This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Marina, N. Articles by Olson, T. Search for Related Content PubMed PubMed Citation Articles by Marina, N. Articles by Olson, T. Social Bookmarking                            What's this?

Prognostic Factors in Children With Extragonadal Malignant Germ Cell Tumors: A Pediatric Intergroup Study

Neyssa Marina, Wendy B. London, A. Lindsay Frazier, Stephen Lauer, Frederick Rescorla, Barbara Cushing, Marcio H. Malogolowkin, Robert P. Castleberry, Richard B. Womer, Thomas Olson

From the Stanford University Medical Center, Stanford, CA; University of Florida and Children's Oncology Group Statistics and Data Center, Gainesville, FL; Dana-Farber Cancer Center, Boston, MA; Children's Healthcare of Atlanta at Egleston, Atlanta, GA; Indiana University Riley Children's Hospital, Indianapolis, IN; Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Children's Hospital Los Angeles, Los Angeles, CA; University of Alabama at Birmingham, AL; and the Children's Hospital of Philadelphia, Philadelphia, PA

Address reprint requests to Neyssa Marina, MD, Stanford University Medical Center, 1000 Welch Rd, Suite 300, Stanford, CA 94304-1812; e-mail: neyssa.marina{at}stanford.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To investigate prognostic factors for pediatric extragonadal malignant germ cell tumors (PEMGCT).

MATERIALS AND METHODS: Between 1990 and 1996, patients with stage I through IV PEMGCT were eligible for a trial of cisplatin dose intensity. We retrospectively investigated prognostic factors for PEMGCT, including age, stage, primary site, treatment, and elevated alfa fetoprotein by univariate and multivariate analysis.

RESULTS: The 165 patients had a median age of 1.9 years (range, 3 days to 18.5 years); 109 were female; and 99 had alfa fetoprotein 10,000. There were 30 stage I/II, 61 stage III, and 74 stage IV tumors; primary sites included 88 sacrococcygeal, 39 thoracic, and 38 others. The 5-year overall survival (OS) and event-free survival (EFS) rates with standard deviations were 83.4% ± 3.7% and 79.0% ± 4.1%, respectively. Univariate analysis identified age 12 years as a highly significant prognostic factor for EFS (5-year EFS, 48.9% ± 15.6% v 84.1% ± 3.9%; P < .0001) and for OS (5-year OS, 53.7% ± 14.9% v 88.5% ± 3.4%; P < .0001), whereas treatment was of borderline significance (P = .0777). Multivariate Cox proportional hazards regression identified only age 12 years as a significant prognostic factor for EFS (P = .0002). In multivariate Cox regression for OS, the combination of age and primary site was highly significant (P < .0001). Patients 12 years of age with thoracic tumors had six times the risk of death compared with patients younger than 12 years with other primaries.

CONCLUSION: Age is the most predictive factor of EFS in PEMGCT. There is a significant interaction between age and primary site, suggesting that patients 12 years of age with thoracic tumors are a biologically distinct group.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Pediatric germ cell tumors (GCTs) are rare, accounting for 3% to 4% of childhood malignancies.^1,2 They arise from pluripotent stem cells,³ occur in gonadal and extragonadal sites, and are composed of tissues foreign to the organ or site of origin.⁴ Patients with GCTs typically have a bimodal age distribution, with a peak before three years of age and a second peak during adolescence.¹ The most common histologic subtype in pediatric series is endodermal sinus tumor.^5,6

The outcome for patients with malignant GCTs was poor before the use of systemic chemotherapy, with 3-year survival rates of approximately 20%.^7,8 The introduction of cyclophosphamide-based therapy improved the outcome for patients with localized tumors, but patients with advanced disease continued to respond poorly.^9-12 The introduction of the Einhorn regimen (cisplatin, vinblastine, and bleomycin) in adults with testicular tumors dramatically improved the prognosis for these patients,¹³ and several pediatric studies have documented markedly improved survival with the use of cisplatin-based therapy.^14-16

The International Germ Cell Consensus Classification developed staging criteria for adults with testicular tumors using primary site, tumor markers, and the presence of visceral metastases.¹⁷ A subsequent study by the French Society of Pediatric Oncology developed prognostic factors for children with localized GCTs using alfa fetoprotein (AFP), disease stage, and primary site.¹⁸ These authors, however, excluded children younger than one year of age from their analysis because of concerns about the age-related elevation of AFP in this subgroup. Because patients with pediatric extragonadal malignant (PEMGCTs) are generally considered a high risk group and because a large proportion of these patients are infants, we sought to identify risk factors in patients with PEMGCTs and to determine whether age was of prognostic importance.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patients
We retrospectively evaluated patients enrolled in our Intergroup study (POG 9049/CCG 8882) evaluating the role of cisplatin dose intensity on outcome for patients with high-risk malignant GCTs (defined as stage III/IV gonadal and stage I through IV extragonadal tumors). Two hundred ninety-nine eligible patients were enrolled onto that study; 165 of those had stage I through IV PEMGCTs and constituted this study population. Those 165 patients were treated between March 1990 and February 1996. Eligibility requirements for the study included age 21 years, stage I through IV PEMGCT, and lack of prior therapy other than surgical resection or biopsy. The presence of malignant elements within the tumor was required and included the presence of yolk sac carcinoma (endodermal sinus tumor), embryonal carcinoma, choriocarcinoma, or dysgerminoma (seminoma). Histology was confirmed by central pathology review.

Pretreatment Evaluation
Details of therapy for patients enrolled onto this study have been published.¹⁶ In general, treatment included attempted resection of the tumor, if feasible without producing significant morbidity. Patients unable to undergo complete resection underwent biopsy with surgical staging. Medical evaluation at study entry included medical history, physical examination, complete blood count with differential, urinalysis, tumor markers (AFP, beta human chorionic gonadotropin, and lactic dehydrogenase), electrolytes, creatinine, bilirubin, ALT, alkaline phosphatase, total protein, albumin, phosphorus, magnesium, calcium. Diagnostic imaging evaluation included chest radiograph, chest/abdomen/pelvis computed tomography, or magnetic resonance imaging (MRI) and bone scan.

Chemotherapy
Written informed consent was obtained from all patients or legal guardians as appropriate. Patients were randomly assigned in a 1:1 distribution to one of two chemotherapy regimens: bleomycin 15 units/m² on day 1 and etoposide 100 mg/m² on days 1 through 5 combined with either high-dose cisplatin 40 mg/m² on days 1 through 5 (HDPEB, n = 149) or standard-dose cisplatin 20 mg/m² on days 1 through 5 (PEB, n = 150). Treatment was repeated every 21 days for four cycles. Chemotherapy doses for infants younger than 12 months of age were calculated by body weight: cisplatin 0.7 mg/kg/dose PEB or 1.3 mg/kg/dose HDPEB, etoposide 3 mg/kg/dose, and bleomycin 0.5 mg/kg/dose.

After four cycles of chemotherapy, patients underwent a complete evaluation, including diagnostic imaging and tumor marker determinations. Patients with normal serum tumor markers and resolution of all imaging abnormalities were considered complete responders and received no further chemotherapy. Patients with a partial response based on residual imaging abnormalities at either the primary or metastatic sites underwent attempted resection. Postsurgical treatment depended on histologic findings. If the resected specimen showed no malignant disease, patients were considered pathologic complete responders and received no further therapy. Patients with malignant residual disease in the resected specimen were considered pathologic partial responders and received two additional cycles of their assigned regimen. Patients with progressive disease or no response after the initial four cycles of chemotherapy were declared treatment failures and were taken off therapy.

Study Design and Statistical Analysis
Outcome analyses were performed for event-free survival (EFS). Time to an event was defined as the time from study entry until the first occurrence of disease progression, relapse, second malignancy, or death, or until last reported contact if no events occurred. Overall survival (OS) was defined as the time from study entry until death or last reported contact. EFS and OS rates were expressed as the rate ± SE, using Kaplan-Meier analysis to calculate the rates¹⁹ and the methods of Peto used to calculate SEs.²⁰ We investigated prognostic factors by univariate (two-sided log-rank test) and multivariate (Cox proportional hazards model)²¹ analysis in patients PEMGCT. Potential prognostic factors tested in the Cox model were age ( 12 v < 12 years), stage, primary site, AFP (< 10,000 v 10,000), and treatment (HDPEB v PEB).

Log-rank tests for ages 6 to 18 were performed to determine an optimal age cutoff for maximizing the difference in the EFS rates between the two age groups. The optimal age cutoff was selected based on the cutoff that gave the lowest P value (adjusted per the methods of Altman et al²²) for the EFS difference between the two age groups.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Between March 1990 and February 1996, 299 eligible patients were enrolled onto the Intergroup study. One hundred sixty-five of those were identified as having stage I through IV PEMGCTs. Patient characteristics are listed in Table 1. Briefly, patients had a median age of 1.9 years (range, 3 days to 18.5 years); 109 were female, and 99 had AFP 10,000. Primary sites included 88 sacrococcygeal, 39 thoracic, 35 retroperitoneal, and 3 other sites. The stage distribution included 30 patients with stage I/II, 61 with stage III, and 74 with stage IV tumors. Ninety-five patients had pure yolk sac tumors, 41 had immature teratomas with yolk sac tumor component, 14 had mixed GCTs, four had pure germinoma/seminoma/dysgerminomas, two had immature teratoma admixed with a nonclassic GCT, one had mixed GCT admixed with a nonclassic GCT, five had pure choriocarcinomas, and three had unknown histology.

View larger version (6K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves of event-free survival (EFS) rates by age (< 12 v 12 years) for 165 patients with extragonadal germ cell tumors (P < .0001).

Multivariate Cox regression models were built for EFS and OS, testing age, treatment, sex, stage, primary site, and age with primary site interaction terms. Only age was found to be a statistically significant prognostic factor for EFS (P = .0002), with a relative risk of 3.9 for age 12 years. After adjusting for age in the EFS analysis, treatment with HDPEB was of borderline statistical significance (P = .0734). In the model for OS, the interaction term of age and primary site was highly significant (P < .0001); patients 12 years of age with thoracic tumors had six times the risk of death compared with patients younger than 12 years of age with tumors at other sites.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The introduction of multiagent chemotherapy has dramatically improved the outcome of adult^13,23and pediatric^5,6,14,18,24 patients with malignant germ cell tumors. The survival for these patients now exceeds 80%, so identification of patients at high risk of treatment failure is an important consideration. Two recent publications have looked at the development of a risk stratification schema for patients with GCTs.^17,18 The study in adults identified patients with mediastinal tumors, highly elevated markers, and the presence of visceral metastases as high risk¹⁷; the pediatric publication about a small number of patients identified those with sacrococcygeal or mediastinal tumors and highly elevated AFP (> 10,000) as high risk.¹⁸ The latter series included a subset of patients treated with carboplatin, etoposide, and bleomycin. As reported in adults,^25,26 the use of that combination provided an inferior outcome. Unlike in adults, however, the administration of cisplatin after carboplatin cured the majority of pediatric patients.

Because the standard of care in adults has become the use of PEB and because the Pediatric Oncology Group and Children's Cancer Group have recently completed two studies evaluating the impact of cisplatin, etoposide, and bleomycin on outcome,^16,27 we sought to identify risk factors in patients with PEMGCTs exclusively treated with cisplatin-based therapy. We chose to evaluate patients with extragonadal tumors because this subset traditionally has been considered high risk, both in adult and pediatric series, and because the prior pediatric study¹⁸ included patients treated with both cisplatin and carboplatin.

Our study revealed that, for patients with PEMGCTs treated with cisplatin-based therapy, age 12 years was the most important prognostic factor. Furthermore, the combination of age 12 years and thoracic primary site resulted in six times the risk of death compared with patients younger than 12 years with tumors at other sites. These results suggest that this subset of patients have biologically different tumors. Schneider et al²⁸ demonstrated that genetic changes, specifically at isochromosome 12, in mediastinal tumors resembled those reported in adults with testicular tumors and were distinct from pediatric GCTs diagnosed at an earlier age, which more typically showed alterations in (1p, 6q). These authors also documented a poorer outcome, suggesting that patients with mediastinal tumors are biologically different than other pediatric GCT.

The treatment for this subset of patients remains challenging. A randomized study in adults demonstrated that cisplatin dose intensification did not impact outcome²³; however, the randomized pediatric study, and in particular this multivariate analysis, identified that treatment with HDPEB in patients with extragonadal tumors improved outcome, although this result was of only borderline significance. These findings suggest that dose intensification might be important for the pediatric subset. Based on these results, the Children's Oncology Group designed a study evaluating whether amifostine could ameliorate the toxicity of HDPEB. Unfortunately, the results of that trial suggest that amifostine in the dosages used did not ameliorate the toxicity of HDPEB. Particularly concerning was the 60% to 70% incidence of high-frequency hearing loss,²⁹ which can be devastating in children. Based on those results, PEB remains the standard of care in both adult and pediatric patients with malignant GCTs.

Investigators in Germany and the United Kingdom share significant concerns about nonhematologic toxicities of high-dose cisplatin. These investigators have taken two different approaches to maintain improved survival while minimizing the risks of nonhematologic toxicities. Gobel et al¹⁵ in Germany have chosen to combine ifosfamide, cisplatin, and etoposide to maintain EFS and minimize ototoxicity. Mann et al¹⁴ have chosen to use carboplatin, etoposide, and bleomycin. Interestingly, these investigators report an outcome similar to that using cisplatin-based therapy.

Unlike the French study, our study did not identify elevated AFP as a significant prognostic factor. This difference in our study could be related to the inclusion of infants younger than 12 months known to have elevated AFP based on age, which may have reduced the prognostic impact of AFP on our study. A meta-analysis evaluating all patients with PEMGCT treated by the different groups will better define prognostic factors in pediatric patients. This will provide a large number of patients and may yield important information essential for further development of targeted therapy.

In conclusion, age 12 years is the most important prognostic factor for EFS, and age 12 years and thoracic site are the most important prognostic factors for OS in patients with PEMGCT consistently treated with cisplatin-based therapy. The combination of age 12 years and thoracic primary site results in six times the risk of death compared with younger patients with tumors at other primary sites. Understanding the biology of this combination may be the best way to improve the prognosis of this group of patients. The investigation of novel strategies appears warranted; however, clinical trials may be limited because of the small number of patients available to study.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Neyssa Marina, Barbara Cushing, Richard B. Womer Administrative support: Robert P. Castleberry Collection and assembly of data: Wendy B. London, Frederick Rescorla, Barbara Cushing Data analysis and interpretation: Neyssa Marina, Wendy B. London, A. Lindsay Frazier, Stephen Lauer, Frederick Rescorla, Barbara Cushing, Marcio H. Malogolowkin, Richard B. Womer, Thomas A. Olson Manuscript writing: Neyssa Marina, Wendy B. London, A. Lindsay Frazier, Marcio H. Malogolowkin, Richard B. Womer, Thomas A. Olson Final approval of manuscript: Neyssa Marina, Wendy B. London, A. Lindsay Frazier, Frederick Rescorla, Barbara Cushing, Marcio H. Malogolowkin, Robert P. Castleberry, Thomas A. Olson

 

	NOTES

 
Presented in part at the 33rd Annual Meeting of the International Society of Pediatric Oncology, Brisbane, Australia, October 10-13, 2001.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
1. Bernstein L, Smith MA, Liu L, et al: Germ Cell, Trophoblastic and Other Gonadal Neoplasms, in Ries LAG SM, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds): Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. Bethesda, Cancer Statistics Branch Cancer Surveillance Research Program Division of Cancer Control and Population Sciences National Cancer Institute, Bethesda, MD, 1999, pp 125-138

2. Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75:395-405, 1995[CrossRef][Medline]

3. Mulligan RM: Pathogenesis of teratoid tumors of the ovary and testis. Pathol Annu 10:271-298, 1975[Medline]

4. Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14:493-511, 1983[Medline]

5. Marina N, Fontanesi J, Kun L, et al: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70:2568-2575, 1992[CrossRef][Medline]

6. Mann JR, Pearson D, Barrett A, et al: Results of the United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies. Cancer 63:1657-1667, 1989[Medline]

7. Chretien PB, Milam JD, Foote FW, et al: Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region: Clinical and pathologic aspects of 21 cases. Cancer 26:522-535, 1970[CrossRef][Medline]

8. Kurman RJ, Norris HJ: Endodermal sinus tumor of the ovary: A clinical and pathologic analysis of 71 cases. Cancer 38:2404-2419, 1976[CrossRef][Medline]

9. Slayton RE, Hreshchyshyn MM, Silverberg SC, et al: Treatment of malignant ovarian germ cell tumors: Response to vincristine, dactinomycin, and cyclophosphamide (preliminary report). Cancer 42:390-398, 1978[CrossRef][Medline]

10. Slayton RE, Park RC, Silverberg SG, et al: Vincristine, dactinomycin, and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary. A Gynecologic Oncology Group Study (a final report). Cancer 56:243-248, 1985[CrossRef][Medline]

11. Cangir A, Smith J, van Eys J: Improved prognosis in children with ovarian cancers following modified VAC (vincristine sulfate, dactinomycin, and cyclophosphamide) chemotherapy. Cancer 42:1234-1238, 1978[CrossRef][Medline]

12. Brodeur GM, Howarth CB, Pratt CB, et al: Malignant germ cell tumors in 57 children and adolescents. Cancer 48:1890-1898, 1981[CrossRef][Medline]

13. Einhorn LH, Donohue J: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87:293-298, 1977[Abstract/Free Full Text]

14. Mann JR, Raafat F, Robinson K, et al: The United Kingdom Children's Cancer Study Group's second germ cell tumor study: Carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18:3809-3818, 2000[Abstract/Free Full Text]

15. Gobel U, Schneider DT, Calaminus G, et al: Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups. Ann Oncol 11:263-271, 2000[Abstract/Free Full Text]

16. Cushing B, Giller R, Cullen JW, et al: Randomized Comparison of Combination Chemotherapy With Etoposide, Bleomycin, and Either High-Dose or Standard-Dose Cisplatin in Children and Adolescents With High-Risk Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9049 and Children's Cancer Group 8882. J Clin Oncol 22:2691-2700, 2004[Abstract/Free Full Text]

17. International Germ Cell Consensus Classification: A prognostic factor- based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15:594-603, 1997[Abstract/Free Full Text]

18. Baranzelli MC, Kramar A, Bouffet E, et al: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17:1212, 1999[Abstract/Free Full Text]

19. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

20. Peto R, Peto J: Assymptotically efficient rank invariant test procedures. J R Stat Soc A 135:185-198, 1972[CrossRef]

21. Cox DR: Regression Models and Life Tables (with discussion). J R Stat Soc B 34:187-220, 1972

22. Altman DG, Lausen B, Sauerbrei W, et al: Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:829-835, 1994[Free Full Text]

23. Nichols CR, Williams SD, Loehrer PJ, et al: Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: A Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:1163-1172, 1991[Abstract]

24. Cushing B, Giller R, Lauer S, et al: Comparison of high dose or standard dose cisplatin with etoposide and bleomycin (HDPEB vs PEB) in children with stage I-IV extragonadal malignant germ cell tumors (MGCT): A Pediatric Intergroup report (POG9049/CCG8882), in Perry MC (ed): American Society of Clinical Oncology. Los Angeles, CA, W.B. Saunders Co, 1998, p 525

25. Horwich A, Sleijfer D, Fossa S, et al: Randomized trail of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: A multi-institutional medical research council/European organization for research and treatment of cancer trial. J Clin Oncol 15:1844-1852, 1997[Abstract/Free Full Text]

26. Hartmann JT, Nichols CR, Droz JP, et al: Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors. J Natl Cancer Inst 92:54-61, 2000[Abstract/Free Full Text]

27. Rogers PC, Olson TA, Cullen JW, et al: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891: J Clin Oncol 22:3563-3569, 2004[Abstract/Free Full Text]

28. Schneider DT, Schuster AE, Fritsch MK, et al: Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 34:115-125, 2002[CrossRef][Medline]

29. Marina N, Chang KW, Malogolowkin M, et al: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors. Cancer 104:841-847, 2005[CrossRef][Medline]

Submitted September 7, 2005; accepted March 3, 2006.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Marina, N. Articles by Olson, T. Search for Related Content PubMed PubMed Citation Articles by Marina, N. Articles by Olson, T. Social Bookmarking                            What's this?