Uterine artery pulsatility index and serum BMP-9 predict resistance to methotrexate therapy in gestational trophoblastic neoplasia: A cohort study |
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| Authors: | Richard A. Harvey Kevin M. Elias Adrian Lim Alexandra Bercow Dee Short Neil S. Horowitz Ross S. Berkowitz Roshan Agarwal Michael J. Seckl |
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| Affiliation: | 1. Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Campus of Imperial College Healthcare NHS Trust, London, UK;2. New England Trophoblastic Disease Center, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women''s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;3. Imaging Department of Imperial College Healthcare NHS Trust, London, UK;4. Molecular Oncology, Department of Surgery and Cancer, Hammersmith Hospital Campus of Imperial College London, London, UK;1. Bezmialem Vakif University, School of Medicine Hospital, Department of Medical Oncology, Istanbul, Turkey;2. Necmettin Erbakan University, Meram School of Medicine Hospital, Department of Medical Oncology, Konya, Turkey;3. Trakya University School of Medicine Hospital, Department of Medical Oncology, Edirne, Turkey;4. Van Yüzünzü Y?l University Hospital, Department of Medical Oncology, Van, Turkey;5. Bezmialem Vakif University, School of Medicine Hospital, Department of Pathology, Istanbul, Turkey;6. Bezmialem Vakif University, School of Medicine Hospital, Department of Urology, Istanbul, Turkey;1. Department of Gynecology and Obstetrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, 519000, China;2. Department of Gynecologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China;3. Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China;1. Department of Respiration, First People''s Hospital of Changzhou, Third Affiliated Hospital of Soochow University, Juqian Road No.185, Changzhou, China;2. Department of Tumor Biological Treatment, First People''s Hospital of Changzhou, Third Affiliated Hospital of Soochow University, Juqian Road No.185, Changzhou, China;1. Department of Bioengineering and Technology, Laboratory of Molecular Virology and Oncology, GUIST, Gauhati University, Guwahati, India;2. Department of Gastroenterology, Gauhati Medical College Hospital, Guwahati, India;3. Department of Head and Neck Oncology, North East Cancer Hospital and Research Institute, Jorabat, India;4. Department of Statistics, Gauhati University, Guwahati, India;1. Department of Medical Biology and Genetics, Near East University, Graduate School of Health Sciences, Nicosia, North Cyprus, Mersin 10, Turkey;2. Department of Urology, Faculty of Medicine, Near East University, Nicosia, North Cyprus, Mersin 10, Turkey;3. Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense C, Denmark;4. Department of Medical Microbiology and Clinical Microbiology, Near East University, Graduate School of Health Sciences, Nicosia, North Cyprus, Mersin 10, Turkey;5. Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, North Cyprus, Mersin 10, Turkey;6. Department of Molecular Biology and Genetics, Faculty of Art and Sciences, Near East University, Nicosia, North Cyprus, Mersin 10, Turkey;1. Division of Radiation Oncology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;2. Northern Thai Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;3. Chiang Mai Cancer Registry, Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;4. Division of Radiation Oncology, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand;5. Udon Thani Cancer Hospital, Udon Thani, Thailand;6. Lampang Cancer Hospital, Lampang, Thailand;7. Chonburi Cancer Hospital, Chonburi, Thailand;8. Research Center in Bioresources for Agriculture, Industry, and Medicine, Department of Statistics, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand |
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| Abstract: | ![]()
Background: Methotrexate is the most common first-line chemotherapy for low-risk gestational trophoblastic neoplasia (GTN). Uterine artery pulsatility index (UAPI) is an ultrasound marker for tumor vascularity that has been associated with an increased risk of methotrexate resistance. The combination of circulating angiogenic factor levels with UAPI data may improve the capacity of this model to predict chemoresistance. Methods: This was a single-center cohort study of women newly diagnosed between January 2008 and June 2012 with low-risk GTN during postmolar surveillance and treated with single-agent methotrexate at Charing Cross Hospital, a UK national center for treatment of gestational trophoblastic disease. Two hundred seventeen women underwent an ultrasound for UAPI measurement prior to initiation of chemotherapy. To examine serologic markers of methotrexate resistance among this cohort, we performed a case-control study using archived serum from 76 patients who could be matched based on prognostic risk score. Serum samples were examined by immunoassay to measure 8 different angiogenic factors (VEGF-A, FGF-basic, PLGF-1, PDGF-BB, EGF, ANGPT2, BMP-9, and ENG). Receiver-operator characteristic area under the curve (AUC) values were calculated for the ability of each analyte to correctly classify patients as methotrexate sensitive (MTX-S) or resistant (MTX-R). Results: Total human chorionic gonadotropin levels were similar between the MTX-S and MTX-R groups. UAPI values were significantly higher in MTX-S (median 1.30 [interquartile range {IQR} = 0.80-1.90]) compared to MTX-R patients (median 0.875 [IQR = 0.60-1.30]; P < 0.0001) with AUC 0.68 (95% confidence interval 0.61-0.76; P < 0.0001). In univariate analysis, only BMP-9 concentrations were significantly different between groups, lower among MTX-S (median of 225 ng/L, IQR = 170-287) compared to MTX-R patients (median 280 ng/L [IQR = 200-339]; P= 0.03). Combining UAPI with BMP-9 concentration improved prediction for chemoresistance with AUC 0.77 (95% confidence interval 0.66-0.88; P < 0.0001). Conclusion: Circulating levels of BMP-9 are elevated in newly diagnosed women with low-risk GTN destined to fail primary methotrexate therapy. A combined test using serum BMP-9 plus UAPI might improve prediction of MTX-R in low-risk GTN. |
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