Bone metastasis occurs as a result of a complex pathophysiologic process between host and tumor cells leading to cellular invasion, migration adhesion, and stimulation of osteoclastic and osteoblastic activity. The process is mediated by parathyroid hormones, cytokines, and tumor-derived factors. Several sequelae occur as a result of osseous metastases and resulting bone pain can lead to significant debilitation. Pain associated with osseous metastasis is thought to be distinct from neuropathic or inflammatory pain. Several mechanisms-such as invasion of tumor cells, spinal cord astrogliosis, and sensitization of nervous system-have been postulated to cause pain. Pharmaceutical therapy of bone pain includes nonsteroidal analgesics and opiates. These drugs are associated with side effects, and tolerance to these agents necessitates treatment with other modalities. Bisphosphonates act by inhibiting osteoclast-mediated resorption and have been increasingly used in treatment of painful bone metastasis. While external beam radiation therapy remains the mainstay of pain palliation of solitary lesions, bone-seeking radiopharmaceuticals have entered the therapeutic armamentarium for the treatment of multiple painful osseous lesions. (32)P has been used for >3 decades in the treatment of multiple osseous metastases. The myelosuppression caused by this agent has led to the development of other bone-seeking radiopharmaceuticals, including (89)SrCl, (153)Sm-ethylenediaminetetramethylene phosphonic acid ((153)Sm-EDTMP), (179m)SnCl, and (166)Ho-Labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonate ((166)Ho-DOTMP). (89)Sr is a bone-seeking radionuclide, whereas (153)Sm-EDTMP is a bone-seeking tetraphosphonate; both have been approved by the Food and Drug Administration for the treatment of painful osseous metastases. While both agents have been shown to have efficacy in the treatment of painful osseous metastases from prostate cancer, they may also have utility in the treatment of painful osseous metastases from breast cancer and perhaps from non-small cell lung cancer. This article illustrates the salient features of these radiopharmaceuticals, including the approved dose, method of administration, and indications for use. We conclude with recommended guidelines for therapy and follow-up.

/pdf/radiopharmaceutical-therapy-for-palliation-of-bone-pain-from-3u6o0h794t.pdf

Radiopharmaceutical Therapy for Palliation of Bone Pain from Osseous Metastases

Background
Opsoclonus-myoclonus-ataxia (OMA) is a paraneoplastic neurologic syndrome affecting 2–3% of children with neuroblastoma. Although children with OMA and neuroblastoma may have higher survival, many experience a significant amount of late neurologic impairment, which may be immunologically mediated. The aim of this study was to compare the outcome of neuroblastoma patients with and without OMA, relating to prognostic factors, treatment, and the presence or absence of anti-neuronal antibodies.

Procedure
Questionnaires were mailed out requesting information on the current neurologic status of patients who submitted sera at diagnosis to the Children's Cancer Group serum bank from 1980 to 1994. Information was requested on clinical and biological patient characteristics as well as clinical aspects of the patients identified as having OMA syndrome, including presentation and treatment for OMA, late sequelae of OMA, the presence or absence of antineuronal antibodies, and survival. Sera from 16 of the OMA patients and 48 case-controls with neuroblastoma were assayed for anti-neuronal antibodies.

Results
Of the 675 responses received, 21 patients had OMA. Ninety percent of OMA patients presented with non-metastatic disease, vs. 35% of non-OMA patients. Estimated 3-year survival for the OMA patients with nonmetastatic disease (stage I, II, III) greater than 1 year of age was 100% vs. 77% for similar non-OMA patients (P = 0.0222). At follow-up, 14/19 evaluable OMA patients displayed some form of developmental or neurologic abnormality. There was no significant correlation of late sequelae with antineuronal antibodies, age, time between OMA symptoms and diagnosis, or treatment given for tumor or OMA. There was a significant correlation of late sequelae with lower stage disease (I and II) compared to more advanced disease (III and IV).

Conclusions
Patients with OMA and neuroblastoma have excellent survival but a high risk of neurologic sequelae. Favorable disease stage correlates with a higher risk for development of neurologic sequelae. The role of anti-neuronal antibodies in late sequelae of OMA needs further clarification. Med. Pediatr. Oncol. 36:612–622, 2001. © 2001 Wiley-Liss, Inc.

Opsoclonus‐myoclonus‐ataxia syndrome in neuroblastoma: Clinical outcome and antineuronal antibodies—a report from the children's cancer group study

Neuroblastoma is a common malignancy observed in infants and young children. It has a varied prognosis, ranging from spontaneous regression to aggressive metastatic tumors with fatal outcomes despite multimodality therapy. Patients are divided into risk groups on the basis of age, stage, and biologic tumor factors. Multiple clinical and imaging tests are needed for accurate patient assessment. Iodine 123 ((123)I) metaiodobenzylguanidine (MIBG) is the first-line functional imaging agent used in neuroblastoma imaging. MIBG uptake is seen in 90% of neuroblastomas, identifying both the primary tumor and sites of metastatic disease. The addition of single photon emission computed tomography (SPECT) and SPECT/computed tomography to (123)I-MIBG planar images can improve identification and characterization of sites of uptake. During scan interpretation, use of MIBG semiquantitative scoring systems improves description of disease extent and distribution and may be helpful in defining prognosis. Therapeutic use of MIBG labeled with iodine 131 ((131)I) is being investigated as part of research trials, both as a single agent and in conjunction with other therapies. (131)I-MIBG therapy has been studied in patients with newly diagnosed neuroblastoma and those with relapsed disease. Development and implementation of an institutional (131)I-MIBG therapy research program requires extensive preparation with a focus on radiation protection.

MIBG in Neuroblastoma Diagnostic Imaging and Therapy

Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18F-FDG, 18F-DOPA and 68Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.

Guidelines on nuclear medicine imaging in neuroblastoma

Metaiodobenzylguanidine (MIBG) was developed 18 yr ago for scintigraphic imaging of the adrenomedullary tumors pheochromocytoma and neuroblastoma Many studies have shown the usefulness of this agent for the management of patients with neuroblastoma or pheochromocytoma, and the 131I-labeled form was recently approved by the Food and Drug Administration for use in the US This article summarizes our current concepts on the diagnostic use of MIBG in children The radioisotopes available for labeling of MIBG and related compounds, the dosimetry, metabolism and mechanisms of uptake and retention are discussed Our protocols for imaging both 131I-MIBG and 123I-MIBG, along with the normal distribution of these compounds, are reviewed The use of MIBG for the management of neuroblastoma, and comparisons with other radiotracers available for imaging neuroblastomas are also addressed

https://jnm.snmjournals.org/content/jnumed/39/4/679.full.pdf

Current Concepts on the Diagnostic Use of MIBG in Children

There have been several reports of etidronate disodium (EHDP) interference upon the biodistribution of 99mTc-methylene diphosphonate (MDP). With the increasing use of etidronate for the treatment of Paget's disease, hypercalcemia, and osteoporosis, nuclear physicians can expect to encounter increasing numbers of cases in which EHDP-induced artifacts impair the diagnostic utility of bone scans. The temporal duration of this effect is unknown yet obviously important. We report serial bone scintigraphy in a patient who received a single dose of EHDP for hypercalcemia. Normal biodistribution of 99mTc-MDP was noted at 15 days, suggesting that 2 wk are sufficient before performing a bone scan after a single intravenous dose of etidronate.

Duration of etidronate effect demonstrated by serial bone scintigraphy.

Infantile myoclonic encephalopathy (opsoclonus-myoclonus or IME) is a rare clinical syndrome associated with occult neuroblastoma in 20%-50% of all cases. IME is the initial presentation of neuroblastoma in 1%-3% of children. Imaging approaches including chest radiography and abdominal computed tomography (CT) have been proposed to detect neuroblastoma in IME. Metaiodobenzylguanidine (MIBG) is highly effective in the detection of neuroblastoma. These scans can identify both soft-tissue and skeletal lesions anywhere in the body. Our purpose was to attempt to determine the best screening method for detection of occult neuroblastoma in patients with IME. Records of all neuroblastoma patients from 1983 to May 1991 were reviewed. Four cases of IME with neuroblastoma were identified in which imaging studies included an MIBG scan. All four patients had positive MIBG scans (100%) while only two had masses on initial CT (50%). In the three patients initially evaluated by traditional methods, the mean time to diagnosis and the mean number of advanced radiologic studies were 7.5 mo and 7.3 studies respectively. The patient screened with MIBG had only cranial and abdominal CT prior to surgery. Although based on a limited number of patients, results suggest that MIBG may prove to be a useful screening procedure in patients with IME. Traditional imaging modalities can then be directed to evaluate sites of disease identified by MIBG scans.

https://jnm.snmjournals.org/content/jnumed/34/11/1922.full.pdf

Optimized Diagnostic Strategy for Neuroblastoma in Opsoclonus-Myoclonus

UNLABELLED Asymmetric chest activity with malignant and benign pleural effusions has been described in bone scans. However, the clinical utility of this finding is not elucible from the literature. We developed specific scintigraphic criteria for malignant pleural effusion and retrospectively assessed their sensitivity and specificity in a group of patient scans. METHODS Pleural fluid was submitted for cytopathology from 850 patients over a 5-yr period. Bone scans were done within 2 mo of the thoracentesis in 74 patients. As a consensus panel, we reread the scans and reviewed the cytology. RESULTS The effusions were cytologically malignant in 25/74 patients (34%), indeterminate in 9/74 (12%) and benign in 40/74 (54%). Based on cytopathology, malignant pleural effusions were detected by bone scans with a sensitivity of 34%-50% and a specificity of 78%-89%; true sensitivity and specificity was somewhere in between averaging 42% (95% confidence interval 24%-60%) and 84% (95% confidence interval 73%-95%), respectively. CONCLUSIONS The bone scan is frequently the first examination suggesting pleural metastasis, and when it is detected it should be pursued beyond pleural fluid cytology, if negative or indeterminate.

Clinical Utility of Bone Scan Features of Pleural Effusion: Sensitivity and Specificity for Malignancy Based on Pleural Fluid Cytopathology

A 99mTc-HIDA scan was performed on a 4-mo-old female, six days after hepatic transplantation. Gradually, a diffuse increase in activity was seen over the peritoneal region, consistent with a slow bile leak into ascitic fluid. Although the scintigraphic appearance of a bile leak has been previously described, it is usually seen as a focal area of extrabiliary activity. In this case, we report a pattern identified when the leak occurs in conjunction with ascites.

http://jnm.snmjournals.org/content/33/1/115.full.pdf

Unique scintigraphic findings of bile extravasation in the presence of ascites: a complication of hepatic transplantation.

https://jnm.snmjournals.org/content/34/5/865.3.full.pdf

Lesion detection in neuroblastoma with iodine-131-MIBG.

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