Planar visual fusion scintigraphy.

Planar scintigraphy, while providing useful information about the distribution of a particular radiopharmaceutical being imaged, often does not provide adequate information about the surrounding anatomical structures, thereby complicating diagnosis. We have therefore explored a means of fusing planar scintigraphic images with visual photographic images to supply an anatomic correlate to regions of radiopharmaceutical accumulation. The digital visual image will provide a context for the relevant structures in the scintigraphic image. Phantom data confirm registration accuracy to within 1 pixel. Inaccuracy of camera-patient distance results in <1% image size change per cm height error. Initial clinical imaging has subjectively been very useful in low background applications such as lymphoscintigraphy, whole body I-131 NaI imaging for thyroid cancer and In-111 white blood cell infection imaging.

A historical survey of scintigraphic methodology for evaluation of the reproductive tract.

Scintigraphic techniques have contributed to many aspects of our understanding of genital and reproductive physiology and pathophysiology. Few of these methods have become mainstream diagnostic techniques; nonetheless, their flexible, physiologic, and intrinsically quantitative nature have contributed information and insights not readily available by other means. The techniques discussed in this review measure various dynamic processes within the body, including blood flow, variation of blood volume, and lymphatic and fallopian tube transport. Dynamic measurement of these processes exploits nuclear medicine's ability to radiolabel and monitor substances while preserving normal physiologic behavior. Consideration of these methods will potentially stimulate future development and application of radionuclide techniques to emerging questions in the fields of reproductive and genital physiology.

Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS).

The sodium-iodide symporter (NIS), which transports iodine into the cell, is expressed in thyroid tissue and was recently found to be expressed in approximately 80% of human breast cancers but not in healthy breast tissue. These findings raised the possibility that therapeutics targeting uptake by NIS may be used for breast cancer treatment. To increase the efficacy of such therapy it would be ideal to identify a radioactive therapy with enhanced local emission. The feasibility of using the powerful beta-emitting radiometal (188)Re in the form of (188)Re-perrhenate was therefore compared with 131I for treatment of NIS-expressing mammary tumors. In the current studies, using a xenografted breast cancer model induced by the ErbB2 oncogene in nude mice, (188)Re-perrhenate exhibited NIS-dependent uptake into the mammary tumor. Dosimetry calculations in the mammary tumor demonstrate that (188)Re-perrhenate is able to deliver a dose 4.5 times higher than (131)I suggesting it may provide enhanced therapeutic efficacy.

Enhanced lung scan diagnosis of pulmonary embolism with the use of ancillary scintigraphic findings and clinical correlation.

Analysis of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) and modified PIOPED studies has suggested that an experienced observer is capable of more accurate lung scan interpretation than the less experienced individual. This has been attributed to the use of unique Gestalt factors not contained in published diagnostic algorithms, which are acquired through extensive experience in reviewing and interpreting lung scans. How fully these factors can be codified and transmitted to less experienced observers is uncertain; however, there is a large body of published data that attempts to convey fine points of lung scan interpretation, including a large body of ancillary scintigraphic findings and a number of refinements in the application of diagnostic algorithms. Review of these factors will accelerate the training of less experienced readers. Finally, an understanding of lung scan language and an appreciation of clinically relevant factors, particularly pretest probability, will maximize the reader's ability to use the lung scan in managing patients who are suspected of having pulmonary embolic disease.

The mammary gland iodide transporter is expressed during lactation and in breast cancer.

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

Influence of affinity and antigen density on antibody localization in a modifiable tumor targeting model.

A persistent question in the field of antibody imaging and therapy is whether increased affinity is advantageous for the targeting of tumors. We have addressed this issue by using a manipulatable model system to investigate the impact of affinity and antigen density on antibody localization. In vitro enzyme-linked immunosorbent assays and bead-binding assays were carried out using BSA conjugated with high and low densities (HD and LD, respectively) of the chemical hapten rho-azophenyl-arsonate as an antigen. Isotype-matched monoclonal antibodies (mAbs) 36-65 and 36-71, with identical epitope specificity but 200-fold differences in affinity, were chosen as targeting agents. The relative in vitro binding of 36-65 and 36-71 was compared with an artificial "tumor" model in vivo using antigen-substituted beads s.c. implanted into SCID mice. Nonsubstituted BSA beads were implanted in the contralateral groin as a nonspecific control. The efficacy of the targeting of [125I]-labeled antibodies was assessed by the imaging of animals on a gamma-scintillation camera using quantitative region-of-interest image analysis over the course of 2 weeks and by postmortem tissue counting. In vitro, both antibodies bound well to the HD antigen, whereas only the high-affinity mAb 36-71 bound effectively to the LD antigen. In vivo, high-affinity mAb 36-71 bound appreciably to both LD and HD beads. In contrast, there was no specific localization of low-affinity mAb 36-65 to LD antigen beads, although the antibody did bind to the beads with the HD antigen. Whereas the high-affinity mAb 36-71 increased its binding to HD beads throughout the 14 days of observation, binding of the high affinity antibody to LD beads and of the low affinity antibody to HD beads plateaued between 10-14 days. These in vitro and in vivo findings demonstrate that the need for a high-affinity antibody is dependent on the density of the target antigen. High-affinity antibodies bind effectively even with a single antigen-Fab interaction, irrespective of the antigen density. In contrast, low-affinity antibodies, because of weak individual antigen-Fab interactions, require the avidity conferred by divalent binding for effective attachment, which can only occur if antigen density is above a certain threshold. An understanding of the differential behavior of high- and low-affinity antibodies and the impact of avidity is useful in predicting the binding of monovalent antibody fragments and engineered antibody constructs and underlies the trend toward development of multivalent immunological moieties. Consideration of the relative density of the antigen on the tumor and the background tissues may enable and even favor targeting with low-affinity antibodies in selected situations.

Scintigraphy in the evaluation of disorders of reproductive and sexual function.

The genital tract is a complex anatomic region with overlapping endocrinologic, anatomic, and functional features. Nuclear medicine has value in examining functional aspects of reproductive and sexual function, ranging from testicular or cavernosal perfusion in the male, to fallopian tube transport in the female. Blood pool imaging has been helpful in detecting subclinical varicoceles. Proper understanding of the role that these tests play is important for their success and credibility.

Remotely pollable Geiger-Müller detector for continuous monitoring of iodine-131 therapy patients.

UNLABELLED: In many countries, patients treated with therapeutic amounts of (131)I are hospitalized because of radiation safety considerations. To determine when they can return home, radiation levels are intermittently monitored at bedside using a handheld Geiger-MIller (GM) counter, although this procedure can be cumbersome and inexact. METHODS: We have developed and tested a remotely pollable system for continuous radiation monitoring of (131)I therapy inpatients, using readily available hardware and standard telephone lines. The remote detector system, consisting of a palmtop IBM-compatible personal computer, specialized software, PCMCIA modem and miniature serial port-based GM detector, is placed opposite the patient's bed at a fixed distance, and continuous 1-min acquisitions are started. Initially and at least twice daily, the remote palmtop is contacted by modem, and all interval data are uploaded onto the operator's base computer over the telephone line, including measurements taken with the patient in a predetermined standardized position. Continuous minute-to-minute data may be viewed in native form or can be imported into graphing and spreadsheet programs. Points acquired with the patient in standardized position are specially marked to highlight the constant geometry used. The ratio of initial counting rate to administered dose is used to estimate residual (131)I body burden by proportionality. Display of data as a semilogarithmic plot facilitates extrapolation of the activity curves and prediction of the patient's earliest time of discharge. RESULTS: We have characterized the remote GM detector system to confirm accuracy, counting rate linearity and reliability of data transfer. We describe examples that illustrate the applicability and usefulness of this method for remote monitoring of inpatient (131)I therapy levels. CONCLUSION: Monitoring patients with the described remotely pollable GM detector is an accurate and easy-to-implement technique that could conceivably lead to shortened hospital stays for (131)I therapy inpatients. Continuous quantitative data obtained are useful for kinetic and dosimetric analyses, which may be applied to study other gamma-emitting radiopharmaceuticals as well. The flexibility of the technique may permit its use in the monitoring of therapy on an outpatient basis, where allowed.

Chimeric human-mouse IgG antibodies with shuffled constant region exons demonstrate that multiple domains contribute to in vivo half-life.

Structural features that determine the differing rates of immunoglobulin catabolism are of great relevance to the engineering of immunologically active reagents. Sequences in the CH2 and CH3 region of IgG have been shown to regulate the rate of clearance through their interaction with FcRn. In an attempt to probe additional structural features that regulate antibody half-life, we have investigated two families of chimeric antibodies, composed of identical murine heavy and light antidansyl variable regions joined to human kappa light-chains and wild-type or shuffled human IgG heavy-chain constant regions. These antibodies were iodinated, and their clearance was studied in severe combined immunodeficient mice hosts by whole-body radioactivity measurements. Clearances of the wild-type and recombinant antibodies were biphasic. In a panel of immunoglobulins derived from IgG2 and IgG3, as successive domains were varied from gamma2 to gamma3, beta-phase half-life gradually decreased from 337.0 h to 70.6 h. Statistical analysis suggested that the composition of each of the three domains affected half-life, and no single region of the molecule by itself determined the rate of clearance. In the second panel of immunoglobulins derived from IgG1 and IgG4, the construct with the amino terminus portion of the molecule derived from IgG4, joined within the CH2 domain to the COOH terminus portion of IgG1, had a half-life paradoxically greater than either IgG1, or IgG4 (P < 0.012). All four IgG1/IgG4 constructs demonstrated presence of the concentration catabolism phenomenon, which is a unique hallmark of immunoglobulin catabolism. The contribution of all three constant region domains to immunoglobulin half-life may be due to distant conformational effects in addition to direct binding to protective receptors, and emphasizes the importance of distant sequences on the rate of immunoglobulin catabolism. Interesting possibilities regarding mechanisms controlling immunoglobulin metabolism are raised by the hybrid gamma4/gamma1 molecule with a half-life greater than either parental immunoglobulin. Understanding the relationships between the structure of these molecules and their clearance rate will further our ability to produce immunoglobulins with improved pharmacokinetic properties.

Evaluation in a mouse model of a thyroid-blocking protocol for 131I antibody therapy (short communication).

PURPOSE: We describe a murine model to evaluate variations of a published multicenter thyroid blocking protocol described for 131I antibody therapy, using doses of blocking agents proportional to those used in man. Variables include duration of super-saturated potassium iodide (SSKI) pretreatment and use of supplemental KClO4. MATERIALS AND METHODS: Whole-body activity measurements were performed 0, 24, 48 and 72 hours following 131I-NaI administration in control and thyroid-blocked mice. Retained whole-body activity was calculated as a percentage of the injected dose (%ID), primarily reflecting radioiodine sequestered in the thyroid gland. In blocked groups, SSKI was begun one or 7 days preceding 131I-NaI therapy, and was supplemented in one half of the cases with KClO4 from time of therapy. RESULTS: In control mice, %ID was 11.23 +/- 1.47%, 10.15 +/- 1.11% and 9.29 +/- 1.50% at 24, 48 and 72 hrs respectively. %IDs of blocked groups were markedly lower than controls (p = .0001). In the one day SSKI pretreatment group, %ID was reduced from 1.73 +/- 0.58, 1.42 +/- 0.45 and 1.20 +/- 0.38 at 24, 48 and 72 hours to 0.49 +/- 0.08, 0.50 +/- 0.07 and 0.44 +/- 0.06 with addition of supplemental KClO4. In the 7 day SSKI pretreatment group, %ID was reduced from 1.87 +/- 0.73, 1.48 +/- 0.49 and 1.36 +/- 0.57 at 24, 48 and 72 hours to 0.60 +/- 0.36, 0.45 +/- 0.13 and 0.41 +/- 0.14 with addition of supplemental KClO4. %IDs in the 7 day pretreatment animals were not statistically different from those in the one day pretreatment groups (all p >> 0.05). CONCLUSION: SSKI reduces retention of radioiodide approximately six-fold whereas supplemental KClO4 enhances thyroid blocking an additional three-fold. Seven day SSKI pretreatment appears no more effective than one day pretreatment.

Pharmacokinetics and biodistribution of a monoclonal antibody to Cryptococcus neoformans capsular polysaccharide antigen in a rat model of cryptococcal meningitis: implications for passive immunotherapy.

Several investigators have developed monoclonal antibodies against the capsular polysaccharide of Cryptococcus neoformans which have potential therapeutic applications. Using a rat model of C. neoformans meningitis, we studied the biodistribution and pharmacokinetics of a murine anticryptococcal capsular monoclonal antibody (mAb 2H1) after intravenous and intracisternal administration. After intravenous administration of 125I-labelled 2H1 to infected rats, there was no detectable localization of 125I in the brain or cerebrospinal fluid by either gamma-camera imaging of the whole animal or organ scintillation counting. In contrast, direct intracisternal instillation of 2H1 to infected rats resulted in persistent intracranial activity. In addition, the whole body half-life of intravenously administered radio labelled mAb 2H1 was significantly reduced in infected rats compared with uninfected rats. Our observations suggest that if high central nervous system (CNS) levels of mAb are needed to achieve a therapeutic effect in human C. neoformans meningoencephalitis, direct administration of mAb into the cerebrospinal fluid or modification of the mAb to increase penetration into the CNS may be required. Furthermore, higher or more frequent dosing of mAb may be required to maintain therapeutic levels in the presence of infection. This study demonstrates the usefulness of the rat as an experimental system for studying issues related to cryptococcosis.

Analysis of hepatocyte distribution and survival in vascular beds with cells marked by 99mTC or endogenous dipeptidyl peptidase IV activity.

Knowledge of the kinetics of cell distribution in vascular beds will help optimize engraftment of transplanted hepatocytes. To noninvasively localize transplanted cells in vivo, we developed conditions for labeling rat hepatocytes with 99mTc-pertechnetate. The incorporated o9mTc was bound to intracellular proteins and did not impair cell viability. When 99mTc hepatocytes were intrasplenically injected into normal rats, cells entered liver sinusoids with time-activity curves demonstrating instantaneous cell translocations. 99mTc activity in removed organs was in liver or spleen, and lungs showed little activity. However, when cells were intrasplenically transplanted into rats with portasystemic collaterals, 99mTc appeared in both liver sinusoids and pulmonary alveolar capillaries. To further localize cells, we transplanted DPPIV+ F344 rat hepatocytes into syngeneic DPPIV-recipients. Histochemical staining for DPPIV activity demonstrated engraftment of intrasplenically transplanted cells in liver parenchyma. In contrast, when 99mTc hepatocytes were injected into a peripheral vein, cells were entrapped in pulmonary capillaries but were subsequently broken down with redistribution of 99mTc activity elsewhere. Intact DPPIV+ hepatocytes were identified in lungs, whereas only cell fragments were present in liver, spleen, or kidneys. These findings indicate that although the pulmonary vascular bed offers advantages of easy accessibility and a relatively large capacity, significant early cell destruction is an important limitation.

Use of radioactive tracers in the evaluation of penile hemodynamics: history, methodology and measurements.

Radionuclide tracer techniques are intimately associated with some of the early ground-breaking investigations in erectile dysfunction and have evolved along with the field. At the present time, the various investigations can be grouped into four categories: labeled blood-pool; tracer washout; tracer washin and combined blood-pool/tracer and tracer washout examinations. Blood pool studies are most useful in assessing the integrity of arterial inflow, but may also be used to generate indices of venous leak. A non-imaging version of the blood-pool test may represent a simple and cost-effective alternative. Washout of intracavernosal xenon during erection seems the most rigorous method of testing venous integrity. Washout using 99mTc-labeled substances may emerge as a convenient alternative to the more technically difficult xenon examinations. Dual-isotope blood pool and washout examinations, though complicated, represent an ideal method of analyzing penile hemodynamics, with potential to contribute significantly to the understanding of penile physiology. Development of improved pharmacologic stimuli and augmentation of testing protocols by intracavernosal pressure monitoring may further improve the utility of quantitative and physiologic nuclear medicine examinations in erectile dysfunction.

Trials and tribulations: oncological antibody imaging comes to the fore.

At the present time, there are three radiolabeled antibodies that have been approved by the US Food and Drug Administration (FDA) for imaging of cancer, a fourth commercially sponsored product recommended for approval (as of 10/29/96, cap romab pendetide (ProstaScint; Cytogen Corp., Princeton, NJ) was upgraded from recommended for approval to approved), and several additional agents in FDA-monitored trials. The majority of antibodies studied to date have been whole or fragmented murine monoclonals whereas the first of the human and humanized immunoglobulins are now entering clinical trials. While no antibody has behaved as a perfect imaging agent, they have consistently been shown to contribute to diagnosis, complementing and often exceeding the diagnostic ability of conventional modalities. Many promising new trends in antibody imaging, relating to the radiolabeled immunoglobulin, its route and manner of administration, and mode of detection, are under development. Because of the requisite several-year delay inherent in the (FDA) testing process, there is a lag before the most-promising of these innovations will achieve (FDA) approval and be incorporated into routine imaging studies. In spite of this effective performance, as "new kid on the block," radioimmunoscintigraphy may have often been expected to perform in an unrealistic manner, considering the great variation in biological behavior of primary and metastatic cancer and the consequent limitation of all diagnostic tests. Nonetheless, because radioimmunoscintigraphy identifies antigens on a cellular level, differing fundamentally from anatomic imaging modalities such as computed tomography and ultrasound which identify gross morphological changes, it has potential to impact significantly on patient care. With adequate resources focused on radioimmunoscintigraphy, this technology will continue to emerge as an important and unique diagnostic tool in the care of cancer patients, with demonstrable clinical efficacy and cost effectiveness.

Effect of prior radiopharmaceutical administration on Schilling test performance: analysis and recommendations.

UNLABELLED: Previously administered diagnostic and therapeutic radiopharmaceuticals may interfere with performance of the Schilling test for prolonged periods of time. Additionally, presence of confounding radionuclides in the urine may not be suspected if baseline urine measurements have not been performed before the examination. METHODS: We assumed that a spurious contribution of counts corresponding to 1% of the administered Schilling dose would begin to contribute clinically significant interference. Based on the typical amounts of radiopharmaceuticals administered, spectra of commonly used radionuclides and best available pharmacokinetic models of biodistribution and excretion, we estimated the interval required for 24-hr urinary excretion of diagnostic and therapeutic radiopharmaceuticals to drop below this threshold of significant interference. RESULTS: For previously administered 99mTc-based radiopharmaceuticals and 123I-Nal, the interval required for urinary levels of activity to fall below thresholds of allowable interference are between 2-5 days. For 67Ga-citrate, several 111In compounds, 131I-MIBG and 201Tl-thallous chloride, periods of 12-44 days are estimated. Estimates for 131I-Nal vary greatly between 4 and 115 days, depending on the amount administered, and the degree of thyroid uptake. CONCLUSION: Patients should be interviewed before performing the Schilling test to ensure that interfering radiopharmaceuticals have not been recently administered. The estimates developed in this paper can serve as guidelines for the necessary waiting time between prior radiopharmaceutical administration and the Schilling examination.

Appearance of a hepatic hemangioma on prostate immunoscintigraphy. Value of early images.

In this case, the authors describe the appearance of hemangioma, the most common benign tumor of the liver, on early and delayed in-111 CP antibody images. The early immunoscintigraphic images show intense blood pool activity comparable in appearance to labeled RBC imaging, the current procedure of choice for confirming the diagnosis of hemangioma. In combination with disappearance of blood pool activity on the late scintigraphic images, these findings are pathognomonic for hemangioma and sufficiently distinct from the appearance of hepatic metastases on in-111 labeled antibody images to obviate the need for further confirmatory diagnostic studies.