Noninvasive detection of clinically occult lymph-node metastases in prostate cancer.

BACKGROUND Accurate detection of lymph-node metastases in prostate cancer is an essential component of the approach to treatment. We investigated whether highly lymphotropic superparamagnetic nanoparticles, which gain access to lymph nodes by means of interstitial-lymphatic fluid transport, could be used in conjunction with high-resolution magnetic resonance imaging (MRI) to reveal small nodal metastases. METHODS Eighty patients with presurgical clinical stage T1, T2, or T3 prostate cancer who underwent surgical lymph-node resection or biopsy were enrolled. All patients were examined by MRI before and 24 hours after the intravenous administration of lymphotropic superparamagnetic nanoparticles (2.6 mg of iron per kilogram of body weight). The imaging results were correlated with histopathological findings. RESULTS Of the 334 lymph nodes that underwent resection or biopsy, 63 (18.9 percent) from 33 patients (41 percent) had histopathologically detected metastases. Of these 63 nodes, 45 (71.4 percent) did not fulfill the usual imaging criteria for malignancy. MRI with lymphotropic superparamagnetic nanoparticles correctly identified all patients with nodal metastases, and a node-by-node analysis had a significantly higher sensitivity than conventional MRI (90.5 percent vs. 35.4 percent, P<0.001) or nomograms. CONCLUSIONS High-resolution MRI with magnetic nanoparticles allows the detection of small and otherwise undetectable lymph-node metastases in patients with prostate cancer.

[1]  J. Cheville,et al.  Cancer volume of lymph node metastasis predicts progression in prostate cancer. , 1998, The American journal of surgical pathology.

[2]  R. Weissleder,et al.  Detection of lymph node metastases by contrast‐enhanced MRI in an experimental model , 2002, Magnetic resonance in medicine.

[3]  Martin J Graves,et al.  In Vivo Detection of Macrophages in Human Carotid Atheroma: Temporal Dependence of Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced MRI , 2004, Stroke.

[4]  W. Yuh,et al.  Initial clinical experience with dextran-coated superparamagnetic iron oxide for detection of lymph node metastases in patients with head and neck cancer. , 1994, Radiology.

[5]  R. Weissleder,et al.  Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. , 1990, Radiology.

[6]  J A Frank,et al.  Imaging macrophage activity in the brain by using ultrasmall particles of iron oxide. , 2000, AJNR. American journal of neuroradiology.

[7]  R B Jeffrey,et al.  Prostatic carcinoma: staging by clinical assessment, CT, and MR imaging. , 1987, Radiology.

[8]  A. D'Amico,et al.  MRI-guided diagnosis and treatment of prostate cancer. , 2001, The New England journal of medicine.

[9]  F. Gilbert,et al.  Axillary lymph node metastases: A statistical analysis of various parameters in MRI with USPIO , 2002, Journal of magnetic resonance imaging : JMRI.

[10]  R Weissleder,et al.  MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic-pathologic correlation. , 1999, AJR. American journal of roentgenology.

[11]  J. Witjes,et al.  Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared-rapid gradient-echo sequence. , 1996, AJR. American journal of roentgenology.

[12]  P. Walsh.  A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. , 2003, The Journal of urology.

[13]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[14]  R. Lenkinski,et al.  Clinical utility of proton magnetic resonance spectroscopy in characterizing breast lesions. , 2002, Journal of the National Cancer Institute.

[15]  Anna Moore,et al.  In vivo magnetic resonance imaging of transgene expression , 2000, Nature Medicine.

[16]  Taylor Murray,et al.  Cancer Statistics, 2001 , 2001, CA: a cancer journal for clinicians.

[17]  J. Pruim,et al.  Visualization of prostate cancer with 11C-choline positron emission tomography. , 2002, European urology.

[18]  R. Link,et al.  Indications for pelvic lymphadenectomy in prostate cancer. , 2001, The Urologic clinics of North America.

[19]  C. Metz.  ROC Methodology in Radiologic Imaging , 1986, Investigative radiology.

[20]  Juni Palmgren,et al.  A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. , 2002, The New England journal of medicine.

[21]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[22]  J Kurhanewicz,et al.  The prostate: MR imaging and spectroscopy. Present and future. , 2000 .

[23]  J. Debatin,et al.  Magnetic Resonance Imaging of Atherosclerotic Plaque With Ultrasmall Superparamagnetic Particles of Iron Oxide in Hyperlipidemic Rabbits , 2001, Circulation.

[24]  Ralph Weissleder,et al.  Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells , 2000, Nature Biotechnology.

[25]  P. Walsh.  Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. , 2000, The Journal of urology.

[26]  D. Sackett,et al.  Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. , 1991, The New England journal of medicine.

[27]  Ralph Weissleder,et al.  Magnetic relaxation switches capable of sensing molecular interactions , 2002, Nature Biotechnology.

[28]  B J McNeil,et al.  Advances in biomedical imaging. , 2001, JAMA.

[29]  M. Riggs,et al.  Frozen section diagnosis of metastatic prostate adenocarcinoma in pelvic lymphadenectomy compared with nomogram prediction of metastasis. , 2002, Urology.

[30]  H. Pannu,et al.  MR imaging of mediastinal lymph nodes: Evaluation using a superparamagnetic contrast agent , 2000, Journal of magnetic resonance imaging : JMRI.

[31]  P. Kantoff,et al.  Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. , 2001, The New England journal of medicine.

[32]  Colin B Begg,et al.  Variations in morbidity after radical prostatectomy. , 2002, The New England journal of medicine.

[33]  Daniel J. Culkin,et al.  Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. , 1998, New England Journal of Medicine.

[34]  H. Levin,et al.  Open pelvic lymph node dissection for prostate cancer: a reassessment. , 1995, Urology.

[35]  P. Walsh,et al.  Surgery and the reduction of mortality from prostate cancer. , 2002, The New England journal of medicine.

[36]  B. Chauvet,et al.  [Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin]. , 1998, Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique.

[37]  W D Wagner,et al.  A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[38]  R Weissleder,et al.  Monocrystalline iron oxide nanocompounds (MION): Physicochemical properties , 1993, Magnetic resonance in medicine.

[39]  Bruno Brochet,et al.  Macrophage Imaging in Central Nervous System and in Carotid Atherosclerotic Plaque Using Ultrasmall Superparamagnetic Iron Oxide in Magnetic Resonance Imaging , 2004, Investigative radiology.

[40]  A W Partin,et al.  Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. , 1997, JAMA.

[41]  B. Seifert,et al.  Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall superparamagnetic iron oxide enhancement. , 2002, Radiology.

[42]  M. Kattan,et al.  Incidence, Location, and Significance of Periprostatic and Periseminal Vesicle Lymph Nodes in Prostate Cancer , 2001, The American journal of surgical pathology.

[43]  J Bittoun,et al.  Cell internalization of anionic maghemite nanoparticles: Quantitative effect on magnetic resonance imaging , 2003, Magnetic resonance in medicine.

[44]  J. Trapman,et al.  Prostate cancer schemes for androgen escape , 2000, Nature Medicine.