 1994;74:1817–1820.[CrossRef][Medline]
44. Weeks DA, Beckwith JB, Luckey DW. Relapse-associated variables in stage I favorable histology Wilms’ tumor. A report of the National Wilms’ Tumor Study. Cancer 1987;60:1204–1212.[CrossRef][Medline]
45. Shamberger RC. Pediatric renal tumors. Semin Surg Oncol 1999;16:105–120.[CrossRef][Medline]
46. Farber S. Chemotherapy in the treatment of leukemia and Wilms’ tumor. JAMA 1966;198:826–836.[Abstract/Free Full Text]
47. Vietti TJ, Sullivan MP, Haggard ME et al. Vincristine sulfate and radiation therapy in metastatic Wilms’ tumor. Cancer 1970;25:12–20.[CrossRef][Medline]
48. D’Angio GJ, Evans A, Breslow N et al. The treatment of Wilms’ tumor: results of the Second National Wilms’ Tumor Study. Cancer 1981;47:2302–2311.[CrossRef][Medline]
49. Green DM, Grigoriev YA, Nan B et al. Congestive heart failure after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study group. J Clin Oncol 2001;19:1926–1934.[Abstract/Free Full Text]
50. Boccon-Gibod L, Rey A, Sandstedt B et al. Complete necrosis induced by preoperative chemotherapy in Wilms’ tumor as an indicator of low risk: report of the international society of paediatric oncology (SIOP) nephroblastoma trial and study 9. Med Pediatr Oncol 2000;34:183–190.[CrossRef][Medline]
51. Weirich A, Leuschner I, Harms D et al. Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to the trial and study SIOP-9/GPOH. Ann Oncol 2001;12:311–319.[Abstract/Free Full Text]
52. Green DM, Breslow NE, Beckwith JB et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998;16:3744–3751.[Abstract/Free Full Text]
53. de Kraker J, Lemerle J, Voute PA et al. Wilms’ tumor with pulmonary metastases at diagnosis: the significance of primary chemotherapy. International Society of Pediatric Oncology Nephroblastoma Trial and Study Committee. J Clin Oncol 1990;8:1187–1190.[Abstract]
54. Pritchard J, Imeson J, Barnes J et al. Results of the United Kingdom Children’s Cancer Study Group first Wilms’ Tumor Study. J Clin Oncol 1995;13:124–133.[Abstract/Free Full Text]
55. Dome JS, Green DM, Cotton CA et al. Treatment of anaplastic Wilms’ Tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2005 (ASCO Annual Meeting Proceedings):8508.
56. Zuppan CW, Beckwith JB, Luckey DW. Anaplasia in unilateral Wilms’ tumor: a report from the National Wilms’ Tumor Study Pathology Center. Hum Pathol 1988;19:1199–1209.[CrossRef][Medline]
57. Montgomery BT, Kelalis PP, Blute ML et al. Extended follow-up of bilateral Wilms’ tumor: results of the National Wilms’ Tumor Study. J Urol 1991;146:514–518.[Medline]
58. Horwitz JR, Ritchey ML, Moksness J et al. Renal salvage procedures in patients with synchronous bilateral Wilms’ tumors: a report from the National Wilms’ Tumor Study Group. J Pediatr Surg 1996;31:1020–1025.[CrossRef][Medline]
59. Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. Philadelphia/Baltimore/New York/London/Buenos Aires/Hong Kong/ Sydney/Tokyo: Lippincott Williams & Wilkins, 2001.
60. Bishop HC, Tefft M, Evans AE et al. Survival in bilateral Wilms’ tumor–review of 30 National Wilms’ Tumor Study cases. J Pediatr Surg 1977;12:631–638.[CrossRef][Medline]
61. Blute ML, Kelalis PP, Offord KP et al. Bilateral Wilms’ tumor. J Urol 1987;138:968–973.[Medline]
62. Coppes MJ, de Kraker J, van Dijken PJ et al. Bilateral Wilms’ tumor: long-term survival and some epidemiological features. J Clin Oncol 1989;7:310–315.[Abstract]
63. Jones B, Hrabovsky E, Kiviat N et al. Metachronous bilateral Wilms’ tumor, National Wilms’ Tumor Study. Am J Clin Oncol 1982;5:545–550.[Medline]
64. Paulino AC, Thakkar B, Henderson WG. Metachronous bilateral Wilms’ tumor: the importance of time interval to the development of a second tumor. Cancer 1998;82:415–420.[CrossRef][Medline]
65. Coppes MJ, Arnold M, Beckwith JB et al. Factors affecting the risk of contralateral Wilms’ tumor development: a report from the National Wilms’ Tumor Study Group. Cancer 1999;85:1616–1625.[CrossRef][Medline]
66. Groot-Loonen JJ, Pinkerton CR, Morris-Jones PH et al. How curable is relapsed Wilms’ tumour? The United Kingdom Children’s Cancer Study Group. Arch Dis Child 1990;65:968–970.[Abstract/Free Full Text]
67. Grundy P, Breslow N, Green DM et al. Prognostic factors for children with recurrent Wilms’ tumor: results from the Second and Third National Wilms’ Tumor Study. J Clin Oncol 1989;7:638–647.[Abstract]
68. Pinkerton CR, Groot-Loonen JJ, Morris-Jones PH et al. Response rates in relapsed Wilms’ tumor. A need for new effective agents. Cancer 1991;67:567–571.[CrossRef][Medline]
69. Wilimas JA, Champion J, Douglass EC et al. Relapsed Wilms’ tumor. Factors affecting survival and cure. Am J Clin Oncol 1985;8:324–328.[Medline]
70. Tournade MF, Lemerle J, Brunat-Mentigny M et al. Ifosfamide is an active drug in Wilms’ tumor: a phase II study conducted by the French Society of Pediatric Oncology. J Clin Oncol 1988;6:793–796.[Abstract/Free Full Text]
71. Abu-Ghosh AM, Krailo MD, Goldman SC et al. Ifosfamide, carboplatin and etoposide in children with poor-risk relapsed Wilms’ tumor: a Children’s Cancer Group report. Ann Oncol 2002;13:460–469.[Abstract/Free Full Text]
72. de Camargo B, Melaragno R, Saba e Silva N et al. Phase II study of carboplatin as a single drug for relapsed Wilms’ tumor: experience of the Brazilian Wilms’ Tumor Study Group. Med Pediatr Oncol 1994;22:258–260.[Medline]
73. Ettinger LJ, Gaynon PS, Krailo MD et al. A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the Children’s Cancer Group. Cancer 1994;73:1297–1301.[CrossRef][Medline]
74. Kung FH, Desai SJ, Dickerman JD et al. Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 1995;17:265–269.[Medline]
75. Loss JF, Santos PP, Leone LD et al. Outcome of pediatric recurrent and refractory malignant solid tumors following ifosfamide/carboplatin/etoposide (ICE): A phase II study in a pediatric oncology centre in Brazil. Pediatr Blood Cancer 2004;42:139–144.[CrossRef][Medline]
76. Pein F, Pinkerton R, Tournade MF et al. Etoposide in relapsed or refractory Wilms’ tumor: a phase II study by the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. J Clin Oncol 1993;11:1478–1481.[Abstract/Free Full Text]
77. Pein F, Tournade MF, Zucker JM et al. Etoposide and carboplatin: a highly effective combination in relapsed or refractory Wilms’ tumor–a phase II study by the French Society of Pediatric Oncology. J Clin Oncol 1994;12:931–936.[Abstract/Free Full Text]
78. Pinkerton CR, Pritchard J. A phase II study of ifosfamide in paediatric solid tumours. Cancer Chemother Pharmacol 1989;24(suppl 1):S13–S15.
79. Pratt CB, Horowitz ME, Meyer WH et al. Phase II trial of ifosfamide in children with malignant solid tumors. Cancer Treat Rep 1987;71:131–135.[Medline]
80. Pratt CB, Douglass EC, Etcubanas E et al. Clinical studies of ifosfamide/ mesna at St Jude Children’s Research Hospital, 1983–1988. Semin Oncol 1989;16:51–55.
81. Saylors RL III, Stewart CF, Zamboni WC et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study. J Clin Oncol 1998;16:945–952.[Abstract]
82. Schwartzman E, Scopinaro M, Angueyra N. Phase II study of ifosfamide as a single drug for relapsed paediatric patients. Cancer Chemother Pharmacol 1989;24(suppl 1):S11–S12.
83. Tournade MF. A phase II study of ifosfamide in the treatment of relapses in Wilms’ tumor. Cancer Chemother Pharmacol 1989;24(suppl 1):S31–S33.
84. Dome JS, Liu T, Krasin M et al. Improved survival for patients with recurrent Wilms’ tumor: the experience at St. Jude Children’s Research Hospital. J Pediatr Hematol Oncol 2002;24:192–198.[CrossRef][Medline]
85. Marina NM, Wilimas JA, Meyer WH et al. Refining therapeutic strategies for patients with resistant Wilms’ tumor. Am J Pediatr Hematol Oncol 1994;16:296–300.[Medline]
86. Green DM, Breslow NE, Ii Y et al. The role of surgical excision in the management of relapsed Wilms’ tumor patients with pulmonary metastases: a report from the National Wilms’ Tumor Study. J Pediatr Surg 1991;26:728–733.[CrossRef][Medline]
87. Santana VM, Zamboni WC, Kirstein MN et al. A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 2003;9:633–640.[Abstract/Free Full Text]
88. Saylors RL III, Stine KC, Sullivan J et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 2001;19:3463–3469.[Abstract/Free Full Text]
89. Rowe DH, Kayton ML, O’Toole KM et al. Pathological angiogenesis in a murine model of human Wilms’ tumor. J Pediatr Surg 1999;34:676–679.[CrossRef][Medline]
90. Frischer JS, Huang J, Serur A et al. Effects of potent VEGF blockade on experimental Wilms’ tumor and its persisting vasculature. Int J Oncol 2004;25:549–553.[Medline]
91. Huang J, Frischer JS, Serur A et al. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade. Proc Natl Acad Sci U S A 2003;100:7785–7790.[Abstract/Free Full Text]
92. Green DM. The treatment of stages I–IV favorable histology Wilms’ tumor. J Clin Oncol 2004;22:1366–1372.[Free Full Text]
93. Green DM, Breslow NE, Beckwith JB et al. Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998;16:237–245.[Abstract/Free Full Text]
94. Breslow NE, Ou SS, Beckwith JB et al. Doxorubicin for favorable histology, Stage II–III Wilms’ tumor: results from the National Wilms’ Tumor Studies. Cancer 2004;101:1072–1080.[CrossRef][Medline]
95. Tournade MF, Com-Nougue C, de Kraker J et al. Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms’ tumor in children older than 6 months: results of the Ninth International Society of Pediatric Oncology Wilms’ Tumor Trial and Study. J Clin Oncol 2001;19:488–500.[Abstract/Free Full Text]
96. Mitchell C, Jones PM, Kelsey A et al. The treatment of Wilms’ tumour: results of the United Kingdom Children’s Cancer Study Group (UKCCSG) second Wilms’ tumour study. Br J Cancer 2000;83:602–608.[CrossRef][Medline]
97. Sutow WW, Breslow NE, Palmer NF et al. Prognosis in children with Wilms’ tumor metastases prior to or following primary treatment: results from the first National Wilms’ Tumor Study (NWTS-1). Am J Clin Oncol 1982;5:339–347.[Medline]
98. Green DM, Breslow NE, Evans I et al. The effect of chemotherapy dose intensity on the hematological toxicity of the treatment for Wilms’ tumor. A report from the National Wilms’ Tumor Study. Am J Pediatr Hematol Oncol 1994;16:207–212.[Medline]
99. Reinhard H, Semler O, Burger D et al. Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms’ Tumor. Klin Padiatr 2004;216:132–140.[CrossRef][Medline]
100. Grundy RG, Hutton C, Middleton H et al. Outcome of patients with stage III or inoperable WT treated on the second United Kingdom WT protocol (UKWT2); a United Kingdom Children’s Cancer Study Group (UKCCSG) study. Pediatr Blood Cancer 2004;42:311–319.[CrossRef][Medline]
101. Burger D, Moorman-Voestermans CG, Mildenberger H et al. The advantages of preoperative therapy in Wilms’ tumour. A summarised report on clinical trials conducted by the International Society of Paediatric Oncology (SIOP). Z Kinderchir 1985;40:170–175.[Medline]
102. Lemerle J, Voute PA, Tournade MF et al. Preoperative versus postoperative radiotherapy, single versus multiple courses of actinomycin D, in the treatment of Wilms’ tumor. Preliminary results of a controlled clinical trial conducted by the International Society of Paediatric Oncology (S.I.O.P.). Cancer 1976;38:647–654.[CrossRef][Medline]
103. Lemerle J, Voute PA, Tournade MF et al. Effectiveness of preoperative chemotherapy in Wilms’ tumor: results of an International Society of Paediatric Oncology (SIOP) clinical trial. J Clin Oncol 1983;1:604–609.[Abstract]
104. Tournade MF, Com-Nougue C, Voute PA et al. Results of the Sixth International Society of Pediatric Oncology Wilms’ Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms’ tumor. J Clin Oncol 1993;11:1014–1023.[Abstract/Free Full Text]
105. Garaventa A, Hartmann O, Bernard JL et al. Autologous bone marrow transplantation for pediatric Wilms’ tumor: the experience of the European Bone Marrow Transplantation Solid Tumor Registry. Med Pediatr Oncol 1994;22:11–14.[Medline]
106. Hempel L, Kremens B, Weirich A et al. High dose consolidation with autologous stem cell rescue (ASCR) for nephroblastoma initially treated according to the SIOP 9/GPOH trial and study. Klin Padiatr 1996;208:186–189.[Medline]
107. Pein F, Michon J, Valteau-Couanet D et al. High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms’ tumor: a French Society of Pediatric Oncology study. J Clin Oncol 1998;16:3295–3301.[Abstract]
108. Kremens B, Gruhn B, Klingebiel T et al. High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma. Bone Marrow Transplant 2002;30:893–898.[CrossRef][Medline]
109. Campbell AD, Cohn SL, Reynolds M et al. Treatment of relapsed Wilms’ tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: the experience at Children’s Memorial Hospital. J Clin Oncol 2004;22:2885–2890.[Abstract/Free Full Text]

	ADDITIONAL READING

Top Learning objectives Abstract Introduction Prognostic factors Treatment of wilms’ tumor... Treatment of anaplastic... Treatment of bilateral... Treatment of recurrent... Future directions Summary Disclosure of potential... References Additional reading

D’Angio GJ. Pre or postoperative treatment of Wilms’ tumor? Who, what, when, where, how, why–and which. Med Pediatr Oncol 2003;41:545–549.

de Kraker J, Pritchard-Jones K. Treatment of Wilms’ tumor: an international perspective. J Clin Oncol 2005;23:3156–3157.[Free Full Text]

Dome JS, Coppes MJ. Recent advances in Wilms’ tumor genetics. Curr Opin Pediatr 2002;14:5–11.[CrossRef][Medline]

Green DM. The treatment of stages I–IV favorable histology Wilms’ tumor. J Clin Oncol 2004;22:1366–1372.

Kalapurakal JA, Dome JS, Perlman EJ et al. Management of Wilms’ tumor: current practice and future goals. Lancet Oncol 2004;5:37–46.

This article has been cited by other articles:

				A. A. Morrison, R. L. Viney, M. A. Saleem, and M. R. Ladomery New insights into the function of the Wilms tumor suppressor gene WT1 in podocytes Am J Physiol Renal Physiol, July 1, 2008; 295(1): F12 - F17. [Abstract] [Full Text] [PDF]

				P. R. Bhosale, M. Patnana, C. Viswanathan, and J. Szklaruk The Inguinal Canal: Anatomy and Imaging Features of Common and Uncommon Masses RadioGraphics, May 1, 2008; 28(3): 819 - 835. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Metzger, M. L. Articles by Dome, J. S. Search for Related Content PubMed PubMed Citation Articles by Metzger, M. L. Articles by Dome, J. S.