Radioimmunoscintigraphy of colorectal carcinoma using technetium-99m-labeled, totally human monoclonal antibody 88BV59H21-2.

Radioimmunoscintigraphy (RIS) using human monoclonal antibodies offers the important clinical advantage of repeated imaging over murine monoclonal antibodies by eliminating the cross-species antibody response. This article reports a Phase I-II clinical trial with Tc-99m-labeled, totally human monoclonal antibody 88BV59H21-2 in patients with colorectal carcinoma. The study population consisted of 34 patients with colorectal cancer (20 men and 14 women; age range, 44-81 years). Patients were administered 5-10 mg antibody labeled with 21-41 mCi Tc-99m by the i.v. route and imaged at 3-10 and 16-24 h after infusion using planar and single-photon emission computed tomographic (CT) techniques. Pathological confirmation was obtained in 25 patients who underwent surgery. Human antihuman antibody (HAHA) titers were checked prior to and 1 and 3 months after the infusion. RIS with Tc-99m-labeled 88BV59H21-2 revealed a better detection rate in the abdomen-pelvis region compared with axial CT. The combined use of both modalities increased the sensitivity in both the liver and abdomen-pelvis regions. Ten patients developed mild adverse reactions (chills and fever). No HAHA response was detected in this series. Tc-99m-labeled human monoclonal antibody 88BV59H21-2 RIS shows promise as a useful diagnostic modality in patients with colorectal cancer. RIS alone or in combination with CT is more sensitive than CT in detecting tumor within the abdomen and pelvis. Repeated RIS studies may be possible, due to the lack of a HAHA response.

Radioimmunoscintigraphy of recurrent, metastatic, or occult colorectal cancer with technetium 99m-labeled totally human monoclonal antibody 88BV59: results of pivotal, phase III multicenter studies.

PURPOSE: To assess the performance and potential clinical impact of a totally human monoclonal antibody, 88BV59 (HumaSPECT) (INTRACEL, Corp, Rockville, MD), in 202 assessable presurgical patients with recurrent, metastatic, or occult colorectal cancer. METHODS: 88BV59, labeled with technetium Tc 99m (99mTc) (HumaSPECT-Tc), was injected intravenously, and planar and single photon emission tomography (SPECT) images were obtained 14 to 20 hours postinjection. Surgical and pathologic verification of tumor were used as the standard against which the performance of HumaSPECT-Tc imaging and computed tomography (CT) analysis were evaluated. RESULTS: All patients entered onto the recurrent disease study had at least one tumor site defined on CT. The sensitivity of HumaSPECT-Tc in those CT-positive patients was 87%. The specificity of HumaSPECT-Tc was 57% compared with 17% for CT and the difference was statistically significant (P < .001). The diagnostic information provided by HumaSPECT-Tc significantly (P < .001) improved the accuracy of the identification of resectable and nonresectable disease over that of CT (80% v 62%). HumaSPECT-Tc scans resulted in a significant (P < .001) reduction versus CT in terms of the proportion of patients understaged (27% v 41%) and overstaged (4% v 26%). In patients with occult disease (increasing carcinoembryonic antigen [CEA] titer, negative diagnostic work-up, negative CT), HumaSPECT-Tc correctly identified disease in 15 of 22 (68%) patients. HumaSPECT-Tc images provided additional clinical data that would have affected patient management decisions in 40 of 202 (19.8%) patients. In 365 patients who received 88BV59, only a single detectable human anti-human antibody (HAHA) response (90 ng/mL) at 9 weeks postinfusion was observed. CONCLUSION: HumaSPECT-Tc can provide important and accurate information about the presence and location of disease in patients with a high clinical suspicion of metastatic or recurrent colorectal cancer and either positive (known disease) or negative (occult disease) CT scans.

Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial.

PURPOSE: To evaluate the effectiveness and safety of samarium-153 (153Sm) lexidronam (EDTMP) in a double-blind, placebo-controlled study. PATIENTS AND METHODS: Patients with painful bone metastases secondary to a variety of primary malignancies were randomized to receive 153Sm-EDTMP 0.5 or 1.0 mCi/kg, or placebo. Treatment was unblinded for patients who did not respond by week 4, with those who had received placebo eligible to receive 1.0 mCi/kg of active drug in an open-label manner. Patient and physician evaluations were used to assess pain relief, as was concurrent change in opioid analgesia. RESULTS: One hundred eighteen patients were enrolled onto the study. Patients who received 1.0 mCi/kg of active drug had significant reductions in pain during each of the first 4 weeks in both patient-rated and physician-rated evaluations. Pain relief was observed in 62% to 72% of those who received the 1.O-mCi/kg dose during the first 4 weeks, with marked or complete relief noted in 31% by week 4. Persistence of pain relief was seen through week 16 in 43% of patients who received 1.0 mCi/kg, of active drug. A significant correlation (P = .01) was observed between reductions in opioid analgesic use and pain scores only for those patients who received 1.0 mCi/kg 153Sm-EDTMP. Bone marrow suppression was mild, reversible, and not associated with grade 4 toxicity. CONCLUSION: A single dose of 1.0 mCi/kg of 153Sm-EDTMP provided relief from pain associated with bone metastases. Pain relief was observed within 1 week of administration and persisted until at least week 16 in the majority of patients who responded.

Diagnostic studies in patients with sickle cell anemia and acute abdominal pain.

Twenty-eight patients with sickle cell disease who presented with acute abdominal pain were evaluated with clinical laboratory, ultrasound, and biliary scintigraphic studies to determine their predictive capabilities for differentiating veno-occlusive disease (sickle cell crisis) from acute biliary disease. Eleven patients were treated surgically and 17 medically. Gallstones were demonstrated in 25 (90%) of the patients studied by ultrasound, and biliary scans were abnormal in nine patients (32%). Abnormal laboratory and radiological studies (ultrasound, biliary scintigraphy) were not significantly different in the two groups and had a low positive predictive value for detection of acute biliary disease. Nevertheless, normal biliary scintigraphy had high negative predictive value in that, if normal, it gave assurance that the cystic duct was patent and unnecessary surgery could be obviated in this high-risk category of patients.

Current status of systemic intravenous radiopharmaceuticals for the treatment of painful metastatic bone disease.

PURPOSE: Intractable bone pain secondary to bone metastasis from prostate, lung, breast, and other malignancies is a major problem in the management of the oncological patient. Because a number of factors are implicated in the pathophysiology of bone pain, a multidisciplinary approach in its assessment and treatment is often required. Treatment often includes the use of analgesic drug therapy; however, radiation therapy, hormonal therapy, chemotherapy, and surgery may also be needed. METHODS AND MATERIALS: The use of systemic radionuclide therapy may often be helpful to relieve bone pain and improve the quality of life. In the setting of diffuse bone metastasis, intractable to conventional therapy, various radioisotopes have been advocated. These include phosphorous-32, iodine-131, strontium-89, yttrium-90, samarium-153, and rhenium-186, often as either the anionic phosphate or as a ligand (HEDP, EDTMP). RESULTS: When these agents are used, pain relief often occurs in approximately 2-4 weeks and lasts several weeks to months with responses seen in 60-80% of patients, depending on the extent of disease and stage the patient is treated. Retreatment has been possible in certain cases with further palliation being offered and improvement in the various quality of life parameters being noted. CONCLUSION: Myelotoxicity has been a limiting factor with certain isotopes and has led to the development of less toxic bone seeking agents. Although these each have unique physical and biokinetic properties requiring different doses and protocols for administration, they all appear to localize in osteoblastic metastatic sites in sufficient amounts to provide bone pain palliation.

From monoclonal antibodies to peptides and molecular recognition units: an overview.

Various antigen-specific monoclonal antibodies (Mabs) are now being used clinically. Applications include in vitro testing (radioimmunoassay) and in vivo imaging (radioimmunoscintigraphy) for the early detection and staging of disease. Mabs can also be used as vehicles for delivering therapy (radioimmunotherapy) or to assess effects of therapeutic interventions. This review delineates those components making up antibody structure and discusses their functional significance. The method for radiolabeling immunoconjugates without altering their immunoreactivity or biological properties is dependent on an understanding of the structural units of the antibody and the labeling technique used. With the advent of genetic engineering, it has become feasible to design antibodies to circumvent certain adverse features or enhance a certain property. A review of the various "designer" antibodies and their relative advantages in the clinical setting is presented.

Therapy of metastatic bone pain.

Bone metastasis is a common sequella of solid malignant tumors such as prostate, breast, lung, and renal cancers, which can lead to various complications, including fractures, hypercalcemia, and bone pain, as well as reduced performance status and quality of life. A multidisciplinary approach is usually required not only to address the etiology of the pain and its complicating factors but also to treat the patient appropriately. Currently, the treatment of bone pain remains palliative at best with systemic therapy (analgesics, hormones, chemotherapy, steroids, and bisphosphonates) as well as local treatments (such as surgery, nerve blocks, and external beam radiation). However, many of these treatments are limited in their efficacy or duration and have significant side effects that seriously limit the cancer patient's quality of life. Various radiopharmaceuticals have shown good efficacy in relieving bone pain secondary to bone metastasis. This systemic form of metabolic radiotherapy is simple to administer and complements other treatment options. This has been associated with improved mobility in many patients, reduced dependence on narcotic and non-narcotic analgesics, improved performance status and quality of life, and, in some studies, improved survival. Additional radiopharmaceuticals are under investigation and appear promising. All of these agents, although comprising different physical and chemical characteristics, offer certain advantages in that they are simple to administer, are well tolerated by the patient if used appropriately, and can be used alone or in combination with the other forms of treatment.

The diagnostic role of nuclear medicine in the acquired immunodeficiency syndrome.

This paper is a review of (a) the pathophysiology of the autoimmune deficiency syndrome (AIDS), and (b) the diagnostic procedures nuclear medicine has to evaluate human immunodeficiency virus related disorders. This article is organized in an organ system approach to AIDS pathology. The application of [67Ga]citrate, 111In-labeled white blood cells, [201Tl]chloride, single photon emission computed tomographic, and positron emission tomographic brain agents, [99mTc]sulfur colloid and [99mTc]methylene diphosphonate to the pulmonary, nervous, gastrointestinal, dermatologic, musculoskeletal, and renal systems is discussed. These radioisotopes allow earlier diagnosis than routine radiographic studies, and can monitor the effect of therapy on disease activity. In this review an attempt is made to provide clinically useful algorithms to suggest a specific pathogen based on the pattern of radionuclidic uptake.

Theoretical and experimental analysis of the single-coil pulsed-NMR method for measuring fluid flow.

A theoretical and experimental analysis of the application of pulsed proton nuclear magnetic resonance (NMR) to the measurement of fluid flow has been made. Calculations of the detector signal line shapes, S(t), for a single-coil NMR laboratory experiment, were performed using a computer to identify the optimum choice of flow signature. The theoretical model included the influence of coil-field shape, coil length, and effects of flow phase. High flow rates, typical of arterial blood flow, were simulated. Good correlation between theory and experiment was observed. The maximum amplitude of the slope of the signal [dS(t)/dt] was found to be the optimum flow signature. The line shape S(t) was found to depend on flow phase. Comparison between theory and experiment provided a better understanding of the potential of NMR for measuring fluid or blood flow.

Clinical comparison of technetium-99m-teboroxime and thallium-201 utilizing a continuous SPECT imaging protocol.

To examine the advantages of a 99mTc-labeled cardiac perfusion agent, teboroxime or SQ30,217 (Squibb Diagnostics), a prospective study was undertaken comparing it to 201Tl stress testing in 17 patients suspected or known of having coronary artery disease (CAD). All patients were studied utilizing a single-detector SPECT camera with a continuous acquisition imaging protocol. Testing was performed on a treadmill to comparable levels with both agents within a 2-wk period. Concordance between the two studies on a patient by patient basis was seen in 16/17 (94%) patients, and discordance was seen in 1/17 (6%) patients. Comparison of findings between 201Tl and 99mTc-teboroxime on a segment by segment basis showed concordance in 107/119 (90%) segments, and 12/119 (10%) were discordant. Both examinations independently detected an equal number of normal (77) and abnormal (42) segments. There was no significant difference between the two agents in classifying lesions as ischemic, although there were significant differences between thallium and teboroxime in classifying infarct and infarct/ischemia. Technetium-99m-teboroxime SPECT imaging is a clinically useful method for detecting CAD, with a major advantage being the shorter examination time per individual patient study. The mean total examination time for completion of the 99mTc-teboroxime study was 2.5 hr versus 4.0 hr for 201Tl.

Early recognition of recurrent hepatocellular carcinoma utilizing gallium-67 citrate scintigraphy.

Gallium-67 scintigraphy is a valuable test together with other screening tests such as alpha feto-protein (AFP) and other imaging modalities in following up recurrent hepatocellular carcinoma (HCC). Three patients were followed in our institution for intervals varying from 2-24 mo after successful resection of uninodular localized hepatomas. In the first patient, gallium scan showed abnormal localized activity while the computed tomography (CT) scan and the magnetic resonance imaging were negative. Liver function tests and AFP were also normal and the patient was operated upon only on the basis of the gallium scan. The second patient had a follow-up gallium scan 2 mo after the first operation that showed an area of increased activity along the inferior aspect of the right lobe. A CT scan done after that showed no evidence of recurrence, but subsequently became positive when repeated 4 mo later. The third patient had abnormal simultaneous gallium scan and CT scan demonstrating a recurrence in the left adrenal gland while both AFP and carcinoembryonic antigen were normal. This has led us to consider every patient a candidate for a baseline and follow-up gallium scan for evaluation for recurrence following HCC.

Comparison of the physical characteristics of I-131 and I-123, with respect to differentiating the relative activity in the kidneys.

Iodine-123 (159 keV, T1/2 = 13.3 hr) has been proposed for renal investigations, as opposed to I-131 (364 keV, T1/2 = 8.06 days), because of its more practical photon energy and lower radiation dose to the patient. The cyclotron production method 124Te (p,2n) 123I for I-123 results in contamination with I-124 (T1/2 = 4.5 days). The latter emits high-energy photons whose relative abundance increases with time after end of bombardment (EOB). This paper is an evaluation of the effects of photon penetration, scatter, and attenuation on the phantom calibration measurements required for determining relative renal uptake using I-123. Measurements using I-131 were performed for comparison. Parameters investigated included: (a) the relationship between the integrated count and ROI size, (b) the magnitude of the "cross-talk" in counts between the kidneys, and (c) the attenuation corrections for source (kidney) depth. Phantom results obtained for I-123 suggest that this radionuclide will allow a better measurement of the activity in individual kidneys. Collimator penetration effects were greater for I-131 than for I-123. With I-123 for example, a higher fraction of the counts due to the activity in the kidney phantom were observed within the ROI enclosing its image. However, the attenuation corrections for source depth for I-123 were dependent on both the size of the ROI and time after EOB.

Endotoxin testing with limulus amoebocyte lysate in a radiopharmaceutical containing chelated metallic radionuclides and chelating agents.

The gel formation by endotoxin with limulus amoebocyte lysate (LAL) solution requires the presence of free calcium ions. The chelating agents and radiopharmaceuticals prepared from the chelating agents always reduce the available free calcium levels present in the kits used for the testing of apyrogenicity and thus inhibit gel formation of LAL with E. Coli endotoxin (ET). This inhibition of gel formation could be reversed by the addition of excess free calcium ions or the excessive dilution of radiopharmaceuticals and chelating agents. The tests of positive control (0.2 ml ET units and LAL), inhibition control (0.1 ml sample, 0.1 ml ET and LAL), and negative control (0.1 ml sterile saline and LAL) were carried out with the fresh preparation (0.1 ml) of samples (triplicate), tropolone, ACD anticoagulant, and 99mTc-labeled radiopharmaceuticals. In the Ca-supplemented tests, 0.1 ml of 60 mM sterile calcium chloride solution was added to the test solutions and incubated for 60 min at 37 degrees centigrade. The results of gel formation (+ve and -ve) and normalization of inhibition control tests with Ca-supplement indicate that commercial LAL kits need extra calcium ions for the correct testing of the apyrogenicity of chelate-containing radiopharmaceuticals and chelating agents.

Somatostatin receptor expression in Hürthle cell cancer of the thyroid.

Somatostatin receptor expression, which was not a previously described marker for Hürthle cell cancer of the thyroid, was demonstrated by in vivo imaging with (111)In-pentetreotide in three patients. This phenomenon not only adds another imaging technique to the nuclear medicine armamentarium for detecting recurrent and metastatic cancer in patients with Hürthle cell cancer but also opens up an alternative therapeutic avenue with somatostatin analogs or their radiolabeled compounds.

Iodine-123-Rose bengal: An improved hepatobiliary imaging agent.

A practical method for preparing )23-I-rose bengal that allows for its rapid and efficient incorporation into the molecule is reported. Administration of 123-I-rose bengal to normal healthy patients showing the normal uptake and excretory pattern visualized with this radio pharmaceutical is also presented. The overall reduction in imaging time and radiation exposure together with the improved images possible should greatly improve our diagnostic capabilities in evaluating the jaundiced patient.

Clinical evaluation of a scintigraphic method for diagnosing inflammations/infections using indium-111-labeled nonspecific human IgG.

This study was undertaken as part of a Phase II study to assess the sensitivity and safety of 111In-DTPA-human IgG, an imaging agent for the detection of inflammations and/or infections. Forty patients with infection/inflammation on the basis of clinical findings, microbiologic results, and/or the basis of results from other imaging modalities were studied. For evaluation of sensitivity, whole-body images were obtained at 6-12 hr (early) and 20-28 hr (delayed) postinjection and occasionally at 48 hr. No adverse reactions were recorded in any of the 40 patients studied. Positive results were obtained in 37 of 37 evaluable subjects (100%). The test appears to be a promising method for the detection of inflammation and/or infection.

Noninvasive imaging of c-myc oncogene messenger RNA with indium-111-antisense probes in a mammary tumor-bearing mouse model.

UNLABELLED: The c-myc oncogene is amplified in leukemia and solid tumors, thus making the c-myc messenger RNA (mRNA) a suitable target for following the progression of malignancy by noninvasive imaging with radiolabeled antisense pharmaceuticals or radiolabeled antisense oligodeoxynucleotide (RASON) probes. Considering the higher stability of phosphorothioate over phosphodiester, the probe stability and tumor localization was compared with both derivatives. METHODS: The 15-mer oligonucleotide sequence was synthesized, aminolinked [sense and antisense phosphodiester (O) and monothioester (S)] and coupled with diethylenetriamine pentaacetate (DTPA)-isothiocyanate and aliquots were lyophilized to make a DTPAAHON kit. The radionuclide 111In was chelated to DTPAAHON derivatives, and free 111In was separated by gel filtration. The radiolabeled antisense and sense probes were injected intravenously in mammary tumor-bearing BALB/c mice (1 x 10(6) cells, 8 days postinoculation). RESULTS: The highest uptake was observed at 2 hr with both thio and oxo derivatives of RASON probes, and small tumors could be imaged noninvasively. Tumor uptake and tumor/blood and tumor/muscle ratios for the sense probe (control) were significantly lower (p < 0.001) than those of the antisense probe. CONCLUSION: The radiolabeled antisense probe may provide a new sensitive tool for noninvasive imaging of c-myc oncogene mRNA for a variety of malignant tumors at an earlier stage.

Colorectal cancer imaging with iodine-123-labeled CEA monoclonal antibody fragments.

This prospective, randomized multicenter study in 62 patients was designed to evaluate the efficacy and safety of radioimmunodetection (RAID) with 123I-labeled fragments, F(ab')2 and Fab', of IMMU-4, an anti-CEA monoclonal antibody (Immu-RAID-CEA). It was found that ImmuRAID-CEA was safe and disclosed colorectal cancer sites at least 1 cm in size. The positive predictive value by lesions was 77% initially, and increased to 91% after 7 mo of follow-up. Only one patient developed a low level of HAMA. In 17 patients with 32 surgically confirmed lesions, there were 9% true-positive lesions for CT when RAID was false-negative, and 22% for RAID when CT was false-negative. Either CT or RAID detected all 32 lesions. In this small series, therefore, RAID was shown to complement CT findings by confirming suspected tumors and disclosing new lesions which had previously been occult.

Preoperative scintigraphy and operative probe scintimetry of colorectal carcinoma using technetium-99m-88BV59.

UNLABELLED: We report a pilot study of radioimmunoscintigraphy (RIS) and operative gamma probe scintimetry (OPS) using a 99mTc-labeled anti-cytokeratin human monoclonal antibody (MAb) (99mTc-88BV59) in patients with newly diagnosed, recurrent or metastatic colorectal cancer. METHODS: Twelve presurgical patients with biopsy- or contrast radiographic-proven colorectal cancer or recurrent colorectal carcinoma were studied. After chest roentgenography and abdominopelvic CT, 99mTc-88BV59 was administered intravenously, planar and SPECT external imaging was performed 3 to 6 hr after injection and planar imaging was performed 18 to 24 hr after injection. Surgery was performed immediately after late planar imaging. OPS of a standardized list of sites to document background radiation activity and of tumor sites, resection margins and tumor beds was performed. RESULTS: The patients had 23 histologically proven tumor sites. Overall sensitivity for CT, planar RIS, SPECT, surgery and OPS was 43%, 61%, 78%, 96% and 91%, respectively. SPECT was superior to CT for imaging extrahepatic abdominal and pelvic disease. OPS detected all liver and extrahepatic abdominal tumor sites and correctly predicted histological tumor-free margins and tumor beds in all cases. OPS did not identify tumor deposits that the surgeon could neither see nor feel. No patient demonstrated human anti-human immune responsiveness 1 and 3 mo after 99mTc-88BV59 infusion. CONCLUSION: Technetium-99m-88BV59 is a safe, effective radioimmunoconjugate for colorectal cancer imaging, with superior sensitivity as compared to CT.

Sentinel lymph node localization in early breast cancer.

METHODS: Thirty-two patients with clinical node-negative breast cancer underwent sentinel node localization study as part of a National Cancer Institute-sponsored multicenter trial. Anatomical and histopathologic characteristics of sentinel lymph node (SLN) and a kinetic analysis of nodal uptake were studied. Patients were injected with 1 mCi/4 ml unfiltered 99mTc-sulfur colloid in four divided doses around the palpable lesion or immediately adjacent to the excision cavity if prior biopsy was performed. SLN biopsy was performed 1.5-6 hr (mean = 3 hr) postinjection. Intraoperative localization was performed using a gamma probe. All patients underwent complete axillary dissection. RESULTS: SLN was identified in 30 of 32 (94%) patients. There were no false-negative SLN biopsies. CONCLUSION: This study supports the clinical validity of SLN biopsy in breast cancer and confirms that, unlike the blue dye technique, the learning curve with unfiltered 99mTc-sulfur colloid and the gamma detection probe is short, and SLN localization is achievable in over 90% of cases by surgeons with modest experience. The use of unfiltered 99mTc-sulfur colloid (larger particle size) with larger injected volume permits effective localization of SLNs.