Millie Whatley

Comparison of 18F-Fluoro-L-DOPA, 18F-Fluoro-Deoxyglucose, and 18F-Fluorodopamine PET and 123I-MIBG Scintigraphy in the Localization of Pheochromocytoma and Paraganglioma

CONTEXT Besides (123)I-metaiodobenzylguanidine (MIBG), positron emission tomography (PET) agents are available for the localization of paraganglioma (PGL), including (18)F-3,4-dihydroxyphenylalanine (DOPA), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), and (18)F-fluorodopamine ((18)F-FDA). OBJECTIVE The objective of the study was to establish the optimal approach to the functional imaging of PGL and examine the link between genotype-specific tumor biology and imaging. DESIGN This was a prospective observational study. INTERVENTION There were no interventions. PATIENTS Fifty-two patients (28 males, 24 females, aged 46.8 +/- 14.2 yr): 20 with nonmetastatic PGL (11 adrenal), 28 with metastatic PGL (13 adrenal), and four in whom PGL was ruled out; 22 PGLs were of the succinate dehydrogenase subunit B (SDHB) genotype. MAIN OUTCOME MEASURES Sensitivity of (18)F-DOPA, (18)F-FDG, and (18)F-FDA PET, (123)I-MIBG scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) for the localization of PGL were measured. RESULTS Sensitivities for localizing nonmetastatic PGL were 100% for CT and/or MRI, 81% for (18)F-DOPA PET, 88% for (18)F-FDG PET/CT, 78% for (18)F-FDA PET/CT, and 78% for (123)I-MIBG scintigraphy. For metastatic PGL, sensitivity in reference to CT/MRI was 45% for (18)F-DOPA PET, 74% for (18)F-FDG PET/CT, 76% for (18)F-FDA PET/CT, and 57% for (123)I-MIBG scintigraphy. In patients with SDHB metastatic PGL, (18)F-FDA and (18)F-FDG have a higher sensitivity (82 and 83%) than (123)I-MIBG (57%) and (18)F-DOPA (20%). CONCLUSIONS (18)F-FDA PET/CT is the preferred technique for the localization of the primary PGL and to rule out metastases. Second best, equal alternatives are (18)F-DOPA PET and (123)I-MIBG scintigraphy. For patients with known metastatic PGL, we recommend (18)F-FDA PET in patients with an unknown genotype, (18)F-FDG or (18)F-FDA PET in SDHB mutation carriers, and (18)F-DOPA or (18)F-FDA PET in non-SDHB patients.

Evaluation of Biologic End Points and Pharmacokinetics in Patients With Metastatic Breast Cancer After Treatment With Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

PURPOSE To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.

Staging and Functional Characterization of Pheochromocytoma and Paraganglioma by 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography

BACKGROUND Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [(123)I]-metaiodobenzylguanidine single photon emission CT ((123)I-MIBG SPECT), CT, and magnetic resonance imaging (MRI). METHODS A total of 216 patients (106 men, 110 women, aged 45.2 ± 14.9 years) with suspected PPGL underwent CT or MRI, (18)F-FDG PET/CT, and (123)I-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. RESULTS Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of (18)F-FDG was similar to that of (123)I-MIBG but less than that of CT/MRI (sensitivity of (18)F-FDG = 76.8%; of (123)I-MIBG = 75.0%; of CT/MRI = 95.7%; (18)F-FDG vs (123)I-MIBG: difference = 1.8%, 95% confidence interval [CI] = -14.8% to 14.8%, P = .210; (18)F-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for (18)F-FDG, 91.8% for (123)I-MIBG, and 90.2% for CT/MRI. (18)F-FDG uptake was higher in succinate dehydrogenase complex- and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for (18)F-FDG and CT/MRI than for (123)I-MIBG (sensitivity of (18)F-FDG = 82.5%; of (123)I-MIBG = 50.0%; of CT/MRI = 74.4%; (18)F-FDG vs (123)I-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs (123)I-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, (18)F-FDG was more sensitive than CT/MRI (sensitivity of (18)F-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). CONCLUSIONS Compared with (123)I-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by (18)F-FDG PET. (18)F-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL.

Comparison of 6-18F-Fluorodopamine PET with 123I-Metaiodobenzylguanidine and 111In-Pentetreotide Scintigraphy in Localization of Nonmetastatic and Metastatic Pheochromocytoma

We compared functional imaging modalities including PET with 6-18F-fluorodopamine (18F-DA) with 123I-metaiodobenzylguanidine (123I-MIBG) and somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide in nonmetastatic and metastatic pheochromocytoma (PHEO). Methods: We studied 25 men and 28 women (mean age ± SD, 44.2 ± 14.2 y) with biochemically proven nonmetastatic (n = 17) or metastatic (n = 36) PHEO. Evaluation included anatomic imaging with CT or MRI and functional imaging that included at least 2 nuclear medicine modalities: 18F-DA PET, 123I-MIBG scintigraphy, or SRS. Sensitivity of functional imaging versus anatomic imaging was assessed on a per-patient and a per-region basis. Results: For this available cohort, on a per-patient basis overall sensitivity (combined for nonmetastatic and metastatic PHEO) was 90.2% for 18F-DA PET, 76.0% for 123I-MIBG scintigraphy, and 22.0% for SRS. On a per-region basis, overall sensitivity was 75.4% for 18F-DA PET, 63.4% for 123I-MIBG scintigraphy, and 64.0% for SRS. Conclusion: If available, 18F-DA PET should be used in the evaluation of PHEO, because it is more sensitive than 123I-MIBG scintigraphy or SRS. If 18F-DA PET is not available, 123I-MIBG scintigraphy (for nonmetastatic or adrenal PHEO) and SRS (for metastatic PHEO) should be the first alternative imaging methods to be used.

The Effects of Carbidopa on Uptake of 6-18F-Fluoro-l-DOPA in PET of Pheochromocytoma and Extraadrenal Abdominal Paraganglioma

6-18F-fluoro-l-3,4-dihydroxyphenylalanine (18F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves 18F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of 18F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa. Methods: Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline 18F-DOPA PET, and 18F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of 18F-DOPA in normal tissues were recorded. Results: Seventy-eight lesions were detected by CT or MRI, 54 by baseline 18F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by 18F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline 18F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for 18F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (±SD) peak standardized uptake value in index tumor lesions from 6.4 ± 3.9 to 9.1 ± 5.6 (P = 0.037). Pancreatic physiologic 18F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa. Conclusion: Carbidopa enhances the sensitivity of 18F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of 18F-DOPA PET for metastases of paraganglioma appears to be limited.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2–3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 107 to 5.8 × 109 vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 109 vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Functional Imaging of SDHx-Related Head and Neck Paragangliomas: Comparison of 18F-Fluorodihydroxyphenylalanine, 18F-Fluorodopamine, 18F-Fluoro-2-Deoxy-d-Glucose PET, 123I-Metaiodobenzylguanidine Scintigraphy, and 111In-Pentetreotide Scintigraphy

RATIONALE Accurate diagnosis of head and neck paragangliomas is often complicated by biochemical silence and lack of catecholamine-associated symptoms, making accurate anatomical and functional imaging techniques essential to the diagnostic process. METHODS Ten patients (seven SDHD, three SDHB), with a total of 26 head and neck paragangliomas, were evaluated with anatomical and functional imaging. This study compares five different functional imaging techniques [(18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET), (18)F-fluorodopamine ((18)F-FDA) PET/computed tomography (CT), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy, and (111)In-pentetreotide scintigraphy] in the localization of head and neck paragangliomas. RESULTS Prospectively (18)F-FDOPA PET localized 26 of 26 lesions in the 10 patients, CT/magnetic resonance imaging localized 21 of 26 lesions, (18)F-FDG PET/CT localized 20 of 26 lesions, (111)In-pentetreotide scintigraphy localized 16 of 25 lesions, (18)F-FDA PET/CT localized 12 of 26 lesions, and (123)I-MIBG scintigraphy localized eight of 26 lesions. Differences in imaging efficacy related to genetic phenotype, even in the present small sample size, included the negativity of (18)F-FDA PET/CT and (123)I-MIBG scintigraphy in patients with SDHB mutations and the accuracy of (18)F-FDG PET/CT in all patients with SDHD mutations, as compared with the accuracy of (18)F-FDG PET/CT in only one patient with an SDHB mutation. CONCLUSION Overall, (18)F-FDOPA PET proved to be the most efficacious functional imaging modality in the localization of SDHx-related head and neck paragangliomas and may be a potential first-line functional imaging agent for the localization of these tumors.

Brown Fat Imaging with 18F-6-Fluorodopamine PET/CT, 18F-FDG PET/CT, and 123I-MIBG SPECT: A Study of Patients Being Evaluated for Pheochromocytoma

Several radiopharmaceuticals such as 18F-FDG, 123I-metaiodobenzylguanidine (MIBG), and 99mTc-tetrofosmin have demonstrated uptake in brown adipose tissue (BAT). It is important to recognize these normal variants so that they are not misinterpreted as a significant pathologic state. In addition, these radiopharmaceuticals may shed light on BAT physiology. 18F-6-fluorodopamine (F-DA) is being used as a PET radiopharmaceutical to image adrenergic innervation and suspected pheochromocytoma. Past reports have suggested that BAT is increased in pheochromocytoma patients. Methods: The images of 96 patients evaluated with 18F-F-DA or 18F-FDG PET/CT for known or suspected pheochromocytoma were reviewed retrospectively to determine whether localized uptake of a pattern typically associated with BAT was present. When available, contemporaneous images obtained using 123I-MIBG were also reviewed for the presence of BAT. Results: Of 67 patients imaged with 18F-F-DA, BAT was found in 17.9%. Of 83 patients imaged with 18F-FDG, 19.2% had BAT. Discordant findings related to uptake in BAT were often seen in patients studied with 18F-FDG, 18F-F-DA, or 123I-MIBG. Overall, 26 (27.0%) of 96 patients showed BAT on at least 1 of the 3 imaging modalities. Conclusion: 18F-F-DA can image BAT, most likely by localizing to sympathetic innervations in a manner similar to 123I-MIBG. Patients with pheochromocytoma may have a greater BAT tissue mass or activation because of elevated levels of circulating catecholamines. Quantitative PET with 18F-FDG and 18F-F-DA may have a role in in vivo studies of BAT physiology in humans or animal models.

The role of 18F-FDG-PET in the local/regional evaluation of women with breast cancer.

AbstractPurpose. In women with breast cancer, knowledge of the local/regional extent of the tumor is essential for staging, treatment planning, monitoring response to therapy, and follow-up. Positron emission tomography (PET) is an important imaging test which can detect tumor at multiple sites in women with breast cancer. We compared the ability of PET to provide a comprehensive view of the local/regional extent of tumor in women with stage I, II and stage III, IV breast cancer. Materials and methods. Forty-six women with breast cancer underwent PET using 18F-FDG. 18FDG uptake in the breast primary tumor, associated skin, axillary and internal mammary lymph nodes, and the contralateral breast was determined qualitatively, and correlated with histologic, clinical and radiographic findings. Results. Twenty-four patients were premenopausal and 22 were postmenopausal, with the following distribution according to clinical stage: stage I – 2 patients, stage II – 16, stage III – 16, stage IV – 12 patients. Among stage I, II patients, the sensitivity for detection of the primary tumor was 83.3%, and for detection of axillary lymph node metastases was 42.9%. 18FDG-PET was negative for the breast skin, contralateral breast, and internal mammary lymph nodes in all stage I, II patients, in agreement with clinical and radiographic findings. Among 28 stage III, IV patients, the sensitivity of 18FDG-PET for detection of the primary tumor was 90.5%, and for detection of axillary lymph node metastases 83.3%. Fourteen patients had clinically advanced changes in the skin, and the sensitivity of PET for detection of skin changes was 76.9%. 18FDG-PET was positive in the internal mammary lymph nodes in 25.0%, and negative in the contralateral breast in all patients with stage III, IV breast cancer. 18FDG-PET was studied in 10 patients following neoadjuvant chemotherapy, and showed a strong correlation with clinical response, and with clinical and pathological findings post-treatment at multiple local/regional sites. Conclusion.18FDG-PET can provide a comprehensive image of local/regional tumor in women with breast cancer. 18FDG-PET may play a greater role in women with stage III, IV breast cancer because of increased sensitivity and the increased involvement of multiple local/regional sites with tumor.

A Prospective Study of 2-[18F] Fluoro-2-Deoxy-D-Glucose/Positron Emission Tomography Scan, 99mTc-Labeled Arcitumomab (CEA-Scan), and Blind Second-Look Laparotomy for Detecting Colon Cancer Recurrence in Patients With Increasing Carcinoembryonic Antigen Levels

BACKGROUND An increasing carcinoembryonic antigen (CEA) level in the absence of disease on imaging studies can present a diagnostic challenge. We evaluated 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography (FDG-PET) scan and CEA scan before second-look laparotomy as a means of localizing recurrent colorectal cancer. METHODS Patients underwent computed tomography scan, bone scan, colonoscopy, and magnetic resonance imaging, and those without evidence of disease or resectable disease in the abdomen had FDG-PET and CEA scans. At second-look laparotomy, a surgeon blinded to the results of the FDG-PET and CEA scans performed an exploration and mapped findings. A second surgeon, with knowledge of the FDG-PET and CEA scans, then explored the patient; all lesions were biopsied or resected for pathology. RESULTS In 28 patients explored, disease was found at operation in 26 (94%). Ten had unresectable disease. FDG-PET scans predicted unresectable disease in 90% of patients. CEA scans failed to predict unresectable disease in any patient. In 16 patients found to have resectable disease or disease that could be treated with regional therapy, FDG-PET scan predicted this in 81% and CEA scan in 13%. CONCLUSIONS FDG-PET scan can predict those patients who would likely benefit from a laparotomy. If the FDG-PET scan indicates resectable disease, laparotomy can be considered. However, if the findings predict unresectable disease or the absence of disease, the patient should pursue systemic therapy or continued observation.