An overview of the diagnostic and therapeutic use of monoclonal antibodies in medicine.

Monoclonal antibodies, which include murine, chimeric, humanized and fully human antibodies, bind to their target receptors with high affinity and specificity. In the last two decades several different monoclonal antibodies have been approved by the Food and Drug Administration for therapeutic purposes, and some of these and others have also been radiolabelled for diagnostic and therapeutic purposes. This field is in continuous evolution and this overview highlights the role of radiolabelled antibodies in research and clinical setting.

The value of Ga-67 scintigraphy and F-18 fluorodeoxyglucose positron emission tomography in staging and monitoring the response of lymphoma to treatment.

Gallium-67 scintigraphy (GS) has the ability to provide important diagnostic and prognostic information for the evaluation of patients with lymphoma. GS is superior to morphologic imaging techniques because of its affinity to viable lymphoma cells. The value of GS lies not in the initial diagnosis but primarily in assessing the results of treatment and in the follow-up of patients with lymphoma. Nevertheless, GS has not gained the expected wide acceptance, possibly because of the meticulous technique required and the expertise needed for optimal interpretation. The introduction of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) as a tumor-seeking agent, which provides images of superior quality, may have an impact on the current role of GS in the management of patients with lymphoma. FDG-PET seems to share with GS the advantages of a tumor viability agent. It appears to be more sensitive for detecting nodal and extranodal sites of disease than GS and may have predictive value during and after therapy for lymphoma. These potential clinical and economic advantages of FDG-PET need to be confirmed in systematic, large-scale prospective studies.

Oedipus or Orestes? Homosexual men, their mothers, and other women revisited.

The psychodynamic relationship between homosexual sons, their mothers, and other women in their lives is reexamined. The limitations of earlier writings on the topic are discussed, and a reconceptualized psychoanalytic model is presented for understanding some aspects of the relationships between these sons and their mothers during childhood. In particular, the oedipal stage of development is reformulated to coincide with the sexual orientation of the developing boy. This stage is then examined in the context of the discordant psychosocial environment in which it is often played out. The usefulness of this construct for understanding aspects of the psychosocial development of gay men throughout their lives, particularly their relationships with women, is explored through the examination of clinical data from a number of sources. Finally, the implications of this model for psychotherapeutic endeavors with homosexual men are considered.

Imaging Multidrug Resistance in Hematological Malignancies.

In hematological malignancies, multidrag resistance (MDR) has been associated with the drag efflux pumps: one is the classical Mr 170,000 P-glycoprotein (Pgp) and the other Mr 190,000 multidrag resistance-associated protein (MRP). In addition, the overexpression of a recently identified protein, lung resistance protein (LRP), is also associated with reduced intracellular drag accumulation and retention. Currently available detection methods may provide variable results among laboratories, as there is no single set of standards for detection techniques at the mRNA or protein level. Moreover, these methods may not be informative about the in vivo function of Pgp, MRP or LRP. Single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for the non-invasive determination of Pgp- and MRP- mediated transport systems. Tc-99m-hexaxis-2-methoxyisobutyl isonitrile (Tc-99m-Sestamibi), an agent used in myocardial perfusion and tumor imaging, is a substrate for Pgp and MRP, and has been used for tumor imaging, and to visualize Pgp expression. Tc-99m-Tetrofosmin and several Tc-99m-Q complexes, are also recognized as substrates by Pgp pump mechanism. Moreover, radiopharmaceuticals including carbon-11-labeled colchicine, verapamil and daunorabicin have been used for the assessment of Pgp-mediated transport functions in vivo using PET technology. The results suggest that the potential exists for nuclear medicine imaging using either Tc-99m-labeled compounds and SPECT or carbon-11-labeled compounds and PET to detect MDR in tumors prior to or after exposure to chemotherapeutic agents.

Fluorine-18 fluorodeoxyglucose positron emission tomography in the staging and follow-up of lymphoma: is it time to shift gears?

Positron emission tomography (PET) imaging has become a very useful technique for staging and monitoring therapy response in lymphoma, providing unique information about the biological behavior of disease. Increased fluorine-18 fluorodeoxyglucose (FDG) uptake in lymphoma is based on elevated glycolysis and longer residence time of FDG in malignant cells compared with most normal tissues. The metabolic information provided by this technique suggests that FDG-PET may be more sensitive than the anatomical imaging modalities. Computed tomography (CT) is the principal imaging modality for the staging and restaging of lymphoma. Nonetheless, this technique has significant shortcomings, particularly in the post-therapy setting. Gallium-67 scintigraphy has played an important role in monitoring response to therapy and follow-up of patients; however, the sensitivity of 67Ga depends on the subtype of lymphoma and the size and location of disease. Published results strongly indicate that FDG-PET is superior to 67Ga imaging and may be equal or superior to CT for the detection of nodal as well as extranodal involvement in lymphoma.

In vitro characterization of radiolabeled monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is a well-characterized cell surface antigen expressed by virtually all prostate cancers (PCas). PSMA has been successfully targeted in vivo with (111)In-labeled 7E11 monoclonal antibody (mAb; ProstaScint; Cytogen, Princeton, NJ), which binds to an intracellular epitope of PSMA. This work reports the in vitro characterization of three recently developed mAbs that bind the extracellular domain of PSMA (PSMAext). Murine mAbs J415, J533, J591, and 7E11 were radiolabeled with 131I and evaluated in competitive and saturation binding studies with substrates derived from LNCaP cells. J415 and J591 were conjugated to 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid labeled with (111)In. The uptake and cellular processing of these antibodies were evaluated in viable LNCaP cells. All four mAbs could be labeled with 131I up to a specific activity of 350 MBq/mg with no or little apparent loss of immunoreactivity. Competition assays revealed that J415 and J591 compete for binding to PSMAext antigen. J533 bound to a region close to the J591 binding epitope, but J533 did not interfere with J415 binding to PSMA. mAb 7E11 did not inhibit the binding of J415, J533, or J591 (or vice versa), consistent with earlier work that these latter mAbs bind PSMAext whereas 7E11 binds the intracellular domain of PSMA. Saturation binding studies demonstrated that J415 and J591 bound with a similar affinity (Kds 1.76 and 1.83 nM), whereas J533 had a lower affinity (Kd, 18 nM). In parallel studies, all four mAbs bound to a similar number of PSMA sites expressed by permeabilized cells (1,000,000-1,300,000 sites/cell). In parallel studies performed with viable LNCaP cells, J415, J533, and J591 bound to a similar number of PSMA sites (i.e., 600,000-800,000 sites/cell), whereas 7E11 bound only to a subpopulation of the available PSMA sites (95,000 sites/cell). This apparent binding of 7E11 to viable cells can be accounted for by a 5-7% subpopulation of permeabilized cells produced when the cells were trypsinized and suspended. Up to five DOTA chelates could be bound to either J415 or J591 without compromising immunoreactivity. A comparison of the cellular uptake and metabolic processing of the 131I- and (111)In-labeled antibodies showed a rapid elimination of 131I from the cell and a high retention of (111)In. All four mAbs recognized and bound to similar numbers of PSMAs expressed by ruptured LNCaP cells (i.e., the exposed intracellular and extracellular domains of PSMA). By comparison to J415 and J591, J533 had a lower binding affinity. Both J415 and J591 recognized and bound to the same high number of PSMAs expressed by intact LNCaP. By contrast, 7E11 bound to fewer sites expressed by intact LNCaP cells (i.e., the exposed extracellular domain of PSMA). Both J415 and J591 are promising mAbs for the targeting of viable PSMA-expressing tissue with diagnostic and therapeutic metallic radionuclides.

Nuclear medicine imaging of lung cancer.

Although nuclear medicine imaging is still widely under-appreciated and underused by the medical and radiologic communities, FDG PET imaging and Tc 99m depreotide SPECT imaging are safe, cost-effective methods with advantages over CT and other imaging methods in the diagnosis and management of patients suspected or known to have lung cancer. Physicians involved in the care of these patients should familiarize themselves with both of these relatively new nuclear medicine imaging procedures. Both F-18 FDG PET imaging and Tc 99m depreotide SPECT imaging have a high degree of sensitivity, specificity, overall accuracy, and both PPV and NPV in the management of patients with a solitary pulmonary nodule. Nuclear imaging with either of these agents provides a noninvasive, cost-effective method to select patients for aggressive intervention without contributing to increased morbidity. There has not been a direct comparison of these two techniques in terms of their relative role and cost-effectiveness in the management of patients with a solitary pulmonary nodule. Both methods have incremental value over CT imaging in selecting patients with solitary pulmonary nodules either for invasive biopsy or for thoracotomy. To date, only FDG PET has been proved to have additional application in: 1. Improving the staging of patients by identifying or excluding mediastinal disease. Some authors are reluctant at the present time to deny patients an opportunity for curative resection based on the finding of foci of increased metabolism in the mediastinum (characterized by increased FDG activity) because there are occasional false-positive studies. They propose, however, that a negative study justifies a surgical approach (and an opportunity for cure) regardless of the findings on CT. 2. Evaluation of therapy and early detection of recurrence by using FDG PET imaging as a monitoring procedure. Tc 99m depreotide may have a role also in these other clinical indications for imaging in patients with lung carcinoma. It is too soon, however, to know if Tc 99m depreotide SPECT imaging, properly performed, can mimic the success of FDG PET in the detection or exclusion of mediastinal metastases, evaluating the response to therapy, and the early detection of recurrent disease during post-therapeutic monitoring.

Role of nuclear medicine in the evaluation of the solitary pulmonary nodule.

Tomographic imaging with either F-18 fluoro deoxyglucose (FDG) (a nonmetabolizable glucose analog that reflects tumor increased glucose metabolism) or technetium Tc-99m Depreotide (a synthetic peptide that binds with high affinity to cell surface receptors with increased expression on certain tumor cells) provides improved sensitivity and specificity in the differential diagnosis of solitary pulmonary nodules (SPN) compared with noninvasive and some invasive procedures. F-18 FDG requires instrumentation capable of coincident imaging whereas Tc-99m Depreotide can be imaged on standard gamma cameras equipped to perform single photon emission computed tomography (SPECT) imaging. Either technique performs better than CT alone, and both are cost effective on the basis of reducing unnecessary biopsies and thoracotomies in patients with negative studies indicating that the SPN is nonmalignant.

Positron emission tomography in lymphoma: comparison with computed tomography and Gallium-67 single photon emission computed tomography.

With the advent of positron emission tomography (PET), metabolic imaging has become a reality for tumor staging and monitoring response to therapy in lymphoma. Increased Fluorine-18 fluorodeoxyglucose ([(18)F]FDG) uptake in lymphomas has been well documented in the literature; it is based upon elevated glycolysis and longer residence time of FDG in malignant cells compared to most normal tissues. This suggests that in tumor staging, FDG-PET may be more sensitive and specific than the anatomic imaging modalities. Computed tomography (CT) is the standard imaging modality for the staging and restaging of lymphoma, and Gallium-67 ((67)Ga) scintigraphy has played an important role in monitoring response to therapy and follow-up of patients. Published results suggest that FDG-PET is superior to (67)Ga imaging and may be equal or superior to CT for the detection of nodal as well as extranodal involvement in lymphoma.

Bremsstrahlung radiation exposure from pure beta-ray emitters.

UNLABELLED: With increasing therapeutic use of radionuclides that emit relatively high-energy (>1 MeV) beta-rays and the production in vivo of bremsstrahlung sufficient for external imaging, the potential external radiation hazard warrants evaluation. METHODS: The exposure from a patient administered beta-ray-emitting radionuclides has been calculated by extending the National Council on Radiation Protection and Measurement model of a point source in air to account for biologic elimination of activity, the probability of bremsstrahlung production in vivo and its mean energy and the absorption by the patient's body of the bremsstrahlung thus produced. To facilitate such calculations, a quantity called the "specific bremsstrahlung constant" (in C/kg-cm2/MBq-h), betaBr, was devised and calculated for several radionuclides. The specific bremsstrahlung constant is the bremsstrahlung exposure rate (in C/kg/h) in air at 1 cm from a 1 MBq beta-ray emitter of a specified maximum beta-ray energy and frequency of emission in a medium of a specified effective atomic number. RESULTS: For pure beta-ray emitters, the retained activities at which patients can be released from medical confinement (i.e., below which the effective dose equivalent at 1 m will not exceed the maximum recommended value of 0.5 cSv for infrequently exposed members of the general public) are extremely large: on the order of hundreds of thousands to millions of megabecquerels. CONCLUSION: Radionuclide therapy with pure beta-ray emitters, even high-energy beta-ray emitters emitted in bone, does not require medical confinement of patients for radiation protection.

Rhenium-186-labeled hydroxyethylidene diphosphonate dosimetry and dosing guidelines for the palliation of skeletal metastases from androgen-independent prostate cancer.

Rhenium-186 (tin)-labeled hydroxyethylidene diphosphonate (186Re-labeled HEDP) was evaluated in 27 men with progressive androgen-independent prostate cancer and bone metastases. Administered activities ranged from 1251 to 4336 MBq (33.8-117.2 mCi). The primary objectives were to assess tumor targeting, normal organ dosimetry, and safety. Antitumor effects were assessed by posttherapy changes in prostate-specific antigen and, when present, palliation of pain. Whole-body kinetics, blood and kidney clearance, skeletal dose, marrow dose, and urinary excretion of the isotope were assessed. Targeting of skeletal disease was observed over the period of quantification (4-168 h). Radiation doses to whole body, bladder, and kidney were well tolerated. The dose-limiting toxicity was myelosuppression (grade III) at 4107 MBq (111 mCi) and grade II at 296 MBq (80 mCi). Probe clearance (whole body) and urinary excretion measurements were highly correlated. Of the six patients treated at the highest dosage schedules (three at 1510 MBq/m2 and three at 1665 MBq/m2), three showed a posttherapy decline in prostate-specific antigen of 50% or more. The declines were not sustained. The determination of total activity retained at 24 h, as well as an estimate of marrow dose, correlated with the amount of myelosuppression observed. These results suggest that a single 24-h measurement of retained activity would allow individualized dosing and an improved therapeutic index relative to fixed dosing schema. Repetitive dosing is required to increase palliation.

Thyroid uptake of liquid versus capsule 131I tracers in hyperthyroid patients treated with liquid 131I.

The amount of 131I used to treat hyperthyroid patients is based in part on the 24-hour thyroid uptake of a diagnostic amount of radioiodine (tracer). We compared the 24-hour uptake of an 131I tracer administered in liquid or capsule form to the 24-hour uptake of 131I therapy administered as liquid. Sixty-five hyperthyroid patients with Graves' disease were evaluated and subsequently treated with radioiodine. The liquid group (45 patients) received a liquid 131I tracer (1.85 MBq [0.05 mCi]) and the capsule group (20 patients) received a capsule 131I tracer (1.63 MBq [0.044 mCi]). Probe calibration factors were the same for the liquid and capsule 131I standards. All patients received therapeutic amounts of 131I [114.7-1106.3 MBq [3.1-29.9 mCi]) in liquid form. Therapy uptakes were obtained using the same collimated uptake probe modified with a calibrated lead shield to attenuate the high photon flux. The mean therapeutic uptake was the same for both groups (58%). The mean diagnostic uptake for the capsule group, however, was less than the mean diagnostic uptake for the liquid group (44% vs. 63%). The mean diagnostic uptake for the capsule group was significantly lower than the mean therapeutic uptake for this group (44% vs. 58%), whereas the mean diagnostic and therapeutic uptakes were similar for the group receiving a liquid tracer (63% vs. 58%). In conclusion, diagnostic uptakes performed with a liquid tracer more accurately predicted liquid therapy uptakes than diagnostic uptakes performed with a capsule tracer. This raises concern about the bioavailability of 131I in capsule form and has implications for determining the amount of 131I to administer for therapy. Patients whose 131I therapy was based on the uptake of a capsule tracer received a higher than intended amount of radiation to the thyroid gland.

SPECT and lumbar MRI in back pain with emphasis on changes in end plates in association with disc degeneration.

Over a two-year period, 48 sequential patients were selected because they showed type I or II end plate changes on magnetic resonance imaging (MRI) and/or had positive single-photon emission computerized tomography (SPECT) scan in the area of disc degeneration. They were selected out of a large group of patients who were being evaluated by MRI and SPECT scan for low back pain. In this group of 48 patients, 47 had positive SPECT scans at the disc space, which on MRI indicates degenerative disc disease. Of these, 38 had end plate changes on the MRI, but 10 did not have end plate changes on the MRI even though their SPECT was positive. None of the 48 patients had evidence of other pathology such as fracture, metastatic disease or spondylolysis. The MRI changes were both of type I and type II and thought to represent increased vascularization of the fibrous tissue or fatty replacement of marrow in the area of the end plate. Based on this study, we are proposing that a positive end plate SPECT in degenerative disc disease is related to marrow changes in the region of the end plate of the disc. Also, we are proposing that SPECT may be of value in delineating early end plate changes prior to the MRI showing type I or type II change in the same area.

Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart.

OBJECTIVES: Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function. METHODS: Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10(8) pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed. RESULTS: SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 animals. CONCLUSIONS: An Ad vector expressing the VEGF121 cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible.

Receptor imaging: competitive or complementary to antibody imaging?

Both radiolabeled ligands to specific receptors on cell surfaces and radiolabeled antibodies to specific cell surface epitopes provide new opportunities to scintigraphically identify tumors. Both radiolabeled ligands and antibodies are characterized by high orders of affinity for their respective binding sites and offer greater specificity over the agents previously used for tumor imaging including gallium 67, thallium 201, technetium 99m MIBI, and flourine-18-labeled deoxyglucose. The two classes of tumor-binding tracers differ primarily based on molecular weight although the nonspecific portion of the immunoglobulins are also antigenic. Increased molecular weight results in prolonged plasma survival, which increases the interval available for tumor permeation but also produces increased nonspecific background activity, which impairs image contrast. At the present time, encouraging clinical results have been obtained with both agent types, but further development is necessary. Receptor-ligand tracers provide better contrast than antibodies or antibody fragments. Receptor-ligand imaging technology awaits further developments in an understanding of the biology of receptor expression in normal tissue and tumors and improved radio-chemical techniques and pharmacology to define the radioligands of choice. Radiolabeled antibodies will probably evolve in the direction of increased use of antibody fragments and possibly the identification and polymerization of epitope-recognition units in order to provide high-affinity, nonantigenic, small molecular weight tracers that will be more permeable in tumors and clear more rapidly from background tissue. Rather than compete or complement each other, the techniques will likely produce a hybrid technology, radiolabeled molecular recognition units, with the better features of both technologies including high binding affinity (low dissociation constant) for surface membrane epitopes, including receptor sites.

Psychiatric symptoms in clients presenting for commercial weight reduction treatment.

OBJECTIVE: To study the prevalence and severity of psychiatric symptoms in a group of clients presenting to a commercial weight reduction program, compared with a group of patients seeking outpatient medical treatment. METHOD: Sixty-six clients presenting for commercial weight loss treatment and 52 patients presenting for general outpatient medical treatment were given self-report measures of anxiety (Spielberger State and Trait Inventory), depression (Beck Depression Inventory), body dissatisfaction (Body Shape Questionnaire), and overall impairment in functioning (Sheehan Disability Scale). RESULTS: Weight loss clients had significantly higher rates of depressive symptomatology and psychosocial disability than patients presenting for medical treatment. Weight loss clients were also more likely to demonstrate body dissatisfaction regardless of actual weight. Levels of anxiety were not significantly different, despite the medical group reporting themselves to be in poorer health as compared with the weight loss group. DISCUSSION: Regular screening for psychiatric symptoms in clients presenting for commercial weight reduction treatment may be valuable as this group may constitute an as yet unidentified cohort requiring psychiatric intervention.

Visualization of myocardial metastasis of carcinoid tumor by indium-111-pentetreotide.

We present a case of metastatic carcinoid tumor metastatic to the heart, presenting as ventricular arrhythmia and diagnosed by 111Inpentetreotide scintiscan despite negative endocardial biopsy. The incidence and diagnosis of carcinoid heart disease is discussed, as well as the complementary role of high-resolution anatomical images (CT, MRI) with functional images (SPECT, PET) to determine the correct diagnosis of this rare condition.

Evaluation of four radiopharmaceuticals for imaging inflammation in a rabbit model of arthritis.

We compared the utility of four radiopharmaceuticals; 111In-chloride, 67Ga-citrate, 111In labeled leukocytes (WBCs) and 99mTc-MDP for assessing the inflammatory response in antigen induced arthritis in a rabbit model. A total of 20 rabbits, divided into four equal groups, were included in this study. Each group was studied twice with a single radiotracer; a baseline study and a follow-up study after induction of the arthritis. Knee to knee, knee to whole body, and knee to liver (except for the group studied with 99mTc-MDP) ratios were generated. Knee to knee ratios showed no significant change from baseline to arthritis studies in any of the four groups. Significantly increased knee to total body ratios were seen in all of the groups, except for the group studied with 99mTc-MDP. The greatest increase was seen in the group studied with 111In-chloride. Significantly increased knee to liver ratios were observed in all three groups for which these ratios were generated and again the greatest increase was observed in the group studied with 111In-chloride. In summary, based on the higher uptake observed in this group, of the four radiotracers evaluated, 111In-chloride is probably the most useful for monitoring the inflammatory response in antigen induced arthritis. The symmetry of the response suggests that it may also be useful in monitoring the response to therapy.

Detection of bony metastases of androgen-independent prostate cancer by PET-FDG.

Fourteen F-18 fluorodeoxyglucose (FDG) studies were carried out in 13 patients known to have bony metastases from carcinoma of the prostate. One patient was newly diagnosed. The remaining patients had various types of therapy and were considered hormonally resistant. The average age was 67. All patients had extensive bony metastases shown on the conventional Tc99m-MDP bone scans. Only about 18% of bony lesions apparent on the conventional bone scans showed corresponding increase of FDG uptake. Anatomical correlation was performed by using co-registered images of SPECT and PET in the same area. The positive FDG uptake was not related to the duration of illness, level of PSA, previous therapy, and magnitude of disease involvement. It appears that only a small percentage of bony metastases is associated with increased glycolysis. It is possible that other metabolic processes are more important than glycolysis for providing prostate cancer with a source of energy and nutrients.