Technetium-99m monoclonal antibody fragment (FAb) scintigraphy in the evaluation of small cell lung cancer: a preliminary report

Small cell lung cancer (SCC) has the most rapid growth rate of the four cell types and metastasizes early. Present imaging modalities for staging include chest x-ray, CT, MRI and bone scans. In this preliminary study, we assessed the clinical role of ^99mTc-monoclonal antibody (MOAB) scintigraphy in five patients with histologically proven SCC. Each patient was infused with 20–30 mCi of ^99mTc labeled Fab fragment of MOAB (NR-LU-10, NeoRx, Seattle, Wash.). Total body simultaneous anterior and posterior images were obtained 14–16 h post injection. SPECT images of the chest were obtained through a 360 ° rotation of the gamma camera and recorded on a 62 × 64 × 16 matrix. Images (1.2cm thick) were generated in transaxial, sagittal and coronal views.Fourteen of fifteen chest lesions detected by CT were confirmed by ^99mTc MOAB scintigraphy. Scintigraphy detected one additional chest lesion not seen by CT. Scintigraphy failed to detect a brain lesion (2 cm), a chest lesion, and two adrenal lesions, all of which were seen by CT. In one patient with multiple (more than 10) lesions in the liver, both scintigraphy and CT detected all lesions. Three spine lesions seen on ^99mTc MDP scan and positive for metastasis on MRI concentrated ^99mTc MOAB, but two rib lesions seen on ^99mTc MDP bone scan did not concentrate ^99mTc MOAB. It is concluded from these preliminary results that the potential usefulness of ^99mTc MOAB scintigraphy as a complementary imaging modality in the staging of small cell lung cancer should be investigated further.     

Apport de la scintigraphie au 99mTc-dépréotide pour le diagnostic de lésions osseuses secondaires dans le cancer bronchopulmonaire non à petites cellules stade III–IV

ObjectiveIn non-small cell lung cancer (NSCLC), metastatic bone involvement is usually assessed using conventional ^99mTc-HMDP bone scintigraphy, which has a high sensitivity but a poor specificity. The purpose of this study was to assess the usefulness of the ^99mTc-D scintigraphy for the detection of malignant bone metastases in patients with NSCLC stage III or IV and to compare these results with ^99mTc-HMDP bone scan findings.MethodsNineteen patients (13 M and 6 F, mean age 59 years) with proven NSCLC, suspected to have stage III or IV were enrolled prospectively. All patients underwent whole body ^99mTc-HMDP and ^99mTc-D scintigraphy to detect bone metastases within a mean interval of 14 days. Each focal uptake of ^99mTc-D or ^99mTc-HMDP was considered benign or malignant, leading to positive or negative diagnosis for bone involvement. The final diagnosis of bone metastases was established by a lung specialist, on the basis of additional imaging modalities and of 12 months follow-up.ResultsTwelve bone lesions were identified by ^99mTc-D scintigraphy, 10 were classified as bone metastases and two were classified as inflammatory bone lesions. Four patients were metastatic. Fifty eight bone lesions were detected by ^99mTc-HMDP scintigraphy, 26 of whom were considered malignant, eight patients were thus considered metastatic. Thereby, the two nuclear medicine modalities were concordant for 13 patients, that is 68% of cases and were discordant for six patients, representing 32% of cases. Diagnostic sensitivity, specificity and accuracy of depreotide scintigraphy and ^99mTc-HMDP bone scintigraphy were 75% for both, 93.3 and 73.3%, and 89.5 and 73.3% respectively.ConclusionOur data suggest that depreotide scintigraphy with the same sensitivity, a better accuracy and specificity than those of ^99mTc-HMDP bone scan can detect metastatic bone lesions in patients with NSCLC suspected to have stage III or IV disease.     

Lung scintigraphy with [123I]IMP in patients with pulmonary tuberculosis

Lung scintigraphy using N-isopropyl-p-[¹²³I]iodoamphetamine (IMP) was performed on 26 patients with pulmonary tuberculosis. Early (5 min after injection) and late images (4 h after injection) were obtained with a large-field γ-camera equipped with a digital computer. Lung scintigraphy using [^99mTc]MAA (MAA) was also done. Although early IMP images showed the same findings as [^99mTc]MAA images, a discrepancy between delayed IMP images and [^99mTc]MAA images was seen in some patients. Increment of activities seen in late images was demonstrated in most patients whose chest x-ray findings included exudative inflammatory changes. Uptake and clearance of IMP was considered to be affected by the active phase of pulmonary tuberculosis.     

Mécanisme de fixation du 99mTc-HMDP sur les carcinomes urothéliaux calcifiés de vessie

We report a case of transitional cell carcinoma of the bladder visualized on a ^99mTc-HMDP bone scintigraphy. CT demonstrated irregular tumor of the bladder with curvilinear calcifications on the surface areas and multiple bilateral pulmonary metastases. Bone scintigraphy showed intense uptake corresponding to the bladder tumor and two bone metastases on the left femur. A few days later, the patient underwent retrograde injection of ^99mTc-HMDP into the bladder. Imaging made after voiding showed a tumour uptake of the skeletal labelled agent. Through this case report, we debate ^99mTc-biphosphonate uptake mechanisms in transitional cell carcinoma.     

Skeletal Scintigraphy: The Use of Technetium 99M-Labeled Complexes in the Detection of Early Osseous Involvement by Metastatic Tumors

Skeletal scintigraphy using Technetium-99m (^99mTc) complexes was carried out in a series of 332 cancer patients. The results of scintigraphy were compared with the results of roentgenography and with the diagnostic usefulness of serum alkaline and acid phosphatase levels and the presence or absence of bone pain. In 25 percent of cases, lesions were first identified with scintigraphs. When metastastic lesions were present on both scintigraphs and roentgenograms, the number was greater on scintigraphs in 72 percent of cases. Six false negative studies were recorded (1 percent). Sixty percent of patients with early metastasis—that is, those with abnormal scintigraphs and negative roentgenograms—were asymptomatic. Serum alkaline and acid phosphatase levels were normal in 40 percent and 42 percent respectively of those with early skeletal involvement. Skeletal scintigraphy with ^99mTc complexes is superior to other commonly employed techniques used to assess bone metastasis.     

Evaluation of a DMSA kit for instant preparation of 99mTc(V)—DMSA for tumour and metastasis scintigraphy

A kit has been developed to instantly prepare ^99mTc(V)—DMSA. The freeze-dried kit consisting of DMSA, stannous chloride and ascorbic acid in appropriate proportions, produces quality ^99mTc(V)—DMSA when mixed with 0.2 mL of 3.5% NaHCO₃ solution and 2–4 mL of [^99mTc] pertechnetate. The radiopharmaceutical characterized by chromatography with ITLC-SG in 0.9% saline and horizontal paper electrophoresis in 50 mM vernol buffer, pH 8.6, at a potential gradient of 15 V/cm showed a different mobility with respect to ^99mTc(III)-DMSA, a known agent for kidney imaging. The new agent exhibited less plasma protein binding as compared to that of ^99mTc(III)-DMSA. Biodistribution of the pentavalent DMSA in mouse demonstrated greater uptake in bone and muscle and lower uptake in liver and kidney with respect to trivalent DMSA. The soft tissue tumour specificity and its suitability for tumour scintigraphy was apparent from the scintigrams of mammary carcinoma in a C₃H Jax mouse and medullary carcinoma in a patient. Brain metastatic lesions were also visible in a breast carcinoma patient after administering him with the agent.     

Quelle est la signification des anomalies observées en scintigraphie osseuse ?: Retour sur les mécanismes de fixation des bisphosphonates-(99mTc)

Likely, but still controversial, mechanisms of uptake of bisphosphonates-(^99mTc) are recalled: uptake on organic phase, on mineral phase and/or cellular internalization (osteoclasts and osteoblasts). These hypotheses are critically reviewed in the light of recent progress in pathophysiology of malignant (bone metastases, myeloma) and benign (Paget's disease of bone, fibrous dysplasia) disorders at tissular, cellular and molecular levels, from pharmacology of therapeutic bisphosphonates. Such knowledge improvements have been allowed through in vitro studies, animal models and clinical cases in multimodality imaging (radiology, scintigraphy, pathology).     

Synthesis of Tc-99m labeled 1,2,3-triazole-4-yl c-met binding peptide as a potential c-met receptor kinase positive tumor imaging agent

The mesenchymal-epithelial transition factor (c-Met), which is related to tumor cell growth, angiogenesis and metastases, is known to be overexpressed in several tumor types. In this study, we synthesized technetium-99m labeled 1,2,3-triazole-4-yl c-Met binding peptide (cMBP) derivatives, prepared by solid phase peptide synthesis and the ‘click-to-chelate’ protocol for the introduction of tricarbonyl technetium-99m, as a potential c-Met receptor kinase positive tumor imaging agent, and evaluated their in vitro c-Met binding affinity, cellular uptake, and stability. The ^99mTc labeled cMBP derivatives ([^99mTc(CO)₃]12, [^99mTc(CO)₃]13, and [^99mTc(CO)₃]14) were prepared in 85-90% radiochemical yields. The cold surrogate cMBP derivatives, [Re(CO)₃]12, [Re(CO)₃]13, and [Re(CO)₃]14, were shown to have high binding affinities (0.13 μM, 0.06 μM, and 0.16 μM, respectively) to a purified cMet/Fc chimeric recombinant protein. In addition, the in vitro cellular uptake and inhibition studies demonstrated the high specific binding of these ^99mTc labeled cMBP derivatives ([^99mTc(CO)₃]12–14) to c-Met receptor positive U87MG cells.     

A refined method for assessing 99mTc-MDP whole body retention in prostate cancer patients

Whole body retention (WBR) of ^99mTc labeled methylene diphosphonate (MDP) has been shown to significantly differentiate various clinical stages of prostate cancer. Whole body measurements, when performed at 5 min and 24 h after i.v. administration of ^99mTc-MDP, allows for the calculations of percentage whole body retention (% WBR) after one day. The latter can be expressed relative to either the anterior or posterior projection, or in combination as the geometric mean value.In an attempt to better describe the clinical course of prostate cancer patients with bone metastases we have refined the % WBR calculations to include a normalization factor. The latter consists of the mean 24-h value of WBR's as obtained from 10 prostate cancer patients without bony métastases as determined by bone scintigram. These values were determined for each projection to be: anterior = 26.5 ± 4.7%, posterior = 37.5 ± 7.4%, and geometric mean = 31.5 ± 5.7%. The % WBR is then divided by the normalization factor of choice and expressed as (% WBR)^N.These data are used to better express ^99mTc MDP 24-h whole body retentions when following the clinical course of patients with metastatic carcinoma of the prostate. Caution should be exercised when interpreting these data when metabolic bone pathology is present. A false negative (% WBR)^N value will result if an infiltration of the ^99mTc-MDP occurs during administration.     

Cancer de la prostate et masses abdominopelviennes fixant le 99mTc-HDP. Apport de la tomographie d’émission monophotonique couplée à la tomodensitométrie (TEMP–TDM)

We report the case of a 63-year-old man, investigated for staging of a prostatic cancer, diagnosed by biopsy, following a rise in the prostatic specific antigen (PSA) on a systematic assessment. The interrogation before examination revealed signs of beginning right crural neuropathy. The hydroxymethylene diphosphonate technetium 99m-labeled (^99mTc-HDP) whole-body bone scintigraphy highlighted two extraosseous uptake images, the first of moderated intensity in the right iliac area, the second milder, in the abdominal median area. Osseous metastases were not visualized. The single photon emission computerized tomography guided by computerized tomography (SPECT/CT) identified the median abdominal mass which corresponded to a bulky aneurysm of the under renal abdominal aorta. The right iliac mass could be accurately analyzed and differentiated from the various organs of the abdominopelvic cavity. Its lymphatic origin was hypothetised, but the diagnosis of lymphatic metastasis of the prostatic cancer was obtained by the pathologic examination of CT scan-guided biopsy.     

Immunoscintigraphy using different methods of applying a 99mTc labeled monoclonal anti-CEA-antibody in the staging of patients with liver metastases before partial hepatectomy

It was the aim of this study to determine the value of portal-venous (p.v.), intra-arterial (i.a.) or intravenous (i.v.) IS in the detection of liver metastases. Immediately after angiography and i.a. CT (20 patients) or p.v. CT (6 patients), 0.7–1.2 GBq of the ^99mTc labeled anti-CEA MoAb were injected via the i.a. catheter, and in 10 patients i.v. Planar scanning was performed. Using IS in the detection of liver metastases a total sensitivity of 61% was established. However, IS was still found to be the decisive method of excluding extrahepatic tumor deposits.     

Comparison of 99mTc-3PRGD2 Integrin Receptor Imaging with 99mTc-MDP Bone Scan in Diagnosis of Bone Metastasis in Patients with Lung Cancer: A Multicenter Study

Purpose

^99mTc-3PRGD2, a promising tracer targeting integrin receptor, may serve as a novel tumor-specific agent for single photon emission computed tomography (SPECT). A multi-center study was prospectively designed to evaluate the diagnostic accuracy of ^99mTc-3PRGD2 imaging for bone metastasis in patients with lung cancer in comparison with the conventional ^99mTc-MDP bone scan.

Methods

The patients underwent whole-body scan and chest tomography successively at both 1 h and 4 h after intravenous injection of 11.1 MBq/Kg ^99mTc-3PRGD2. ^99mTc-MDP whole-body bone scan was routinely performed within 1 week for comparison. Three experienced nuclear medicine physicians blindly read the ^99mTc-3PRGD2 and ^99mTc-MDP images. The final diagnosis was established based on the comprehensive assessment of all available data.

Results

A total of 44 patients (29 male, 59±10 years old) with suspected lung cancer were recruited from 4 centers. Eighty-nine bone lesions in 18 patients were diagnosed as metastases and 23 bone lesions in 9 patients were benign. In a lesion-based analysis, ^99mTc-3PRGD2 imaging demonstrated a sensitivity, specificity, and accuracy of 92.1%, 91.3%, and 92.0%, respectively. The corresponding diagnostic values for ^99mTc-MDP bone scan were 87.6%, 60.9%, and 82.1%, respectively in the same patients. ^99mTc-MDP bone scan had better contrast in most lesions, whereas the ^99mTc-3PRGD2 imaging seemed to be more effective to exclude pseudo-positive lesions and detect bone metastases without osteogenesis.

Conclusion

^99mTc-3PRGD2 is a novel tumor-specific agent based on SPECT technology with a promising value in diagnosis of bone metastasis in patients with lung cancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01737112","term_id":"NCT01737112"}}NCT01737112     

The evaluations of 99mTc cyclopentadienyl tricarbonyl triphenyl phosphonium cation for multidrug resistance

A triphenylphosphonium cation, [^99mTc]Technetium cyclopentadienyltricarbonyl-6-hexanoyl-triphenylphosphonium cation ([^99mTc]3) was prepared to target multidrug resistance (MDR). The radiotracer was evaluated in the MDR-negative MCF-7 and MDR-positive MCF-7/ADR cell lines in vitro, as well as animal models in vivo. [^99mTc]3 was proofed to be a substrate of P-glycoprotein and multidrug resistant protein 1, and showed a higher accumulation in the MDR-negative MCF-7 cells compared to ^99mTc-sestamibi in vitro. The MCF-7 tumor-to-MCF-7/ADR tumor ratio of [^99mTc]3 was ～3 at 1 h p.i. in the biodistribution study. These results demonstrated the capability of the radiotracer to detect multidrug resistance in tumor cells.     

Comparison of relative renal functions calculated with 99mTc-DTPA and 99mTc-DMSA for kidney patients of wide age ranges

Renal scintigraphy is an imaging method that uses small amount of radioactive materials called radiotracers, a Gamma camera and a computer to evaluate kidney functions and its anatomy. The present work reports the comparison of the relative renal functions (RRF) calculated with technetium-99m dimercaptosuccinic acid (^99mTc‑DMSA) and technetium-99m diethylenetriaminepentaacetic acid (^99mTc‑DTPA) for kidney patients of ages between 5 months and 71 years. A total of 50 patients including 29 male and 21 female has been selected and studied for renography. The mean RRFs have been found to be 52.68 ± 23.63% and 47.32 ± 23.63% respectively for the left and right kidneys with ^99mTc-DMSA measurement. With ^99mTc-DTPA the values are 52.74 ± 23.54% and 47.26 ± 23.54% for the same. In bivariate correlation analysis, a significant positive correlation (r = 0.996, P < .001) has been found between the RRFs calculated with the two methods. Following the patients’ diagnosis, in ANOVA test, no difference has been found between the RRFs calculated for the left and right kidneys. In Bland-Altman plots, the mean difference between the two methods has been found to be 0.1 and the correlation limit lies between −4.3 and 4.2. According to the result obtained in the present work, both the ^99mTc-DMSA and ^99mTc-DTPA scanning methods provide almost the same RRF values. It is, therefore, always not necessary to calculate the RRFs with both the methods. This study suggests that ^99mTc-DMSA may be the primary choice for the evaluation of RRF, but if the glomerular filtration rate (GFR) and renogram curve are required, ^99mTc-DTPA can be the obvious selection.     

Tetraamine‐modified octreotide and octreotate: labeling with 99mTc and preclinical comparison in AR4‐2J cells and AR4‐2J tumor‐bearing mice

Two somatostatin analogues, [^99mTc]Demotide and [^99mTc]Demotate 4, were compared with [^99mTc]Demotate 1, a previously reported somatostatin receptor subtype 2 (sst₂) targeting tracer. Conjugates were prepared by coupling an open‐chain tetraamine chelator to D ‐Phe¹ of [Tyr³]‐octreotide or [Tyr³]‐octreotate, respectively, via a p‐benzylaminodiglycolic acid spacer adopting solid‐phase peptide synthesis techniques. Peptide conjugates were collected in a highly pure form after chromatographic purification. Eventually, [^99mTc]Demotide and [^99mTc]Demotate 4 were obtained in ～1 Ci/µmol specific activity and >96% purity after labeling under alkaline conditions. Demotide and Demotate 4 exhibited similar high binding affinities for the sst₂ expressed in AR4‐2J cells with IC₅₀ values 0.16 and 0.10 nM, respectively. The (radio)metallated analogues [^99mTc]Demotide and [^99mTc]Demotate 4 showed equally high affinities to the sst₂ during saturation binding assays in AR4‐2J cell membranes (K_ds 0.08 and 0.07 nM, respectively). During incubation at 37 °C with AR4‐2J cells, the radiopeptides internalized effectively via a receptor‐mediated process, with [^99mTc]Demotate 4 exhibiting a faster internalization rate than [^99mTc]Demotide. After injection in athymic mice bearing sst₂‐expressing AR4‐2J tumors, the radiotracers showed high and specific uptake in the tumor (>25%ID/g at 1 h) and in the sst₂–positive organs. However, both [^99mTc]Demotide and [^99mTc]Demotate 4 showed unfavorably higher background activity, especially in the abdomen, in comparison to [^99mTc]Demotate 1 and are, therefore, less suited than [^99mTc]Demotate 1 for sst₂‐targeted tumor imaging in man. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.     

Effect of alterations in erythropoiesis on distribution of 99mTc sulfur colloid in the rat

The distribution of ^99mTc sulfur colloid and ⁵⁹Fe was assessed in rats following long or short term stimulation or suppression of erythropoiesis. Acute stimulation of erythropoiesis did not alter ^99mTc sulfur colloid distribution, whereas, long term stimulation resulted in increased marrow colloid uptake. Suppression of erythropoiesis by hypoxia-induced plethora or hypertransfusion did not alter the marrow uptake of ^99mTc sulfur colloid. ^99mTc sulfur colloid blood clearance was not altered by any of the experimental conditions utilized. These observations suggest that marrow RE activity as assessed by ^99mTc sulfur colloid uptake increases with erythropoietic stimulation and varies with the duration and intensity of the stimulus.     

A novel method for labelling of leukocytes with technetium-99m and its comparative evaluation for abscess scintigraphy

A new method, based on the pretreatment of leukocytes with glucoheptonate prior to treating with reduced ^99mTc, has been developed for the preparation of ^99mTc labelled leukocytes. The leukocytes labelled with a ^99mTc concentration (5.59%/g tissue) similar to that of ¹¹¹In-leukocytes (6.27%/g tissue), in the experimental abscess were in rat thigh. Concentration of ^99mTc-leukocytes in blood at 24 h was only about 35% as compared to that of ¹¹¹In-leukocytes. Biodistribution in the rat organs was similar in both cases, except in the liver where ^99mTc-leukocytes exhibited about 4-fold greater concentration. Images of experimental abscess in rat by using ^99mTc-leukocytes were comparable to those obtained with ¹¹¹In-leukocytes.     

Control of the carcinogenic potential of 99mTechnetium by the immunologic hormone lymphotoxin

Summary Immunologic prevention of the carcinogenicity of the diagnostic gamma-emitting radionuclide ^99mTechnetium (^99mTc) by lymphotoxin was evaluated using an in vivo-in vitro assay of carcinogenesis. Pregnant Syrian golden hamsters received 125–2,300 Ci ^99mTc/kg body weight by injection, and 7 days later colonies of morphologically transformed cells were quantitated in vitro. The transformation frequency increased directly with the radionuclide concentration, and cells derived from transformed colonies produced tumors in athymic nude mice. The total absorbed ^99mTc dose was 0.20 rad following injection of 250 Ci ^99mTc/kg hamster body weight; this compares with an exposure of 0.13 rad following injection of 143 Ci ^99mTc/kg body weight in humans. Intravenous injection of purified hamster lymphotoxin immediately after ^99mTc caused a dose-dependent reduction in the transformation frequency. Transformation was essentially completely prevented (97%) by injection of 8,000 U of lymphotoxin. Thus, the immune system, through the action of lymphotoxin, has the potential to prevent carcinogenesis induced by gamma-radiation from ^99mTc. This emphasizes the importance of considering the recipient's immune and other homeostatic mechanisms as part of a complete diagnostic or therapeutic gamma-radiation regimen.     

99mTc(Cu)—mannitol complex: a new agent for dynamic renal function studies

Mannitol has been labelled with ^99mTc by using cuprous chloride as a reducing agent. Blood and kidney clearance of ^99mTc(Cu)-mannitol was slightly faster than that of ^99mTc(Sn)-DTPA in rat and maximum radioactivity ratio of kidneys to blood was 84.6 at 5 min. A comparative study of ^99mTc(Cu)-mannitol, ^99mTc(Sn)-DTPA was made in rabbits by taking serial images of kidneys and bladder with a γ camera. Results show superiority of ^99mTc(Cu)-mannitol over other agents for dynamic renal function studies.