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Obesity and Outcome in Pediatric Acute Lymphoblastic Leukemia

Anna M. Butturini, Frederick J. Dorey, Beverly J. Lange, David W. Henry, Paul S. Gaynon, Cecilia Fu, Janet Franklin, Stuart E. Siegel, Nita L. Seibel, Paul C. Rogers, Harland Sather, Michael Trigg, W. Archie Bleyer, William L. Carroll

From the Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles; Children's Oncology Group Statistical Center, Arcadia, CA; Children's Hospital of Philadelphia, Philadelphia, PA; Pharmacy Practice, University of Kansas Medical Center, Kansas City, KS; Children's National Medical Center, Washington, DC; Paediatric Oncology/Haematology/Bone Marrow Transplantation, British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada; Medical and Scientific Affairs, Merck, North Wales, PA; Doernbecher Children's Hospital, Oregon Health and Science University, Bend, OR; and the New York University Medical Center, New York, NY

Address reprint requests to Anna M. Butturini, MD, Division of Hematology Oncology, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027; e-mail: abutturini{at}chla.usc.edu

	ABSTRACT

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Purpose: To evaluate the effect of obesity (defined as a body mass index > 95th percentile for age and sex at diagnosis) on outcome of pediatric acute lymphoblastic leukemia (ALL).

Patients and Methods: We retrospectively analyzed data from 4,260 patients with newly diagnosed ALL enrolled from 1988 to 1995 onto five concurrent Children's Cancer Group studies. Results were verified in a second cohort of 1,733 patients enrolled onto a sixth study from 1996 to 2002.

Results: The 1988 to 1995 cohort included 343 obese and 3,971 nonobese patients. The 5-year event-free survival rate and risk of relapse in obese versus nonobese patients were 72% ± 2.4% v 77% ± 0.6% (P = .02) and 26 ± 2.4 v 20 ± 0.6 (P = .02), respectively. After adjusting for other prognostic variables, obesity's hazard ratios (HRs) of events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively. The effect of obesity was prominent in the 1,003 patients 10 years old at diagnosis; in this subset, obesity's adjusted HRs of events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively. In a second cohort of 1,160 patients 10 years old, obesity's adjusted HRs of events and relapses were 1.42 (95% CI, 1.03 to 1.96; P = .032) and 1.65 (95% CI, 1.13 to 2.41; P = .009), respectively. The effect of obesity on outcome was unrelated to changes in chemotherapy doses, length of intervals between chemotherapy cycles, or incidence and severity of therapy-related toxicity.

Conclusion: Obesity at diagnosis independently predicts likelihood of relapse and cure in preteenagers and adolescents with ALL.

	INTRODUCTION

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Obesity is now an alarming problem worldwide.¹ Aside from its well-known long-term complications, obesity may also affect cancer incidence and cure.² Here, we report the relationship between obesity and outcome in patients with pediatric acute lymphoblastic leukemia (ALL). Our initial hypothesis was that obese patients are at higher risk of relapse because, when dosed based on body-surface area, they receive lower doses of drug per kilogram of weight than nonobese patients.

	PATIENTS AND METHODS

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Definition of Obesity
Obesity was defined as a body mass index (BMI) the 95th percentile for age and sex according to the American Academy of Pediatrics guidelines.³ BMI percentiles were calculated using the US Centers for Disease Control and Prevention program for children between 2 and 20 years of age (http://www.cdc.gov/growthcharts/).³

Database
We analyzed databases of six Children's Cancer Group (CCG) studies. Data from 5,122 patients enrolled onto the CCG-1881,⁴ CCG-1922,⁵ CCG-1891,⁶ CCG-1882,^7,8 and CCG-1901⁹ studies were analyzed together; this cohort, referred to as the study cohort, included all of the children with newly diagnosed ALL entered onto CCG studies from 1988 to 1995. CCG-1881, CCG-1922, and CCG-1891 enrolled children aged 1 to 10 years at diagnosis with initial WBC counts of less than 50 x 10⁹/L (low- and standard-risk patients, criteria varied); CCG-1882 and CCG-1901 enrolled high-risk patients (age 10 years or initial WBC 50 x 10⁹/L). Information about initial age, WBC, and sex was recorded in 99% or more of patients, race was recorded in 98%, height and weight at diagnosis in 97%, and leukemia immunophenotype in 67%. Data regarding bone marrow response after 7 days of therapy were available for 95% of the patients enrolled onto the CCG-1922, CCG-1891, CCG-1882, and CCG-1901⁹ studies and for none of the patients enrolled onto the CCG-1881 study.

The database of a sixth study, CCG-1961,¹⁰ which enrolled 2,057 high-risk patients from 1996 to 2002, was used to verify the results in a distinct population treated at a later point in time (verification cohort). At the time of this analysis, there was no CCG database available to verify results in the low- and standard-risk patients.

Patients
We excluded from the analysis patients in whom it was impossible to calculate the BMI percentile, either because their correct weight and height at diagnosis were not available or because they were diagnosed at younger than 2 or older than 20 years. We also excluded patients with Down syndrome and/or with CNS leukemia (defined as > 5 WBCs in the initial lumbar puncture) because of the possible association of these conditions with both obesity and leukemia outcome. Therefore, we analyzed 4,260 patients in the study cohort and 1,733 patients in the verification cohort.

Therapy
All patients received vincristine, prednisone, L-asparaginase, methotrexate, and mercaptopurine; most patients received dexamethasone, daunorubicin, doxorubicin, cyclophosphamide, cytarabine, and thioguanine. Drugs were dosed by body-surface area; doses of vincristine were capped at 2 mg. All patients received CNS therapy with intrathecal methotrexate (capped at 12 mg in patients > 3 years of age); cranial radiation was administered to most high-risk patients in the study cohort^6-8 but only to patients with delayed bone marrow response to chemotherapy in the verification cohort.⁹ There were no protocol-required treatment modifications for obesity. Individual reports from the obese patients in the study cohort have been reviewed to assess for off-protocol dose modifications as a result of obesity.

Statistics
Median follow-up times were 7.8 years (range, 0.1 to 13.3 years) in the study cohort and 3.8 years (range, 0.4 to 7.5 years) in the verification cohort. Because of the shorter observation time, analyses in the verification cohort were limited to the first 3 years. Events included death by any cause, failure to achieve remission after induction therapy, relapse in any site, and second malignancy. Statistics were calculated using STATA 8.0 statistical software (STATA Corp, College Station, TX). Event-free survival (EFS) and risk of leukemia relapse were calculated using the Kaplan-Meier approach, with comparisons by log-rank statistics. Cox proportional hazard analyses were used to calculate the effect of each variable on outcomes in Table 1; multivariate Cox proportional hazard models were used to calculate the relationships among variables using a stepwise selection procedure. Results were expressed as hazard ratios (HRs) and 95% CIs.

	RESULTS

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Obesity at Diagnosis and Outcome
Three hundred forty-three (8%) of the 4,260 patients in the study cohort were obese at diagnosis. Obese patients were more likely to be male (P = .03), Hispanic (P = .001), and older (P = .012) and have a higher WBC count at diagnosis (P = .017) than nonobese patients (Table 1). Most obese patients (338 of 343 patients) received chemotherapy doses calculated on their actual body-surface area; five obese patients had doses reduced by different formulas to correct for their obesity. Even after censoring patients who had off-protocol dose modifications, the outcome of the obese patients was significantly poorer than the outcome of the 3,917 nonobese patients, with 5-year EFS rate being 72% ± 2% v 77% ± 0.6% (P = .02), respectively, and the risk of relapse being 26 ± 2.4 v 20 ± 0.6 (P = .02), respectively. By multivariate analyses, obesity had an independent effect on outcome, as did initial age and WBC count, race, and bone marrow response at day 7. After adjusting for competing variables, obesity's HRs for events and relapses were 1.36 (95% CI, 1.04 to 1.77; P = .021) and 1.29 (95% CI, 1.02 to 1.56; P = .04), respectively.

Obesity was consistently associated with worse outcomes (even if at a different level of significance, Table 1) in patients with different sex, race, initial WBC count, and bone marrow response at day 7 but not in patients younger than 10 years at diagnosis. Further analyses were performed separately in patients diagnosed before or after their 10th birthday.

Patients older than 10 years. The study cohort (1988 to 1995) included 1,003 patients with an initial age of older than 10 years; 95 of these patients (9.5%) were obese at diagnosis. Obese patients were more likely to be Hispanic (29% of obese v 13% of nonobese, P = .001; Table 2). Initial response to chemotherapy, including bone marrow response at day 7 (Table 2) and remission rate at the end of induction (Table 3), was similar in obese and nonobese patients, but long-term outcomes were poorer in obese patients (Fig 1; Table 3). By multivariate analysis, obesity, initial WBC count, and bone marrow response at day 7 predicted outcome; age had a borderline significance (Table 4). After adjusting for the other prognostic variables, the HRs for obese patients for events and relapses were 1.5 (95% CI, 1.1 to 2.1; P = .009) and 1.5 (95% CI, 1.2 to 2.1; P = .013), respectively.

View this table: [in this window] [in a new window]   Table 2. Demographics and Disease Characteristics of Patients 10 Years of Age in the Study and Verification Cohorts

View this table: [in this window] [in a new window]   Table 3. Toxicities and Outcomes in Obese and Nonobese Patients 10 Years of Age in the Study and Verification Cohorts

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Effect of obesity on event-free survival (EFS) in the study cohort. EFS in 95 obese and 908 nonobese patients 10 years of age at diagnosis included in the study cohort is shown. The difference between the curves is significant (P = .01). (B) Effect of obesity on EFS in the verification cohort. EFS in 167 obese and 993 nonobese patients 10 years of age at diagnosis included in the verification cohort is shown. The difference between the curves is significant (P = .006).

View this table: [in this window] [in a new window]   Table 4. Multivariate Analyses: Adjusted HR for Events and Relapses of Different Prognostic Variables in Patients 10 Years Old

Patients younger than 10 years. In the study cohort, 3,257 patients were younger than 10 years old at diagnosis; 248 of these patients (8%) were obese. In this setting, race, initial age and WBC count, and bone marrow response at day 7 predicted outcome, but obesity did not.

Because our hypothesis linked obesity to inadequate therapy, we then limited the analysis to patients at higher risk of therapy failure, in whom therapy doses might have higher impact. Obesity had a borderline effect on EFS in the 1,169 patients who were not in bone marrow remission at day 7. EFS rate was 75% ± 1% in the 1,069 nonobese patients compared with 67% ± 5% in the 100 obese patients (P = .09); by multivariate analysis, obesity's adjusted HR for events was 1.25 (95% CI, 0.9 to 1.8; P = .2).

The verification cohort included only 593 patients younger than 10 years; most of these patients had initial WBC counts of 50 x 10⁹/L. There were no significant differences in the outcomes of the 524 nonobese and the 69 obese patients.

Effects on Outcome of BMI Less Than the 95th Percentile and Weight
Because our hypothesis implied that the increased risk of relapse in obese patients was a result of dosing chemotherapy by body-surface area, we expected that the risk of poor outcome would increase proportionally with BMI or body weight. This was true for weight (and absolute BMI), but not for BMI percentile. Higher weight at diagnosis, as absolute weight and as weight more than 75th percentile, correlated with poor outcome in both the univariate (data not shown) and multivariate analyses (Table 4). In contrast, there was no linear relationship between variations in BMI percentile and outcome. Patients with a BMI less than the fifth percentile had poorer EFS by univariate analysis only. Variations of BMI between the fifth and 85th percentiles did not affect outcome. Patients with a BMI between the 85th and 95th percentiles (who are defined as at risk of obesity) had worse outcomes than patients with a BMI between the fifth and 85th percentiles only in the verification cohort (data not shown).

Obesity at Diagnosis and Toxicity
The studies included in the study cohort did not uniformly use the National Cancer Institute Common Toxicity Criteria; hence, toxicity by system could not be analyzed. Instead, we analyzed the effect of obesity on parameters related to early toxicity,¹¹ such as the length of the interval from diagnosis to the completion of the fourth phase of therapy, days of hospitalization during such period, deaths in induction, and deaths caused by late toxicity. Overall, there were no differences associated with obesity (Table 3).

In the verification cohort, obesity had no effect on rate of toxic deaths. This database recorded toxicity by system; obese patients, compared with nonobese patients, had an increased risk of pancreatic toxicity (grade 3 or 4: 40% v 28%, respectively; P = .04; grade 4: 18% v 11%, respectively; P = .019) and a trend toward increased risk of liver toxicity (grade 3 or 4: 56% v 51%, respectively; P = .18; grade 4: 20% v 15%, respectively; P = .09). The incidence and severity of other toxicities, including infections, were similar. Pancreatic and hepatic toxicities were not associated with increased risk of relapse by univariate or multivariate analysis (data not shown).

	DISCUSSION

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In this study, obesity seems to be one of the main determinants of relapse in more than 2,000 patients diagnosed with ALL after their 10th birthday and enrolled onto CCG studies during the last 20 years. This is unrelated to a possible increased incidence of obesity in patients with Down syndrome or in patients with CNS relapse because both of these groups were excluded from the analysis. This finding is also likely unrelated to the excess of obese Hispanics and African Americans, who are reportedly at high risk of ALL relapse,¹² because, by multivariate analysis, race poorly correlated with outcome in children older than 10 years at diagnosis.

The major limitation of our study is that the databases we analyzed had not been designed to address the issue of obesity and outcome. For example, BMI may not be the best indicator of obesity in patients with chronic diseases,¹³ and we cannot be certain whether our findings relate to obesity per se or to other factors possibly associated with either obesity or high BMI, such as nutrient intake and physical activity. Also, we cannot determine the variations of BMI percentile during the follow-up. However, we had enough patients to verify results in two separate cohorts of preteenagers and adolescents with ALL across a 20-year period. A separate study in adults with ALL also reached similar conclusions.¹⁴

Other retrospective studies associated high BMI with poor outcome after cancer chemotherapy. Obese children¹⁵ and adults¹⁶ with acute myelogenous leukemia had increased risk of treatment-related mortality, whereas obese adults with ALL,¹⁴ breast cancer,¹⁷ or colon cancer¹⁸ had an increased risk of relapse. In the breast cancer study,¹⁷ increased relapse was ascribed to off-protocol reduction in chemotherapy dose in obese patients. In the colon cancer study¹⁸ and in the present study, most of the obese patients were at least initially treated as prescribed by the protocols; therefore, the mechanisms underlying the effect of obesity on cancer cure are unknown.

We initiated this analysis with the hypothesis that obese patients receive inadequate doses of chemotherapy because they are dosed by body-surface area. In fact, pharmacokinetic studies in small numbers of obese children reported an inverse relationship between weight and plasma drug levels for mercaptopurine¹⁹ (used in ALL maintenance therapy) and dactinomycin.²⁰ However, other similarly small studies suggest the opposite for anthracyclines²¹ (used in induction in high-risk ALL and in the postinduction intensification in every ALL) and busulfan.²² Our findings, which link high weight and poor outcome and show that obese patients have no problem in achieving remission, support the possibility that the increased risk of relapse in obese patients might be caused by differences in pharmacology of mercaptopurine or other drugs used in maintenance.

However, recent data suggest that the interaction between obesity, cancer, and cancer therapy may be more complex. Growth factors and lymphokines, either directly secreted by adipocytes or produced in the context of the metabolic syndrome, may alter anticancer effects and toxicity of chemotherapy. Insulinlike growth factor 1 and leptin²⁴ are known to affect cancer cell growth. Tumor necrosis factor, adiponectin, interleukin-6 and -8, vascular endothelial growth factor, and pre–B colony–enhancing factor are obesity-related lymphokines that might increase toxicity by affecting inflammation and oxidation^25,26 and alter tumor biology by affecting angiogenesis and cancer cell growth.^25-27 Glucose itself regulates the cell cycle²⁸; high fasting levels of insulin and hyperglycemia were associated with increased recurrences and toxicity, respectively, in adults with breast cancer²⁹ and ALL.³⁰ Evaluation of cancer biology is beyond the possibility of a retrospective study; however, the trend of higher initial WBC count in obese patients is consistent with an effect of obesity on cell growth.

Obesity is now an epidemic, and the challenge of providing curative chemotherapy to obese children is a major issue faced by pediatric oncologists. The outcome of obese patients will be improved only through a better understanding of the interactions between obesity, cancer, and cancer therapy.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Anna M. Butturini, Frederick J. Dorey, Beverly J. Lange, David W. Henry, Paul S. Gaynon, Janet Franklin, Stuart E. Siegel, Nita L. Seibel, Paul C. Rogers, Harland Sather, Michael Trigg, W. Archie Bleyer, William L. Carroll

Provision of study materials or patients: Beverly J. Lange, Paul S. Gaynon, Nita L. Seibel, Harland Sather, Michael Trigg, William L. Carroll

Collection and assembly of data: Harland Sather

Data analysis and interpretation: Anna M. Butturini, Frederick J. Dorey, Beverly J. Lange, William L. Carroll

Manuscript writing: Anna M. Butturini, Beverly J. Lange, David W. Henry, Cecilia Fu, Paul C. Rogers, William L. Carroll

Final approval of manuscript: Anna M. Butturini, Frederick J. Dorey, Beverly J. Lange, David W. Henry, Paul S. Gaynon, Cecilia Fu, Janet Franklin, Stuart E. Siegel, Nita L. Seibel, Paul C. Rogers, Harland Sather, Michael Trigg, W. Archie Bleyer, William L. Carroll

	ACKNOWLEDGMENTS

 
We thank the patients, their families, the physicians, the nurses, and the data managers who were involved in the Children's Cancer Group studies. We also thank Peter Steinherz, MD, Bruce Bostrom, MD, Ray Hutchison, MD, and James Nachman, MD, who were the chairmen of studies 1901, 1922, 1881, and 1882, respectively.

	NOTES

 
The Children's Cancer Group studies that originated the databases analyzed in this article were supported by Grants No. CA98543 and CA13539.

Presented in part in abstract format at the 46th Annual Meeting of the American Society of Hematology, December 4-7, 2004, San Diego, CA; and the 20th Annual Meeting of the International Society of Pediatric Oncology, April 15-17, 2005, Los Angeles, CA.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Hedley AA, Ogden CL, Johnson CL, et al: Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. JAMA 291: 2847-2850, 2004[Abstract/Free Full Text]

2. Calle EE, Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4: 579-591, 2004[CrossRef][Medline]

3. Krebs NF, Jacobson MS: Prevention of pediatric overweight and obesity. Pediatrics 12: 424-430, 2003

4. Hutchinson RJ, Gaynon PS, Sather H, et al: Intensification of therapy for children with low risk acute lymphoblastic leukemia: Long term follow up of patients treated on Children's Cancer Group Trial 1881. J Clin Oncol 21: 1790-1797, 2003[Abstract/Free Full Text]

5. Bostrom BC, Sensel MR, Sather H, et al: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patient with standard-risk acute lymphoblastic leukemia: A report from Children's Cancer Group. Blood 101: 3809-3817, 2003[Abstract/Free Full Text]

6. Lange BJ, Bostrom BC, Cherlow JM, et al: Double delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: A report from Children's Cancer Group. Blood 99: 825-833, 2002[Abstract/Free Full Text]

7. Nachman J, Sather H, Cherlow JM, et al: Response of children with high risk acute lymphoblastic leukemia treated with or without cranial irradiation: A report from Children's Cancer Group. J Clin Oncol 16: 920-930, 1998[Abstract]

8. Nachman J, Sather H, Sensel MR, et al: Augmented post induction therapy for children with high risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338: 1663-1671, 1998[Abstract/Free Full Text]

9. Heath JA, Steinherz P, Alman A, et al: Human granulocyte colony stimulating factor in children with high risk acute lymphoblastic leukemia: A report from Children's Cancer Group. J Clin Oncol 21: 1612-1617, 2003[Abstract/Free Full Text]

10. Seibel NL, Steinherz P, Sather H, et al: Early treatment intensification improves outcome in children and adolescents with acute lymphoblastic leukemia presenting with unfavorable features who show a rapid early response to induction chemotherapy: A report of CCG 1961. Blood 102: 224a, 2003 (abstr)

11. Gaynon PS, Bostrom BC, Hutchinson R, et al: Duration of hospitalization as a measure of cost on Children's Cancer Group acute lymphoblastic leukemia studies. J Clin Oncol 19: 1916-1925, 2001[Abstract/Free Full Text]

12. Carroll WL: Race and outcome in childhood acute lymphoblastic leukemia. JAMA 290: 2061-2063, 2003[Free Full Text]

13. Warner JT, Cowan FJ, Dunstan FD, et al: The validity of body mass index for the assessment of adiposity in children with disease states. Ann Hum Biol 24: 209-215, 1997[CrossRef][Medline]

14. Butturini A, Vignetti M, Gubbiotti S, et al: Obesity independently affects event free survival (EFS) in adults with BCR-ABL-negative acute lymphoblastic leukemia (ALL): A retrospective analysis of two GIMEMA studies. Blood 106: 520a, 2005 (abstr)

15. Lange BJ, Gerbing RB, Feusner J, et al: Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293: 203-211, 2005[Abstract/Free Full Text]

16. Meloni G, Proia A, Capria S, et al: Obesity and autologous stem cell transplantation in acute myeloid leukemia. Bone Marrow Transplant 28: 365-367, 2001[CrossRef][Medline]

17. Colleoni M, Li S, Gelber RD, et al: Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 366: 1108-1110, 2005[CrossRef][Medline]

18. Meyerhardt JA, Tepper JE, Niedzwiecki D, et al: Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: Findings from Intergroup Trial 0114. J Clin Oncol 22: 648-657, 2004[Abstract/Free Full Text]

19. Zuccaro P, Guandalini S, Pacifici R, et al: Fat body mass and pharmacokinetics of oral 6-mercaptopurine in children with acute lymphoblastic leukemia. Ther Drug Monit 13: 37-41, 1991[Medline]

20. Veal GJ, Cole M, Errington J: Pharmacokinetics of dactinomycin in a pediatric patient population: A United Kingdom Children's Cancer Group Study. Clin Cancer Res 11: 5895-5899, 2005

21. Berg SL, Bomgaars L, Twist C, et al: Impact of body composition on pharmacokinetics of doxorubicin in pediatric patients: A Glass Pediatric Research Network study. J Clin Oncol 23: 804s, 2005 (suppl; abstr 8519)

22. Cheymol G: Effect of obesity on pharmacokinetics. Clin Pharmacokinet 39: 215-231, 2000[CrossRef][Medline]

23. Ngo TH, Barnard RJ, Leung PS, et al: Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: Possible mediators for the effects of diet and exercise on cancer cell survival. Endocrinology 144: 2319-2324, 2003[Abstract/Free Full Text]

24. Onuma M, Bub JD, Rummel TL, et al: Prostate cancer cell-adipocyte interaction: Leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J Biol Chem 278: 42660-42667, 2003[Abstract/Free Full Text]

25. Furukawa S, Fujita T, Shimabukuro M, et al: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752-1761, 2004[CrossRef][Medline]

26. Brakenhielm E, Veitonmaki N, Cao R, et al: Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A 101: 2476-2481, 2004[Abstract/Free Full Text]

27. Fukuhara A, Matsuda M, Nishizawa M, et al: Visfatin: A protein secreted by visceral fat that mimics the effect of insulin. Science 305: 426-430, 2005

28. Wilson WA, Roach PJ: Nutrient-regulated protein kinases in budding yeast. Cell 111: 155-158, 2002[CrossRef][Medline]

29. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20: 42-51, 2002[Abstract/Free Full Text]

30. Weiser MA, Cabanillas ME, Konopleva M, et al: Relation between the duration of remission and hyperglycemia during induction chemotherapy for acute lymphocytic leukemia with a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate-cytarabine regimen. Cancer 100: 1179-1185, 2004[CrossRef][Medline]

Submitted June 5, 2006; accepted February 16, 2007.

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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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Butturini, A. M. Articles by Carroll, W. L. Search for Related Content PubMed PubMed Citation Articles by Butturini, A. M. Articles by Carroll, W. L.