PET in clinical oncology

Positron Emission Tomography (PET) is an imaging technique that produces cross sectional images based on tissue biochemical and physiological processes. PET complements other anatomic imaging techniques such as x-ray CT and magnetic resonance imaging (MRI). Fundamental processes such as glucose metabolism, oxygen metabolism, and blood flow can be imaged and quantified with PET, in addition to many other processes of both clinical and investigative interest. PET is now emerging as a clinical tool in oncology and is useful in noninvasively grading tumors, in determining tumor activity and recurrence, and in monitoring the effects of a variety of therapeutic interventions with tumors. While most of the applications of PET in oncology to date have been in brain tumors, the technique is now being applied in tumor evaluations outside of the central nervous system.Operated for the U.S. Department of Energy by the University of California under Contract #DE-AC03-76-SF00012.     

Imaging tumour hypoxia with positron emission tomography

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.     

The evolution of imaging in cancer: current state and future challenges

Molecular imaging allows for the remote, noninvasive sensing and measurement of cellular and molecular processes in living subjects. Drawing upon a variety of modalities, molecular imaging provides a window into the biology of cancer from the subcellular level to the patient undergoing a new, experimental therapy. As signal transduction cascades and protein interaction networks become clarified, an increasing number of relevant targets for cancer therapy--and imaging--become available. Although conventional imaging is already critical to the management of patients with cancer, molecular imaging will provide even more relevant information, such as early detection of changes with therapy, identification of patient-specific cellular and metabolic abnormalities, and the disposition of therapeutic, gene-tagged cells throughout the body--all of which will have a considerable impact on morbidity and mortality. This overview discusses molecular imaging in oncology, providing examples from a variety of modalities, with an emphasis on emerging techniques for translational imaging.     

Advancing animal models of neoplasia through in vivo bioluminescence imaging

Malignant disease is the final manifestation of complex molecular and cellular events leading to uncontrolled cellular proliferation and eventually tissue destruction and metastases. While the in vitro examination of cultured tumour cells permits the molecular dissection of early pathways in tumorigenesis on cellular and subcellular levels, only interrogation of these processes within the complexity of organ systems of the living animal can reveal the full range of pathophysiological changes that occur in neoplastic disease. Such analyses require technologies that facilitate the study of biological processes in vivo, and several approaches have been developed over the last few years. These strategies, in the nascent field of in vivo molecular and cellular imaging, combine molecular biology with imaging modalities as a means to real-time acquisition of functional information about disease processes in living systems. In this review, we will summarise recent developments in in vivo bioluminescence imaging (BLI) and discuss the potential of this imaging strategy for the future of cancer research.     

State-of-the-art molecular imaging in esophageal cancer management: implications for diagnosis,prognosis, and treatment

Molecular imaging techniques are increasingly being used in addition to standard imaging methods such as endoscopic ultrasound (EUS) and computed tomography (CT) for many cancers including those of the esophagus. In this review, we will discuss the utility of the most widely used molecular imaging technique, ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET). ¹⁸F-FDG PET has a variety of potential applications ranging from improving staging accuracy at the time of initial diagnosis to assisting in radiation target volume delineation. Furthermore, ¹⁸F-FDG PET can be used to evaluate treatment response after completion of neoadjuvant therapy or potentially during neoadjuvant therapy. Finally, we will also discuss other novel molecular imaging techniques that have potential to further improve cancer care.     

Application of PET/CT in the development of novel anticancer drugs

Combined positron emission tomography/computed tomography (PET/CT) is a relatively new imaging modality, combining the functional images of PET with the anatomical information of CT. Since its commercial introduction about 5 years ago, PET/CT has become an important tool in oncology. Currently, the technique is used for primary staging and restaging of cancer patients, as well as for surgery and radiation therapy planning. The abilities of PET/CT to measure early treatment response as well as drug distribution within the body make this technique very useful in the development of novel anticancer drugs. In this paper, the recent literature on the current role of PET/CT in drug development is reviewed.     

Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients

Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.     

基于LI-RADS多参数MRI诊断肝细胞癌的研究进展

肝细胞癌是常见的恶性肿瘤，早期与准确地诊断对于临床治疗与患者预后至关重要。MRI在软组织病变的显示方面有着巨大优势，随着近年来MRI功能成像技术的不断发展，诸如扩散加权成像、磁共振动态增强成像等在内的多种新技术能够无创地从细胞甚至分子层面了解肝脏的能量代谢、血流等方面的变化，结合传统的T1、T2加权成像及脂肪抑制技术使得肝癌的检出率、准确率大大提高。肝脏影像报告和数据管理系统旨在规范病变的影像描述，标准化影像诊断术语。本文就基于LI-RADS的多参数MRI诊断肝细胞癌的研究进展进行综述。     

Current status of positron emission tomography in oncology

Positron emission tomography (PET) has emerged as a powerful diagnostic tool in oncology patients. There is evidence of the superior utility over conventional imaging methods of the principal PET tracer ¹⁸F‐fluoro‐2‐deoxy‐glucose in the staging of a range of cancers and monitoring disease recurrence, as well as changing patient management to more appropriate therapy. The methods for evaluating the evidence for PET remain complex, particularly as the standard evidence‐based approach of randomized controlled trials is not generally applicable to imaging technologies. PET has the potential to dramatically improve our ability to manage patients with cancer and is also making major contributions to the development of new therapies. (Intern Med J 2000; 31 : 27–36)     

A case of Lhermitte-Duclos disease presenting high FDG uptake on FDG-PET/CT

Lhermitte-Duclos Disease (LDD) is a rare cerebellar lesion that has long been controversial as to whether the entity is a hamartoma, a malformation, or a neoplasm. Recent advances in metabolic imaging and molecular biology have unveiled biological features of LDD and a close relationship between LDD and Cowden disease. Adult onset LDD is now considered identical to Cowden disease in a US guideline. We present a case of LDD, in which high fluorodeoxy glucose (FDG) uptake was shown on PET/CT. We performed dual time point scans, in which a delayed scan exhibited more intense FDG uptake by the hamartomatous lesion than an early scan. We must remain aware of the possibility of LDD when intense accumulation is observed in a cerebellar lesion on FDG-PET/CT imaging.     

Molecular imaging for personalized cancer care

Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization and measurement of the key biomolecules and molecularly based events that are fundamental to the malignant state. This article outlines the basic principles of molecular imaging as applied in oncology with both established and emerging techniques. It provides examples of the advantages that current molecular imaging techniques offer for improving clinical cancer care as well as drug development. It also discusses the importance of molecular imaging for the emerging field of theranostics and offers a vision of how molecular imaging may one day be integrated with other diagnostic techniques to dramatically increase the efficiency and effectiveness of cancer care.     

Computational oncology

Oncology research has traditionally been conducted using techniques from the biological sciences. The new field of computational oncology has forged a new relationship between the physical sciences and oncology to further advance research. By applying physics and mathematics to oncologic problems, new insights will emerge into the pathogenesis and treatment of malignancies. One major area of investigation in computational oncology centers around the acquisition and analysis of data, using improved computing hardware and software. Large databases of cellular pathways are being analyzed to understand the interrelationship among complex biological processes. Computer-aided detection is being applied to the analysis of routine imaging data including mammography and chest imaging to improve the accuracy and detection rate for population screening. The second major area of investigation uses computers to construct sophisticated mathematical models of individual cancer cells as well as larger systems using partial differential equations. These models are further refined with clinically available information to more accurately reflect living systems. One of the major obstacles in the partnership between physical scientists and the oncology community is communications. Standard ways to convey information must be developed. Future progress in computational oncology will depend on close collaboration between clinicians and investigators to further the understanding of cancer using these new approaches.     

Imaging of tumor glucose utilization with positron emission tomography

In recent years, imaging of tumor glucose metabolism with positron emission tomography and fluorodeoxyglucose (FDG-PET) has become a routine test for detection, staging and restaging of malignant lymphomas and many solid tumors. FDG-PET is also increasingly used to monitor the effects of chemotherapy. The success of FDG-PET in oncologic imaging has generated considerable interest in understanding the molecular mechanisms underlying the markedly accelerated glucose use of almost all human cancers. Recent studies have indicated that there may be a close relation between the activation of oncogenic signaling pathways and cellular glucose utilization. For example deregulation of Akt, ras and MYC as well as loss of p53 function have been reported to confer increased glucose metabolic rates in cancer cells. These findings suggest that imaging of tumor glucose utilization may represent a marker for the activity of oncogenic pathways and metabolic changes during therapy may be used as a readout for the effectiveness of drugs targeting these pathways. However, the mechanisms for increased glucose metabolic activity of cancers cells are multifactorial and clinical studies will be necessary to determine in which context imaging of tumor glucose metabolism may be used for treatment monitoring.     

Implementation of hypoxia imaging into treatment planning and delivery

Purpose

To review the current status of implementation of functional hypoxia imaging in radiotherapy (RT) planning and treatment delivery.

Methods

Before biological imaging techniques such as positron emission tomography (PET) or magnetic resonance (MR) can be used for individual RT adaptation, three main requirements have to be fulfilled. First, tissue parameters have to be derived from the imaging data that correlate with individual therapy outcome. Then, the spatial and temporal stability of hypoxia PET images needs to be established. Finally, the dose painting (DP) concepts have to be practically feasible to be used as a basis for clinical trials.

Results

A number of recent clinical studies could show the correlation of hypoxia PET imaging with different tracers and RT outcome. Most of the studies revealed a correlation between mean or maximum values and parameters assessed from the PET avid volume and treatment success, only few investigations used quantitative imaging. Multiparametric imaging seems to be very valuable. Recently, the spatial and temporal stability of hypoxia PET attracted attention. Temporal changes in the distribution of functional tumour properties were reported. Furthermore, technical feasibility of DP by contours (DPC) as well as DP by numbers (DPBN) was shown by several investigators. The challenge is now to design clinical studies in order to prove the impact of DP treatments on individual therapy success.

Conclusion

A patient-specific adaptation of RT based on functional hypoxia imaging with PET is possible and promising. Conceptual feasibility could be shown for DPBN whereas to date, only DPC seems to be plausible and feasible in a clinical context.     

Optical Coherence Tomography: Feasibility for Basic Research and Image-guided Surgery of Breast Cancer

Diagnostic trends in medicine are being directed toward cellular and molecular processes, where treatment regimens are more amenable for cure. Optical imaging is capable of performing cellular and molecular imaging using the short wavelengths and spectroscopic properties of light. Diffuse optical tomography is an optical imaging technique that has been pursued as an alternative to X-ray mammography. While this technique permits non-invasive optical imaging of the whole breast, to date it is incapable of resolving features at the cellular level. Optical coherence tomography (OCT) is an emerging high-resolution biomedical imaging technology that for larger and undifferentiated cells can perform cellular-level imaging at the expense of imaging depth. OCT performs optical ranging in tissue and is analogous to ultrasound except reflections of near-infrared light are detected rather than sound. In this paper, an overview of the OCT technology is provided, followed by images demonstrating the feasibility of using OCT to image cellular features indicative of breast cancer. OCT images of a well-established carcinogen-induced rat mammary tumor model were acquired. Images from this common experimental model show strong correlation with corresponding histopathology. These results illustrate the potential of OCT for a wide range of basic research studies and for intra-operative image-guidance to identify foci of tumor cells within surgical margins during the surgical treatment of breast cancer.     

Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease.

BACKGROUND: Positron emission tomographic (PET) scanning utilizing [18F]fluorodeoxyglucose (FDG) is a new method of tumor imaging based on the increased glucose metabolic activity of malignant tumors. In Hodgkin's disease (HD), PET has proven value for the evaluation of residual masses following treatment and for the early diagnosis of relapse. In the initial staging of HD, PET frequently shows a higher stage than conventional methods (upstaging by PET). In the present study, we evaluated the frequency of stage changes by PET in a multicenter setting and determined its prognostic relevance. PATIENTS AND METHODS: A total of 73 patients with newly diagnosed HD were staged with both conventional methods and whole-body PET scanning. All histological types and stages were represented. The median time of follow-up after the initial diagnosis was 25 months (range 1 month to 5 years). The response to treatment was determined by standard clinical and diagnostic criteria. For the purpose of this analysis, data from a PET center associated with a university medical center and a PET center associated with a group oncology practice were combined. RESULTS: A total of 21 patients (28.8%) were upstaged by PET compared with conventional methods. In two cases (2.7%), a lower stage was suggested by PET scanning. With one possible exception, the upstaging had no obvious clinical or biological correlate. Among 12 patients in stage I (A + B) by conventional methods, seven were upstaged by PET (58.3%), four to stage II, one to stage III and two to stage IV. Among 42 patients in stage II, eight were upstaged by PET (19.0%), six to stage III and two to stage IV. Among 12 patients in stage III, six (50%) were upstaged to stage IV by PET. If only early-stage patients and major changes are considered (stages IA-IIB to III or IV), among 49, 10 were upstaged to III or IV, whereas in 39 staging was unchanged following PET. In the former group, three relapsed or were refractory compared with none in the latter group (P<0.006). In advanced stage patients (IIIA or IIIB) a trend toward treatment failure was apparent in patients who were upstaged by PET. CONCLUSIONS: PET scanning is an interesting new modality for the accurate staging of patients with HD and frequently shows a higher stage than conventional methods. PET should be performed at initial diagnosis and should be included in prospective studies of patients with HD. Upstaging by PET may represent a risk factor for a more advanced stage or a biologically more aggressive tumor. Patients with early-stage disease as identified by conventional methods have a significant risk of treatment failure if a more advanced stage is indicated by PET. At present, major stage changes suggested by PET imaging should be confirmed by an independent diagnostic method.     

Molecular imaging in oncology.

Cancer is a genetic disease that manifests in loss of normal cellular homeostatic mechanisms. The biology and therapeutic modulation of neoplasia occurs at the molecular level. An understanding of these molecular processes is therefore required to develop novel prognostic and early biomarkers of response. In addition to clinical applications, increased impetus for the development of such technologies has been catalysed by pharmaceutical companies investing in the development of molecular therapies. The discipline of molecular imaging therefore aims to image these important molecular processes in vivo. Molecular processes, however, operate at short length scales and concentrations typically beyond the resolution of clinical imaging. Solving these issues will be a challenge to imaging research. The successful implementations of molecular imaging in man will only be realised by the close co-operation amongst molecular biologists, chemists and the imaging scientists.     

Quelles perspectives pour l’imagerie photonique in vivo en pratique clinique ?

With the increasing molecular understanding of disease processes, there has been a dramatic change, over the past years, in our consideration of non invasive imaging of cancer in humans. The miniaturization of optical devices, and fiber optic coupling greatly improved the ability of in-vivo photon imaging to emphasis pathological pathways at molecular level or to achieve true “optical biopsy”. Innovative fluorescent imaging agents called “smart probes” can provide in-vivo readouts of some of the key activities known to underlie human disease states in oncology. The current contribution of biophotonics in clinical imaging remains limited but diffuse optical tomography of the breast has paved the way. New optical concepts come to age and should soon find their place among the other imaging modalities.     

The role of PET in the surgical approach to adrenal disease

Positron emission tomography provides a new approach to the investigation of adrenal disease and has created a new imaging paradigm with hybrid PET/CT where high resolution anatomy and tissue function can be mapped simultaneously. Of the principal radiopharmaceuticals available for adrenal PET studies, ¹⁸F-FDG has the greatest utility in identifying adrenal cancer and in distinguishing benign from malignant disease in incidentally discovered adrenal masses. Despite the obvious value of FDG imaging in cancer, it's accumulation in benign processes – infection and inflammation may actually confound functional characterization in some instances, where a more specific agent for cancer would be welcome. The adrenocortical imaging agent ¹⁸F-MTO depicts tissues of cortical origin and may, like radiolabeled cholesterol, be used to functionally characterize the adrenal cortex in Cushing syndrome and aldosteronism, perhaps with the use of pharmacologic suppression of inner cortical function, but it cannot distinguish adrenocortical carcinoma from adrenal adenoma, an important utility in the non-invasive evaluation of an adrenal mass. Positron-labeled intermediates of catecholamine metabolism, in particular ¹⁸F-DA and perhaps gallium-68 labeled somatostatin-analogs, can be used to localize tumors of sympathomedulla origin and may outperform ¹³¹I- and ¹²³I-labeled MIBG and ¹¹¹In-octreotide in depicting remote metastases of pheochromocytoma. It is obvious that each of these imaging agents can provide important information and play a critical role, along with other non-PET radiopharmaceuticals in the pre- and postsurgical evaluations and management of specific adrenal diseases, but they must be used judiciously in the proper clinical context with an awareness of their diagnostic weaknesses.

Conflict of interest

Dr. Milton D. Gross, Dr. Paul Gauger, Dr. Mehdi Djekidel and Dr. Domenico Rubello stated that they had no relationship with other persons or organisations, both financial and personal that could potentially bias the present work.     

L’imagerie en radiothérapie

The goal of radiation therapy is to deliver a high-dose of radiation to the tumour or target region to improve local control of disease and a low-dose to normal soft tissues to limit side effects. Conformal radiation therapy, intensity modulated radiotherapy (IMRT), brachytherapy and stereotactic radiosurgery have been developed to achieve the desired dose distribution. They require precise imaging of internal anatomy so that it is well adapted to the tumour and organs at risk. Indeed, morphological imaging such as computed tomography is already recommended for radiotherapy planning. But radiation oncologists are also considering other imaging modalities for treatment planning and imaging tools capable of controlling patient motion during treatment. The aim of this article is to present and illustrate the place of imaging during treatment planning and delivery via techniques such as: 4D computed tomography, morphological and functional MRI, positron emission tomography, and imaging devices mounted on accelerators.