Generating lung tumor internal target volumes from 4D-PET maximum intensity projections.

PURPOSE: Positron emission tomography (PET) of lung tumors suffers from breathing-motion induced blurring. Respiratory-correlated PET ameliorates motion blurring and enables visualization of lung tumor functional uptake throughout the breathing cycle but has achieved limited clinical use in radiotherapy planning. In this work, the authors propose a process for generating a gated PET maximum intensity projection (MIP), a breathing-phase projection of the 4D image set comprising gated PET images, as a technique to quantitatively and efficiently incorporate respiratory-correlated PET information into radiotherapy treatment planning. METHODS: 4D-CT and respiratory-gated PET using [(18)F]fluorodeoxyglucose (FDG) were acquired of three patients with a total of four small (4-18 cc), clearly defined lower-lobe lung tumors. Internal target volumes (ITVs) for the lung tumors were generated by threshold-based segmentation of PET-MIP images and ungated PET images (ITV(PET-MIP) and ITV(3D-PET), respectively), and by manual contouring of CT-MIP and end-exhale and end-inhale phases of 4D-CT (ITV(CT-MIP)) by a radiation oncologist. Because of the sensitivity of tumor segmentation to threshold value, several different thresholds were tested for ITV generation, including 40%, 30%, and 20% of maximum standardized uptake value (SUV(max)) for FDG as well as absolute SUV thresholds of 2.5 and 3.0. The normalized overlap and relative volumes of ITV(PET-MIP) and ITV(3D-PET) with respect to ITV(CT-MIP) were compared. The images were also visually compared. ITV(CT-MIP) was considered a gold standard for these tumors with CT-visible morphology. RESULTS: The mean and standard deviation normalized overlap and relative volumes between ITV(PET-MIP) and ITV(CT-MIP) were 0.68 ± 0.07 and 1.07 ± 0.42, respectively, averaged over all four tumors and all five threshold values. The mean and standard deviation normalized overlap and relative volumes of ITV(3D-PET) and ITV(CT-MIP) were 0.47 ± 0.12 and 0.69 ± 0.56, respectively. CONCLUSIONS: PET-MIP images better match CT-MIP images for this sample of four small CT-visible tumors as compared to ungated PET images, based on the metrics of volumetric overlap and relative volumes as well as visual interpretation. The PET-MIP is a way to incorporate 4D-PET imaging into the process of lung tumor contouring that is time-efficient for the radiation oncologist and involves minimal effort to implement in treatment planning software, because it requires only a single PET image beyond contouring on CT alone.

Long-Term Outcomes of Cervical Cancer Patients Treated With Definitive Chemoradiation Following a Complete Metabolic Response.

AIMS: A complete metabolic response (CMR) on early post-treatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a positive prognostic factor for cervical cancer patients treated with definitive chemoradiation, but long-term outcomes of this group of patients are unknown. Patterns of failure and risk subgroups are identified. MATERIALS AND METHODS: Patients who received curative-intent chemoradiation from 1998 to 2018 for International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IVA cervical cancer and had a CMR on post-treatment FDG-PET within 5 months of treatment completion were included. Cox proportional hazards models determined factors associated with locoregional and distant failure. Kaplan-Meier estimates of freedom from any recurrence (FFR) of patient subgroups were compared with Log-rank tests. RESULTS: There were 402 patients with a CMR after chemoradiation on FDG-PET. Initial T stage was T1 (38%)/T2 (40%)/T3 (20%)/T4 (2%); initial FDG-avid nodal status was no nodes (50%)/pelvic lymph nodes (40%)/pelvic and para-aortic lymph nodes (10%). After a median follow-up of 6 years, 109 (27%) recurred. The pattern of recurrence was locoregional (27%), distant (61%) or both (12%). No factors were associated with locoregional failure. Distant recurrence was more likely in patients with T3-4 lesions (hazard ratio = 2.4, 95% confidence interval 1.5-3.8) and involvement of pelvic (hazard ratio = 1.6, 95% confidence interval 1.0-2.7) or para-aortic lymph nodes (hazard ratio = 2.7, 95% confidence interval 1.4-5.0) at diagnosis. The 5-year FFR rates for T1-2 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 85, 76 and 62%, respectively (P = 0.04, none versus para-aortic nodes). The 5-year FFR for T3-4 patients with no nodes, pelvic nodes alone or para-aortic nodes at diagnosis were 68, 56 and 25%, respectively (P = 0.09, none versus para-aortic nodes). CONCLUSIONS: T3-4 tumours and para-aortic nodal involvement at diagnosis are poor prognostic factors, even after a CMR following chemoradiation.

Lymph node staging by positron emission tomography in patients with carcinoma of the cervix.

PURPOSE: The aim of this study was to compare the results of computed tomography (CT) and positron emission tomography (PET) with [18F]-fluoro-2-deoxy-D-glucose (FDG) for lymph node staging in patients with carcinoma of the cervix and to evaluate the relationship of the imaging findings to prognosis. PATIENTS AND METHODS: We retrospectively compared the results of CT lymph node staging and whole-body FDG-PET in 101 consecutive patients with carcinoma of the cervix. Patients were treated with standard irradiation and chemotherapy (as clinically indicated) and observed at 3-month intervals for a median of 15.4 months (range, 2.5 to 30 months). Progression-free survival was evaluated by the Kaplan-Meier method. RESULTS: CT demonstrated abnormally enlarged pelvic lymph nodes in 20 (20%) and para-aortic lymph nodes in seven (7%) of the 101 patients. PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67 (67%), in para-aortic lymph nodes in 21 (21%), and in supraclavicular lymph node in eight (8%). The 2-year progression-free survival, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (P <.0001). A multivariate analysis demonstrated that the most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes as detected by PET imaging (P =.025). CONCLUSION: This study demonstrates that FDG-PET detects abnormal lymph node regions more often than does CT and that the findings on PET are a better predictor of survival than those of CT in patients with carcinoma of the cervix.

Metabolic flare: indicator of hormone responsiveness in advanced breast cancer.

PURPOSE: The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog [(18)F]fluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-[(18)F]fluoroestradiol-17 beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer. PATIENTS AND METHODS: Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy. RESULTS: In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003). CONCLUSION: The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.

Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy.

We assessed the value of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and 16alpha-[18F]fluoro-17beta-estradiol (FES) in women with breast cancer for predicting response to systemic therapy. Results of FES-PET were correlated with estrogen receptor (ER) status. Forty-three women with locally advanced or metastatic breast cancer underwent FDG-PET and FES-PET prior to institution of systemic therapy. All patients had measurable disease and had tumors submitted for ER determination. Cancers were considered functionally hormone sensitive if the standardized uptake value of the lesion on FES-PET was >/=1.0 (FES+) and hormone resistant if the standardized uptake value was <1.0 (FES-). Information obtained by FES-PET was compared with the results of ER assays. The tumor response to chemotherapy and hormonal therapy was correlated with intensity of uptake by both FDG-PET and FES-PET. The ER status of the breast cancers was negative (ER-) in 20 patients, positive (ER+) in 21 patients, and unknown in 2 patients. All 20 of the ER- tumors were also FES-. However, of the 21 ER+ tumors, 16 were FES+ and 5 were FES-. Thirty patients were treated initially with chemotherapy, and 21 (70%) demonstrated objective responses. We were unable to correlate the response to chemotherapy with information obtained by FDG-PET or FES-PET. Thirteen patients were treated with hormone therapy, and 8 (61%) responded to that therapy. Only 1 of the 5 patients whose tumors were ER+ but FES- received hormone therapy, and this treatment resulted in disease stabilization only. Multiple sites of disease were assessed by FES-PET in 17 patients with metastatic breast cancer. Functional hormone sensitivity, defined by FES-PET, was concordant with multiple lesions in 13 (76%). Ten patients with locally advanced breast cancer developed recurrent disease. The initial site of recurrence was the breast in 5 patients. Of the 5 patients with systemic recurrence, 4 had disease detected at the site of recurrence on the pretreatment FDG-PET study but not detected on pretreatment computed tomography. In our experience, FDG-PET imaging is more sensitive than conventional imaging methods, including computed tomography, in staging women with breast cancer. When compared with the in vitro assay of ER status, FES-PET has an apparent sensitivity of 76% and specificity of 100%. Our finding of a subset of patients who have tumors that are ER+ and FES- suggests that the functional assessment of hormone sensitivity by PET imaging can identify patients with ER+ disease whose tumors are likely to be hormone refractory.

Characterizing tumors using metabolic imaging: PET imaging of cellular proliferation and steroid receptors.

Treatment decisions in oncology are increasingly guided by information on the biologic characteristics of tumors. Currently, patient-specific information on tumor biology is obtained from the analysis of biopsy material. Positron emission tomography (PET) provides quantitative estimates of regional biochemistry and receptor status and can overcome the sampling error and difficulty in performing serial studies inherent with biopsy. Imaging using the glucose metabolism tracer, 2 -deoxy-2- fluoro-D-glucose (FDG), has demonstrated PET's ability to guide therapy in clinical oncology. In this review, we highlight PET approaches to imaging two other aspects of tumor biology: cellular proliferation and tumor steroid receptors. We review the biochemical and biologic processes underlying the imaging, positron-emitting radiopharmaceuticals that have been developed, quantitative image-analysis considerations, and clinical studies to date. This provides a basis for evaluating future developments in these promising applications of PET metabolic imaging.

A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy.

PURPOSE: Locoregional tumor control for locally advanced cancers with radiation therapy has been unsatisfactory. This is in part associated with the phenomenon of tumor hypoxia. Assessing hypoxia in human tumors has been difficult due to the lack of clinically noninvasive and reproducible methods. A recently developed positron emission tomography (PET) imaging-based hypoxia measurement technique which employs a Cu(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) tracer is of great interest. Oxygen electrode measurements in animal experiments have demonstrated a strong correlation between low tumor pO(2) and excess (60)Cu-ATSM accumulation. Intensity-modulated radiation therapy (IMRT) allows selective targeting of tumor and sparing of normal tissues. In this study, we examined the feasibility of combining these novel technologies to develop hypoxia imaging (Cu-ATSM)-guided IMRT, which may potentially deliver higher dose of radiation to the hypoxic tumor subvolume to overcome inherent hypoxia-induced radioresistance without compromising normal tissue sparing. METHODS AND MATERIALS: A custom-designed anthropomorphic head phantom containing computed tomography (CT) and positron emitting tomography (PET) visible targets consisting of plastic balls and rods distributed throughout the "cranium" was fabricated to assess the spatial accuracy of target volume mapping after multimodality image coregistration. For head-and-neck cancer patients, a CT and PET imaging fiducial marker coregistration system was integrated into the thermoplastic immobilization head mask with four CT and PET compatible markers to assist image fusion on a Voxel-Q treatment-planning computer. This system was implemented on head-and-neck cancer patients, and the gross tumor volume (GTV) was delineated based on physical and radiologic findings. Within GTV, regions with a (60)Cu-ATSM uptake twice that of contralateral normal neck muscle were operationally designated as ATSM-avid or hypoxic tumor volume (hGTV) for this feasibility study. These target volumes along with other normal organs contours were defined and transferred to an inverse planning computer (Corvus, NOMOS) to create a hypoxia imaging-guided IMRT treatment plan. RESULTS: A study of the accuracy of target volume mapping showed that the spatial fidelity and imaging distortion after CT and PET image coregistration and fusion were within 2 mm in phantom study. Using fiducial markers to assist CT/PET imaging fusion in patients with carcinoma of the head-and-neck area, a heterogeneous distribution of (60)Cu-ATSM within the GTV illustrated the success of (60)Cu-ATSM PET to select an ATSM-avid or hypoxic tumor subvolume (hGTV). We further demonstrated the feasibility of Cu-ATSM-guided IMRT by showing an example in which radiation dose to the hGTV could be escalated without compromising normal tissue (parotid glands and spinal cord) sparing. The plan delivers 80 Gy in 35 fractions to the ATSM-avid tumor subvolume and the GTV simultaneously receives 70 Gy in 35 fractions while more than one-half of the parotid glands are spared to less than 30 Gy. CONCLUSION: We demonstrated the feasibility of a novel Cu-ATSM-guided IMRT approach through coregistering hypoxia (60)Cu-ATSM PET to the corresponding CT images for IMRT planning. Future investigation is needed to establish a clinical-pathologic correlation between (60)Cu-ATSM retention and radiation curability, to understand tumor re-oxygenation kinetics, and tumor target uncertainty during a course of radiation therapy before implementing this therapeutic approach to patients with locally advanced tumor.

64Cu-TETA-octreotide as a PET imaging agent for patients with neuroendocrine tumors.

UNLABELLED: 64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans. METHODS: Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined. RESULTS: In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ. CONCLUSION: The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.

Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma.

The positron-emitting estrogenic steroid 16 alpha-[18F]fluoro-17 beta-estradiol (FES) has been shown to exhibit selective uptake in primary breast carcinomas; the uptake of tracer by positron emission tomography (PET) is strongly correlated with the tumor estrogen-receptor concentration. We have now extended the use of this radiopharmaceutical for imaging of metastases of breast carcinoma by PET in 16 patients with clinical or radiographic evidence of metastatic disease. Increased uptake of FES was identified on PET images in 53 of 57 metastatic lesions (93%); only two apparent false-positive foci of FES uptake were seen. In seven of the patients, evaluable PET studies were obtained both before and after initiation of antiestrogen therapy. In all cases, there was a decrease in FES uptake in the tumor deposits after initiation of antiestrogen therapy, and the mean (+/- standard deviation) uptake decreased from 2.22 (+/- 1.23) to 0.80 (+/- 0.42) x 10(3)+ dose/ml. These results indicate that PET with FES has high sensitivity and specificity for detecting metastatic breast carcinoma and provide additional confirmatory evidence that the tumor uptake of this ligand is a receptor-mediated process.

Assessment of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas.

We have used 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP) for imaging progestin receptors by PET in patients with primary carcinoma of the breast. In vitro binding and in vivo tissue distribution studies in rats have shown that FENP has high specific activity, high affinity for progestin receptors, and receptor-mediated uptake in target tissues. Eight patients with primary breast carcinoma were studied. Breast carcinoma was identified correctly in 50% of the patients with progestin-receptor-positive tumors; however, the FENP uptake was not correlated with progestin-receptor levels. We noted a low target-to-background ratio in humans, with high relative activity in the spine, blood pool, and normal breast tissue. Our findings indicate that FENP is not a suitable agent for imaging progestin receptors in humans.

Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays.

UNLABELLED: The purpose of this study was to assess the results of PET with 16 alpha-[18F]fluoro-17 beta-estradiol (FES) and [18F]fluoro-2-deoxy-D-glucose (FDG) to validate the concordance between tumor estrogen-receptor (ER) status as determined by FES-PET and in vitro assays and to assess the relationship between tumor metabolic activity determined by FDG-PET and tumor ER status, both of which may provide information about tumor aggressiveness and prognosis. METHODS: We studied 32 patients with primary breast masses and 21 patients with clinical or radiological evidence of recurrent/metastatic breast carcinoma. A diagnosis of breast carcinoma was subsequently proven in 43 patients (24 primary, 15 metastatic and 4 recurrent tumors). In vitro assessment of ER status was available for 40 malignant lesions (23 primary and 17 metastatic/recurrent). The patients underwent PET with both FES and FDG, and the uptake of each tracer within each lesion was evaluated qualitatively as well as semiquantitatively using the standardized-uptake-value (SUV) method. RESULTS: We found good overall agreement (88%) between in vitro ER assays and FES-PET. This degree of agreement is similar to that observed between replicate in vitro assays (with discordances due to interlaboratory, interassay and specimen variability). We were, however, unable to demonstrate any significant relationship between tumor FDG uptake and ER status or between tumor FDG and tumor FES uptake in these patients. CONCLUSION: These results indicate that in vitro ER assays and/or FES-PET provide unique direct information about breast cancer ER status that cannot be obtained indirectly by FDG-PET.

RadioimmunoPET: detection of colorectal carcinoma with positron-emitting copper-64-labeled monoclonal antibody.

UNLABELLED: Detection of tumor foci may be improved by combining the selective tumor-targeting properties of a monoclonal antibody with the superior sensitivity and contrast resolution of PET. METHODS: An anti-colorectal carcinoma monoclonal antibody (MAb 1A3) was labeled with 64Cu, a positron-emitting radionuclide, by use of a bifunctional chelate (bromoacetamidobenzyl-TETA) and evaluated in 36 patients with suspected advanced primary or metastatic colorectal cancer. After radiopharmaceutical injection (5-20 mg protein, 10 mCi 64Cu), PET was performed once or twice, 4 to 36 hr later. All patients had CT scans and 18 patients were also studied with [18F]fluorodeoxyglucose (FDG) PET. RESULTS: In 29 patients, one or more tumor sites (n = 56) were proven, in 5 patients the absence of active tumor was confirmed and in the remaining 2, tumor status is not yet confirmed. Of the 56 confirmed tumor sites, 40 were detected by MAb-PET as foci of increased activity (sensitivity 71%). The positive predictive value of MAb-PET was excellent, ranging from 89% (40/45) to 96% (43/45), depending on the ultimate classification of three image-positive, but as yet unconfirmed tumor sites. Also, MAb-PET detected 11 new occult tumor sites, including 9 small abdominopelvic foci less than 2.0 cm in diameter that were not detected by CT or MRI. There were no complications, but significantly elevated HAMA titers were found in 28% of the 29 patients tested 1 to 12 mo after injection. There was no apparent dose-related effect from 5 to 20 mg MAb 1A3. CONCLUSION: These Phase I/II results suggest that PET with radiolabeled MAbs (radioimmunoPET) may have important applications in clinical oncology, particularly for detecting smaller colorectal tumor foci in the abdomen or pelvis and for determining accurate dosimetry.

PET in breast cancer.

Over the past decade, the role of radiology in breast cancer has changed significantly because of the technical advances in mammography, greater use of ultrasonography, and the emergence of magnetic resonance imaging (MRI), as well as development of functional imaging techniques that add new dimensions to the noninvasive evaluation of patients with breast cancer. Currently, radiological evaluation of breast cancer is important not only for early detection of this disease, but also for staging, assessing certain prognostic factors, and monitoring response to treatment. This review focuses on the potential applications and limitations of positron emission tomography (PET) as a functional imaging method in breast cancer. PET with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) has been used successfully in an increasing number of oncological applications and is considered a valuable adjunct to anatomical imaging methods, providing unique functional information for better characterization of disease. The contributions of PET to breast cancer imaging can be considered in two main categories. First, by providing qualitative and/or quantitative information, FDG-PET can aid in detection and discrimination of breast cancer in its primary location. Although, FDG-PET is certainly not necessary in every potential case of breast cancer, it can be very useful in clinically and radiologically "difficult-to-examine breasts," eg, following breast surgery. Qualitative assessment of the extent of the tumor spread provides prognostic information and allows for selection of appropriate therapy. The identification of tumor spread to the axillary nodes or to more remote nodal groups, i.e., internal mammary, or supraclavicular nodes, is probably the most practical information that qualitative FDG-PET can offer. Although it is still too early to formulate definite clinical recommendations, it appears likely that FDG-PET has the potential to reduce the number of patients requiring nodal dissection. Second, PET imaging can provide an assessment of the biological behavior of breast cancer. Quantitative and/or semi-quantitative FDG-PET yields valuable information regarding prognosis and response to therapy in a timely fashion. Preliminary studies have indicated that serial assessment of tumor metabolism by FDG-PET early during effective chemohormonotherapy may predict subsequent response to such therapy. The use of PET with the estrogen analogue 16 alpha-[18F]fluoro-17 beta-estradiol (FES) to monitor receptor function and response to hormonal therapy opens up intriguing new ways to monitor patients with breast cancer at a cellular level.

Evaluation of fluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid carcinoma and pheochromocytoma: a clinical and molecular study.

BACKGROUND: Imaging of metastatic sites of medullary thyroid carcinoma (MTC) is successful in less than 60% of cases of residual or recurrent disease. Positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (FDG) takes advantage of the fact that malignant tumors are capable of increased uptake and use of glucose, which is mediated by the members of the glucose transporter family of proteins (GLUT 1 through GLUT 5). METHODS: FDG-PET images of 10 patients with recurrent or persistent MTC after primary operation were compared with images by computed tomography or magnetic resonance imaging. Identified metastatic lesions were assessed by intraoperative findings and pathology reports. Expression of GLUT 1 through GLUT 5 was examined by Western blot analysis of tumor tissue from eight of the patients evaluated and an additional panel of 10 MTCs and seven pheochromocytomas. RESULTS: FDG-PET identified 31 foci of FDG accumulation in 10 patients, and 16 of these metastatic sites were resected and confirmed by histologic analysis. Only 11 foci were demonstrated by computed tomographic or magnetic resonance imaging. None of the glucose transporters examined displayed significant expression. Two pheochromocytomas were successfully imaged by FDG-PET. CONCLUSIONS: FDG-PET imaging can be useful in the localization of cervicomediastinal MTC metastases and pheochromocytoma. The increased glucose uptake in these tumors, as evidenced by FDG-PET, does not appear to be attributable to the expression of the glucose transporter proteins GLUT 1 through GLUT 5.

Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography.

BACKGROUND: Thyroid tumors often exhibit increased metabolic activity, as evidenced by enhanced glucose uptake on positron emission tomography (PET) with use of (18)F-fluorodeoxyglucose (FDG). The incidence of new thyroid lesions found on routine FDG-PET has not been previously reported. METHODS: A retrospective review of all patients who underwent FDG-PET imaging at our institution from June 1, 1996, through March 15, 2001, identified patients with a newly diagnosed thyroid lesion. Thyroid incidentaloma was defined as a thyroid lesion seen initially on FDG-PET in a patient without a history of thyroid disease. Available follow-up data were documented. RESULTS: One hundred and two of 4525 FDG-PET examinations (2.3%) demonstrated thyroid incidentalomas. Eighty-seven of 102 patients had no thyroid histology because of other malignancies. Fifteen patients had thyroid biopsy: 7 (47%) with thyroid cancer, 6 (40%) with nodular hyperplasia, 1 with thyroiditis, and 1 with atypical cells of indeterminate origin. The average standardized uptake values were higher for malignant compared with benign lesions. CONCLUSIONS: Thyroid incidentaloma identified by FDG-PET occurred with a frequency of 2.3%. Of the thyroid incidentalomas that underwent biopsy, 47% were found to be malignant. Given the risk of malignancy, patients with new thyroid lesions on PET scan should have a tissue diagnosis if it will influence outcome and management. Standardized uptake values may be helpful in predicting benign versus malignant histology.

Improvement in staging of esophageal cancer with the addition of positron emission tomography.

BACKGROUND: Positron emission tomography with the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (FDG) has been used to detect and stage a variety of malignancies. We hypothesized that FDG-positron emission tomography would improve staging of patients with esophageal cancer and thereby facilitate selection of candidates for resection. METHODS: Fifty-eight patients (42 men and 16 women) with biopsy-proven esophageal cancer were evaluated with both FDG-positron emission tomography and computed tomography. RESULTS: In all but 2 patients, increased FDG uptake was identified at the site of the primary tumor. Six patients were not operative candidates. Seventeen patients were not candidates for resection because of metastatic disease. Positron emission tomography identified the metastatic disease in all 17 (12 of whom underwent confirmatory biopsy), whereas computed tomography was positive for metastases in only 5. The remaining 35 patients underwent surgical exploration, were judged to have resectable disease and had esophagectomy. Pathologic examination of resected specimens identified lymph node metastases in 21 patients. These nodes were detected by positron emission tomography in 11 patients and by computed tomography in 6. CONCLUSIONS: Positron emission tomography improved staging and facilitated selection of patients for operation by detecting distant disease not identified by computed tomography alone.

Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes.

16beta-[18F]Fluoromoxestrol ([18]betaFMOX) is an analog of 16alpha-[18F]fluoroestradiol-17beta ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F]betaFMOX was predicted to be as effective an imaging agent as [18F]FES. However, in a preliminary PET imaging study with [18F]FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]betaFMOX was observed. In search for an explanation for the unsuccessful [18F]betaFMOX clinical trial, we have examined the rate of metabolism of [18F]FMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F]betaFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]betaFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]betaFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]betaFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]betaFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.

The development of estrogen and progestin radiopharmaceuticals for imaging breast cancer.

BACKGROUND: The presence of receptors for estrogens and progestins in many breast tumors provides a means for imaging these tumors using positron emission tomography (PET) with appropriate fluorine-18 labeled estrogen and progestin radiopharmaceuticals. In this context, the estrogen analog 16 alpha-[18F]fluoroestradiol (FES) has already proven to be an effective imaging agent for estrogen receptor-positive tumors. METHODS: Clinical studies comparing FES images with those based on the metabolic probe 2-[18F]fluoro-2-deoxyglucose (FDG) in patients before and after tamoxifen hormone therapy are underway. Several fluorine-18 labeled progestins have been prepared, and efforts are underway to develop methods for labeling steroid receptor imaging agents with the widely available radionuclide technetium-99m, using both pendant and integrated approaches. RESULTS AND CONCLUSION: Breast tumor imaging with FES and FDG shows an interesting relationship between tumor metabolic response (assessed with FDG) and tumor estrogen receptor levels (assessed with FES). The fluorine-18 labeled progestins show excellent target tissue selective distribution in experimental animals and are ready for imaging studies in humans. The development of steroids labeled with technetium-99m poses special challenges because of the metallic nature of this radioisotope.

Radiologic diagnosis of extrathoracic metastases to the lung.

Because many types of cancers metastasize to the lungs, early detection may affect both tumor staging and treatment planning. On the other hand, it is also important to refrain from subjecting patients to procedures that are unnecessary because of the low likelihood of positive yield. The radiologic modalities of greatest benefit in screening for pulmonary metastases are the standard chest radiograph and thoracic computed tomography (CT). Other modalities that may be of value in answering specific questions are positron emission tomography (PET) and magnetic resonance imaging (MRI). Factors that help determine which tests will be most useful in demonstrating pulmonary metastasis from extrathoracic primary tumors include the mechanisms of hematogenous tumor spread, the likelihood of distant metastasis vs spread to nearby nodal groups, and the probability of distant metastasis in the absence of local invasion.

Hepatic hydatid disease in Iran, with review of the literature.

We retrospectively reviewed 126 surgically proven cases of hydatid cyst of the liver selected from medical records of patients diagnosed clinically over the eight-year period 1972 to 1980. Sixty percent of the patients were in the third and fourth decades of life. The most common initial complaint was either right upper abdominal pain or a sensation of fullness, generally for more than two months. One or more cysts were more apt to be in the right lobe, and were subject to infection, rupture, or fistula formation. In 6% of patients, other intraabdominal cysts were found during surgery. In a few patients, the plain abdominal radiographs revealed curvilinear calcification. Upper gastrointestinal barium studies showed extrinsic pressure on the stomach or duodenum. Chest radiographs occasionally showed elevated right hemidiaphragm, right lower lobe infiltrate/atelectasis, right pleural effusion, and a pulmonary hydatid cyst. Liver-spleen scintigraphy often revealed a space-occupying lesion, but there were discrepancies either in number or location of cysts when compared with the surgical findings. All angiographic results were abnormal. Patients with infected cysts differed from the rest by a more common history of fever, and a greater incidence of right pleural effusion on chest x-ray. Literature on pathophysiology, radiologic findings (including CT scan and ultrasonography), and surgical and medical therapy of hydatid disease of the liver is reviewed.