Ovarian Cancer - Current Status of Blood Biomarker and Imaging Screening Strategies
Main Article Content
Abstract
Ovarian cancer is most lethal of all the gynecologic malignancies and the fifth leading cause of cancer deaths in women overall, accounting for about 5% of female cancer deaths. To improve the outcomes, an efficient screening tool for early detection of the disease at an earlier, curable stage would be required. Since the vast majority of ovarian cancer cases are sporadic in nature with relatively low incidence, a screening test has to offer very high specificity to avoid unnecessary interventions in false-positive cases to be considered suitable for general population use. Another approach to screening would entail increasing the pretest likelihood by focusing on patients at increased risk only. Several larger scale, randomized controlled trials are working on establishing screening strategies for the general population with the most promising results so far shown by the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which revealed improvement in survival rates and reduction in mortality within screened patients. However, more data is required to establish the benefits, warranting further validation. Currently, research is ongoing on OC screening benefits and developing a suitable algorithm in order to have better patient outcomes. In this review article, we discuss current updates on OC screening strategies with special focus on novel development in biomarkers and sonography, as screening tools.
Keywords:
Cancer Antigen-125, Contrast Enhanced Ultrasound, Ovarian Cancer, Serum Human epididymis 4, Transvaginal Ultrasound, Ultrasound Molecular Imaging
Article Details
How to Cite
LUTZ, Amelie; ANTIL, Neha.
Ovarian Cancer - Current Status of Blood Biomarker and Imaging Screening Strategies.
Medical Research Archives, [S.l.], v. 8, n. 6, june 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2116>. Date accessed: 20 apr. 2024.
doi: https://doi.org/10.18103/mra.v8i6.2116.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. Vol. 70, CA: A Cancer Journal for Clinicians. 2020;70,7–30.
2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284–96.
3. Menon U, Ryan A, Kalsi J, Gentry-Maharaj A, Dawnay A, Habib M, et al. Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening. J Clin Oncol. 2015;33(18):2062–71.
4. Mathieu KB, Bedi DG, Thrower SL, Qayyum A, Bast RC. Screening for ovarian cancer: imaging challenges and opportunities for improvement. Ultrasound Obstet Gynecol. 2018;51(3):293–303.
5. Naumann RW, Brown J. Ovarian cancer screening with the risk of ovarian cancer algorithm (ROCA): Good, bad, or just expensive? Obstet Gynecol Surv. 2018;73(6):352–3.
6. Pandharipande P V., Lowry KP, Reinhold C, Atri M, Benson CB, Bhosale PR, et al. ACR Appropriateness Criteria® Ovarian Cancer Screening. J Am Coll Radiol. 2017;14(11):S490–9.
7. Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10(4):327–40.
8. Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: Findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193(5):1630–9.
9. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA - J Am Med Assoc. 2011;305(22):2295–302.
10. Pinsky PF, Prorok PC, Yu K, Kramer BS, Black A, Gohagan JK, et al. Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer. 2017;123(4):592–9.
11. Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian Cancer Screening and Mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A Randomized Controlled Trial. Obstet Gynecol Surv. 2016;71(6):346–8.
12. Henderson JT, Webber EM, Sawaya GF. Screening for ovarian cancer updated evidence report and systematic review for the US preventive services task force. JAMA - J Am Med Assoc. 2018;319(6):595–606.
13. Kobayashi H, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, et al. A randomized study of screening for ovarian cancer: A multicenter study in Japan. Int J Gynecol Cancer. 2008;18(3):414–20.
14. Menon U, Griffin M, Gentry-Maharaj A. Ovarian cancer screening - Current status, future directions. Gynecol Oncol. 2014;132(2):490–5.
15. Cramer DW, Bast RC, Berg CD, Diamandis EP, Godwin AK, Hartge P, et al. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res. 2011;4(3):365–74.
16. Scaletta G, Plotti F, Luvero D, Capriglione S, Montera R, Miranda A, et al. The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: a systematic review. Expert Rev Anticancer Ther. 2017;17(9):827–39.
17. Gentry-Maharaj A, Burnell M, Dilley J, Ryan A, Karpinskyj C, Gunu R, Mallett S,Deeks J, Campbell S, Jacobs I, Sundar S. Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses. American journal of obstetrics and gynecology. 2020 Jan 1;222(1):56-e1.
18. Lutz AM, Willmann JK, Drescher CW, Ray P, Cochran F V., Urban N, et al. Early diagnosis of ovarian carcinoma: Is a solution in sight. Radiology. 2011;259(2):329–45.
19. Lutz AM, Willmann JK, Cochran F V., Ray P, Gambhir SS. Cancer screening: A mathematical model relating secreted blood biomarker levels to tumor sizes. PLoS Med. 2008;5(8):1287–97.
20. Kamal R, Hamed S, Mansour S, Mounir Y, Abdel Sallam S. Ovarian cancer screening—ultrasound; impact on ovarian cancer mortality. The British journal of radiology. 2018 Oct;91(1090):20170571.
21. Blyuss O, Burnell M, Ryan A, Gentry-Maharaj A, Mariño IP, Kalsi J, et al. Comparison of longitudinal CA125 algorithms as a first-line screen for ovarian cancer in the general population. Clin Cancer Res. 2018;24(19):4726–33.
22. Das PM, Bast Jr RC. Early detection of ovarian cancer. Biomarkers in Medicine 2008;2:291-303.
23. Dewan R, Dewan A, Jindal M, Bhardawaj M. Diagnostic Performance of Serum Human Epididymis Protein 4 (HE4) for Prediction of Malignancy in Ovarian Masses. Asian Pac J Cancer Prev. 2019;20(4):1103–1108.
24. Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(1):81–5.
25. Choi HJ, Lee YY, Sohn I, Kim YM, Kim JW, Kang S, Kim BG. Comparison of CA 125 alone and risk of ovarian malignancy algorithm (ROMA) in patients with adnexal mass: A multicenter study. Current problems in cancer. 2019 Nov 1:100508.
26. Whitwell HJ, Worthington J, Blyuss O, Gentry-Maharaj A, Ryan A, Gunu R, et al. Improved early detection of ovarian cancer using longitudinal multimarker models. Br J Cancer. 2020;122(6):847–56
27. Simmons AR, Fourkala EO, Gentry-Maharaj A, Ryan A, Sutton MN, Baggerly K, Zheng H, Lu KH, Jacobs I, Skates S, Menon U. Complementary longitudinal serum biomarkers to CA125 for early detection of ovarian cancer. Cancer Prevention Research. 2019 Jun 1;12(6):391-400.
28. Menon U, Kalsi J, Jacobs I. The UKCTOCS experience-reasons for hope? Int J Gynecol Cancer. 2012;22(SUPPL. 1):18–20.
29. Timmerman D, Testa AC, Bourne T, Ameye L, Jurkovic D, Van Holsbeke C, et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol. 2008;31(6):681–90.
30. Andreotti RF, Timmerman D, Benacerraf BR, Bennett GL, Bourne T, Brown DL, et al. Ovarian-Adnexal Reporting Lexicon for Ultrasound: A White Paper of the ACR Ovarian-Adnexal Reporting and Data System Committee. J Am Coll Radiol. 2018;15(10):1415
31. Andreotti RF, Timmerman D, Strachowski LM, Froyman W, Benacerraf BR, Bennett GL, et al. O-RADS US risk stratification and management system: A consensus guideline from the ACR ovarian-Adnexal Reporting and Data System committee. Radiology. 2020;294(1):168–85.
32. Timmerman D, Van Calster B, Testa A, Savelli L, Fischerova D, Froyman W, et al. Predicting the risk of malignancy in adnexal masses based on the Simple Rules from the International Ovarian Tumor Analysis group. Am J Obstet Gynecol. 2016;214(4):424–37.
33. Van Calster B, Van Hoorde K, Valentin L, Testa AC, Fischerova D, Van Holsbeke C, et al. Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: Prospective multicentre diagnostic study. BMJ. 2014;349(October):1–14.
34. Liu Z, Yang F, Zhang Y, Yu H, Zhu H, Yang R, et al. Conventional, Doppler and Contrast-Enhanced Ultrasonography in Differential Diagnosis of Ovarian Masses. Cell Physiol Biochem. 2016;39(6):2398–408.
35. Sharma SK, Nemieboka B, Sala E, Lewis JS, Zeglis M, Sloan M, et al. HHS Public Access. 2016;57(6):827–33.
36. Zhang X, Mao Y, Zheng R, Zheng Z, Huang Z, Huang D, et al. The contribution of qualitative CEUS to the determination of malignancy in adnexal masses, indeterminate on conventional US - A multicenter study. PLoS One. 2014;9(4).
37. Xiang H, Huang R, Cheng J, Gulinaer S, Hu R, Feng Y, Liu H. Value of three-dimensional contrast-enhanced ultrasound in the diagnosis of small adnexal masses. Ultrasound in medicine & biology. 2013 May 1;39(5):761-8.
38. Szymanski M, Socha MW, Kowalkowska ME, Zielińska IB, Eljaszewicz A, Szymanski W. Differentiating between benign and malignant adnexal lesions with contrast-enhanced transvaginal ultrasonography. Int J Gynecol Obstet. 2015;131(2):147–51.
39. Qiu L, Yang F, Luo H. A preliminary study: The sequential use of the risk malignancy index and contrast-enhanced ultrasonography in differential diagnosis of adnexal masses. Medicine (Baltimore). 2018;97(29):e11536.
40. Willmann JK, Lutz AM, Paulmurugan R, Patel MR, Chu P, Rosenberg J, et al. Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo. Radiology. 2008;248(3):936–44.
41. Gao Y, Hernandez C, Yuan HX, Lilly J, Kota P, Zhou H, et al. Ultrasound molecular imaging of ovarian cancer with CA-125 targeted nanobubble contrast agents. Nanomedicine Nanotechnology, Biol Med. 2017;13(7):2159–68.
42. Willmann JK, Bonomo L, Testa AC, Rinaldi P, Rindi G, Valluru KS, et al. Ultrasound molecular imaging with BR55 in patients with breast & ovarian lesions: First-in-human results. J Clin Oncol. 2017;35(19):2133–40.
43. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79(2):185–8.
44. Naumov GN, Akslen LA, Folkman J. Role of angiogenesis in human tumor dormancy: Animal models of the angiogenic switch. Cell Cycle. 2006;5(16):1779–87.
45. Lutz AM, Bachawal S V., Drescher CW, Pysz MA, Willmann JK, Gambhir SS. Ultrasound molecular imaging in a human CD276 expression-modulated murine ovarian cancer model. Clin Cancer Res. 2014;20(5):1313–22.
46. Willmann JK, Cheng Z, Davis C, Lutz AM, Schipper ML, Nielsen CH, et al. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-pet in Mice. Radiology. 2008;249(1):212–9.
47. https://projectreporter.nih.gov/project_info_description.cfm?aid=9693050&icde=4942
0384&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=
2. Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284–96.
3. Menon U, Ryan A, Kalsi J, Gentry-Maharaj A, Dawnay A, Habib M, et al. Risk algorithm using serial biomarker measurements doubles the number of screen-detected cancers compared with a single-threshold rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening. J Clin Oncol. 2015;33(18):2062–71.
4. Mathieu KB, Bedi DG, Thrower SL, Qayyum A, Bast RC. Screening for ovarian cancer: imaging challenges and opportunities for improvement. Ultrasound Obstet Gynecol. 2018;51(3):293–303.
5. Naumann RW, Brown J. Ovarian cancer screening with the risk of ovarian cancer algorithm (ROCA): Good, bad, or just expensive? Obstet Gynecol Surv. 2018;73(6):352–3.
6. Pandharipande P V., Lowry KP, Reinhold C, Atri M, Benson CB, Bhosale PR, et al. ACR Appropriateness Criteria® Ovarian Cancer Screening. J Am Coll Radiol. 2017;14(11):S490–9.
7. Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol. 2009;10(4):327–40.
8. Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: Findings from the initial screen of a randomized trial. Am J Obstet Gynecol. 2005;193(5):1630–9.
9. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening randomized controlled trial. JAMA - J Am Med Assoc. 2011;305(22):2295–302.
10. Pinsky PF, Prorok PC, Yu K, Kramer BS, Black A, Gohagan JK, et al. Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer. 2017;123(4):592–9.
11. Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian Cancer Screening and Mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A Randomized Controlled Trial. Obstet Gynecol Surv. 2016;71(6):346–8.
12. Henderson JT, Webber EM, Sawaya GF. Screening for ovarian cancer updated evidence report and systematic review for the US preventive services task force. JAMA - J Am Med Assoc. 2018;319(6):595–606.
13. Kobayashi H, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, et al. A randomized study of screening for ovarian cancer: A multicenter study in Japan. Int J Gynecol Cancer. 2008;18(3):414–20.
14. Menon U, Griffin M, Gentry-Maharaj A. Ovarian cancer screening - Current status, future directions. Gynecol Oncol. 2014;132(2):490–5.
15. Cramer DW, Bast RC, Berg CD, Diamandis EP, Godwin AK, Hartge P, et al. Ovarian cancer biomarker performance in prostate, lung, colorectal, and ovarian cancer screening trial specimens. Cancer Prev Res. 2011;4(3):365–74.
16. Scaletta G, Plotti F, Luvero D, Capriglione S, Montera R, Miranda A, et al. The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: a systematic review. Expert Rev Anticancer Ther. 2017;17(9):827–39.
17. Gentry-Maharaj A, Burnell M, Dilley J, Ryan A, Karpinskyj C, Gunu R, Mallett S,Deeks J, Campbell S, Jacobs I, Sundar S. Serum HE4 and diagnosis of ovarian cancer in postmenopausal women with adnexal masses. American journal of obstetrics and gynecology. 2020 Jan 1;222(1):56-e1.
18. Lutz AM, Willmann JK, Drescher CW, Ray P, Cochran F V., Urban N, et al. Early diagnosis of ovarian carcinoma: Is a solution in sight. Radiology. 2011;259(2):329–45.
19. Lutz AM, Willmann JK, Cochran F V., Ray P, Gambhir SS. Cancer screening: A mathematical model relating secreted blood biomarker levels to tumor sizes. PLoS Med. 2008;5(8):1287–97.
20. Kamal R, Hamed S, Mansour S, Mounir Y, Abdel Sallam S. Ovarian cancer screening—ultrasound; impact on ovarian cancer mortality. The British journal of radiology. 2018 Oct;91(1090):20170571.
21. Blyuss O, Burnell M, Ryan A, Gentry-Maharaj A, Mariño IP, Kalsi J, et al. Comparison of longitudinal CA125 algorithms as a first-line screen for ovarian cancer in the general population. Clin Cancer Res. 2018;24(19):4726–33.
22. Das PM, Bast Jr RC. Early detection of ovarian cancer. Biomarkers in Medicine 2008;2:291-303.
23. Dewan R, Dewan A, Jindal M, Bhardawaj M. Diagnostic Performance of Serum Human Epididymis Protein 4 (HE4) for Prediction of Malignancy in Ovarian Masses. Asian Pac J Cancer Prev. 2019;20(4):1103–1108.
24. Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(1):81–5.
25. Choi HJ, Lee YY, Sohn I, Kim YM, Kim JW, Kang S, Kim BG. Comparison of CA 125 alone and risk of ovarian malignancy algorithm (ROMA) in patients with adnexal mass: A multicenter study. Current problems in cancer. 2019 Nov 1:100508.
26. Whitwell HJ, Worthington J, Blyuss O, Gentry-Maharaj A, Ryan A, Gunu R, et al. Improved early detection of ovarian cancer using longitudinal multimarker models. Br J Cancer. 2020;122(6):847–56
27. Simmons AR, Fourkala EO, Gentry-Maharaj A, Ryan A, Sutton MN, Baggerly K, Zheng H, Lu KH, Jacobs I, Skates S, Menon U. Complementary longitudinal serum biomarkers to CA125 for early detection of ovarian cancer. Cancer Prevention Research. 2019 Jun 1;12(6):391-400.
28. Menon U, Kalsi J, Jacobs I. The UKCTOCS experience-reasons for hope? Int J Gynecol Cancer. 2012;22(SUPPL. 1):18–20.
29. Timmerman D, Testa AC, Bourne T, Ameye L, Jurkovic D, Van Holsbeke C, et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol. 2008;31(6):681–90.
30. Andreotti RF, Timmerman D, Benacerraf BR, Bennett GL, Bourne T, Brown DL, et al. Ovarian-Adnexal Reporting Lexicon for Ultrasound: A White Paper of the ACR Ovarian-Adnexal Reporting and Data System Committee. J Am Coll Radiol. 2018;15(10):1415
31. Andreotti RF, Timmerman D, Strachowski LM, Froyman W, Benacerraf BR, Bennett GL, et al. O-RADS US risk stratification and management system: A consensus guideline from the ACR ovarian-Adnexal Reporting and Data System committee. Radiology. 2020;294(1):168–85.
32. Timmerman D, Van Calster B, Testa A, Savelli L, Fischerova D, Froyman W, et al. Predicting the risk of malignancy in adnexal masses based on the Simple Rules from the International Ovarian Tumor Analysis group. Am J Obstet Gynecol. 2016;214(4):424–37.
33. Van Calster B, Van Hoorde K, Valentin L, Testa AC, Fischerova D, Van Holsbeke C, et al. Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: Prospective multicentre diagnostic study. BMJ. 2014;349(October):1–14.
34. Liu Z, Yang F, Zhang Y, Yu H, Zhu H, Yang R, et al. Conventional, Doppler and Contrast-Enhanced Ultrasonography in Differential Diagnosis of Ovarian Masses. Cell Physiol Biochem. 2016;39(6):2398–408.
35. Sharma SK, Nemieboka B, Sala E, Lewis JS, Zeglis M, Sloan M, et al. HHS Public Access. 2016;57(6):827–33.
36. Zhang X, Mao Y, Zheng R, Zheng Z, Huang Z, Huang D, et al. The contribution of qualitative CEUS to the determination of malignancy in adnexal masses, indeterminate on conventional US - A multicenter study. PLoS One. 2014;9(4).
37. Xiang H, Huang R, Cheng J, Gulinaer S, Hu R, Feng Y, Liu H. Value of three-dimensional contrast-enhanced ultrasound in the diagnosis of small adnexal masses. Ultrasound in medicine & biology. 2013 May 1;39(5):761-8.
38. Szymanski M, Socha MW, Kowalkowska ME, Zielińska IB, Eljaszewicz A, Szymanski W. Differentiating between benign and malignant adnexal lesions with contrast-enhanced transvaginal ultrasonography. Int J Gynecol Obstet. 2015;131(2):147–51.
39. Qiu L, Yang F, Luo H. A preliminary study: The sequential use of the risk malignancy index and contrast-enhanced ultrasonography in differential diagnosis of adnexal masses. Medicine (Baltimore). 2018;97(29):e11536.
40. Willmann JK, Lutz AM, Paulmurugan R, Patel MR, Chu P, Rosenberg J, et al. Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo. Radiology. 2008;248(3):936–44.
41. Gao Y, Hernandez C, Yuan HX, Lilly J, Kota P, Zhou H, et al. Ultrasound molecular imaging of ovarian cancer with CA-125 targeted nanobubble contrast agents. Nanomedicine Nanotechnology, Biol Med. 2017;13(7):2159–68.
42. Willmann JK, Bonomo L, Testa AC, Rinaldi P, Rindi G, Valluru KS, et al. Ultrasound molecular imaging with BR55 in patients with breast & ovarian lesions: First-in-human results. J Clin Oncol. 2017;35(19):2133–40.
43. Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79(2):185–8.
44. Naumov GN, Akslen LA, Folkman J. Role of angiogenesis in human tumor dormancy: Animal models of the angiogenic switch. Cell Cycle. 2006;5(16):1779–87.
45. Lutz AM, Bachawal S V., Drescher CW, Pysz MA, Willmann JK, Gambhir SS. Ultrasound molecular imaging in a human CD276 expression-modulated murine ovarian cancer model. Clin Cancer Res. 2014;20(5):1313–22.
46. Willmann JK, Cheng Z, Davis C, Lutz AM, Schipper ML, Nielsen CH, et al. Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-pet in Mice. Radiology. 2008;249(1):212–9.
47. https://projectreporter.nih.gov/project_info_description.cfm?aid=9693050&icde=4942
0384&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=