Sentinel-Lymph-Node Multicenter Trials.

Well executed multicenter clinical trials often provide significant evidence and support for, or against, foundational aspects of clinical procedures perceived to improve clinical management of a medical condition. In this review, discussed are reports of multicenter clinical trials designed to investigate sentinel lymph node biopsy procedures in seven types of cancer: breast, melanoma, head and neck, gastric, colon, uterine, and vulvar-with focus on the most recent reports of the hypotheses, objectives, parameters, data, results, implications, and impacts of the included trials. Such trials generally enroll more subjects, in shorter time periods, than do single-center studies. Such studies generally also have greater diversities among investigator practitioners and investigative environments than do single-center studies. The greater number of subjects provides more power to statistical analyses performed in such studies. The more rapid accrual usually results in data being more consistently acquired. The diversities of practitioners and environments may produce results that are more conservative than might be obtained from more "focused" studies; however, diversities in a study often identify implicitly results that are more robust-that is results applicable by more practitioners and applicable in more environments.

Sentinel Lymph Node Biopsy Procedures.

Accurate staging of many cancers with no clinical evidence of lymph node involvement is often a critical component of the management of such cancers and is generally and historically accomplished by accurate pathological assessment of multiple nodes. Unfortunately, such assessment usually involves excision of the multiple nodes and can result in significant morbidities. Over the past half century, and particularly over the last quarter century, investigators have defined and refined the "sentinel lymph node(s)" concept and have developed and investigated sentinel lymph node biopsy (SLNB) procedures. Such procedures are designed to stage cancers primarily via assessment of the sentinel nodes of the cancers and to do so with limited risk of morbidities. For some cancers (e.g., breast, melanoma, head and neck, penile), there are SLNB procedures that are used routinely. For other cancers, there are SLNB procedures being investigated that will yet prove successful and practical or successful but not practical or neither practical nor successful. In this review, SLNB procedures for breast, melanoma (adult and pediatric), head-and-neck, gastrointestinal (gastric, esophageal, colon), genitourinary (penile, prostate), and gynecological (uterine, cervical, vulvar, ovarian) cancers are discussed, including results of significant clinical trials performed using such in the management of these various cancers.

Harmonic subtraction for evaluating right ventricle ejection fraction from planar equilibrium radionuclide angiography.

We report an initial investigation of a subtraction-based method to estimate right ventricle ejection fraction (RVEF) from ECG-gated planar equilibrium radionuclide angiography (ERNA) data. Twenty-six consecutive patients referred for scintigraphic evaluation of cardiac function prior to chemotherapy had ECG-gated first-pass (FP) imaging and ERNA imaging performed following the same radiotracer injection. RVEF was computed from FP images (RVEFFP) and separately from ERNA images (RVEFERNA). Standard methods for computing ejection fractions were used to obtain RVEFFP values. RVEFERNA values were obtained using harmonic subtraction of the left ventricular contribution from a biventricular region of interest contoured on the equilibrium images acquired in the shallow right anterior oblique projection. Clinically acquired chest CT data were used to derive information regarding the relative position of the left and right ventricle and about the presence of pulmonary artery enlargement. Computation of RVEFERNA was successful for each of the 26 patients. Computation of RVEFFP failed for four patients. For the 22 patients for which RVEF was computed using both methods, the average RVEFFP was 49% and the average RVEFERNA was 51%, with coefficients of variation of 11 and 7.5%, respectively. Low RVEFERNA values were associated with pulmonary artery dilation. Estimation of RVEFERNA, using a harmonic subtraction-based method of computation is clinically feasible and accurate in the patient population studied. The results support further investigation in patients with frank heart failure.

Sodium 18F-Fluoride Bone Scintigraphy in Deep Ocean Diver.

Sodium ¹8F-fluoride (NaF) is a diagnostic marker for new bone formation in bone scintigraphy that was approved by US FDA in 1972 but discontinued in 1984. We report a case of a US naval officer who spent time living and working in an oceanic lab, 205 feet below the surface. Plain skeletal films of femurs 4 years later demonstrate bilateral bone infarcts. Corresponding sodium ¹8F-fluoride bone scintigraphy demonstrates low-normal to decreased tracer activity. This rectilinear scan image is of historical interest. Other bone scintigraphic radiotracers used in the past and present will be briefly discussed.

Lymphoscintigraphy and sentinel nodes.

It has been validated that sentinel lymph node biopsy (SLNB) shows whether a patient's breast cancer or melanoma has spread to regional lymph nodes. As a result, management of patients with these cancers has been revolutionized. SLNB has replaced axillary lymph node dissection (ALND) as the staging modality of choice for early breast cancer and has replaced complete lymph node dissection as the staging modality of choice for melanoma in patients whose SLNBs indicate no metastases. Recently concluded multicenter, randomized trials for breast cancer with 5- to 10-y outcome data have shown no significant differences in disease-free survival rates or overall survival rates between SLNB and ALND groups but have shown significantly lower morbidity with SLNB than with ALND. The lowest false-negative rates (5.5%-6.7%) were seen in studies that used preoperative lymphoscintigraphy and dual mapping during surgery. To assess the survival impact of SLNB in melanoma, the Multicenter Selective Lymphadenectomy Trial I was performed. Melanoma-specific survival rates were not different between subjects randomized to SLNB with lymphadenectomy for nodal metastasis on biopsy and subjects randomized to observation with lymphadenectomy for nodal relapse. However, the 10-y disease-free survival rates were better for the SLNB group than for the observation group, specifically among patients with intermediate-thickness melanomas or thick melanomas.

Clinical intervention for quality improvement of gastric-emptying studies.

UNLABELLED: Prompted by clinical concerns for false-negative tests, we implemented a clinical intervention consisting of a training session and an image-based verification procedure to document homogeneous radioactivity distribution in the radiolabeled meal (egg substitute per the guideline). METHODS: A technologist training session emphasized the importance of thorough mixing of (99m)Tc-sulfur colloid in the egg meal. For 6 mo after training, an image of the prepared mixed egg was acquired before patient ingestion. Consecutive gastric-emptying studies performed 6 mo before and after training were reviewed by 2 experienced physicians. RESULTS: There were 7 abnormal and 44 normal studies before and 15 abnormal and 29 normal studies after training (P < 0.05). Subjective evaluations of images for meal-mixing quality by 2 readers correlated with each other and with an objective measure of expected gastric-emptying physiology (correlation coefficients, 0.54 and 0.38, respectively). CONCLUSION: The described clinical intervention improved the accuracy of our gastric-emptying studies by decreasing false-negative studies.

Nuclear medicine imaging and therapy: gender biases in disease.

Gender-based medicine is medical research and care conducted with conscious consideration of the sex and gender differences of subjects and patients. This issue of Seminars is focused on diseases for which nuclear medicine is part of routine management and for which the diseases have sex- or gender-based differences that affect incidence or pathophysiology and that thus have differences that can potentially affect the results of the relevant nuclear medicine studies. In this first article, we discuss neurologic diseases, certain gastrointestinal conditions, and thyroid conditions. The discussion is in the context of those sex- or gender-based aspects of these diseases that should be considered in the performance, interpretation, and reporting of the relevant nuclear medicine studies. Cardiovascular diseases, gynecologic diseases, bone conditions such as osteoporosis, pediatric occurrences of some diseases, human immunodeficiency virus-related conditions, and the radiation dose considerations of nuclear medicine studies are discussed in the other articles in this issue.

The EANM and SNMMI practice guideline for lymphoscintigraphy and sentinel node localization in breast cancer.

PURPOSE: The accurate harvesting of a sentinel node in breast cancer includes a sequence of procedures with components from different medical specialities, including nuclear medicine, radiology, surgical oncology and pathology. The aim of this document is to provide general information about sentinel lymph node detection in breast cancer patients. METHODS: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the European Association of Nuclear Medicine (EANM) have written and approved these guidelines to promote the use of nuclear medicine procedures with high quality. The final result has been discussed by distinguished experts from the EANM Oncology Committee, the SNMMI and the European Society of Surgical Oncology (ESSO). CONCLUSION: The present guidelines for nuclear medicine practitioners offer assistance in optimizing the diagnostic information from the SLN procedure. These guidelines describe protocols currently used routinely, but do not include all existing procedures. They should therefore not be taken as exclusive of other nuclear medicine modalities that can be used to obtain comparable results. It is important to remember that the resources and facilities available for patient care may vary.

Status of sentinel lymph node for breast cancer.

Long-awaited results from randomized clinical trials designed to test the validity of sentinel lymph node biopsy (SLNB) as replacement of axillary lymph node dissection (ALND) in management of early breast cancer have recently been published. All the trials conclude SLNB has survival rates comparable to those of ALND (up to 10 years in one study) and conclude SLNB has less morbidity than ALND. All the trials support replacing ALND with SLNB for staging in early breast cancer; all support SLNB as the standard of care for such cancer. The SLNB protocols used in the trials varied, and no consensus that would suggest a standard protocol exists. The results of the trials and of other peer-reviewed research do, however, suggest a framework for including some specific methodologies in accepted practice. This article highlights the overall survival and disease-free survival data as reported from the clinical trials. This article also reviews the status of SLN procedures and the following: male breast cancer, the roles of various imaging modalities (single-photon emission computed tomography/computed tomography, positron emission tomography/computed tomography, and ultrasound), ductal carcinoma in situ, extra-axillary SLNs, SLNB after neoadjuvant chemotherapy, radiation exposure to patients and medical personnel, and a new radiotracer that is the first to label SLNs not by particle trapping but by specific macrophage receptor binding. The proper Current Procedural Terminology (CPT) code for lymphoscintigraphy and SLN localization prior to surgery is 78195.

Extravasation of a therapeutic dose of 131I-metaiodobenzylguanidine: prevention, dosimetry, and mitigation.

UNLABELLED: After the extravasation of a therapeutic dose of (131)I-metaiodobenzylguanidine that produced a radiation burn to a patient's forearm, we instituted a catheter placement verification protocol. METHODS: Before therapy infusion, proper placement is verified by administering 37 MBq of (99m)Tc-pertechnetate through the catheter, and monitoring activity at the administration site and on the contralateral extremity. A dosimetric model describing both high-rate and low-rate dose components was developed and predicted that the basal epidermal layer received a radiation dose consistent with the observed moist desquamation radiation skin toxicity. RESULTS: No extravasation incidents have occurred since the verification procedure was instituted. CONCLUSION: To protect against radiation injury from extravasation of therapeutic radionuclides, test administration of a small (99m)Tc dose with probe monitoring of comparable sites in both upper extremities appears to be an effective preventive measure.

The role of single-photon emission computed tomography and SPECT/computed tomography in oncologic imaging.

Single-photon emission computed tomography (SPECT) and hybrid SPECT/computed tomography (SPECT/CT) cameras have emerged as a dominant technology providing invaluable tools in the diagnosis, staging, therapy planning, and treatment monitoring of multiple cancers over the past decade. In the same way that positron emission tomography (PET) benefited from the addition of CT, functional SPECT and anatomic CT data obtained as a single study have shown improvements in diagnostic imaging sensitivity and specificity by improving lesion conspicuity, reducing false positives, and clarifying indeterminate lesions. Furthermore, the anatomic imaging better localizes the functional data, which can be critical in surgical and therapy planning. As more disease-specific imaging agents become available, the role of SPECT/CT in the new paradigms of molecular imaging for personalized medicine will expand. Established and emerging uses of SPECT/CT in a wide variety of oncologic diseases, as well as radiation exposure issues, are reviewed.

Fracture assessment tool risk scores in bone density reports do not change physician prescribing behavior for osteoporosis.

INTRODUCTION: Prevention of osteoporotic fractures is desirable to decrease morbidity, mortality and health care costs. The World Health Organization Fracture Assessment Tool (FRAX) enhances physician treatment decisions by combining epidemiologic fracture risk calculations with bone density. The authors sought to determine the effect of reporting FRAX results and treatment recommendations in bone density reports on clinician prescribing behavior. METHODS: Retrospective review of adherence to treatment recommendations for 368 osteopenic patients at a VA Medical Center 7 months before (pre-FRAX) and after (post-FRAX) inclusion of fracture risk assessment data into the dual energy X-ray absorptiometry. Only osteopenic patients were included (T score: -1.0

The utilization of Gleason grade as the primary criterion for ordering nuclear bone scan in newly diagnosed prostate cancer patients.

Utilization of nuclear bone scans for staging newly diagnosed prostate cancer has decreased dramatically due to PSA-driven stage migration. The current criteria for performing bone scans are based on limited historical data. This study evaluates serum PSA and Gleason grade in predicting positive scans in a contemporary large series of newly diagnosed prostate cancer patients. Eight hundred consecutive cases of newly diagnosed prostate cancer over a 64-month period underwent a staging nuclear scan. All subjects had histologically confirmed cancer. The relationship between PSA, Gleason grade, and bone scan was examined by calculating series of crude, stratified, and adjusted odds ratios with corresponding 95% confidence intervals. Four percent (32/800) of all bone scans were positive. This proportion was significantly lower in patients with Gleason score or=8 (18.8%, p < 0.001). Among patients with Gleason score 30 ng/ml compared to or=8, the rate was significantly higher (27.9 vs. 0%) when PSA was >10 ng/ml compared to 30 ng/ml. However, for patients with a high Gleason score (8-10), we recommend a bone scan if the PSA is >10 ng/ml.

A comparison of the diagnostic accuracy of 18F-FDG PET and CT in the characterization of solitary pulmonary nodules.

UNLABELLED: CT and PET are widely used to characterize solitary pulmonary nodules (SPNs). However, most CT accuracy studies have been performed with outdated technology and methods, and previous PET studies have been limited by small sample sizes and incomplete masking. Our objective was to compare CT and PET accuracy in veterans with SPN. METHODS: Between January 1999 and June 2001, we recruited 532 participants with SPNs newly diagnosed on radiography and untreated. The SPNs were 7-30 mm. All patients underwent (18)F-FDG PET and CT. A masked panel of 3 PET and 3 CT experts rated the studies on a 5-point scale. SPN tissue diagnosis or 2-y follow-up established the final diagnosis. RESULTS: A definitive diagnosis was established for 344 participants. The prevalence of malignancy was 53%. The average size was 16 mm. Likelihood ratios (LRs) for PET and CT results for combined ratings of either definitely benign (33% and 9% of patients, respectively) or probably benign (27% and 12%) were 0.10 and 0.11, respectively. LRs for PET and CT results for combined ratings of indeterminate (1% and 25%), probably malignant (21% and 39%), or definitely malignant (35% and 15%) were 5.18 and 1.61, respectively. Area under the receiver operating characteristic curve was 0.93 (95% confidence interval, 0.90-0.95) for PET and 0.82 (95% confidence interval, 0.77-0.86) for CT (P < 0.0001 for the difference). PET inter- and intraobserver reliability was superior to CT. CONCLUSION: Definitely and probably benign results on PET and CT strongly predict benign SPN. However, such results were 3 times more common with PET. Definitely malignant results on PET were much more predictive of malignancy than were these results on CT. A malignant final diagnosis was approximately 10 times more likely than a benign final diagnosis in participants with PET results rated definitely malignant.

Cardiovascular disease risk stratification with stress single-photon emission computed tomography technetium-99m tetrofosmin imaging in patients with the metabolic syndrome and diabetes mellitus.

The metabolic syndrome represents a constellation of risk factors caused by insulin resistance, dyslipidemia, hypertension, and obesity, resulting in elevated coronary disease risk. From a multicenter prospective registry of 7,849 patients, the relation among the metabolic syndrome, diabetes, and risk stratification with stress technetium-99m tetrofosmin single photon-emission computed tomography (SPECT) was evaluated. The percentage of stress myocardial defects was calculated as < or = 5%, 5.1% to 10%, 10.1% to 15%, and > 15%. A Cox proportional-hazards model was used to estimate cardiovascular death or myocardial infarction (n = 752). Of 7,849 patients, 42% had the metabolic syndrome. Patients with the metabolic syndrome had an 84% 2-year event-free survival rate, lower than patients with normal metabolic status (p <0.0001). In patients with the metabolic syndrome, the percentage of moderate to severely abnormal SPECT findings ranged from 11% to 44% for those with 3 to 5 risk factors for the metabolic syndrome. There was an additive relation between the number of risk factors for the metabolic syndrome and the extent and severity of abnormalities in SPECT findings (p <0.0001). Patients with 5 risk factors for the metabolic syndrome were at the greatest risk, with hazard ratios from 7.8- to 14.1-fold for mild to severely abnormal SPECT findings. For diabetic patients requiring combined oral and insulin therapy, relative risk ratios increased from 15 to 21.4 for patients with > 5% to > 15% stress myocardial perfusion defects. In conclusion, cardiovascular prognosis is affected by the degree of metabolic dysfunction, and stress-induced reductions in myocardial perfusion provide an accurate means for near-term risk stratification.

Intraoperative gamma imaging of axillary sentinel lymph nodes in breast cancer patients.

Sentinel lymph node (SLN) biopsy is now standard practice in the management of many breast cancer patients. Localization protocols vary in complexity and rates of success. The least complex involve only intraoperative gamma counting of radiotracer uptake or intraoperative visualization of blue-dye uptake; the most complex involve preoperative gamma imaging, intraoperative counting and intraoperative dye visualization. Intraoperative gamma imaging may improve some protocols. This study was conducted to obtain preliminary experience and information regarding intraoperative imaging. Sixteen patients were enrolled: 8 in a protocol that included intraoperative counting and dye visualization (probe/dye), 8 in a protocol that involved intraoperative imaging, counting and dye visualization (camera/probe/dye). Preoperative imaging of all 16 patients was performed using a GE 500 gamma camera with a LEAP collimator (300 cpm/muCi). The results of this imaging were not, however, given to the surgeon until the surgeon had completed the procedures required for the study. A Care Wise C-Trak probe was used for intraoperative counting. A Gamma Medica Inc. GammaCAM/OR (12.5 x 12.5 cm FOV) with a LEHR collimator (135 cpm/muCi) was used for intraoperative imaging. Times from start of surgery to external detection of a radioactive focus and to completion of excision of SLNs were recorded. Foci were detected preoperatively via imaging in 16/16 patients. Intraoperative external detection using the probe was accomplished in less than 4 min (mean = 1.5 min) in 15/16 patients, and via intraoperative imaging in 6/8 patients. The average time for completion of excision of nodes was 19 min for probe/dye and 28 min for camera/probe/dye. In one probe/dye case, review of the preoperative images prompted the surgeon to resume axillary dissection and remove one additional SLN.

Difference in filtered-back projection and iterative reconstruction in a patient with increased splanchnic uptake.

We performed a dual isotope, gated adenosine stress myocardial perfusion study on a 44-year-old man. Using filtered-back projection, images showed an inferior wall defect. However, intense liver uptake during adenosine stress was suspected to inaccurately cause diminished inferior wall counts. The patient has end-stage renal disease, diabetes mellitus, and hypertension. The excessive hepatic uptake was noted on planar rotating images and is likely related (at least in part) to reduced renal uptake (not shown subsequently). Using iterative reconstruction, the inferior cardiac defect was markedly reduced. The patient subsequently underwent surgery without complication.

Ethnic differences in the prognostic value of stress technetium-99m tetrofosmin gated single-photon emission computed tomography myocardial perfusion imaging.

OBJECTIVES: This study was designed to evaluate the differential prognostic value of gated single-photon emission computed tomographic imaging (SPECT) imaging in an ethnically diverse multicenter registry. BACKGROUND: Ethnic minority patient populations have reportedly higher coronary heart disease mortality with greater comorbidity and a clustering of risk factors at a significantly younger age when compared with Caucasian, non-Hispanic patients. Despite our increasingly diverse population, the predictive accuracy of cardiac imaging in ethnic minority patients is ill-defined. METHODS: A total of 7,849 patients were prospectively enrolled in a registry of patients undergoing exercise (44%) or pharmacologic stress (56%) technetium-99m tetrofosmin SPECT. Scans were scored using a 20-segment myocardial model with a 5-point severity index. Multivariable Cox proportional hazards models were employed to assess time to death or myocardial infarction. RESULTS: A total of 1,993 African-American, 464 Hispanic, and 5,258 Caucasian non-Hispanic patients underwent SPECT imaging. African-American and Hispanic patients more often had a history of stroke, peripheral arterial disease, angina, heart failure, diabetes, hypertension, and smoking at a younger age. Moderate or severely abnormal SPECT scans were noted in 21%, 17%, and 13% of African-American, Hispanic, and Caucasian non-Hispanic patients, respectively (p < 0.0001). Cardiovascular death rates were highest for ethnic minority patients (p < 0.0001). Annual rates of ischemic heart disease death ranged from 0.2% to 3.0% for Caucasian non-Hispanic and 0.8% to 6.5% for African-American patients with low-risk to severely abnormal SPECT scans (p < 0.0001). For post-stress ejection fraction <45%, annualized risk-adjusted death rates were 2.7% for Caucasian non-Hispanic patients versus 8.0% and 14.0% for African-American and Hispanic patients (p < 0.0001). CONCLUSIONS: The current results from a large observational registry reveal that exercise and pharmacologic stress SPECT effectively predicts major cardiovascular events in a large cohort of African-American and Hispanic patients evaluated for suspected myocardial ischemia. These results provide further evidence that ethnic minority patient populations have a worsening outcome related to cardiovascular disease.