Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54 mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

A study investigating the acute dose-response effects of 13 mg and 17 mg Delta 9- tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana.

Heavy use of marijuana is claimed to damage critical skills related to short-term memory, visual scanning and attention. Motor skills and driving safety may be compromised by the acute effects of marijuana. The aim of this study was to investigate the acute effects of 13 mg and 17 mg Delta 9-tetrahydrocannabinol (THC) on skills important for coordinated movement and driving and on subjective and autonomic measures in regular users of marijuana. Fourteen regular users of marijuana were enrolled. Each subject was tested on two separate days. On each test day, subjects smoked two low-nicotine cigarettes, one with and the other without THC. Seventeen mg THC was included in the cigarette on one test day and 13 mg on the other day. The sequence of cigarette types was unknown to the subject. During smoking, heart rate and blood pressure were monitored, and the subjects performed a virtual reality maze task requiring attention and motor coordination, followed by 3 other cognitive tasks (Wisconsin Card Sorting Test (WCST), a "gambling" task and estimation of time and distance from an approaching car). After smoking a cigarette with 17 mg THC, regular marijuana users hit the walls more often on the virtual maze task than after smoking cigarettes without THC; this effect was not seen in patients after they smoked cigarettes with 13 mg THC. Performance in the WCST was affected with 17 mg THC and to a lesser extent with the use of 13 mg THC. Decision making in the gambling task was affected after smoking cigarettes with 17 mg THC, but not with 13 m THC. Smoking cigarettes with 13 and 17 mg THC increased subjective ratings of pleasure and satisfaction, drug "effect" and drug "high". These findings imply that smoking of 17 mg THC results in impairment of cognitive-motor skills that could be important for coordinated movement and driving, whereas the lower dose of 13 mg THC appears to cause less impairment of such skills in regular users of marijuana.

Formation of fluorine-18 labeled diaryl ureas--labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis.

Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[(18)F]fluoro-aniline from 1,4-dinitrobenzene (60min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[(18)F]fluoro-aniline synthon reacted for 30min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[(18)F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3h including HPLC purification with 46+/-1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400+/-37GBq/mmol (n=5).

The neural correlates of understanding the other's distress: a positron emission tomography investigation of accurate empathy.

The purpose of the present study was to assess the relationship between brain metabolism and empathic response. Six right-handed healthy volunteers were scanned with PET and fluorodeoxyglucose twice: during an interview about neutral story themes and during an empathic response eliciting interview about a story of a character in distress. Metabolic values in the medial and superior frontal gyrus, occipitotemporal cortices, thalamus and the cerebellum were higher during empathic response than during the neutral theme interview. Furthermore, the subjects' empathy scores were positively correlated with metabolism in the medial aspects of the superior frontal gyrus. Our results suggest that empathy consists of both affective and cognitive components and hence may involve cortices that mediate simulation of emotional processing and mental state attribution.

Recombinant thyroid-stimulating hormone in differentiated thyroid cancer.

Recombinant TSH is effective in providing exogenous TSH stimulation for patients with differentiated thyroid cancer on thyroid hormone-suppressive therapy. It allows for detection of thyroid remnant and metastases by radioiodine scan and by serum thyroglobulin determination. The sensitivity and image quality of the WBS are similar after rTSH and after THSH withdrawal in the majority of patients. The equivalent 100% sensitivity of rTSH- and withdrawal-stimulated serum thyroglobulin measurement alone in identifying patients with radioiodine uptake outside the thyroid bed [38] may eventually lead to more extensive use of serum thyroglobulin testing after rTSH, with more selective application of radioiodine WBS [39]. Currently, a phase IV trial is in progress to evaluate the efficacy of rTSH-stimulated thyroglobulin levels as the primary modality for long-term follow-up of low risk thyroid cancer patients. The use of rTSH prevents the morbidity, metabolic impairment and the risk of tumor progression associated with THST withdrawal, because of shorter exposure time to elevated TSH [38]. Furthermore, it decreases the radiation exposure of healthy tissues due to faster iodine clearance in euthyroidism. rTSH is well tolerated, with transient nausea in 10.5% and headache in 7.3% of patients. No antibodies specific to rTSH were documented, even after multiple courses of the drug. Currently, rTSH is suggested for patients who do not respond to hormone withdrawal or cannot tolerate hypothyroidism. For patients with low risk of tumor recurrence, rTSH-stimulated testing may be used at 6-12 months after postoperative I-131 ablation and with a repeat cycle of rTSH one year later, followed by testing every 3-5 years. In high risk patients, one set of negative I-131 scan and thyroglobulin test results after hormone withdrawal are recommended before using rTSH testing, because of a greater sensitivity of the withdrawal scan and because rTSH is not currently approved for subsequent I-131 therapy often indicated in these patients [24]. Subsequently, two cycles of rTSH testing are recommended at 6-12 month intervals, followed by testing every 1-3 years for at least the first decade after initial diagnosis. The cost of this commercially available form of rTSH has been considered a major impediment to its common use; however, this should be weighed against the loss of productivity of working hours related to withdrawal [40]. In the therapeutic setting, rTSH is the only acceptable option in a subgroup of patients with hypopituitarism, ischemic heart disease, a history of "myxedema madness," debilitation due to advanced disease, or inability to elicit TSH elevation due to continued production of thyroxine by thyroid remnant or metastatic tumor [33,38]. In conclusion, recombinant TSH facilitates the management of patients with differentiated thyroid carcinoma. It increases the sensitivity of thyroglobulin testing during thyroid hormone suppression therapy and enables radioiodine uptake for whole-body scan and occasionally for radioiodine therapy, without the need for prolonged THST withdrawal and its associated hypothyroidism, reduced quality of life and risk of tumor progression.

Diagnostic dilemmas in parathyroid scintigraphy.

PURPOSE: Tc-99m MIBI scintigraphy can be useful for preoperative localization of parathyroid adenomas, despite its limited sensitivity. To refine interpretation, the authors conducted prospective reviews of the scintigraphic studies of patients with concomitant thyroid nodular disease and revised the false-negative and false-positive results. MATERIALS AND METHODS: Seventy-seven patients with primary hyperparathyroidism, associated with a solitary parathyroid adenoma, underwent dual-phase MIBI scintigraphy with subsequent injection of Tc-99m pertechnetate before surgery. The false-negative and false-positive scintigraphic findings were identified and revised. RESULTS: After surgery, revision of 19 false-negative scans of the total 77 studies led to the demonstration of an adenoma in seven patients. In five of the seven studies, the adenoma had been overlooked as a result of rapid tracer washout. Two additional small focal lesions would have also been identified if subtraction had been used for differences in contour of the MIBI and pertechnetate images. Four studies were interpreted falsely as abnormal, leading to a positive predictive value of 91%; three were associated with thyroid nodular disease. CONCLUSIONS: Differential washout of MIBI from thyroid and parathyroid tissue is not universal. When MIBI is washed out rapidly from parathyroid adenomas, subtraction of a thyroid image should be performed and differences in contour delineated to localize the adenoma accurately. Some, but not all, thyroid lesions account for the false-positive findings.

Tc-99m mercaptoacetyltriglycine clearance: comparison of camera-assisted methods.

PURPOSE: To compare the accuracy of three camera-assisted methods for the measurement of Tc-99m mercaptoacetyltriglycine (MAG3) clearance. MATERIALS AND METHODS: MAG3 renal scintigraphy was performed in 21 adults with different degrees of renal function. Posterior views were obtained that included the heart and the kidneys in the camera field of view. The syringe for injection was imaged before and after injection. Blood samples were drawn 24 and 43 minutes after injection and plasma radioactivity was measured. Three camera-assisted techniques to measure MAG3 clearance were tested: 1) Biexponential fitting of the left ventricular curve, normalized to plasma activity at 24 minutes; 2) calculation of clearance by relating the integral of the plasma curve (normalized to plasma activity) to the kidney activity using the Rutland-Patlak space method; and 3) a regression equation measuring clearance from the percentage of the injected dose accumulating in the kidneys during the 1- to 2.5-minute period. The camera-assisted clearances were compared with the single-sample MAG3 clearances calculated using the Russell equation. Linear regression analysis was used to measure the correlation between the camera-based methods and the single-sample techniques. RESULTS: Correlation with r > 0.900 was found for all three techniques. The difference in correlation coefficients between the three methods was not significant; however, the regression line of method 3 was significantly closer to the line of identity (P = 0.005). CONCLUSION: Method 3 most closely fits the line of identity and is probably the most practical because no blood sample is needed.

Cerebral activation associated with sexual arousal in response to a pornographic clip: A 15O-H2O PET study in heterosexual men.

This study attempted to use PET and 15O-H2O to measure changes in regional cerebral blood flow (rCBF) during sexual arousal evoked in 10 young heterosexual males while they watched a pornographic video clip, featuring heterosexual intercourse. This condition was compared with other mental setups evoked by noisy, nature, and talkshow audiovisual clips. Immediately after each clip, the participants answered three questions pertaining to what extent they thought about sex, felt aroused, and sensed an erection. They scored their answers using a 1 to 10 scale. SPM was used for data analysis. Sexual arousal was mainly associated with activation of bilateral, predominantly right, inferoposterior extrastriate cortices, of the right inferolateral prefrontal cortex and of the midbrain. The significance of those findings is discussed in the light of current theories concerning selective attention, "mind reading" and mirroring, reinforcement of pleasurable stimuli, and penile erection.

Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase.

As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with (18)F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.

[Sentinel lymph node biopsy in breast cancer: a validation study and preliminary results].

INTRODUCTION: Sentinel lymph node biopsy (SLNB) has been recently proven to be an accurate staging method for breast cancer, replacing axillary lymph node dissection (ALND) in selected cases. We present our initial experience and the process of introduction and implementation of SLNB in a University Hospital setting. MATERIAL AND METHODS: 46 SLNB were performed in 42 consecutive female patients with invasive breast cancer. Treatment included 0.4mCi-2mCi of Tc-99m rhenium colloid injected either 2 hours before surgery (0.4 mCi) or the night before surgery (2 mCi). Four milliliters of Patent Blue V were injected peritumoral 10 minutes prior to skin incision in all patients. Following SLNB all women underwent subsequent ALND. Sentinel nodes were processed both with multiple (10-15) H&E sections and immunohistochemistry with cytokeratin antibodies stain. RESULTS: Blue dye, isotope or the combination of both identified 43/46 (93%) of the sentinel lymph nodes. ALND was performed only unilaterally in 4 patients with bilateral breast cancer bringing the total evaluable SLNB to 39. In the 39 patients in whom the sentinel node was successfully identified and underwent ALND, the SLNB was true positive (TP) in 17/39 (44%) true negative (TN) in 20/39 (51%) and false negative in 2/39 [(5%), both T2 lesions] with overall accuracy of 95%. In the last 10 cases all sentinel nodes were successfully identified with 70% TP and 30% TN. CONCLUSIONS: Experience with at least 30-40 consecutive cases for safe implementation of SLNB in clinical practice. Specific training and dedication is required for the entire team involved, including surgeons, nuclear medicine physicians and technicians and pathologists.

FDG-PET standardized uptake values in normal anatomical structures using iterative reconstruction segmented attenuation correction and filtered back-projection.

Filtered back-projection (FBP) is the most commonly used reconstruction method for PET images, which are usually noisy. The iterative reconstruction segmented attenuation correction (IRSAC) algorithm improves image quality without reducing image resolution. The standardized uptake value (SUV) is the most clinically utilized quantitative parameter of [fluorine-18]fluoro-2-deoxy-D-glucose (FDG) accumulation. The objective of this study was to obtain a table of SUVs for several normal anatomical structures from both routinely used FBP and IRSAC reconstructed images and to compare the data obtained with both methods. Twenty whole-body PET scans performed in consecutive patients with proven or suspected non-small cell lung cancer were retrospectively analyzed. Images were processed using both IRSAC and FBP algorithms. Nonquantitative or gaussian filters were used to smooth the transmission scan when using FBP or IRSAC algorithms, respectively. A phantom study was performed to evaluate the effect of different filters on SUV. Maximum and average SUVs (SUVmax and SUVavg) were calculated in 28 normal anatomical structures and in one pathological site. The phantom study showed that the use of a nonquantitative smoothing filter in the transmission scan results in a less accurate quantification and in a 20% underestimation of the actual measurement. Most anatomical structures were identified in all patients using the IRSAC images. On average, SUVavg and SUVmax measured on IRSAC images using a gaussian filter in the transmission scan were respectively 20% and 8% higher than the SUVs calculated from conventional FBP images. Scatterplots of the data values showed an overall strong relationship between IRSAC and FBP SUVs. Individual scatterplots of each site demonstrated a weaker relationship for lower SUVs and for SUVmax than for higher SUVs and SUVavg. A set of reference values was obtained for SUVmax and SUVavg of normal anatomical structures, calculated with both IRSAC and FBP image reconstruction algorithms. The use of IRSAC and a gaussian filter for the transmission scan seems to give more accurate SUVs than are obtained from conventional FBP images using a nonquantitative filter for the transmission scan.

[Contribution of PET using FDG in the diagnosis of lung cancer--first results].

Positron emission tomography (PET), when used with F-18 fluoro-deoxyglucose (FDG), contributes to the evaluation of patients with lung cancer. This technique of imaging detects active tumor tissue by showing increased radiopharmaceutical uptake by metabolically active cells. Thus, PET assists in the early diagnosis of pulmonary malignancies that appear only as non-specific findings on CT-scan or chest X-ray. In addition, it is helpful in staging lung cancer before and after resection, chemotherapy or radiotherapy, or their combined use. We performed 135 FDG-PET studies between July '97-April '99 and present our preliminary results with examples of the main indications for PET in lung cancer.

Incidental focal thyroid uptake on FDG positron emission tomographic scans may represent a second primary tumor.

PURPOSE: This article discusses the value of incidental thyroid uptake of fluorodeoxyglucose (FDG) on whole-body positron emission tomography (PET) scans performed in patients with cancer. This issue has been reported diversely in the literature. MATERIALS AND METHODS: Whole-body PET scans of four patients with cancer (two of them women; age, 49 to 78 years) in whom focal thyroid uptake was visualized and subsequently correlated with thyroid carcinoma based on cytologic or histopathologic data were reviewed. The clinical outcomes of these patients were analyzed retrospectively. Maximum and average standardized uptake values (SUVs) of thyroid accumulation were recalculated in all patients. RESULTS: Two of the four patients referred for FDG PET scans had lung adenocarcinomas, one had prostate carcinoma, and one had an unknown primary tumor. Focal thyroid uptake was visualized, with maximum and average SUVs ranging from 3.7 and 2.3 to 53 and 34, respectively. These findings were correlated with cytologic (two patients) or histopathologic data (two patients) that indicated thyroid carcinoma. In two patients, their treatment was changed and total thyroidectomy was performed; in one of them the SUVs of the focal thyroid accumulation (maximum and average values of 7.9 and 4.8, respectively) were less than the cutoff values for thyroid cancer noted in the literature. The clinical condition of the other two patients did not permit additional investigation or treatment for thyroid carcinoma. CONCLUSION: Increased focal thyroid uptake on whole-body FDG PET scans should not be overlooked, even when it is not marked, and should prompt further investigation to rule out cancer.

The use of external radioactive markers in scintimammography.

In Tc-99m MIBI scintimammography, the exact localization of foci of increased tracer uptake or the exact anatomic correlation of palpated breast masses with a scintigraphic finding is difficult. The authors describe three patients with known or possible malignant breast lesions for whom the use of external radioactive markers successfully helped to provide this information, thus improving the diagnostic accuracy and guiding decision-making in the patients' treatment.

SPECT attenuation artifacts in normal and overweight persons: insights from a retrospective comparison of Rb-82 positron emission tomography and TI-201 SPECT myocardial perfusion imaging.

PURPOSE: Myocardial perfusion imaging can be performed using SPECT or positron emission tomography (PET). SPECT has lower specificity than PET, largely as a result of attenuation artifacts; however, it is more widely available. The authors describe a study of the effect of sex and body weight on the incidence of SPECT attenuation artifacts using a retrospective comparison of TI-201 SPECT and Rb PET. METHODS: One hundred sixty-one persons (101 men, 60 women; 81 normal weight, 80 overweight) underwent TI-201 SPECT and Rb PET. The incidence of observed perfusion defects was studied in territories of the three major coronary arteries. SPECT and PET results were also compared with those of angiography in a subset of 75 patients. RESULTS: One hundred fourteen defects were reported on Rb PET compared with 176 defects with TI-201 SPECT. Excess TI-201 SPECT defects occurred in male and female, normal-weight and overweight persons. The average specificity was 64% for TI-201 SPECT and 84% for Rb PET, reflecting this difference. CONCLUSIONS: Attenuation artifacts in TI-201 SPECT occur frequently and are not confined to easily identifiable subgroups of patients. Therefore, measures to improve specificity of SPECT (e.g., prone or gated imaging) or alternative imaging techniques such as PET have potential advantages for everyone, not simply for obese patients and women with large breasts. In addition, awareness of the prevalence of SPECT attenuation artifacts, in both sexes and all weight categories, may contribute to improved accuracy of interpretation.

The indications of FDG-PET in neck oncology.

FDG-PET imaging in neck oncology has a definite clinical impact in the post-therapy setting, assisting in the management of thyroid cancers and SCC of the neck. Quantitation of FDG uptake in suspicious areas may be helpful but should be regarded cautiously. Overall, wider incorporation of FDG imaging in clinical routine depends also on cost availability issues of FDG and of imaging devices. Dual-coincidence scanners for FDG imaging are much cheaper than dedicated PET scanners and are installed in growing numbers in many centers. These devices have inferior sensitivity; however, series published with these scanners produce encouraging results. Easier and more acceptable clinical application will also be facilitated by the systematic use of coregistration with anatomic images. Both prerequisites might be fulfilled by the emergence on the market of a gamma camera-mounted anatomic X-ray tomograph, which in addition to dual-coincidence scintigraphic imaging provides radiographic images of comparable quality to third-generation CT systems. This type of hybrid gamma camera-CT scanner has great potential in a region of complex anatomy, such as the head and neck.

Gamma camera-mounted anatomical X-ray tomography: technology, system characteristics and first images.

Scintigraphic diagnosis, based on functional image interpretation, becomes more accurate and meaningful when supported by corresponding anatomical data. In order to produce anatomical images that are inherently registered with images of emission computerised tomography acquired with a gamma camera, an X-ray transmission system was mounted on the slip-ring gantry of a GEMS Millennium VG gamma camera. The X-ray imaging system is composed of an X-ray tube and a set of detectors located on opposite sides of the gantry rotor that moves around the patient along with the nuclear detectors. A cross-sectional anatomical transmission map is acquired as the system rotates around the patient in a manner similar to a third-generation computerised tomography (CT) system. Following transmission, single-photon emission tomography (SPET) or positron emission tomography (PET) coincidence detection images are acquired and the resultant emission images are thus inherently registered to the anatomical maps. Attenuation correction of the emission images is performed with the same anatomical maps to generate transmission maps. Phantom experiments of system performance and examples of first SPET and coincidence detection patient images are presented. Despite limitations of the system when compared with a state of the art CT scanner, the transmission anatomical maps allow for precise anatomical localisation and for attenuation correction of the emission images.

Contribution of whole body F-18-FDG-PET and lymphoscintigraphy to the assessment of regional and distant metastases in cutaneous malignant melanoma. A pilot study.

AIM: This pilot study describes use of whole body PET (WB PET) for staging of melanoma. WB PET in conjunction with lymphoscintigraphy (LS) for evaluating status of the sentinel lymph node (SLN) in primary melanoma was investigated with comparison to histopathological results. WB PET was also used both for primary and metastatic melanoma for screening for distant metastases, restaging and follow-up. METHODS: Group I: 17 patients with primary cutaneous melanoma underwent LS, WB PET and SLN dissection. WB PET findings were compared with biopsy results at the SLN site and were used for screening for distant metastases. Group II: 17 patients with a history of melanoma underwent WB PET for follow-up and/or restaging. Results were confirmed or refuted by other radiological modalities or by biopsy or clinical follow-up. RESULTS: Group I: out of 20 SLNs identified by LS in the 17 patients, 18 were negative on WB PET and 2 were positive. 19/20 WB PET findings were confirmed either by histopathology or by clinical follow-up (20 mo). Accuracy was 94% for the assessment of the status of the SLN. Group II: WB PET findings altered staging and treatment in 12/17 patients and confirmed the validity of treatment in 3/17 patients. Overall, in 15/17 patients (88%), WB PET had an impact on treatment strategy. CONCLUSION: Further studies are required to demonstrate if WB PET can become a reliable non-invasive alternative to surgery in the characterization of the SLN. WB PET is important as a baseline in primary localized melanoma and decisively impacts patient management in metastatic melanoma.