Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation for Patients with Metastatic Castrate-Resistant Prostate Cancer.

(1) We hypothesized that adding concurrent stereotactic ablative radiotherapy (SAbR) would increase the time to progression in patients with metastatic castrate-resistant prostate cancer (mCRPCA) treated with sipuleucel-T. (2) Patients with a history of prostate cancer (PC), radiographic evidence of metastatic disease, and rising prostate-specific antigen (PSA) > 0.2 ng/dL on castrate testosterone levels were enrolled in this single-arm phase II clinical trial and treated with sipuleucel-T and SAbR. The primary endpoint was time to progression (TTP). Cellular and humoral responses were measured using ELISpot and Luminex multiplex assays, respectively. (3) Twenty patients with mCRPC were enrolled and treated with SAbR to 1−3 sites. Treatment was well tolerated with 51, 8, and 4 treatment-related grade 1, 2, and 3 toxicities, respectively, and no grade 4 or 5 adverse events. At a median follow-up of 15.5 months, the median TTP was 11.2 weeks (95% CI; 6.8−14.0 weeks). Median OS was 76.8 weeks (95% CI; 41.6−130.8 weeks). This regimen induced both humoral and cellular immune responses. Baseline M-MDSC levels were elevated in mCRPC patients compared to healthy donors (p = 0.004) and a decline in M-MDSC was associated with biochemical response (p = 0.044). Responders had lower baseline uric acid levels (p = 0.05). No clear correlation with radiographic response was observed. (4) While the regimen was safe, the PC-antigen-specific immune response induced by SAbR did not yield a synergistic clinical benefit for patients treated with sipuleucel-T compared to the historically reported outcomes.

Ectopic Thyroid Tissue in the Mediastinum Characterized by Histology and Functional Imaging with I-123 SPECT/CT.

Ectopic thyroid tissue is a rare entity and when discovered it is typically along the pathway of embryologic migration of the thyroid. We present a case of incidental finding of ectopic thyroid tissue within mediastinum in a 61-year-old female patient with a history of total thyroidectomy for thyroiditis and nodules. The patient presented to emergency room with cough and right chest pain and underwent a chest computed tomographic angiogram (CTA) to exclude pulmonary embolism as part of chest pain workup. One right paratracheal mediastinal soft tissue nodule was visualized on the images of CTA. This right paratracheal soft tissue mass was found to be ectopic benign thyroid tissue by histological analysis of the biopsied tissue samples. The function of this ectopic thyroid tissue was characterized by I-123 radioiodine uptake and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. This case illustrates that ectopic thyroid tissue should be included for differential diagnosis of a hyperdense soft tissue mass located within mediastinum. I-123 SPECT/CT is useful for guiding tissue biopsy of ectopic thyroid tissue distant from orthotopic thyroid gland and functional and anatomic characterization of mediastinal ectopic thyroid tissue for surgical resection when it is medically necessary.

Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts.

Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with (111)In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of (111)In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of (111)In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of (111)In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, (111)In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of (111)In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings.

Detection of Widespread Metastasis in a Case of Aggressive Carcinoma Showing Thymuslike Differentiation (CASTLE Disease) Using 18F-FDG PET/CT.

A 30-year-old man had a diagnosis of aggressive carcinoma showing thymuslike differentiation (CASTLE disease) and underwent thyroidectomy for tumor resection and bilateral cervical lymph node dissection. Multiple hypermetabolic nodal metastases were detected in the neck and upper mediastinum with fluorine-18-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ((18)F-FDG PET/CT). The patient received radiation therapy and chemotherapy for treatment of metastases. Follow-up (18)F-FDG PET/CT demonstrated resolution of several hypermetabolic lesions previously seen in the neck, but innumerable new hypermetabolic metastatic lesions were visualized. The patient died of this aggressive CASTLE disease despite treatment with surgery, radiation, and systemic chemotherapy.

Comparison of whole-body versus limited whole-body 18F-FDG PET/CT scan in malignant cutaneous melanoma.

OBJECTIVES: The objectives of this study were to estimate retrospectively the incidence of clinically significant findings in the lower extremities in patients with malignant cutaneous melanoma scanned from the skull vertex to the bottom of the feet and whether these add additional diagnostic and prognostic information and to demonstrate a confidence interval that would support exclusion of lower-extremity scans in these patients. METHODS: This is a retrospective study of 200 patients who underwent (18)F-FDG PET/CT for staging melanoma. Whole-body PET/CT scans including the lower extremities were reviewed. PET/CT findings in the lower extremities were tabulated by location, pathology, and clinical progress notes with documented clinical history and physical examination correlation. RESULTS: Among the 200 PET/CT scans, 3 scans had positive findings in the lower extremities. A biopsy was performed on 1 lesion, which was found to be an incidental squamous cell carcinoma. One lesion was considered a benign finding from inflammation demonstrated by clinical follow-up. One scan had a metastasis to the proximal femur, which is included in the standard FOV (eyes to midthighs). In this case series, the lower extremities' true-positive findings never impacted or changed clinical management. CONCLUSIONS: Our study confirms with a high degree of confidence that in patients with malignant cutaneous melanoma, additional lower-extremity scan results in little additional useful information and could be discontinued in patients whose melanoma did not arise in the lower extremities. PET/CT acquisition of the lower extremities results in increased scan time and unnecessary extra radiation dose from CT to melanoma patients.

A solitary hyperfunctioning thyroid nodule harboring thyroid carcinoma: review of the literature.

Hyperfunctioning nodules of the thyroid are thought to only rarely harbor thyroid cancer, and thus are infrequently biopsied. Here, we present the case of a patient with a hyperfunctioning thyroid nodule harboring thyroid carcinoma and, using MEDLINE literature searches, set out to determine the prevalence of and characteristics of malignant "hot" nodules as a group. Historical, biochemical and radiologic characteristics of the case subjects and their nodules were compared to those in cases of benign hyperfunctioning nodules. A literature review of surgical patients with solitary hyperfunctioning thyroid nodules managed by thyroid resection revealed an estimated 3.1% prevalence of malignancy. A separate literature search uncovered 76 cases of reported malignant hot thyroid nodules, besides the present case. Of these, 78% were female and mean age at time of diagnosis was 47 years. Mean nodule size was 4.13 ± 1.68 cm. Laboratory assessment revealed T3 elevation in 76.5%, T4 elevation in 51.9%, and subclinical hyperthyroidism in 13% of patients. Histological diagnosis was papillary thyroid carcinoma (PTC) in 57.1%, follicular thyroid carcinoma (FTC) in 36.4%, and Hurthle cell carcinoma in 7.8% of patients. Thus, hot thyroid nodules harbor a low but non-trivial rate of malignancy. Compared to individuals with benign hyperfunctioning thyroid nodules, those with malignant hyperfunctioning nodules are younger and more predominantly female. Also, FTC and Hurthle cell carcinoma are found more frequently in hot nodules than in general. We were unable to find any specific characteristics that could be used to distinguish between malignant and benign hot nodules.

Metabolism of [U-13 C]glucose in human brain tumors in vivo.

Glioblastomas and brain metastases demonstrate avid uptake of 2-[(18) F]fluoro-2-deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by (1) H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2-[(18) F]Fluoro-2-deoxyglucose-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ. [U-(13) C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with (13) C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to (13) C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-coenzyme A pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of (13) C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment.

Inframanubrial parathyroid glands in patients with primary hyperparathyroidism: alternatives to sternotomy.

Deep inframanubrial parathyroid tumors have traditionally been excised through a median sternotomy. With the advent of minimally invasive surgical access, we chose to examine the treatment options and outcomes of patients with inframanubrial mediastinal parathyroid tumors. Patients with primary hyperparathyroidism seen at a university medical center over a 12-year period were retrospectively reviewed. The utility of localization studies, methods of treatment, complications, and outcomes were examined in patients with a parathyroid tumor located in the mediastinum inferior to the manubrium. Patients with parathyroid adenomas located at the thoracic inlet were excluded. Sixteen patients with inframanubrial mediastinal tumors were treated during the study period. Altogether, 81% of the patients had undergone at least one prior neck exploration for primary hyperparathyroidism. Preoperative calcium and parathyroid hormone levels were 12.4 +/- 0.36 mg/dl and 273 +/- 70 pg/ml, respectively. Localization studies identified mediastinal parathyroid adenomas in the following locations: anterior mediastinum (n = 8), middle mediastinum (n = 7), posterior mediastinum (n = 1). Mediastinal computed tomography and technetium-sestamibi scans demonstrated the best sensitivity, 92% and 85%, respectively. Seven patients underwent successful excision of the mediastinal adenoma by transcervical mediastinal exploration with the Cooper retractor. The other patients underwent angiographic ablation (n = 4), anterior mediastinotomy (n = 3), video-assisted thoracoscopy (VATS) (n = 1), and VATS plus thoracotomy (n = 1). The mean hospital stay for the study group was 2.9 +/- 0.7 days. The complication rate was 25%. All patients were normocalcemic after a mean follow-up of 15 +/- 7 months. Most inframanubrial mediastinal parathyroid tumors can be successfully managed without median sternotomy.

Directed parathyroidectomy: feasibility and performance in 100 consecutive patients with primary hyperparathyroidism.

HYPOTHESIS: Directed parathyroidectomy (DP) can be successfully completed in most patients with primary hyperparathyroidism. DESIGN AND SETTING: Retrospective review at a tertiary referral center. PATIENTS: One hundred consecutive patients with untreated, sporadic primary hyperparathyroidism operated on by a single surgeon from April 1, 1999, through December 31, 2001. INTERVENTIONS: Following preoperative imaging with sestamibi scintigraphy and ultrasonography, patients underwent parathyroidectomy with intraoperative parathyroid hormone monitoring using a focused approach through a limited neck incision (DP) or bilateral neck exploration (BNE) through a standard collar incision. MAIN OUTCOME MEASURES: Extent of exploration, operative time, length of stay, morbidity, and cure. RESULTS: Directed parathyroidectomy was completed in 70 patients and BNE in 30. Bilateral neck exploration was performed as the initial procedure in 13 patients and following intraoperative conversion from attempted DP in 17. Indications for predetermined BNE were failed preoperative localization (n = 8) and concomitant thyroid disease that required operative treatment (n = 5). The need for predetermined BNE decreased as preoperative localization improved. Intraoperative factors that necessitated conversion to BNE included persistently elevated intraoperative parathyroid hormone levels that accurately predicted multiglandular disease (n = 6), incorrect localization (n = 5), and inadequate exposure (n = 6). Operative time and length of stay were less for DP compared with BNE patients (66 vs 165 minutes and 0.5 vs 1.6 days, respectively). One patient had a temporary vocal cord paresis. All patients were eucalcemic in follow-up (4 months to 3 years). CONCLUSIONS: With accurate preoperative localization and intraoperative parathyroid hormone monitoring, DP can be successfully completed in most patients with sporadic primary hyperparathyroidism. Patients benefit from DP, which reduces operative time and length of stay and facilitates rapid convalescence.

Positron emission tomography in prostate and renal cell carcinoma.

PURPOSE OF REVIEW: The present review addresses technical improvements in [18F]deoxyglucose positron emission tomography (PET) and new tracer developments that may increase detection in prostate cancer and renal cell carcinoma. In addition, we discuss the future of molecular imaging in prostate cancer. RECENT FINDINGS: PET has proven useful in imaging primary and metastatic cancer in a variety of tumor types. Previous work suggested that the most common radiopharmaceutical used in PET imaging - [18F]deoxyglucose - has a limited role in diagnosing primary prostate cancer and renal cell carcinoma. Technical improvements in scanning techniques and in PET scanners have increased detection of primary and metastatic lesions in both tumor types with [18F]deoxyglucose PET, as compared with previous studies. These improvements include increased scanner resolution and improved processing algorithms. In both prostate and renal cell carcinoma, however, better detection may result from the development of new tracers, particularly those that are not excreted into renal collecting systems. Labeled choline shows promise, as does [11C]acetate. New tracers for prostate cancer could be developed to detect changes that signal malignant transformation, as well as tracers that could show expression of genes administered for therapy. SUMMARY: Technical improvements and the development of new tracers will probably make PET imaging a viable diagnostic tool in prostate cancer and renal cell carcinoma.

Validating the performance of the mammary sentinel lymph node team.

BACKGROUND AND OBJECTIVES: The mammary sentinel lymph node (SLN) procedure has the potential to improve the accuracy and lower the morbidity of axillary staging in breast cancer patients, but results are closely linked to experience and can vary widely between institutions. Standardized performance measures need to be established in order to optimize the transition to SLN biopsy only. METHODS: Performance data were prospectively collected for the first 156 mammary SLN procedures performed by three surgeons in our institution. RESULTS: Seventy-five cases were required to achieve an SLN visualization rate of > 80% on preoperative lymphoscintigraphy. The SLN visualization rate was 90% for the last 52 cases. Two surgeons required 25 cases before consistently achieving a > or = 90% SLN identification rate in the operating room and one required 15 cases. The metastasis detection rate increased from 22% for the first 52 cases to 31% for the last 52 cases. The false negative rate for the procedure was 5%. CONCLUSIONS: The following performance criteria and benchmarks are suggested for validating the performance of the SLN team: (1) SLN visualization rate on preoperative lymphoscintigraphy > or = 80%, (2) SLN identification rate in the operating room > or = 90%, (3) False negative rate for the procedure 5%. Thirty procedures per surgeon were sufficient to achieve these benchmarks in our group.