Tumor-seeking Agent Research Articles

Role of Tc-glucoheptonic acid brain single photon emission computed tomography in differentiation of recurrent brain tumour and post-radiation gliosis.

Blood-brain barrier imaging of brain tumours is fast attracting interest now that it has been demonstrated that disruption of the blood-brain barrier is essential for uptake of all tumour-seeking agents. The aim of the present study was to differentiate recurrent tumour from post-radiation gliosis using (99m)technetium-glucoheptonate ((99m)Tc-GHA) as a tumour-seeking agent. Brain single photon emission computed tomography (SPECT) with (99m)Tc-GHA was performed in 73 patients with primary malignant brain tumours after radiotherapy, and the results were correlated with the clinical behaviour of the disease on follow up. The SPECT was suggestive of recurrent tumour in 55 patients. The clinical course was consistent with recurrence in 51 of the 55 patients. The clinical course was consistent with radiation necrosis in the remaining 21 patients, which included 17 patients with a negative SPECT and four patients with a positive SPECT study. Mean GHA index in recurrent tumour and post-radiation gliosis was 7.04 +/- 4.35 and 1.88 +/- 1.70, respectively (P = 0.0001). Mean GHA index in high-grade and low-grade glioma was 7.78 +/- 4.73 and 3.15 +/- 2.44, respectively (P = 0.001). (99m)Technetium-glucoheptonate brain SPECT is a sensitive and reliable diagnostic modality to differentiate recurrent tumour from post-radiation gliosis.

Radiation and gene therapy: rays of hope for the new millennium?

Radiotherapy is, after surgery, the most widely used form of cancer treatment but the main limitation of radiation treatment is damage to normal tissues. This may be overcome by targeted radiotherapy - the selective delivery to malignant deposits of cytotoxic radionuclides bound to tumour-seeking agents. Several gene transfer techniques are being evaluated which combine gene therapy and targeted radiotherapy, rendering malignant cells more sensitive to radiation or causing them to take up radioactive drugs - providing tumour cell kill with reduced damage to normal tissues. This review examines several aspects of targeted radiotherapy/gene therapy strategies. As well as identification of suitable gene/radiopharmaceutical combinations, expression of the transgenes must be confined to tumour cells via tumour specific transcriptional regulation or via delivery vehicles which specifically target tumour cells. The inability of current delivery vehicles to target every cell within a tumour mass must be addressed by maximising collateral cell damage in targeted radiotherapy strategies via radiation mediated bystander effects and suitable in vitro models are described, which allow assessment of promising gene transfer strategies in scenarios where tumour heterogeneity of transgene expression and cell proliferative state are considered.

Detecting vulvar cancer with inguinal lymph node metastases by dual-phase Tl-201 scan.

TI-201 is one of the most common tumor-seeking agents in clinical use, but it has been used principally for imaging lung, thyroid, and head and neck cancer. TI-201 is taken up by viable tumor rather than by necrotic or scar tissue. In the current report, an 80-year-old woman with a protruding and ulcerative mass on her left vulva was hospitalized for dual-phase TI-201 cancer survey with abnormal tracer uptake seen in the vulvar region and pelvic lymph nodes. Histopathologic findings were squamous cell carcinomas of the vulva with pelvic lymph node metastases.

A shifting landscape: what will be next FDG in PET oncology?

The tumor-seeking agent most widely used in positron emission tomography (PET) is 2-(18)F-fluorodeoxy-D-glucose (FDG). The clinical usefulness of FDG PET has already been proved in detecting, staging and restaging various kinds of malignant tumors, but nuclear medicine physicians suffer from a "diagnostic dilemma," in which a relatively high false positive ratio of FDG PET in diagnosing malignant tumors prevails. To increase more specific tumor uptake or more specific tumor characterization, numerous PET radiopharmaceuticals have been developed, and some of them are being tested in clinical trials. This review will briefly survey the tumor uptake mechanism and clinical significance of representative non-FDG PET radiopharmaceuticals used in clinical trials for patients with cancers.

Uptake of 99mTc tetrofosmin in lymphoma cell lines: a comparative study with 99mTc sestamibi

Technetium-99m ( 99mTc) tetrofosmin has been used as a tumor-seeking agent. However, its role in detecting lymphomas has not been widely investigated. The aim of the present study was to determine the uptake and clearance characteristics of 99mTc tetrofosmin in lymphoma cell lines. 99mTc sestamibi was also evaluated for comparison. Three lymphoma cell lines (U-937: monocyte-like, histiocytic lymphoma, human; RAMOS: B-lymphoma cell line, American Burkitt lymphoma, lymphoblastoid, human; Hs445: Hodgkin's disease, lymphoid, human) were studied. After incubation of radiotracers 99mTc tetrofosmin and 99mTc sestamibi in medium for 0, 10, 20, 30, 60, 120 and 180 min, the uptake and clearance of each radiotracer were measured in the three lymphoma cell lines. The uptake of 99mTc tetrofosmin was lower than that of 99mTc sestamibi in these lymphoma cell lines. Among the three cell lines, Hs445 showed the greatest 99mTc tetrofosmin uptake capacity. RAMOS and U-937 showed similar 99mTc tetrofosmin uptake capacities. 99mTc tetrofosmin accumulated in the three tested lymphoma cell lines, especially in the Hodgkin's disease cell line. However, in comparison with 99mTc sestamibi, 99mTc tetrofosmin may not be the best radiotracer for detection of lymphoma.

Comparison of the uptake and clearance of Tc-99m MIBI, Tl-201 and Ga-67 in drug-resistant lymphoma cell lines

Tc-99m sestamibi (MIBI) has been used as a tumor-seeking agent. However, its role in detecting lymphomas has not been widely investigated. The aim of the present study was to determine the uptake and clearance characteristics of Tc-99m MIBI in vincristine-resistant lymphoma cell lines. In addition, thallium-201 (Tl-201) and gallium-67 (Ga-67) uptake and clearance characteristics were evaluated for comparison with Tc-99m MIBI. Drug-resistant lymphoma cell lines (monocyte-like, histiocytic lymphoma, human; B-lymphoma cell line, American Burkitt lymphoma, lymphoblastoid, human; Hodgkin's disease, lymphoid, human) were selected by multistep vincristine treatment up to 50 nM. After incubation of the radiotracers, Tc-99m MIBI, Tl-201 and Ga-67, in medium for 0, 10, 20, 30, 60 or 120 min, the uptake and clearance of each radiotracer were measured in the drug-resistant lymphoma cell lines. In addition, P-glycoprotein expression was determined by immunohistochemical study. In a comparison of the three radiotracers, the uptake of Tc-99m MIBI was the greatest in the studied wild-type lymphoma cell lines. Tc-99m MIBI uptake was much lower in drug-resistant tumor cell lines than in non-resistant cell lines. On the other hand, the uptake characteristics of Tl-201 did not differ between drug-resistant and non-resistant cells. Immunohistochemistry analyses of Ab-1 or JSB indicated that tumor cells expressed MDR-1 protein in all three cell lines. Tc-99m MIBI is a good radiotracer for detecting drug resistance in lymphoma cell lines.

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.

Muscle uptake of 18-fluorine fluorodeoxyglucose

F LUORODEOXYGLUCOSE (FDG) is well established as a tumor-seeking agent that is taken up by a wide variety of malignant tumors. Several nonmalignant lesions also are FDG avid, as are normal organ systems that use glucose as part of their metabolism. Low-grade FDG uptake in muscles is part of the normal biodistribution pattern of FDG, especially during physical activity. When this uptake is symmetric and corresponds to the location of a specific group of muscles, it is easily recognizable. Accurate interpretation of asymmetric muscular activity is more difficult. Recognition of unusual patterns and the location of benign physiologic muscular uptake of FDG is important for avoiding misinterpretations of positron emission tomography (PET) images. I describe 4 cases with unusual muscular FDG uptake that was noted during whole-body FDG imaging of nondiabetic patients. CASE 2

Role of scintigraphy with tumor-seeking agents in the diagnosis and preoperative staging of malignant thyroid nodules

The commonly used procedure for the diagnosis of thyroid nodule malignancy is based on high resolution thyroid ultrasonography (US) combined with US-guided fine needle aspiration cytology (FNAC). The other imaging procedures have a limited role in malignancy diagnosis. However, nuclear medicine procedures, particularly scintigraphy with tumor-seeking agents such as 201-thallium (201-TI), 99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) and 99mTc-tetrofosmin may play an important role in the differential diagnosis between benign and malignant thyroid nodules in cases of non-diagnostic or inadequate FNAC. This type of scintigraphy can also be used in the follow-up of patients with cytologically 'high'-risk thyroid nodules such as Hurtle cell adenomas and follicular adenomas. Furthermore, scans with tumor-seeking agents can be helpful in determining the preoperative staging of thyroid carcinoma patients with locally advanced disease, and in accurately evaluating the extent, and consequently, the surgical management of the disease.

Targeting Radiotherapy to Cancer by Gene Transfer

Targeted radionuclide therapy is an alternative method of radiation treatment which uses a tumor-seeking agent carrying a radioactive atom to deposits of tumor, wherever in the body they may be located. Recent experimental data signifies promise for the amalgamation of gene transfer with radionuclide targeting. This review encompasses aspects of the integration of gene manipulation and targeted radiotherapy, highlighting the possibilities of gene transfer to assist the targeting of cancer with low molecular weight radiopharmaceuticals.

Nuclear medicine procedures in lung cancer.

Although radiography, computed tomography and magnetic resonance imaging are still the methods of choice for the study of lung cancer, they have certain limitations in the determination of the nature of suspicious lung nodules, the evaluation of mediastinal involvement, the assessment of the viability of previously treated lesions and the diagnosis of tumour relapse. There is a wide range of current oncological requirements related to lung cancer: detection of malignant lesions at the earliest stage and in the most effective way; the definition of the biological characteristics of a lesion (proliferation, aggressiveness, differentiation, etc.); the need to define the operability of the patient (function of residual lung and staging); and the need to evaluate the behaviour of the tumour (response to therapy, early detection of recurrences, metastatic spread). Most of the efforts of the nuclear medicine community have been focussed on diagnosis, staging, restaging and therapy monitoring of lung cancer. Many radiopharmaceuticals have been employed for this, including gallium, monoclonal antibodies, somatostatin analogues, lipophilic cations and positron emission tracers. There is ample evidence that nuclear medicine techniques may provide complementary information with respect to anatomical imaging, for example in the assessment of preoperative function by means of ventilation and perfusion scintigraphy, or in tumour localisation by means of specific tumour-seeking agents. However, clinical data suggest that, when properly used, nuclear medicine procedures in some cases may be not only complementary to radiology but essential for the clinical management of lung cancer. An example of such a procedure is fluorodeoxyglucose positron emission tomography (FDG PET) the introduction of which has greatly contributed to confirmation of the clinical value of nuclear medicine in this field. FDG PET has proved of great help in lung cancer management and its cost-effectiveness in lung cancer staging is firmly established. In this review the results of the most important nuclear medicine techniques are summarised and their value in clinical practice is discussed. General, updated information is provided about the epidemiology, biology and clinical management of lung cancer, and about the role of nuclear medicine in these areas.

99mTc-ethylenedicysteine-folate: a new tumor imaging agent. Synthesis, labeling and evaluation in animals.

It is known that membrane folic acid receptors are responsible for cellular accumulation of folate and folate analogs such as methotrexate and overexpressed on various tumor cells. However, these receptors are highly restricted in normal differentiated tissues. Results of limited in vitro and in vivo animal studies suggest that folate receptors could be a potential target for tumor imaging. This study aimed to develop a 99mTc-labeled folic acid using ethylenedicysteine (EC) as a chelator and evaluate its labeling efficiency and potential use as a tumor seeking agent. Tissue distribution of 99mTc-EC-folate was determined in breast tumor-bearing rats at 20 min, 1, 2, and 4 h (n = 3/time interval, 370 KBq/rat, i.v.). Blocking study was employed to determine receptor-mediated process; 99mTc-EC-folate was co-administrated with 50 and 150 mumol/kg of cold folic acid to tumor-bearing rats. Planar imaging and whole-body autoradiograms were performed. The data was compared to that using 99mTc-EC (control). In animal studies, tumor/blood count density ratios at 20 min-4 h increased from 0.81 +/- 0.09 to 1.23 +/- 0.13 with 99mTc-EC-folate. Conversely, these values showed time-dependent decrease from 0.77 +/- 0.32 to 0.65 +/- 0.01 with 99mTc-EC in the same time period. Tumor/muscle and tumor/blood count density ratios significantly decreased with folic acid co-administrations. Planar images and autoradiograms confirmed that the tumors could be visualized clearly with 99mTc-EC-folate.

Gallium-67 as a tumor-seeking agent in lymphomas--a review.

At present 67Ga can be considered one of the most widely used viability radiotracers. There is general consensus in the literature that 67Ga has the highest clinical value in the management of lymphoma patients. We critically discuss the role of gallium scintigraphy in lymphoma patients on the basis of the experience of the Nuclear Medicine Division at the National Cancer Institute of Milan. The sensitivity of gallium scan is very high (80-90%) in the staging and follow-up of Hodgkin's disease, and the method is also of great importance in the follow-up of lymphoma patients. We recommend scintigraphy to study the residual mediastinal mass after treatment. Our experiences during the follow-up of 189 lymphoma patients clearly showed the superior performance of gallium scan compared to MRI in the study of the mediastinal region after treatment. Sensitivity and specificity were both very high (90% and 96.9% vs 88.7% and 89.2%, respectively). Gallium scintigraphy can also be used to study the disease-free interval, post-treatment survival, early signs of recurrence and treatment response times. Comparison of the survival curves of 33 patients with diffuse large cell Non-Hodgkin's lymphoma examined at the National Cancer Institute showed a statistically significant difference (logrank test, P = 0.0125) between patients with positive and those with negative gallium scan after 4-6 cycles of chemotherapy.

Validation of intracoronary delivery of metalloporphyrin as an in vivo "histochemical staining" for myocardial infarction with MR imaging.

During the last CMR meeting in Naantali, Finland, we presented how the research in our laboratories in collaboration with the Institut ftir Diagnostikforschung, Berlin, Germany, has dramatically converted metalloporphyrins from being used as tumor-seeking agents to markers of myocardial infarction (MI) (1). This represents a three-episode story. We started with an investigation in primary and secondary liver tumors and found that the observed specific enhancement could be attributed only to nonviable instead of viable tumoral components (2). A subsequent study on several porphyrin agents in induced benign necrosis supported the finding in tumors (3). Eventually, we ended up with a novel application for metalloporphyrinenhanced MRI to visualize acute myocardial infarction (46). Since intravenous injection of metalloporphyrins has already been demonstrated to be effective for accurate identification and localization of irreversible myocardial infarcts in rats (4,5) and dogs (6), the current study was designed to deliver the porphyrin agent into the coronary artery with only 1/10th of the intravenous dose in order to assess (a) whether the necrotic myocardium can be accurately labeled by virtually a single pass of the agent through reperfused coronary artery and (b) whether this technique can be combined with percutaneous transluminal coronary angioplasty (PTCA) to function as an in vivo

New developments in laser medicine

New developments in the non-thermal application of laser radiation in medicine are discussed. Tumour-seeking agents in combination with laser light are used for early tumour detection through fluorescence and for photodynamic therapy. Laser-induced fluorescence as well as Raman spectroscopy has potential for real-time monitoring of atherosclerotic plaques. Enhanced demarcation can be obtained by working in the time domain, which also opens up the new field of photon propagation studies in tissue. Work towards optical mammography is in progress in many laboratories. Finally, intense laser pulses can be used for generating x-ray radiation with interesting properties for enhanced medical imaging.

Axillary lymph node metastases detection with nuclear medicine approaches in patients with newly diagnosed breast cancer

Three different tracers, Tc-99m-Sesta MIBI, In-111-Pentetreotide and F-18-FDG, were evaluated in a preliminary study in three different groups of 10 breast cancer patients programmed for breast cancer resection and axillary dissection. Planar scintigraphy and single photon emission tomography (SPET) technique were used for imaging with Tc-99m-Sesta-MIBI and In-111-Pentetreotide, positron emission tomography (PET) was used for imaging with F-18-FDG. We studied 30 breast cancer patients; their clinical stage according to the TNM classification was 30 T1-T2, 1 T4 and 1 Tx (one patient had bilateral cancer and one had bifocal cancer). The lymph nodal status ranged from NO to N2 (14 NO, 16 N1, 1 N2). Tc-99m-Sesta MIBI, In-111 Pentetreotide SPET and F-18-FDG PET were randomly performed before surgery to visualize the primary tumors and to detect axillary lymph node invasion. Tc-99m-Sesta MIBI correctly visualized 10 out of 11 primary cancers in 10 patients. In-111-Pentetreotide detected 9 out of 10 primary cancers. F-18-FDG imaged all the tumors (10). As regards the axillary nodes, Tc-99m-MIBI excluded axilla involvement in 7 out of 7 negative axillae (N-), while it was positive in 2 out of 3 positive cases (N+); In-111-Pentetreotide correctly identified 7 out of 8 negative axillae (N-), while it detected 2 of 3 positive sites. F-18-FDG visualized all positive axillary lymph nodes (4 out of 4 N+ patients) and correctly excluded involvement in all negative patients (6 out of 6 N- cases). This study demonstrated that all three tracers are adequate to be proposed as tumor seeking agents with the aim of developing non-invasive diagnostic methods for pre-operative detection of axillary metastases, so that surgical dissection can be limited to selected patients. The authors discuss the advantages and disadvantages of the different radiopharmaceuticals and conclude that in centers with PET facilities F-18-FDG is the best tumor seeking agent for the evaluation of axillary status. Between Tc-99m-Sesta MIBI and In-111-Pentetreotide the former seems to present more advantages in this kind of application, considering also its lower cost and easier availability. These results encourage further study, including the simultaneous comparison of these tracers in breast cancer staging.

Technetium-99m pentavalent dimercaptosuccinic acid imaging in patients with pituitary adenomas

We studied the tumor-seeking agent technetium-99m-labeled pentavalent dimercaptosuccinic acid ([99mTc](V)DMSA) to visualize 21 growth hormone (GH)-, nine prolactin (PRL)-, two mixed GH/PRL-, six adrenocorticotrophin (ACTH)-secreting and 15 clinically non-functioning pituitary adenomas, three craniopharyngiomas and one dysgerminoma of the sella. All non-adenomas and 31 out of 53 adenomas were studied before treatment: 22 after surgery and/or radiotherapy. Eight cases of acromegaly were studied before and after chronic treatment with octreotide, whereas three cases of acromegaly, one of prolactinoma and two of non-functioning adenoma were imaged before and after adenomectomy. As a control group, 27 patients without any clinical evidence of pituitary adenoma were studied: 10 of them were operated on previously and treated with iodine-131 for metastatic thyroid carcinoma, 10 had brain tumors and the remaining seven patients had functional pituitary hypersecretion (four Klinefelter's syndrome, two primary hypothyroidism and one Addison's disease). The scintigraphy was repeated after testosterone in Klinefelter's syndrome, L-thyroxine in primary hypothyroidism and cortisone administration in Addison's disease. Seventeen GH-secreting (81%), seven PRL-secreting (78%), three ACTH-secreting (50%), 15 non-functioning (100%) and one (50%) mixed adenoma significantly concentrated [99mTc](V)DMSA, showing elevated tumor-to-background (T/B) ratios. The T/B ratios were similar in untreated and surgically treated adenomas (11.2 +/- 5.6 vs 11.8 +/- 6.2). Radiotherapy significantly lowered the [99mTc](V)DMSA uptake to 5.1 +/- 2.8 (p < 0.1 vs untreated patients). Non-adenomatous lesions of the sella turcica did not concentrate [99mTc](V)DMSA in the pituitary as well as brain tumors and 8 out of 10 metastatic thyroid cancers. The treatment with octreotide normalized GH and insulin-like growth factor I levels and reduced [99mTc](V)DMSA from 15.7 +/- 4.8 to 13.5 +/- 3.9 (p < 0.05). Conversely, adequate substitutive therapy completely inhibited the uptake of the radiotracer in Klinefelter's syndrome, in primary hypothyroidism and in Addison's disease. The [99mTc](V)DMSA scintigraphy showed an overall sensitivity of 81% (43/53) in detecting pituitary adenomas, which was increased to 95% for lesions greater than 10 mm in size. High-quality images with minimal total body radiation were obtained, enabling a good in vivo characterization of viable adenomatous tissue as well as an accurate monitoring of the effects of different therapeutic regimens.

The Detection of Nasopharynx Carcinoma in Technetium-99m (V) Dimercaptosuccinic Acid SPECT imaging

Twenty-seven patients (24 men, 3 women; ages: 39-74 years) were diagnosed as having squamous cell carcinoma of the nasopharynx (NPC) as confirmed by pathologic findings of biopsies. In addition, three of the 27 patients had metastases to neck lymph nodes. The results of 2-4-hour SPECT images of the head and neck after intravenous injection of 15-20 mCi of Tc-99m (V) DMSA were compared with normal Tc-99m (V) DMSA images and CT of heads and necks. The results showed that of the 27 NPC cases, none of the patients had a significant uptake of Tc-99m (V) DMSA. However, in the three cases complicated with metastases of neck lymph nodes, the metastatic lesions could be detected by Tc-99m (V) DMSA. Our results challenge previous reports in which carcinomas of the head and neck were detected by Tc-99m (V) DMSA. The tumor-seeking agent Tc-99m (V) DMSA is not a good choice for the detection of NPC among malignancies of the head and neck.

AN ATOMIC BASIS OF CANCER—PHOTORADIATION THERAPY AND HEMATOPORPHYRIN DERIVATIVE

The principles of photoradiation therapy employing a tumor-seeking agent such as a hematoporphyrin derivative are described. The properties and preparation of hematoporphyrin derivatives and metalloporphyrin synthesis are briefly summarized. We show that PIXE analysis can be used to indicate the degree of a synthesis.

Fluorescence diagnosis and photochemical treatment of diseased tissue using lasers: Part I.

Lasers are useful in many applications in medicine and biology. Historically, most laser use has involved heat generated in the interaction of the laser beam with the tissue. Today, however, the spectroscopic aspects of this laser use are playing a more dominant role in a number of applications. In this two-part series, Sune Svanberg and co-workers present illustrations of emerging clinical applications from cooperative work performed by the Lund Institute of Technology and the Lund University Hospital. Part I includes a survey of laser techniques for atomic and molecular analyses of samples of medical interest, spectroscopic analysis of the laser-induced plasma obtained when a high-power pulsed laser beam interacts with tissue, and the use of tumor-seeking agents in combination with laser radiation to provide new possibilities for malignant tumor detection and treatment. Part II, which will appear in the January 1, 1990, issue, describes the use of laser-induced fluorescence for tumor and plaque diagnostics. Different lasers have been used, and research efforts increasingly are being focused on excimer lasers and lasers in the IR region for the ablation of atherosclerotic plaques, cell layer by cell layer.