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March 2009

The potential of nanoparticle-enhanced imaging.

Accurate lymph node staging in genitourinary malignancy is an important component in the diagnostic algorithm and therapeutic planning. A promising new method for lymph node staging is lymphotrophic nanoparticle enhanced magnetic resonance imaging. This novel technique uses ultrasmall superparamagnetic iron oxide particles, which localize in lymph nodes and provide detailed characterization of these nodes independent of typically accepted size criteria. This review provides a brief overview of the presently accepted methods for noninvasive lymph node staging and thoroughly discusses lymphotrophic nanoparticle enhanced MR imaging: a technique that can be used for accurate detection of lymph node metastases and will likely play a major role in noninvasive lymph node staging in genitourinary cancer in the near future.

Urol Oncol. 2008 Jan-Feb;26(1):65-73

Colorectal carcinoma: selected issues in pathologic examination and staging and determination of prognostic factors.

CONTEXT: Colorectal carcinoma is one of the most common types of cancer in Western countries and is consistently ranked among the top 3 causes of cancer-related deaths, with approximately 150 000 new cases in the United States and 55 000 deaths in 2006. The pathologist’s assessment of tumor stage and stage-independent morphologic features, such as vascular/lymphatic invasion, influences treatment strategies for the individual patient, such as the decision to offer adjuvant therapy after surgery. However, although the pathologist influences clinical care in colorectal cancer, certain aspects of staging and evaluation of prognostic factors remain challenging and confusing. OBJECTIVES: To present the currently used colorectal cancer staging system; to address challenging areas in pathologic staging, including T category considerations and recommendations for the minimum number of lymph nodes sampled; and to discuss assessment of selected stage-independent prognostic factors, such as vascular/ lymphatic invasion. DATA SOURCES: This review is based on the current staging manual from the American Joint Committee on Cancer, the College of American Pathologists Protocol for Examination of Specimens From Patients With Primary Carcinomas of the Colon and Rectum, and selected articles pertaining to colorectal carcinoma staging and prognostic factors accessible through Ovid Medline (National Library of Medicine, Bethesda, Md). CONCLUSIONS: Proper assessment of pathologic staging for colorectal cancer and of morphologic prognostic factors requires a thorough understanding of staging guidelines and careful specimen dissection and sampling.

Arch Pathol Lab Med. 2008 Oct;132(10):1600-7

Risk factors and clinical outcomes of patients with node-positive muscle-invasive bladder cancer.

Radical cystectomy and lymphadenectomy is a standard treatment for patients with high-grade, invasive bladder cancer. Although the absolute limits of lymphadectomy at the time of surgery have not been precisely defined, there is a growing body of evidence to suggest that an extended lymph node dissection may be beneficial for staging and survival in both node-negative and -positive bladder cancer patients. For lymph node-positive patients, several prognostic factors have been identified to provide risk stratification and direct the need for adjuvant treatment. These include: the pathological stage of the bladder tumor, extent of the lymphadenectomy and nodal tumor burden. The concept of lymph node density has also been identified as a prognostic factor. The literature and data on the extent of lymphadenectomy will be reviewed as well as the current prognostic variables and the benefits of adjuvant chemotherapy.

Expert Rev Anticancer Ther. 2008 Jul;8(7):1091-101

Prognostic factors in patients with carcinoma of the vulva—our own experience and literature review.

AIM OF THE STUDY: The objective was the analysis of prognostic factors and treatment outcomes of 104 patients with vulvar cancer, treated between 1990 and 2003 in the Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Cracow, Poland. MATERIAL AND METHODS: The median age of patients was 67. Advanced disease (TNM III and IVA) was found in 54 (51.9%) patients and grade 2 and 2 in 50 (48.1%). Inguinal lymph nodes were clinically uni- or bilaterally involved in 40.4% of patients. Fifty-seven (54.8%) patients underwent radical vulvectomy with bilateral inguinal lymphadenectomy and 47 (45.2%) radical vulvectomy only. Cancer differentiation was well in 38 (36.2%) of patients, moderate in 38 (36.2%) and poor in 28 (36.6%). Adjuvant radiotherapy was applied in 30 (28.8%) cases. RESULTS: Five-year overall survival rate was observed in 44.4% of patients. Depending on TNM grade, 5-year OS rates were 61.4% for grade 1, 54.9% for grade 2, 40.1% for grade 3 and 13.3% for IVA. In patients aged < 70, 5-year OS rate was 54.7% compared to 30.5% for those > or = 70. Among patients with G1 cancer differentiation 64.4% survived five years, with G2 39.1% and with G3 24.9%, respectively. CONCLUSION: Univariate analysis revealed a statistically significant, unfavorable impact of age > or = 70, with G3 cancer differentiation, clinically confirmed inguinal lymph node involvement and TNM classification stage on 5-year overall survival. Cox multivariate analysis demonstrated that independent prognostic factors for 5-year survival were the age of the patient, clinical status of inguinal lymph nodes and TNM classification grade.

Eur J Gynaecol Oncol. 2008;29(3):260-3

Clinical evidence of breast cancer micrometastasis in the era of sentinel node biopsy.

Sentinel node biopsy for early-stage breast cancer has been established as an excellent surgical and staging procedure developed to enhance the detection of minimal lymph node involvement such as micrometastases. Multisection and the proper use of immunohistochemical staining have led to the increased detection of micrometastases, and this has given rise to new questions about the treatment to be employed concerning micrometastasis. That is whether complete axillary lymph node dissection (ALND) and adjuvant systemic therapy are really required for patients with micrometastasis because of the low prevalence of nonsentinel lymph node metastasis. Some currently published case studies report that selected patients with micrometastases without further ALND would not suffer from a high incidence of regional recurrence. However, the long-term prognostic risk of systemic recurrence and local failure associated with residual axillary disease in the sentinel lymph node-positive patient electing for no further axillary surgery has not been defined. Numerous studies have investigated the impact of occult metastases, which may be regarded as micrometastases or a small tumor deposit. Although data from randomized controlled trials are lacking, these studies suggest that the prognosis of breast cancer patients with micrometastases should not be considered the same as that in truly node-negative patients. Patients with micrometastases should have some adjuvant systemic therapy. Ongoing randomized trials will provide prospective answers to the question of the optimal treatment for micrometastasis.

Int J Clin Oncol. 2008 Feb;13(1):24-32

Sentinel node biopsy: interpretation and management of patients with immunohistochemistry-positive sentinel nodes and those with micrometastases.

The sentinel node procedure is an adequate tool to identify lymph node metastasis in breast cancer. Sentinel nodes are generally examined with greater attention mainly to exclude, as reliably as possible, lymph node metastasis. To achieve this, many protocols are used, resulting in different rates of micrometastasis or isolated tumor cells encountered. Since the prognostic significance of isolated tumor cells or micrometastasis in the sentinel nodes, and the risk of further axillary lymph node involvement in patients with isolated tumor cells, is uncertain and at most limited, these findings may pose difficulties for clinicians in clinical decision making. Protocols that identify lymph node metastasis, from which the clinical relevance is known, are warranted. Unnecessary lymph node dissections should be avoided.

J Clin Oncol. 2008 Feb 10;26(5):698-702

Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: early experience.

PURPOSE: To prospectively evaluate the feasibility of ferumoxtran-10-enhanced magnetic resonance (MR) imaging at high magnetic field strength (3.0 T) and to compare image quality between 1.5- and 3.0-T MR imaging in terms of lymph node detection in patients with prostate cancer. MATERIALS AND METHODS: This study was institutional review board approved, and all patients gave written informed consent. Forty-eight consecutive patients aged 51-79 years (mean, 65.5 years) with prostate cancer were enrolled. T2*-weighted 1.5- and 3.0-T MR images of the pelvis were acquired in a sagittal plane parallel to the psoas muscle 24 hours after ferumoxtran-10 administration. A pelvic and body phased-array coil was used and yielded an in-plane resolution of 0.56 x 0.56 x 3.00 mm at 1.5 T and 0.50 x 0.50 x 2.50 mm at 3.0 T. All images were evaluated by three readers for total image quality, lymph node border delineation, muscle-fat contrast, and vessel-fat contrast. Statistical significance was calculated by using the Mann-Whitney U test. Subsequently, the general linear mixed model was used to estimate the contributions of three factors-patient, reader, and technique-to the variability of the imaging results. RESULTS: Significantly (P < .05) better muscle-fat contrast, vessel-fat contrast, lymph node border delineation, and total image quality were observed at 3.0-T MR imaging. The general linear mixed model revealed that the variability of all results could be attributed to the use of 3.0-T imaging. CONCLUSION: Ferumoxtran-10-enhanced MR imaging can be performed at high magnetic field strengths and result in improved image quality, which may lead to improved detection of small positive lymph nodes. (c) RSNA, 2006.

Radiology. 2006 May;239(2):481-7

Rectal cancer staging.

Endorectal-US is the most suitable imaging technique in the initial staging of rectal cancer and it is mostly accurate in evaluating early stages and in demonstrating the perirectal spread of cancer tissue. CT is not able to demonstrate the layers of the rectal wall and its accuracy in demonstrating the invasion of muscolaris propria and perirectal fat is lower than other techniques, so its use in local staging is not recommended. MRI is mostly accurate in evaluating the mesorectum and the mesorectal fascia which are considered the most relevant prognostic factors for local recurrence. Lymph node evaluation is a challenge for every imaging techniques since lymph node size is not a reliable criterion for diagnosing metastatic involvement. Nuclear medicine has a remarkable role in the work-up of rectal cancer and in the next future the combination of FDG PET in conjunction with a dedicated contrast enhanced CT protocols could become a single-step staging procedure.

Surg Oncol. 2007 Dec;16 Suppl 1:S49-50

MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study.

BACKGROUND: In patients with prostate cancer who are deemed to be at intermediate or high risk of having nodal metastases, invasive diagnostic pelvic lymph-node dissection (PLND) is the gold standard for the detection of nodal disease. However, a new lymph-node-specific MR-contrast agent ferumoxtran-10 can detect metastases in normal-sized nodes (ie, <8 mm in size) by use of MR lymphoangiography (MRL). In this prospective, multicentre cohort study, we aimed to compare the diagnostic accuracy of MRL with up-to-date multidetector CT (MDCT), and test the hypothesis that a negative MRL finding obviates the need for a PLND. METHODS: We included consecutive patients with prostate cancer who had an intermediate or high risk (risk of >5% according to routinely used nomograms) of having lymph-node metastases. All patients were assessed by MDCT and MRL, and underwent PLND or fine-needle aspiration biopsy. Imaging results were correlated with histopathology. The primary outcomes were sensitivity, specificity, accuracy, NPV, and PPV of MRL and MDCT. This study is registered with, number NCT00185029. FINDINGS: The study was done in 11 hospitals in the Netherlands between April 8, 2003, and April 19, 2005. 375 consecutive patients were included. 61 of 375 (16%) patients had lymph-node metastases. Sensitivity was 34% (21 of 61; 95% CI 23-48) for MDCT and 82% (50 of 61; 70-90) for MRL (McNemar’s test p<0.05). Specificity was 97% (303 of 314; 94-98) for MDCT and 93% (291 of 314; 89-95) for MRL. Positive predictive value (PPV) was 66% (21 of 32; 47-81) for MDCT and 69% (50 of 73; 56-79) for MRL. Negative predictive value (NPV) was 88% (303 of 343; 84-91) for MDCT and 96% (291 of 302; 93-98) for MRL (McNemar’s test p<0.05). Of the 61 patients with lymph-node metastases, 50 were detected by MRL, of which 40 (80%) had metastases in normal-sized lymph nodes. The high sensitivity and NPV of MRL imply that in patients with a negative MRL, the chance of positive lymph nodes is less than 11/302 (4%). INTERPRETATION: MRL had significantly higher sensitivity and NPV than MDCT for patients with prostate cancer who had intermediate or high risk of having lymph-node metastases. In such patients, after a negative MRL, the post-test probability of having lymph-node metastases is low enough to omit a PLND.

Lancet Oncol. 2008 Sep;9(9):850-6

Use of ultrasmall superparamagnetic iron oxide in lymph node MR imaging in prostate cancer patients.

A macrophage-specific magnetic resonance (MR) contrast agent allows the detection of small and otherwise undetectable lymph node metastases in patients with prostate cancer. This has an important clinical impact, as the diagnosis will be more precise and less invasive to obtain. Subsequently, this will reduce morbidity and health care costs. However, thorough knowledge of sequence parameters and planes, lymph node anatomy, appearance of normal and abnormal nodes, is essential when using this technique. This will be elaborated in this review.

Eur J Radiol. 2007 Sep;63(3):369-72

Recent advances in iron oxide nanocrystal technology for medical imaging.

Superparamagnetic iron oxide particles (SPIO and USPIO) have a variety of applications in molecular and cellular imaging. Most of the recent research has concerned cellular imaging with imaging of in vivo macrophage activity. According to the iron oxide nanoparticle composition and size which influence their biodistribution, several clinical applications are possible: detection liver metastases, metastatic lymph nodes, inflammatory and/or degenerative diseases. USPIO are investigated as blood pool agents with T1 weighted sequence for angiography, tumour permeability and tumour blood volume or steady-state cerebral blood volume and vessel size index measurements using T2 weighted sequences. Stem cell migration and immune cell trafficking, as well as targeted iron oxide nanoparticles for molecular imaging studies, are at the stage of proof of concept, mainly in animal models.

Adv Drug Deliv Rev. 2006 Dec 1;58(14):1471-504

Detection of pelvic lymph node metastases in patients with clinically localized prostate cancer: comparison of [18F]fluorocholine positron emission tomography-computerized tomography and laparoscopic radioisotope guided sentinel lymph node dissection.

PURPOSE: Accurate detection of lymph node metastases in prostate cancer has important implications for prognosis and approach to treatment. We investigated whether preoperative [18F]fluorocholine combined in-line positron emission tomography-computerized tomography and intraoperative laparoscopic radioisotope guided sentinel pelvic lymph node dissection can detect pelvic lymph node metastases in patients with clinically localized prostate cancer as reliably as extended pelvic lymph node dissection. MATERIALS AND METHODS: A total of 20 patients (mean age 63.9 +/- 6.7 years, range 52 to 75) with clinically localized prostate cancer, prostate specific antigen greater than 10 ng/ml, and/or a Gleason score sum of 7 or greater and negative bone scan were enrolled in the study. [18F]fluorocholine combined in-line positron emission tomography-computerized tomography was performed before surgery. Sentinel pelvic lymph node dissection preceded extended pelvic lymph node dissection including the area of the obturator fossa, external iliac artery/vein and internal iliac artery/vein up to the bifurcation of the common iliac artery. Laparoscopic radical prostatectomy was performed afterward. RESULTS: In 10 of the 20 patients (50%) lymph node metastases were detected, and were exclusively found outside the obturator fossa in 62%. These metastases would not have been identified with standard lymph node dissection of the obturator fossa only. [18F]fluorocholine combined in-line positron emission tomography-computerized tomography was true positive in 1, false-positive in 2, false-negative in 9 and true negative in 8 patients. The largest lymph node metastasis not seen with [18F]fluorocholine combined in-line positron emission tomography-computerized tomography was 8 mm. Laparoscopic sentinel guided lymph node dissection revealed lymph node metastases in 8 of 10 patients. In the other 2 patients sentinel lymph node dissection was not conclusive. In 1 patient normal nodal tissue was completely replaced by cancer and, therefore, there was no tracer uptake in the involved pelvic sidewall/node, and the other patient had no tracer activity at all in the involved pelvic sidewall. Extended pelvic lymph node dissection missed 1 lymph node metastasis (2 mm diameter near pudendal artery) which was detected by sentinel pelvic lymph node dissection only. CONCLUSIONS: Extended pelvic lymph node dissection reveals a higher number of lymph node metastases as described for obturator fossa dissection only. [18F]fluorocholine combined in-line positron emission tomography-computerized tomography is not useful in searching for occult lymph node metastases in clinically localized prostate cancer. Sentinel guided pelvic lymph node dissection allows the detection of even small lymph node metastases. The accuracy of sentinel pelvic lymph node dissection is comparable to that of extended pelvic lymph node dissection when the limitations of the method are taken into consideration.

J Urol. 2006 Nov;176(5):2014-8