肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

磁性纳米粒子在肝细胞癌磁共振成像及靶向治疗方面的研究进展

超顺磁性纳米粒子作为新型材料在临床领域应用广泛,如医学成像及诊断、药物靶向治疗、磁热疗等。它不仅可以在肝细胞癌（HCC）的早期作出特异性诊断,更是一种理想的靶向药物纳米载体。介绍了磁性纳米粒子作为靶向药物载体的性质特点、磁共振成像原理、靶向HCC的作用机制等,重点介绍了磁性纳米粒子的表面修饰及功能化,及其在主动靶向药物输送系统中的应用。认为磁性纳米粒子的应用必将在HCC的诊治中发挥更大的作用。     

Current and potential applications of positron emission tomography for multiple myeloma and plasma cell disorders

Fluorine-18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) allows evaluation of elevated glucose metabolism in malignancies. There has been increasing interest in FDG PET/CT for plasma cell disorders since the International Myeloma Working Group outlined multiple applications of this imaging modality, including distinguishing smoldering myeloma from active multiple myeloma, confirmation of solitary plasmacytoma, and multiple indications in patients with known multiple myeloma, including determining extent of initial disease, monitoring therapy response, and detection of residual disease following therapy. The field of molecular imaging is now shifting focus from evaluation of metabolism to targeted evaluation of specific tumor markers. Targeted PET imaging targeted of CXCR4 and CD38 has advanced into translational clinical trials, bringing us closer to powerful imaging options for myeloma. In this review we discuss the current applications of FDG PET/CT in plasma cell disorders, as well as advances in targeted PET imaging.     

Clinical applications of positron emission tomography in hepatic tumors

Fluorodeoxyglucose (FDG), which allows the evaluation of glucose metabolism, is widely used for tumor diagnosis using positron emission tomography (PET). FDG‐PET, which is used for the diagnosis of intrahepatic tumor lesions, shows high FDG accumulation in cholangiocellular carcinoma (CCC) and metastatic liver cancer. FDG‐PET shows high FDG accumulation in moderately or poorly differentiated hepatocellular carcinoma (HCC) and is useful for the diagnosis of extrahepatic HCC metastases and recurrences. However, because the imaging method frequently shows low FDG accumulation in well‐differentiated HCC, it is not very useful for that diagnosis. For the diagnosis of well‐differentiated HCC, F‐18 fluorocholine for evaluation of phospholipid metabolism and C‐11 acetate for evaluation of free fatty acid metabolism are useful in the diagnosis of that HCC. It is expected that the combination of these PET agents will enhance the diagnostic performance of FDG‐PET for HCC in the future. The problem of a lack of anatomical information is being resolved with the development of the use of PET in combination with computed tomography or magnetic resonance imaging. For the problem of low resolution, PET devices using semiconductors have been developed.     

Fatty Acid Imaging of the Heart

Imaging metabolic processes in the human heart yields valuable insights into the mechanisms contributing to myocardial pathology and allows assessment of the efficacy of therapies designed to treat cardiac disease. Recent advances in fatty acid (FA) imaging using positron emission tomography (PET) include the development of a method to assess endogenous triglyceride metabolism and the design of new fluorine-18 labeled tracers. Studies of patients with diabetes have shown that the heart is resistant to insulin-mediated glucose uptake and that metabolism of nonesterified FA is upregulated. Cardiac PET imaging has also recently shown the increase in myocardial FA uptake seen in obese patients can be reversed with weight loss. And a pilot study of patients with chronic kidney disease demonstrated that PET imaging can reveal myocardial metabolic alterations that parallel the decline in estimated glomerular filtration rate. Recent advances in FA imaging using single photon emission computed tomography (SPECT) have been accomplished with the tracer β-methyl-p-[¹²³I]-iodophenyl-pentadecanoic acid (BMIPP). Two meta-analyses showed this imaging technique has a diagnostic accuracy for the detection of obstructive coronary artery disease that compares favorably with SPECT myocardial perfusion imaging and that BMIPP imaging yields excellent prognostic data in patients across the spectrum of coronary artery disease. A recent multicenter study of patients presenting with acute coronary syndromes found BMIPP SPECT imaging has greater diagnostic sensitivity than, and enhances the negative predictive value of, clinical assessment alone. Because of their exquisite sensitivity, nuclear imaging techniques facilitate the study of physiologic processes that are the key to our understanding of cardiac metabolism in health and disease.     

Human microbiome is a diagnostic biomarker in hepatocellular carcinoma

Background:Hepatocellular carcinoma(HCC)is the third leading cause of cancer mortality worldwide.Increasing evidence indicates a close relationship between HCC and the human microbiota.Herein,we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources:Several innovative studies have investigated the characteristics of the gut and oral micro-biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag-nostic biomarker of HCC.Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords"microbiota"or"microbiome"or"microbe"and"liver cancer"or"hepato-cellular carcinoma",and the results of clinical and experimental studies were analyzed.Results:Specific changes occur in the human microbiome of patients with HCC.Moreover,the gut mi-crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC.Furthermore,they also have certain diagnostic potential for precancerous diseases of HCC.The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future.Conclusions:The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC.The human microbiome may be widely used in the diagnosis,treatment and prognosis for multiple system diseases or cancers in the future.     

Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography

AIMS: The purpose of this study was to determine the feasibility of a new positron emission tomography (PET) imaging approach using an (18)F-labelled alpha(v)beta(3) integrin antagonist ((18)F-Galacto-RGD) to monitor the integrin expression after myocardial infarction. METHODS AND RESULTS: Male Wister rats were subjected to 20 min transient left coronary artery occlusion followed by reperfusion. Autoradiographic analysis and in vivo PET imaging were used to determine myocardial (18)F-Galacto-RGD uptake at different time points following reperfusion. RESULTS: PET imaging and autoradiography demonstrated no significant focal myocardial (18)F-Galacto-RGD uptake in non-operated control rats and at day 1 after reperfusion. However, focal accumulation in the infarct area started at day 3 (uptake ratio = 1.91 +/- 0.22 vs. remote myocardium), peaked between 1 (3.43 +/- 0.57) and 3 weeks (3.43 +/- 0.95), and decreased to 1.96 +/- 0.40 at 6 months after reperfusion. Pretreatment with alpha(v)beta(3) integrin antagonist c(-RGDfV-) significantly decreased tracer uptake, indicating the specificity of tracer uptake. The time course of focal tracer uptake paralleled vascular density as measured by CD31 immunohistochemical analysis. CONCLUSION: Regional (18)F-Galacto-RGD accumulation suggests up-regulation of alpha(v)beta(3) integrin expression after myocardial infarction, which peaks between 1 and 3 weeks and remains detectable until 6 months after reperfusion. This new PET tracer is promising for the monitoring of myocardial repair processes.     

Hepatocellular carcinoma--cause, treatment and metastasis

In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Down-staging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved. Different modes of regional cancer therapy for HCC have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising. Biotherapy, such as cytokines, differentiation inducers, anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progression as well as targets for intervention.     

SPECT Imaging for Detecting Coronary Artery Disease and Determining Prognosis by Noninvasive Assessment of Myocardial Perfusion and Myocardial Viability

Basic knowledge of active and passive transport mechanisms for concentrating monovalent cations in myocardial cells led to the investigation of the application of radioisotopes of potassium, thallium, rubidium, and ammonia to the in vivo noninvasive assessment of regional myocardial perfusion and viability utilizing gamma camera or positron emission tomographic (PET) imaging technology. Subsequently, technetium-99m (Tc-99m)-labeled isonitriles (sestamibi and tetrofosmin), which bind to mitochondrial membranes, emerged as superior imaging agents with single photon emission tomography (SPECT) imaging. When any of these imaging agents are injected intravenously during either exercise or pharmacologic stress, myocardial defects in tracer uptake represent either abnormal regional flow reserve or myocardial scar reflecting of coronary artery disease (CAD). The major clinical indications for stress SPECT or PET myocardial perfusion imaging are for detection of CAD as the cause of chest pain and risk stratification for prognostication. Patients with normal stress myocardial perfusion scans have an excellent prognosis with <1.0% annual rate future annual death or nonfatal infarction. The greater the extent and severity of ischemic perfusion defects (defects seen on stress images but improve on resting images), the greater the subsequent death or infarction rate during follow-up. Rest imaging alone is performed for determination of myocardial viability in patients with CAD and severe left ventricular dysfunction. Myocardial segments showing >50% uptake compared to normal uptake have a better long-term outcome with revascularization than with medical therapy with enhanced left ventricular function and improved survival. Other applications of SPECT imaging include the evaluation of cardiac sympathetic function, assessment of myocardial metabolism in health and disease, and molecular imaging of coronary atherosclerosis and myocardial stem cell therapy.     

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography

The noninvasive functional characterization of the cardiac sympathetic nervous system by imaging techniques may provide important pathophysiological information in various cardiac disease states. Hydroxyephedrine labeled with carbon 11 has been developed as a new catecholamine analogue to be used in the in vivo evaluation of presynaptic adrenergic nerve terminals by positron emission tomography (PET). To determine the feasibility of this imaging approach in the human heart, six normal volunteers and five patients with recent cardiac transplants underwent dynamic PET imaging after intravenous injection of 20 mCi [11C]hydroxyephedrine. Blood and myocardial tracer kinetics were assessed using a regions-of-interest approach. In normal volunteers, blood 11C activity cleared rapidly, whereas myocardium retained 11C activity with a long tissue half-life. Relative tracer retention in the myocardium averaged 79 +/- 31% of peak activity at 60 minutes after tracer injection. The heart-to-blood 11C activity ratio exceeded 6:1 as soon as 30 minutes after tracer injection, yielding excellent image quality. Little regional variation of tracer retention was observed, indicating homogeneous sympathetic innervation throughout the left ventricle. In the transplant recipients, myocardial [11C]hydroxyephedrine retention at 60 minutes was significantly less (-82%) than that of normal volunteers, indicating only little non-neuronal binding of the tracer in the denervated human heart. Thus, [11C]hydroxyephedrine, in combination with dynamic PET imaging, allows the noninvasive delineation of myocardial adrenergic nerve terminals. Tracer kinetic modeling may permit quantitative assessment of myocardial catecholamine uptake, which will in turn provide insights into the effects of various disease processes on the neuronal integrity of the heart.     

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.     

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.     

Cardiac positron emission tomography--current status and future perspectives

Positron emission tomography (PET) permits the non-invasive examination of myocardial metabolism. At present, combined imaging of myocardial blood flow and glucose metabolism are used to distinguish viable myocardium from scar tissue, which is particularly important for deciding on therapeutic interventions. In the future, further indications for PET imaging are foreseeable, with refined imaging techniques and development of new tracer substances. Tracers for assessment of adrenergic and muscarinic myocardial receptor density, as well as new positive markers of myocardial ischemia are currently being explored. Labeled amino acids are being employed for assessment of protein metabolism. Finally, C-11 acetate as a tracer of tricarboxylic acid cycle activity and myocardial oxygen consumption has been suggested for clinical use in initial studies in man.     

Positron Emission Tomography in oncology: Present and future of PET and PET/CT

PET is a crucial technique in molecular imaging, allowing in vivo assessment and localization of pathological processes, thanks to its ability to detect very small amounts of radioactive molecules. This is of particular interest in oncology where abnormal metabolism or synthesis in tumor cells but also various tumor characteristics can be studied using this nuclear medicine technique. FDG is currently the most widely used tracer, nowadays essential in the management of various malignancies, with large applications in diagnosis, initial assessment, therapy monitoring, and recurrence detection. The combination of anatomical information provided by PET/CT further increased its interest. Beyond its spread use in daily practice, future applications of PET will involve other tracers than FDG and develop research applications in humans as well as in small animals.     

Positron emission tomography scanning in the evaluation of hepatocellular carcinoma

BACKGROUND/AIMS: 18F-fluorodeoxyglucose uptake allows estimation of glucose metabolism by tumor cells using positron emission tomography (PET). We evaluated the role of PET imaging in the diagnosis of hepatocellular carcinoma. METHODS: PET images were collected after intravenous injection of 8-12 mCi of 18F-FDG in 20 patients with hepatocellular carcinoma (HCC). PET tumor activity level was assessed on a scale of 1 to 4 compared to normal liver tissue. The PET score was compared with abdominal computerized tomography (CT) scan results and between tumors of different grades and differentiation. RESULTS: Of the 20 patients studied, 11 (55%) had positive PET scans (PET score: 3 or 4) while nine (45%) were negative (PET score: 1 or 2). CT scan was positive in 18 patients (90%) and negative in two (10%). PET, however, revealed metastases in three patients that were not seen on CT. On pathological review, well-differentiated and low-grade tumors had lower PET scores. Comparison of the well-differentiated with the moderately- and poorly-differentiated tumors revealed a statistically significant difference. No statistical significance was observed between the moderately- and poorly-differentiated tumors or between different tumor grades and PET scores. CONCLUSIONS: The sensitivity of PET in diagnosis of HCC was 55% compared to 90% for CT scanning, although only PET detected some tumors (including distant metastases). Well-differentiated and low tumor grades had lower activity on PET and correspondingly lower PET scores. PET imaging may help assess tumor differentiation and may be useful in the diagnosis and staging and prognostication of HCC as an adjunct to CT.     

Positron-emission tomography for hepatocellular carcinoma:Current status and future prospects

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer mortality worldwide. Various imaging modalities provide important information about HCC for its clinical management. Since positron-emission tomography(PET) or PET-computed tomography was introduced to the oncologic setting, it has played crucial roles in detecting, distinguishing, accurately staging, and evaluating local, residual, and recurrent HCC. PET imaging visualizes tissue metabolic information that is closely associated with treatment. Dynamic PET imaging and dual-tracer have emerged as complementary techniques that aid in various aspects of HCC diagnosis. The advent of new radiotracers and the development of immuno-PET and PET-magnetic resonance imaging have improved the ability to detect lesions and have made great progress in treatment surveillance. The current PET diagnostic capabilities for HCC and the supplementary techniques are reviewed herein.     

Use of positron emission tomography with methyl-11C-choline and 2-18F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium

OBJECTIVE: To compare positron emission tomography (PET) and magnetic resonance imaging (MRI) in the evaluation of inflammatory proliferation of synovium. METHODS: Ten patients (mean +/- SD age 36 +/- 13 years) with inflammatory joint disease and with clinical signs of inflammation of the joint were studied. A new tracer for cellular proliferation, methyl-(11)C-choline ((11)C-choline), and a widely used tracer for the detection of inflammation and cancer, 2-(18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG), were applied for PET imaging, and the results were compared with the findings from gadolinium diethylenetriaminepentaacetic acid-enhanced MR images. The uptake of (11)C-choline and (18)F-FDG in the inflamed synovium was measured and expressed as the standardized uptake value (SUV) and the kinetic influx constant (K(i)) obtained from graphic analysis, and these values were compared with quantitative values on MRI. Synovial volumes were measured on the coronal contrast-enhanced T1-weighted MR images using the standard software of the MR imager. RESULTS: All patients showed high accumulation of both (11)C-choline and (18)F-FDG at the site of arthritic changes, where quantification of the tracer uptake was performed. The SUV of (11)C-choline was 1.5 +/- 0.9 gm/ml (mean +/- SD; n = 10) and the SUV of (18)F-FDG was 1.9 +/- 0.9 gm/ml (n = 10) (P = 0.017). The K(i) of (11)C-choline (mean +/- SD 0.048 +/- 0.042 minute(-1)) was 8-fold higher than the K(i) of (18)F-FDG (0.006 +/- 0.003 minute(-1)) (P = 0.009). Both the uptake of (11)C-choline and the uptake of (18)F-FDG correlated highly with the volume of synovium; the highest correlation was observed with the K(i) of (11)C-choline (r = 0.954, P < 0.0001). CONCLUSION: In the use of PET scans,(11)C-choline can be regarded as a promising tracer for quantitative imaging of proliferative arthritis changes. Nevertheless, subsequent prospective studies with larger numbers of patients are necessary to further characterize the relationship between the findings on PET imaging and the clinical and functional measures of inflammation.     

Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma

OBJECTIVE: The detection of increased fluorine-18 fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography (PET) is based on the enhanced glucose metabolism of tumor cells. Because the detection and staging of hepatocellular carcinoma (HCC) in patients with liver cirrhosis can be difficult, we prospectively evaluated the sensitivity of 18F-FDG PET in 14 consecutive patients with HCC. METHODS: Whole body and regional 18F-FDG PET of the liver were obtained. The results were compared with ultrasonography, contrast-enhanced, helical CT, histological grading, p53 protein expression of HCC, and serum alpha-fetoprotein (AFP) level. RESULTS: In 7 patients PET demonstrated increased tumor 18F-FDG uptake, whereas HCC was not distinguishable from nonmalignant liver tissue in 7 other patients. Hepatic lesions were detected by ultrasonography in all patients, whereas only 11 of 14 HCCs could be identified by CT. In 3 patients extrahepatic spread was demonstrated by 18F-FDG PET. Patients with increased tumor 18F-FDG uptake had significantly larger hepatic lesions and higher serum AFP levels than those with normal 18F-FDG uptake. Lesions could be visualized by 18F-FDG PET in 7 of 8 patients with moderately or poorly differentiated HCC, whereas none of the six well-differentiated tumors was detected. Two patients with strong p53 expression demonstrated increased tumor 18F-FDG uptake and extrahepatic metastases. CONCLUSIONS: The sensitivity of 18F-FDG PET for the imaging of HCC is low. Nevertheless, in patients with moderately or poorly differentiated HCC, tumors >5 cm, or with markedly elevated AFP levels 18F-FDG PET may contribute to an effective noninvasive staging.     

Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy

The incidence and mortality of hepatocellular carcinoma(HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.