The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR)最新文献

metastatic Matrix metalloproteinases (MMPs) are zinc-dependent secreted or transmembrane enzymes constituting a family of over 21 proteolytic members that are capable of selectively digesting a wide spectrum of both extracellular matrix (ECM) and nonmatrix proteins. MMPs play a critical role in tumor growth, angiogenesis, and metastatic processes. MMP inhibitors (MMPIs) have been extensively investigated as anti-tumor drugs, although the clinical trials thus far have been disappointing. In order to better understand the role of MMPs in cancer growth and metastasis, as well as improve the therapeutic efficacy of MMPIs, there is a need to develop new procedures to assess and/or monitor MMP activity in vivo. In addition to determining whether MMPs are present in tumors, it would be desirable to have an imaging agent that better probes other processes associated with MMP overproduction, including angiogenesis and the establishment of the growth of metastatic lesions in distant organ sites. In this paper we review the studies relating to the recent development of in vivo imaging of MMP expression. One of the purposes of this review is to discuss the current status of imaging MMP expression, which includes the types of tracers being developed and the types of imaging modalities available. Although imaging MMP expression is a relatively new area of research, the progress thus far is highly promising.

The vascular system that ensures an adequate blood flow is required to provide the cells with sufficient supply of nutrients and oxygen. Two different mechanisms of the formation of new vessels can be distinguished: vasculogenesis, the formation of the first primitive vascular plexus de novo and angiogenesis, the formation of new vessels from preexisting ones. Both processes are regulated by a delicate balance of pro- and anti-angiogenic factors. Physiologically, angiostatic mediators outweigh the angiogenic molecules and angiogenesis does not occur. Under certain conditions such as tumor formation or wound healing, the positive regulators of angiogenesis predominate and the endothelium becomes activated. Angiogenesis is initiated by vasodilatation and an increased permeability. After destabilization of the vessel wall, endothelial cells proliferate, migrate and form a tube, which is finally stabilized by pericytes and smooth muscle cells. Numerous soluble growth factors and inhibitors, cytokines and proteases as well as extracellular matrix proteins and adhesion molecules strictly control this multi-step process. The properties and interactions of angiogenic molecules such as VEGFs, FGFs, angiopoietins, PDGF, angiogenin, angiotropin, HGF, CXC chemokines with ELR motif, PECAM-1, integrins and VE-cadherin as well as angiostatic key players such as angiostatin, endostatin, thrombospondin, CXC chemokines without ELR motif, PEDF are discussed in this review with respect to their molecular impact on angiogenesis.

Tumour-induced angiogenesis plays an important role in tumour progression. Great efforts are made to develop therapeutic strategies to interfere with this process resulting in the starvation of the tumour. However, strategies to monitor conventional therapies seems to be inappropriate to control these approaches. Thus, there is a keen interest in developing methods supplying information about the corresponding therapeutical effects. Several radiotracer-based approaches focused on different targets in the angiogenic process are currently investigated. One class of tracers is based on matrix metalloproteinases inhibitors. These compounds show promising results in in vitro assays. However, initial data from in vivo studies using murine tumour models could not confirm successful non-invasive monitoring of MMP activity yet. Another strategy uses a radiolabelled single chain fragment against the ED-B domain of fibronectin, an extracellular matrix protein. Promising results demonstrated selective accumulation of the tracer in the tumour vasculature of a murine tumour model. Most of the studies are concentrated on the development of radiolabelled antagonists of the integrin alpha(v)beta(3). This heterodimeric transmembrane glycoprotein is involved in the migration of activated endothelial cells during formation of new vessels. Different compounds have been labelled with (18F), (111)In, (99m)Tc, (90)Y and several iodine isotopes. In in vitro assays most of them revealed high alpha(v)beta(3) affinity and selectivity. Moreover, in different murine tumour models successful non-invasive determination of alpha(v)beta(3) expression has been shown. Some of these approaches indicate that tumour-induced angiogenesis can be monitored in animal studies. Nevertheless, translation of these approaches into clinical settings allowing visualisation of tumour-induced angiogenesis in patients needs still to be demonstrated.

Tumor angiogenesis has significant implications in the diagnosis and treatment of various solid tumors. With the advent of fast, multi-slice CT scanners, CT imaging techniques capable of qualitative and quantitative analysis of tumor angiogenesis have been the subject of extensive investigation in the past 2 decades. The fundamental bases for CT imaging of angiogenesis are both the transport by blood flow of intravenously administered iodinated contrast material to tissue and the exchange by diffusion of these contrast molecules between the intravascular space and the extravascular interstitial space. With current fast CT scanners both tissue and vascular enhancement can be measured and traced over time at small time intervals to allow detailed modeling of the distribution of contrast agent in tissue. Both compartmental and distributed parameter models for contrast transport and exchange have been developed to quantify from the CT data the following angiogenesis related parameters: tissue blood flow, blood volume, mean transit time, contrast arrival time, capillary permeability surface area product and hepatic arterial fraction in case of the liver. This review addresses the following aspects of CT imaging of angiogenesis: 1) basic concepts related to the understanding of both compartmental and distributed parameter models; 2) comparison between both types of models; 3) practical issues with respect to the measurement of the arterial input function, which is required for the solution of both types of models; and, 4) illustration of the application of a distributed parameter model, the Johnson and Wilson model, in a number of experimental studies.

A common feature of solid tumors is the formation of new blood vessels (angiogenesis) within the tumor. A receptor called alpha(v)beta(3) is found on endothelial cells lining newly growing blood vessels at a higher density than on mature blood vessels. This receptor may provide a target for radioligands to permit imaging of a wide variety of solid tumors. The radioligands may range from macromolecules such as native ligands or monoclonal antibodies, to small proteins to very small peptides. The differing characteristics of these bio-molecules have an affect on target delivery and clearance time.

It is clear that various imaging modalities have given keen insight into the molecular mechanisms involved in anti-angiogenic treatments. A key to the advancement of anti-angiogenic therapy is not only the discovery of new drugs and treatments, but the analysis of the specific modes of action of these compounds in order to produce the next generation with greater effectiveness. While existing clinical methods incorporate the analysis of serum and urine to measure angiogenic factors, an imaging technique monitoring the effectiveness of anti-angiogenic therapy would be a convenient, noninvasive, cost effective technique to aid in treatment planning and disease management.

Aim: Paraneoplastic syndromes (PS) comprise a variety of clinical symptoms and diseases associated with underlying malignancy. Differentiation towards benign autoimmune diseases is necessary due to different therapeutic options. This diagnostic challenge includes cost- and time-consuming methods and is not successful in many cases. The aim of this study was the evaluation of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for detecting or ruling out malignancy in these patients.

Methods: In this retrospective work-up a total of 30 patients with suspected PS (m:f = 17:13, mean age 55, range 22-76 years) were examined with [(18)F]FDG-PET between 1996 and 2001. Diagnoses were erythrodermia, cerebellar degeneration, dermatomyositis, polyneuropathia and others. PET scans were compared to histopathological (n=14), radiological and follow up data (mean follow up 3.6 years, range 1-6 years).

Results: In 7 out of 30 patients (23%) an underlying malignancy was detected. Six out of 7 malignant neoplasms showed a distinctly increased glucose consumption. One benign neoplasm caused increased tracer uptake, another PET positive patient refused biopsy and showed no growth of a malignant tumour during clinical follow up of 28 months. The remaining 21 patients without suspicious glucose consumption did not demonstrate a malignancy in other diagnostic modalities or during subsequent clinical follow-up.

Conclusion: [(18)F]FDG-PET seems to be a useful tool in the diagnostic work-up of patients with suspected paraneoplastic syndrome.

Aim: To evaluate the usefulness of immunoscintigraphy with an anti-CEA monoclonal antibody fragment labelled with (99m)Tc for early detection of colorectal recurrence in patients with rising serum CEA levels.

Methods: Fifty-one consecutive patients (27 women, 24 men) with colorectal cancer (mean age 68.9+/-10.2 years) and rising CEA levels (16.2+/-18.2 ng/ml) were prospectively studied. Two immunoscintigraphy studies were performed in 8 patients (n=59). Immunoscintigraphy was performed after i.v. injection of 925 MBq of anti-CEA monoclonal antibody. Planar images of the thorax, abdomen and pelvis, as well as SPECT of the abdomen and pelvis were obtained at 4 and 24 hours after injection. In all cases an abdominal CT scan was previously performed. Findings were validated by histopathological analysis (28 cases) or by imaging and clinical follow-up of at least 6 months following the immunoscintigraphy (31 cases).

Results: Forty-one patients did not show recurrence during follow-up. We found 18 cases with confirmed diagnosis of extrahepatic abdominal or pelvic diseases, 11 cases with liver metastases, 9 in the thorax and 2 in the bone. In patients with pelvic and extrahepatic abdominal disease, immunoscintigraphy was positive in 18 cases (14 true positive, 4 false positive). From the 14 true positive only 7 cases had been detected by CT. Immunoscintigraphy was negative in the remaining 41 cases (37 true negative, 4 false negative). Therefore, the sensitivity and specificity for immunoscintigraphy in extrahepatic abdominal and pelvic disease were 78% and 90%, respectively. CT results showed a lower sensitivity of 61% (p<0.05) and specificity of 83%. Liver metastases were detected by CT in 9 cases, but only 2 of these were identified using immunoscintigraphy.

Conclusion: Scintigraphy with anti-CEA monoclonal antibody fragment labelled with (99m)Tc is superior to CT for the detection of pelvic and extrahepatic abdominal recurrence of colorectal cancer, while CT is more sensitive in the detection of liver and lung metastases. Immunoscintigraphy has a limited usefulness in the detection of distant metastases, but it may be helpful in the diagnosis of suspected colorectal recurrence in patients with non-conclusive CT findings, when FDG-PET is not available.

Aim: Monoclonal antibodies (MAb) directed at the extra cellular domain (ECD) of epidermal growth factor receptor (EGFR) offer a promising strategy for diagnosis and therapy of cancers that over-express EGFR. Radiolabelled MAbs against cell surface antigens have improved in vivo tumor diagnosis and treatment. EGFR over-expression has been reported in a wide range of carcinomas especially of the head and neck, breast, etc., and is associated with poor prognosis and resistance to therapy. CIBCNSH3 is a murine MAb generated to the ECD of EGFR in our laboratory and has been extensively characterized and has proven antitumor activity. The tumor targeting potential of (99m)Tc labelled CIBCNSH3 in an experimental tumor model is discussed in this paper.

Methods: A431, an epidermoid carcinoma cell line with overexpression of EGFR, SUDHLH, a lymphoma cell line was used to induce xenografts in inbred adult female BALB/C mice and used for the study. A reduction mediated method of (99m)Tc labelling was adopted to label the MAb. Scintiscan pictures were taken at different time intervals after i.v. administration of the (99m)Tc labelled MAb using a gamma camera and results were correlated with those of biodistribution studies.

Results: Immunoscan pictures taken at different time periods showed high uptake of the radioimmunoconjugate by the tumor providing clear tumor images and no uptake in control animals with lymphoma xenografts. Results of scan pictures correlated well with the biodistribution studies.

Conclusion: The radioimmunoconjugate (99m)Tc-CIBCNSH3 appears to be a promising tool in identifying any early recurrence and micro-metastasis of lesions that overexpress EGFR.

Aim: To determine the additional value of [(18)F]FDG-PET in combination with computed tomography (CT) over CT used alone, for evaluating ovarian cancer patients after primary treatment.

Methods: Twenty-five women (mean age: 53.6 years) had primary debulking surgery followed by chemotherapy for histologically proven ovarian carcinoma. At initial diagnosis, the tumor types were papillary serous adenocarcinoma (n=20), endometroid carcinoma (n=3), mixed mullerian tumor (n=1), and granulosa cell tumor (n=1). All patients underwent [(18)F]FDG-PET and contrast enhanced CT examinations, within 30 days of the completion of chemotherapic treatment. [(18)F]FDG-PET images were interpreted with the knowledge of CT findings (PET+CT); conversely, CT images were evaluated with no knowledge of the [(18)F]FDG-PET results. Within 7 day of imaging studies, 2(nd)-look laparoscopy (n=7) or laparotomy (n=18) was performed for histological confirmation. In all cases, imaging findings were then correlated with results of histopathologic examination.

Results: Of the 23 neoplastic viable lesions, all histologically confirmed, 16 could be detected by CT alone and 19 by PET+CT. An inflammatory lymph-node was misdiagnosed as viable tumor with both PET+CT and CT alone; an area of scar tissue in the presacral region was also misinterpreted as malignant tissue with CT alone. Overall lesion-based sensitivity, specificity and accuracy in assessing focal areas of residual tumor were as follows: 69.56%, 83.33%, 74.28% for CT, and 82.60%, 91.67%, 85.71% for PET+CT. The negative predictive value of PET+CT was markedly higher (73.33%), compared to that of CT alone (58.82%).

Conclusion: PET used in combination with CT allows to accurately assess tumor response. A major advantage of PET+CT over CT alone is in excluding the presence of residual viable lesions after treatment.