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To the Editor: Xu et al¹ previously reported that lysophosphatidic acid (LPA) levels are increased in the plasma of patients with ovarian cancer, and they proposed that LPA may be a useful early marker of ovarian cancer. Other studies have also reported that LPA levels are increased in malignant effusions in patients with cancer,^2-3 particularly of the ovaries.⁴ To assess the utility of LPA as a marker of ovarian cancer, we measured the amount of LPA in plasma from patients with ovarian cancer and from healthy control subjects, as well as LPA levels in fluid from malignant effusions.

Methods
Using liquid chromotography/mass spectroscopy,⁵ we measured plasma concentrations of 5 individual LPA acyl species (LPA 16:0, 18:2, 18:1, 18:0, and 20:4, which comprise more than 90% of total plasma LPA) in 32 patients with ovarian cancer and 32 healthy control subjects (mean [SD] age, 53 [13] and 42 [12] years, respectively). We also determined LPA concentrations in samples of ascites and pleural fluid from patients with malignant effusions related to their ovarian cancer, as part of a previous study.² All patients provided informed consent in accordance with the policies of our institutional review board.

For each LPA species obtained from malignant effusions, 1-way analyses of variance, with site of the tumor as the main effect, were used to analyze log-transformed data. For plasma, data from the 5 fatty LPA acyl species were considered simultaneously; site of tumor and type of LPA acyl species were considered as main effects, with patients nested by tumor type. Power analysis indicated that sample sizes ranging from 9 to 49 were significantly large to detect differences of 1.5 to 0.6 SDs.

Results
The plasma concentrations of neither individual LPA species nor total LPA differed between ovarian cancer patients and control subjects (Table 1). Likewise, plasma LPA levels were not increased in patients with other gynecologic malignancies (data not shown). Patients with ovarian cancer had somewhat higher total plasma LPA levels than did control subjects, but this difference was not statistically significant. The ranges for all individual LPA species, as well as total LPA, overlapped significantly between the 2 groups. However, LPA levels in malignant effusions, including ovarian cancer, were significantly increased compared with those in control subjects. Furthermore, the rank order of individual LPA species differed between LPA in plasma and malignant effusions among patients with ovarian cancer.

View this table: [in this window] [in a new window] Table. Quantitative Analysis of LPA Levels in Plasma and Malignant Effusion Samples From Control Subjects and Patients With Ovarian Cancer*

Comment
Unlike prior studies,^{1, 6} we did not find increased plasma LPA levels in patients with ovarian cancer. One possible explanation is that we used a different centrifugation process to isolate plasma than did Xu et al.^{1, 6} This is important because LPA is generated by activated platelets.⁷ Thus, we made every effort to remove platelets from plasma samples prior to analysis. Our protocol comprised a 2-step process, first using low-speed (1000g) and then high-speed (10 000g) centrifugation to generate platelet-poor plasma. In separate experiments, we found no difference in mean (SD) total plasma LPA levels from healthy volunteers (n = 5) when plasma was centrifuged only at low or at both at low and high speeds (0.40 [0.06] vs 0.42 [0.07] µmol/L, respectively). Likewise, there was no difference in total plasma LPA levels in patients with ovarian cancer (n = 10) when plasma was centrifuged only at low or at both at low and high speeds (0.26 [0.07] vs 0.31 [0.09] µmol/L, respectively). Moreover, the total plasma LPA level in the control group was 0.70 (0.24) µmol/L, which agreed with the value of 0.60 (0.19) µmol/L that Xu et al¹ previously reported, as well as with our previous report in healthy women (0.74 [0.17] µmol/L).⁵

Using a previously validated stable-isotope dilution liquid chromotography/mass spectroscopy assay, we were unable to distinguish patients with ovarian cancer from healthy control subjects through determination of plasma LPA levels. Furthermore, the rank order of LPA molecular species in plasma and malignant effusions was different, suggesting that these LPA pools are distinct. These results raise questions about the utility of plasma LPA levels for early detection of ovarian cancer.

AUTHOR INFORMATION
Dr Miller is now with the Department of Obstetrics and Gynecology, Wake Forest Medical School, Winston-Salem, NC.—ED.

Daniel L. Baker, PhD
Department of Physiology

Patton Morrison, MD; Brigitte Miller, MD
Department of Obstetrics and Gynecology

Caroline A. Riely, MD
Department of Gastroenterology

Betsy Tolley, PhD
Department of Preventive Medicine
University of Tennessee Health Sciences Center
Memphis

Anneke M. Westermann, MD
Division of Medical Oncology

Johannes M. G. Bonfrer, MD; Evert Bais, MD
Department of Clinical Chemistry

Wouter H. Moolenaar, PhD
Department of Cellular Biochemistry
The Netherlands Cancer Institute
Amsterdam

Gabor Tigyi, MD,PhD
Department of Physiology
University of Tennessee Health Sciences Center

1. Xu Y, Shen Z, Wiper DW, et al. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA. 1998;280:719-723. FREE FULL TEXT 2. Westermann AM, Havik E, Postma FR, et al. Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol. 1998;9:437-442. FREE FULL TEXT 3. Xiao Y, Schwartz B, Washington M, et al. Electrospray ionization mass spectrometry analysis of lysophospholipids in human ascitic fluids: comparison of the lysophospholipid contents in malignant vs nonmalignant ascitic fluids. Anal Biochem. 2001;290:302-313. FULL TEXT | WEB OF SCIENCE | PUBMED 4. Xu Y, Gaudette DC, Boynton JD, et al. Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res. 1995;1:1223-1232. ABSTRACT 5. Baker DL, Desiderio DM, Miller DD, Tolley B, Tigyi GJ. Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry. Anal Biochem. 2001;292:287-295. FULL TEXT | WEB OF SCIENCE | PUBMED 6. Xiao Y, Chen Y, Kennedy AW, Belinson J, Xu Y. Evaluation of plasma lysophospholipids for diagnostic significance using electrospray ionization mass spectrometry (ESI-MS) analyses. Ann N Y Acad Sci. 2000;905:242-259. WEB OF SCIENCE | PUBMED 7. Eichholtz T, Jalink K, Fahrenfort I, Moolenaar WH. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J. 1993;291:677-680.

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2002;287:3081-3082.

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