PETCT Imaging in Cancer Current Applications and Future

PET/CT Imaging in Cancer:Current Applications and Future

Directions

Michael D.Farwell,MD;Daniel A.Pryma,MD;and David A.Mankoff,MD,PhD

Positron emission tomography(PET)is a radiotracer imaging method that yields quantitative images of regional in vivo biology and biochemistry.PET,now used in conjunction with computed tomography(CT)in PET/CT devices,has had its greatest impact to date on cancer and is now an important part of oncologic clinical practice and translational cancer research.In this review of current appli-cations and future directions for PET/CT in cancer,the authors first highlight the basic principles of PET followed by a discussion of the biochemistry and current clinical applications of the most commonly used PET imaging agent,18F-fluorodeoxyglucose(FDG).

Then,emerging methods for PET imaging of other biologic processes relevant to cancer are reviewed,including cellular proliferation, tumor hypoxia,apoptosis,amino acid and cell membrane metabolism,and imaging of tumor receptors and other tumor-specific gene products.The focus of the review is on methods in current clinical practice as well as those that have been translated to patients and are currently in clinical trials.Cancer2014;000:000-000.V C2014American Cancer Society.

KEYWORDS:cancer,positron emission tomography,fluorodeoxyglucose F18,metabolism,cell proliferation,hypoxia,protein synthesis, apoptosis.

INTRODUCTION

Conventional imaging modalities,such as plain radiography,ultrasound,computed tomography(CT),and magnetic res-onance imaging(MRI),have been used for many years to identify and characterize tumors based on anatomic differences in density,water content,shape,and size.More recently,functional imaging modalities like18F-fluorodeoxyglucose-posi-tron emission tomography(FDG-PET)have been developed that are capable of characterizing tumors based on biochemi-cal changes at the molecular level.Since the year2000,the number of FDG-PET scans performed in the United States has increased about9-fold,and it is estimated that,in2011,about1.8million studies were performed,and94%of the studies were done for cancer.1This dramatic increase in use is likely being driven by several factors,one of which is the higher sen-sitivity and specificity of FDG-PET for the detection and staging of many tumors compared with anatomic imaging modalities.2,3In addition,PET is being used increasingly to assess therapeutic response and to characterize tumor biology. In this review,we highlight the various applications of PET imaging in cancer,including its role in personalized medicine. Although FDG continues to be the most widely used radiotracer for PET imaging(96%of PET studies in2011used FDG),some of the newer PET imaging agents that have been studied in humans will also be reviewed(Table1). Principles of PET Imaging

PET imaging uses radiopharmaceuticals labeled with positron emitting radioisotopes such as11C,13N,15O,and18F, which are produced in a cyclotron,and68Ga and82Rb,which are produced in a radioisotope generator.After a positron is emitted,it annihilates with a nearby electron and generates2annihilation photons(each with an energy of511keV), which travel in opposite directions.PET scanners are equipped with coincidence electronics to detect these pairs of pho-tons as they hit opposing detectors nearly simultaneously.Single unpaired photons occur when one of the annihilation photons is absorbed in the body or is not detected.Although these single photons are excluded by the coincidence win-dow,additional processes occur in PET imaging that degrade image contrast and need to be accounted for in quantitative PET imaging.Thus,various algorithms and techniques are required to correct for random coincidence events,scatter, dead-time,and various sensitivity among detectors.For accurate quantitative results,one of the most important correc-tions to the acquired PET image is attenuation correction.This correction is necessary because photons released from the Corresponding author:Michael D.Farwell,MD,Division of Nuclear Medicine and Molecular Imaging,Department of Radiology,Hospital of the University of Pennsylvania,3400Spruce Street,Philadelphia,PA19104;Fax:(215)349-5843;michael.farwell@https://www.wendangku.net/doc/f714188811.html,

Department of Radiology,Hospital of the University of Pennsylvania,Philadelphia,Pennsylvania.

DOI:10.1002/cncr.28860,Received:March14,2014;Revised:May5,2014;Accepted:May5,2014,Published online Month00,2014in Wiley Online Library (https://www.wendangku.net/doc/f714188811.html,)

center of the body,on the average,are attenuated to a

greater extent than photons released from the periphery.

One of the advantages of hybrid PET/CT systems is that

the corresponding CT images can be used for anatomic

localization as well as attenuation correction.

FDG-PET Background

FDG has its origin in the work of Sokoloff et al,who

developed a method to measure regional cerebral glucose

metabolism in animals using14C-deoxyglucose autoradi-

ography.4Although14C-deoxyglucose is transported into

cells in parallel with glucose and is phosphorylated by hex-

okinase to14C-deoxyglucose-6-phosphate,because it

lacks a hydroxyl group at the2position,it is prevented

from being a substrate of enzymes farther down the glyco-

lytic pathway.Thus,14C-deoxyglucose-6-phosphate

becomes trapped within cells,providing a measure of the

metabolic rate.This concept was extended when FDG

was developed,because FDG also lacks a hydroxyl group

in the2position.In a similar fashion,FDG is transported

into cells and phosphorylated,and it becomes trapped

within cells as FDG-6-phosphate.5When labeled with 18F,which is a positron-emitting radioisotope,FDG can be imaged with PET and used to quantify regional glucose

metabolism in humans.6

Radiotracer uptake in PET imaging can be quanti-

fied from dynamic acquisitions performed over a period

of time or from static acquisitions performed at a fixed

point in time.In the research setting,dynamic imaging is

often performed to measure the radiotracer uptake over

time,yielding plots of radioactivity concentration versus

time known as time-activity curves.Kinetic modeling can

then be used,sometimes in conjunction with blood sam-

pling,to estimate the rate of uptake and trapping of a

radiotracer or to estimate the density of a receptor of inter-

est.Because dynamic imaging is time consuming and dif-ficult to perform over the whole body,clinical studies usually acquire a single image at approximately60 minutes after injection of FDG.This static image is then used to calculate a simplified measure of FDG uptake, known as the standardized uptake value(SUV).7The SUV represents the concentration of radioactivity in the tumor tissue,normalized to the injected FDG dose and the body weight of the patient;the SUV is equal to1for an evenly distributed tracer.Because the SUV is typically calculated at approximately60minutes after injection of radiotracer,the radioactivity in metabolically active tissues is predominantly due to phosphorylated FDG rather than nonphosphorylated intracellular/intravascular FDG. Thus,the SUV is roughly proportional to the net rate of FDG phosphorylation.8However,SUVs are also affected by a variety of factors other than tumor glucose use;these include the time interval between injection and imaging, the size of the lesion,image reconstruction parameters, and the spatial resolution of the PET scanner.In addition, differences in the affinity and kinetics of glucose trans-porters and hexokinase for FDG versus glucose lead to variation in the relative trapping of each substrate in dif-ferent tissues and tumors.9Thus,although SUVs do not provide an accurate absolute measure of tumor glucose use,they are useful for assessing interval change in metab-olism,because many of the confounding issues with SUVs are negated by measuring relative change.With properly calibrated imaging devices and adherence to standard patient preparation and imaging protocols,the test-retest TABLE1.Overview of Current Positron Emission

T omography Radiotracers Used in Cancer Imaging Class/Radiotracer Target Clinical Status

Metabolism

18F-FDG Hexokinase FDA approved 18F-FLT Thymidine kinase Phase3

18F-FMAU Thymidine kinase Phase1

18F-ISO-1Sigma-2Phase0 Hypoxia

18F-FMISO Low oxygen Phase2

64Cu-ATSM Low oxygen Phase2

18F-EF5Low oxygen Phase2

18F-FAZA Low oxygen Phase2

18F-FETA Low oxygen Preclinical Apoptosis

18F/99m Tc-annexin V Phosphytidylserine Phase2

18F-ML-10Apoptotic changes Phase2

18F-ICMT-11Caspases Phase0

18F-CP18Caspases Phase0 Protein synthesis

11C-MET Amino acid transporters Phase2

18F-FET Amino acid transporters Phase2

18F-FMT Amino acid transporters Phase1

18F-FACBC Amino acid transporters Phase2 Membrane metabolism

11C-choline Choline kinase FDA approved 18F-choline Choline kinase Phase2

Tumor-specific agents

68Ga-DOTA-TOC Somatostatin Phase2

18F-FES Estrogen receptor Phase2

68Ga-PSMA PSMA Phase1

Abbreviations:11C-MET,11C-methionine;64Cu-ATSM,64Cu-diacetyl-bis(N4-methylthiosemicarbazone);18F-CP18,18F-radiolabeled pentapeptide-based substrate of caspase-3;18F-EF5,18F-radiolabeled derivative of etanidazole; 18F-FACBC,1-amino-3-18F-fluorocyclobutane-1-carboxylic acid;18F-FAZA, 18F-fluoroazomycin arabinoside;18F-FDG,18F-fluorodeoxyglucose;18F-FES, 18F-fluoroestradiol;18F-FET,18F-fluoroethyl-tyrosine;18F-FETA,18F-fluoroetani-dazole;18F-FLT,18F-fluorothymidine;18F-FMAU,1-(2’-deoxy-2’-18F-fluoro-beta-D-arabinofuranosyl)thymine;18F-FMISO,18F-fluoromisonidazole;18F-FMT, 18F-fluoromethyl-tyrosine;18F-ICMT-11,18F-radiolabeled derivative of isatin; 18F-ISO-1,N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide;18F-ML-10,18F-radiolabeled derivative of malonic acid;68Ga-DOTA-TOC,68Ga-DOTA-Tyr3-octreotide;68Ga-PSMA, 68Ga-radiolabeled prostate-specific membrane antigen ligand;FDA,US Food and Drug Administration;PSMA,prostate-specific membrane antigen.

reproducibility of SUVs in tumors and normal tissues is

high,and relative changes in SUVs as small as20%can be

used as a criterion for a metabolic response to

therapy.10,11

The use of FDG as an agent for cancer detection is

based on the observation of Warburg in the1920s that can-

cer cells have abnormally high rates of glycolysis.12Even

when tumor cells have sufficient oxygen supply,they pref-

erentially generate energy using anaerobic glycolysis fol-

lowed by metabolism of pyruvate into lactic acid.13In

addition to elevated glycolysis,tumors often have increased

expression of glucose transporters(GLUTs).These trans-

porters allow energy-independent transport of glucose

across the cell membrane down a concentration gradient.

In malignant tumors,GLUT-1is frequently overexpressed,

but expression levels of GLUT-2,GLUT-3,GLUT-4,

GLUT-5,and GLUT-12also reportedly are increased in

several tumors types.14The relative importance of GLUTs

versus hexokinase activity continues to be debated,and it is

likely that,in a given cell type,one may predominate.

FDG has gained widespread use in the clinic for sev-

eral reasons.First,unlike glucose,FDG is excreted in the

urine,which results in relatively rapid clearance of the

radiotracer from the blood pool.Second,hexokinase,the

target of FDG,is ubiquitous and very efficient.The net

result of these2points is that very high target-to-

background ratios are achieved by60minutes,with just

enough background activity to enable localization of FDG-

avid tumors relative to the physiologic pattern of FDG

uptake.Third,there are few radiolabeled metabolites of

FDG in the blood,which makes analysis of FDG uptake

more straightforward.Finally,the110-minute half-life of 18F allows FDG to be produced at a central facility and transported to nearby imaging centers;thus,it is not lim-

ited to large academic centers with cyclotron facilities.

FDG-PET for Cancer Detection

FDG was first used to study tumors in the1980s by Di Chiro,who demonstrated that the degree of malignancy of brain tumors was correlated with their FDG uptake.15 Because FDG accumulates in most cancer cells to a greater degree than noncancer cells,FDG-PET is a very general approach to cancer imaging.Thus,FDG-PET has achieved widespread use for the detection of cancer,pri-marily in staging newly diagnosed or recurrent cancers. Results from the National Oncologic PET Registry, which included data from85,658patients with a wide va-riety of cancer types,concluded that FDG-PET imaging changed physicians’intended management in about36% of patients.16The dominant impact was a change from nontreatment to treatment,which occurred in29%of patients;the reverse pattern,changing from treatment to nontreatment,occurred in about7%of patients.The types of cancer that are most commonly imaged with FDG-PET include lymphoma,head and neck cancer, lung,colorectal cancer,breast cancer,esophageal cancer, melanoma,cervical cancer,thyroid cancer,and pancreatic cancer.17-19Some of these cancers,such as aggressive lym-phoma,squamous cell carcinoma of the head and neck, and melanoma,are usually“hot”on FDG-PET.20Other cancers,such as prostate cancer,neuroendocrine cancer, and well differentiated hepatocellular carcinoma,are often “cold,”which limits the utility of FDG-PET in those tumors.21,22Still other cancers,such as breast and thyroid cancers,demonstrate a range of FDG uptake,which may be related to incompletely understood biologic factors.23 Recent studies have demonstrated that the activation of a variety of oncogenes results in increased FDG uptake.24Thus,in many patients,the degree of FDG uptake is a marker of tumor dedifferentiation.For exam-ple,when prostate cancer and thyroid cancer lose their ability to respond to androgens and trap iodine,respec-tively,they are much more likely to be observed with FDG-PET.25,26Because many factors contribute to increased FDG uptake in cancer cells,some studies have suggested that FDG-PET provides a unique measure of tumor biology that is distinct from in vitro assays.23 False-positive findings are relatively common on FDG-PET,because elevated glycolysis is not limited to cancer cells.17Typical causes of increased FDG uptake unrelated to malignancy include infectious and inflamma-tory etiologies,muscular activity,metabolism in brown fat,and changes in response to bone marrow-stimulating cytokines.Thus,the modest specificity and low sensitivity of FDG-PET for early stage disease limit its utility for cancer screening.However,in patients with an established diagnosis,or strong suspicion,of cancer,FDG-PET is a powerful tool that can help characterize the disease and determine its extent.

FDG-PET for Monitoring Tumor Response

It has been demonstrated that FDG-PET is useful for monitoring during treatment and assessing response after treatment has ended.7,27,28Many studies in breast cancer, lymphoma,lung cancer,and other tumors have demon-strated that FDG-PET can detect an early response to treatment(Fig.1),which,in many patients,correlates well with clinical outcome,such as disease-free sur-vival.18,29-31In addition,FDG-PET has been used to improve management decisions in oncologic settings.For

PET-CT Imaging in Cancer/Farwell et al

example,data from the National Oncologic PET Registry indicated that,of 10,497treatment-monitoring PET scans performed for a wide variety of cancer types,physician-intended management changed in about 50%of patients;this included a switch to another therapy in 27%of patients,an adjustment in dose or duration of therapy in 17%of patients,and a switch from therapy to observation or supportive care in 6%of patients.32The expectation is that there is a strong correlation between changes in physician-intended management and patient health outcomes;however,the relationship is imperfect,and more research is needed.The goal of early monitoring for treatment response is to evaluate the effectiveness of a therapy earlier than is feasible through symptoms or other clinical parameters;ultimately,this could shorten thera-peutic regimens in patients who are responding,allow for earlier changes to a new therapeutic regimen in patients who are not responding,and expedite the development of new treatments for cancer,all of which have the potential to lead to better patient outcomes.

The timing and relative change in FDG uptake dur-ing treatment appears to depend on the type of treatment used as well as the type of cancer being treated.Studies of cytotoxic chemotherapy in breast cancer,lymphoma,gas-trointestinal cancers,and others indicated that FDG-PET is capable of detecting a response after a single cycle of chemotherapy.33-35In addition,in some lymphomas,sig-nificant changes in FDG uptake have been observed as early as 1day after starting chemotherapy.36The reasons for the rapid decline in FDG uptake after cytotoxic chem-otherapy are not known but are likely related to a decrease in the population of viable cells as well as a decrease in the rate of glycolysis per cell.Studies of targeted therapies like imatinib,which inhibits the c-kit growth factor pathway in gastrointestinal stromal tumors,have indicated that FDG uptake is reduced within hours of starting treatment and appears to be related to a rapid decline in glucose transporter expression.37-39Similarly,it has been demon-strated that the inhibition of epidermal growth factor re-ceptor kinase by gefitinib in lung cancer cell lines results in translocation of glucose transporters from the plasma membrane to the cytosol within 4hours.40However,additional studies are needed to further elucidate the mechanisms behind the rapid decline in FDG uptake in response to these classes of drugs.41It is noteworthy that,when treatment was temporarily held in patients with gas-trointestinal stromal tumors who were taking sunitinib,a multitargeted tyrosine kinase inhibitor that also targets the c-kit pathway,many of the tumors demonstrated a rebound in FDG activity after 3weeks,and this was fol-lowed by a decline in FDG activity when treatment resumed.42Thus,the finding that FDG-PET is capable of demonstrating changes in tumor biology hours to days af-ter starting therapy gives it tremendous potential as a bio-marker for tumor response to therapy,in marked contrast to conventional response measures by CT,which take weeks to months to evolve and can be misleading at early time points.43In most patients,successful treatment results in decreased FDG uptake;however,in certain patients,targeted therapy has resulted in increased FDG uptake at early time points during treatment.For exam-ple,a study of patients with breast cancer indicated that increased tumor FDG uptake at 7to 10days after the ini-tiation of tamoxifen therapy was predictive of a subse-quent clinical response.44

Monitoring radiotherapy with FDG-PET can be challenging,because FDG uptake is often unchanged im-mediately after treatment and,in some patients,may be increased.45The reason for this may be because,com-pared with chemotherapy,after radiotherapy,there is a different and longer period of viability for tumor cells or possibly a greater inflammatory response.Conversely,one study indicated that increased rather than decreased FDG uptake in high-grade gliomas after radiotherapy was pre-dictive of a better outcome.46

There is no generally accepted threshold for a reduc-tion in SUV that represents a response to

treatment.

Figure 1.These are 18F-fluorodeoxyglucose positron emission tomography scans from a patient with diffuse large B-cell lymphoma (Left )at baseline and (Right )10weeks later after 3cycles of chemotherapy.There has been a complete meta-bolic response to therapy.Images are displayed in maximum intensity projection (MIP)format.

Review Article

Reproducibility studies suggest that changes in SUV >20%are likely to be significant,and current guidelines recommend using a threshold of25%or30%for tumors with significant baseline activity.47,48However,the SUV thresholds used in clinical studies range from20%to 70%,with smaller thresholds used for studies performed after a single cycle of chemotherapy and larger thresholds used for studies performed later during the course of treat-ment.49To confound matters,inflammatory tumor changes potentially can blunt the apparent reduction in SUV.For example,one study revealed that29%of the tu-mor glucose use could be attributed to macrophages and granulation tissue.50Because different tumors and treat-ments result in various changes in FDG uptake,more data are needed to validate specific response criteria for FDG-PET.

FDG-PET for Prognosis

The ability of FDG to serve as a prognostic indicator in patients with cancer is incompletely understood.Intui-tively,FDG uptake would be expected to reflect tumor grading,because less differentiated and more rapidly pro-liferating tumors should need more glucose for energy production.However,the correlation between FDG uptake and cellular proliferation,although positive,is not very strong.24Compared with FDG,the thymidine analog30-deoxy-30-18F-fluorothymidine(FLT)demon-strates a much closer correlation between uptake and labeling with Ki-67,a cellular marker of proliferation.51 In addition,the correlation between FDG uptake and tu-mor grading is fairly weak for the majority of tumors;only gliomas,sarcomas,and thyroid cancers demonstrate strong correlations.15,52,53To make matters more compli-cated,some benign tumors,such as giant cell tumors,ju-venile pilocytic astrocytomas,and Warthin tumors, frequently demonstrate intense FDG uptake.54-56Thus, although FDG uptake is modulated by several factors that often serve as poor prognostic markers,such as hypoxia, increased cellular proliferation,and the activation of a va-riety of oncogenes,the multifactorial etiology of increased FDG uptake limits its ability to assess for parameters other than glucose metabolism and may explain the variable success of FDG as a prognostic marker.24

Imaging Proliferation

Aberrantly increased cellular proliferation is a hallmark of cancer,and a decline in proliferation is one of the earliest events in response to effective cancer therapy.57It has been demonstrated that,in responding tumors,both chemotherapy and radiotherapy reduce proliferation rates,which precedes a reduction in tumor size.58,59Thus, imaging the rate of cell proliferation could permit the dif-ferentiation of benign from malignant tumors and could provide an earlier measure of therapeutic response than anatomic imaging.In addition,cell proliferation imaging has a marked advantage over anatomic imaging with regard to assessing treatment response to novel targeted agents,such as protein kinase inhibitors or antiangiogene-sis agents,because some of these agents have a predomi-nantly cytostatic effect and may not lead to rapid tumor shrinkage.

Several different radiotracers have been developed to image cell proliferation.Initial efforts focused on synthe-sizing analogs of thymidine,because thymidine is used by proliferating cells for DNA synthesis during the S-phase of the cell cycle but,unlike other nucleosides,is not incor-porated into RNA.60The gold standard for assessing pro-liferation in vitro has long been3H-thymidine incorporation.17More recently,studies using11C-thymi-dine and PET demonstrated promise in assessing response to therapy;however,the short half-life of11C and its rapid metabolism to thymine and other metabolites made11C-thymidine impractical for routine clinical use outside of academic centers.61This problem spurred the develop-ment of FLT,an18F-labeled,nonmetabolized thymidine analogue that has become the most extensively studied radiotracer for imaging tumor proliferation.62,63

After intravenous injection,FLT enters the cell by facilitated diffusion through nucleoside transporters and is trapped in the cytosol through phosphorylation.64 Because FLT lacks a hydroxyl group at the30position,it is not incorporated into DNA,and its accumulation serves as a measure of cellular proliferation.Correlation of FLT uptake with the rate of cell proliferation in various tumor types has been demonstrated using histopathologic markers of cell proliferation,such as the Ki-67labeling index,as the gold standard.65Unfortunately,most tumors demonstrate relatively low FLT uptake compared with FDG,which reduces the sensitivity of FLT-PET for detecting cancer.In addition,FLT demonstrates signifi-cant interfering physiologic activity in bone marrow and liver,and proliferating lymphocytes in reactive lymph nodes still have the potential to yield false-positive find-ings.60,66Thus,it is unlikely that FLT will have a domi-nant role in the initial diagnosis and staging of most cancers.Conversely,there is a general consensus that FLT-PET can be a valuable method for monitoring tumor response to treatment,especially as an early measure of response.This may be particularly important for cyto-static therapy,ie,agents that stop tumor growth but may

PET-CT Imaging in Cancer/Farwell et al

not kill tumor cells,for which proliferation imaging may play a key role in judging therapeutic effectiveness.67

FLT has several attractive properties as an agent for measuring cancer response.Measures of FLT uptake are precise and repeatable,with a test-retest reproducibility <10%for SUV measurements.58This is an important feature in using FLT-PET for serial imaging to assess response.Also,studies have indicated that changes in FLT uptake reflect changes in tumor proliferation with treat-ment.Preclinical work has demonstrated that a decline in FLT uptake occurs early in the course of treatment with a variety of approaches,including chemotherapy,radiother-apy,and biologically targeted agents,and several studies have noted that changes in FLT activity reflected the effects of therapy better than changes in FDG uptake.68,69Also,preliminary clinical studies confirmed the potential of FLT-PET for monitoring tumor response to therapy (Fig.2).In patients with recurrent malignant brain neo-plasms,tumor response assessed by kinetic measures of FLT uptake after 1or 2weeks of treatment with irinote-can and bevacizumab correlated well with overall sur-vival.70Early studies on breast cancer have also demonstrated that changes in FLT uptake during treat-ment predict clinical response,and multicenter trials for breast cancer are ongoing.71,72In patients with nonsmall cell lung cancer,a reduction in FLT uptake after 7days of therapy with gefitinib was highly predictive of tumor

response on CT and of progression-free survival.73This is a notable result,in that proliferation imaging was effective for predicting response to a biologically targeted agent that often has a cytostatic response when used as monotherapy.

However,some studies have reported less striking results.In lymphoma,treatment with rituximab did not result in an early change in FLT uptake,although it has been a highly effective agent in the clinic,and some data support its impact on cellular proliferation.74Some more recent studies suggest that FLT may be taken up in prolif-erating immune cells,and it is possible that the immune effect of rituximab,a monoclonal antibody,could con-found assessment of response by FLT-PET.75Conversely,in some patients,tumor FLT uptake changed significantly in patients who did not go on to have a subsequent clinical response.For example,a study of patients with rectal can-cer who received neoadjuvant chemoradiation revealed that FLT uptake was reduced significantly at day 14in all patients,but there was no difference in uptake reduction for histopathologically responding versus nonresponding lesions,suggesting that inhibition of proliferation,although necessary,may not be sufficient for a favorable response in some tumor types or with some types of treat-ment.76In such a case,the decrease in FLT uptake in his-topathologic nonresponders may be because of treatment-induced growth arrest rather than cell death.

An

Figure 2.These are 18F-fluorothymidine positron emission tomography (FLT-PET)scans from a patient with breast cancer (A)at baseline and (B)after 1cycle of chemotherapy.Arrows indicate a breast mass in which the FLT activity has decreased over the interval,with no associated change in the size of the mass on computed tomography (CT).Axial and coronal PET images are dis-played along with axial CT images and axial PET/CT fused images.

Review Article

alternative hypothesis relates to the finding that FLT traces only the salvage pathway for incorporation of thy-midine into DNA,whereas many gastrointestinal cancers rely heavily on the de novo pathway,which is not tracked by FLT.60,61These findings indicate some potential limi-tations of FLT for monitoring the response to treatment, and it is likely that the choice of approach for early assess-ment of therapeutic response will need to be matched to the cancer and treatment types under study.Also,there is one report of a temporary rise in FLT uptake in patients with lung cancer who were receiving chemoradiation.77 Thus,FLT uptake may be influenced by factors other than proliferation,such as altered vascular permeability, perfusion,or uptake in proliferating inflammatory cells, and additional study is needed.

Other PET proliferation imaging probes have also been tested.78The thymidine analog(1-[20-deoxy-20-18F-fluoro-beta-D-arabinofuranosyl]thymine)(FMAU)can be phosphorylated and subsequently incorporated into DNA.Because FMAU has minimal bone marrow uptake and urinary excretion,it is a promising agent for studying bone metastases and genitourinary malignancies.79Pre-liminary in vitro studies have indicated that FMAU uptake is proportional to the rate of tumor proliferation.80 However,additional studies are needed to evaluate the ability of FMAU to serve as a PET imaging biomarker of cell proliferation.There have also been efforts to image proliferation using methods distinct from probes like FLT and FMAU,which rely on the thymidine salvage pathway for DNA synthesis.A promising example is the use of sigma-2receptor binding agents to measure tumor prolif-eration.81Like FLT,sigma-2ligand binding levels increase with increasing cellular proliferation;however, sigma-2agents have the potential advantage that,unlike FLT,they also produce some uptake in quiescent (nonproliferating)but viable cells.81Promising early stud-ies in humans motivate further work in this area of research.82

Imaging Hypoxia

Tumor hypoxia is a pathologic state in which tumor tis-sues lack enough oxygen for normal metabolism.In solid tumors,oxygen delivery to the tumor cells is frequently reduced or even abolished by a deteriorating diffusion ge-ometry,severe structural abnormalities of tumor micro-vessels,and disturbed microcirculation.83These microregions of hypoxia are distributed heterogeneously within the tumor mass and may be located adjacent to regions with normal oxygen partial pressures.It is note-worthy that>50%of locally advanced solid tumors may contain hypoxic tissue areas,and the presence or absence of hypoxia cannot be predicted by clinical size,stage, grade,histology,or site.84In solid tumors,hypoxia is asso-ciated with restrained proliferation,differentiation,apo-ptosis,and necrosis.At the same time,hypoxia may promote tumor progression through mechanisms that enable tumor cells to overcome nutritive deficiency, escape from a hostile environment,and favor unrestricted growth.85Sustained hypoxia also may lead to cellular changes,resulting in a more clinically aggressive pheno-type.85In addition,tumor hypoxia has been associated with treatment failure after radiotherapy and chemother-apy.86,87Thus,knowledge of the degree and extent of tu-mor hypoxia has the potential to play a significant role in staging and treatment planning for a wide variety of tu-mor types and,in certain patients,may help to direct patients to regional therapy and/or agents that are selective for hypoxic tissue.

Two major classes of PET radiotracers have been developed to image hypoxia:2-nitroimidazoles,such as 18F-fluoromisonidazole(FMISO),18F-EF5,and18F-flu-

oroetanidazole(FETA),and nucleoside conjugates,such as18F-fluoroazomycin arabinoside(FAZA)and64Cu-di-acetyl-bis(N4-methylthiosemicarbazone)(Cu-ATSM). All of these agents undergo intracellular trapping at a rate inversely proportional to intracellular oxygen concentra-tion.85In normal cells,the imaging agents are rapidly reoxidized and cleared,thus providing good demarcation between hypoxic and normoxic regions.Of the hypoxia imaging agents,FMISO has the largest body of preclinical validation studies and clinical experience,although the other PET hypoxia tracers also have been studied in patients.88Recent studies have demonstrated that tumor hypoxia measured by PET is predictive of patient out-come;patients with hypoxia by PET had considerably ear-lier relapse or progression.89,90However,not all studies demonstrate this correlation.For example,a study in patients with head and neck cancer demonstrated no cor-relation between hypoxia on PET imaging and patient outcome.91Thus,although PET hypoxia imaging has tre-mendous potential in treatment planning,more research is needed to better delineate the role of hypoxia imaging in cancer care.

Imaging Apoptosis

Programmed cell death,or apoptosis,is an essential com-ponent of normal human growth and development, immunoregulation and tissue homeostasis.It is generally accepted that effective therapy of tumors by radiation, chemotherapy,or both,leads to induction of apoptosis.92

PET-CT Imaging in Cancer/Farwell et al

Preclinical and clinical studies have shown that the detec-

tion of apoptosis can potentially be used to provide an

early indication of the success of therapy.93Thus,several

different classes of apoptotic imaging agents have been

developed.

The first class of imaging agents targets phosphyti-

dylserine residues that normally reside on the intracellular

membrane surface but that are translocated to the extracel-

lular surface during apoptosis.The single-photon emis-

sion CT(SPECT)agent technetium-99m(99m Tc)-

annexin V,a radiolabeled protein with nanomolar affinity

to phosphytidylserine,is the most widely used imaging

probe in this class.Although99m Tc-annexin V has a

suboptimal biodistribution profile characterized by

high background activity,including confounding uptake

in the liver,multiple studies have demonstrated that 99m Tc-annexin V is able to image apoptosis in vivo and to predict patient outcome after chemotherapy or radiation

therapy.94,95However,more data are needed to support

the ability of99m Tc-annexin V to predict long-term treat-

ment outcomes.More recently,18F-annexin V has been

synthesized,and it has an improved biodistribution pro-

file and can be imaged using PET;preliminary studies of 18F-annexin V have been done in animals but not in humans.96

A second class of imaging agents targets caspases,

which are cysteine-aspartate proteases that play a pivotal

role in the regulation of apoptosis.Two of the main imag-

ing agents in this class are18F-ICMT-11(a caspase-3-

specific small molecule PET tracer based on the caspase

inhibitor isatin)and18F-CP18(a pentapeptide-based

PET tracer that is a substrate of caspase-3).Both of these

agents have demonstrated promise for the early detection

of drug-induced tumor apoptosis in several animal mod-

els,and the biodistribution of both agents has been stud-

ied in humans.97,98However,to date,no clinical trials

have evaluated the ability of these imaging agents to pre-

dict patient outcome.

A third class of imaging agents is thought to detect

plasma membrane depolarization,although the exact

mechanism has not yet been fully elucidated.The most

notable of these imaging agents is the PET tracer18F-ML-

10(an18F-labeled small molecule malonic acid-based

probe).A recent study of10patients with brain metastases

who received whole-brain radiation therapy demonstrated

a significant correlation between early changes in18F-

ML-10PET scans and size changes on MRI at6to8

weeks after treatment.99Multicenter clinical trials are cur-

rently taking place to assess18F-ML-10in multiple tumor

types.99

One of the limitations of imaging apoptosis is

related to its rapid evolution,which renders imaging of

the transient apoptotic biomarkers particularly challeng-

ing.100In fact,in some patients,the ideal temporal win-

dow for imaging occurs between6and24hours after

treatment.101Thus,concern has been expressed that the

relatively small number of cells undergoing apoptosis at

any one time and the small time window to have access to

the biomarkers during the apoptotic process may limit the

widespread use of apoptosis imaging.102However,these

same considerations may provide an advantage for mecha-

nistic studies of early response that are important in deter-

mining optimal timing in multiagent therapy.

Imaging Protein and Cell Membrane Metabolism The process of protein synthesis in tumors is increased

because of the uncontrolled and accelerated growth of can-

cer.103Consequently,the demand for amino acids—the

building blocks of proteins—is increased.In this regard,

studies have demonstrated that many types of tumor cells

have significantly increased L-type amino acid transporter

1(LAT1)expression,which is the major transporter of

large neutral amino acids.104Thus,increased protein syn-

thesis/LAT1expression is an excellent target for tumor

imaging.Although almost all of the amino acids have been

radiolabeled,only a few have been used clinically as PET

imaging agents.These include11C-methionine(MET), 18F-fluoroethyl-tyrosine(FET),18F-fluoromethyl-tyrosine (FMT),1-amino-3-18F-fluorocyclobutane-1-carboxylic

acid(FACBC),and3,4-dihydroxy-6-18F-fluoro-L-

phenylalanine(FDOPA).

MET-PET is the most popular amino acid imaging

modality in oncology,with over300basic scientific and

clinical publications.MET-PET has been used primarily

to image cerebral gliomas,and it has been used for initial

diagnosis,differentiation of tumor recurrence from radia-

tion necrosis,grading,prognostication,delineation of tu-

mor extent,biopsy planning,surgical resection and

radiotherapy planning,and assessment of response to

therapy.105Because large neutral amino acids like MET

are able to cross the blood-brain barrier and enter normal

brain tissue,disruption of the blood-brain barrier(ie,con-

trast enhancement on CT or MRI)is not a prerequisite

for intratumoral accumulation of these amino acids.

Uptake of FLT,conversely,depends on blood-brain bar-

rier damage,because transport across the normal blood-

brain barrier is slow for thymidine.Thus,nonenhancing,

low-grade gliomas can be observed with MET,but not

with FLT.106MET-PET also has been used clinically to

distinguish benign from malignant tissue in head and

Review Article

neck cancer,melanoma,ovarian cancer,and other tumors.107One of the advantages of MET and other radiolabeled amino acids over FDG is their relatively low uptake in normal brain,which makes them more specific for tumor detection and better at tumor delineation and staging.In addition,amino acid radiotracers generally are affected less by inflammation compared with FDG, although tumor specificity is still not perfect.108

The short half-life of11C prevents the widespread use of MET-PET for tumor imaging,and awareness of this limitation has stimulated the development and evalu-ation of18F-labeled amino acids like FET,FMT, FACBC,and FDOPA.Several clinical studies with small numbers of patients have suggested that FMT is superior to FDG for the detection of musculoskeletal tumors,simi-lar to FDG for the detection of head and neck tumors, and is superior to FDG for determining treatment response in lung cancer.109,110Conversely,small clinical studies that used FET indicated that it was generally worse than FDG for the detection of many tumor types,includ-ing head and neck cancer.111,112FET-PET did exhibit better specificity in several of the studies,raising the possi-bility that it may be better at differentiating tumor from inflammatory tissue.Also,when FET-PET was compared directly with MET-PET in42patients with gliomas or brain metastases,the2imaging agents provided compara-ble diagnostic information.113FDOPA-PET also was compared with MET-PET in patients with primary brain tumors or brain metastases and,similarly,yielded compa-rable diagnostic information.114FACBC has been studied primarily in prostate cancer,in which it had higher sensi-tivity for tumor detection compared with111In-capromab pendetide(Prostascint)and11C-choline.115,116In addi-tion,FACBC has demonstrated increased uptake in papil-lary renal cell carcinoma,but not in clear cell carcinoma.117FACBC is especially notable for the lack of associated radioactivity in the urine,which allows for bet-ter evaluation of the genitourinary tract and pelvis.

Choline is a precursor of phosphatidylcholine, which is a major constituent of membrane lipids.Because both membrane lipid synthesis and protein synthesis are activated during cell proliferation,choline is consumed in large quantities by tumor cells.118Thus,11C-choline accumulation is significantly greater in malignant tumors than in benign lesions.Most reports of11C-choline PET imaging involve prostate cancer,although11C-choline uptake also is increased in a wide variety of other tumors.119,120Given its lack of radiotracer activity in the urine,11C-choline is well suited to evaluate pelvic malig-nancies.119In recent studies of patients with prostate can-cer,11C-choline PET identified recurrent disease in66% of patients with a mean prostate-specific antigen(PSA) level of8.3ng/mL,28%of patients with a PSA level<1.5 ng/mL,and21%of patients with a PSA level<0.5ng/ mL.121,122In addition,11C-choline PET demonstrated better sensitivity than MRI for lymph node metastases in prostate cancer.123More recently,18F-choline(FCH), which has the advantage of a much longer half-life com-pared with that of11C,has been developed.To date,stud-ies of FCH have focused largely on prostate cancer,for which FCH has performed similarly to11C-choline.124 Imaging Tumor-Specific Agents

Although tracers for metabolism,proliferation,and hy-poxia provide useful imaging of neoplasms,they are rela-tively nonspecific and are usually less useful for imaging tumors that have very low growth rates.Therefore,the de-velopment of tracers targeting intracellular and cell-surface receptors that are uniquely expressed or overexpressed in cancer cells is essential for the development and usefulness of clinical PET.Examples of radiotracers that target these tumor-specific biomarkers are outlined below.

Prostate-specific membrane antigen(PSMA)is a cell surface protein that is highly expressed in prostate carci-noma cells.Several radiotracers that target PSMA have been developed and studied preclinically.Recently,both 18F-DCFBC(N-[N-([S]-1,3-dicarboxypropyl)carba-

moyl]-4-18F-fluorobenzyl-L-cysteine)and68Ga-PSMA have been studied in humans,and both reportedly were capable of detecting sites of metastatic prostate cancer.125,126In a subsequent,small clinical trial, 68Ga-PSMA detected more lesions than18F-choline.127 Somatostatin receptors are overexpressed on neuro-endocrine tumor cells.Imaging of this biomarker is cur-rently accomplished using SPECT with111In-diethylenetriaminepentaacetic acid(DTPA)-octreotide; however,several new radiotracers have been developed that can be imaged using PET.Examples include68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Tyr3-octreotide(68Ga-DOTA-TOC),68Ga-DOTA-1-Nal3-octreotide(68Ga-DOTA-NOC),and 68Ga-DOTA-Tyr3-octreotate(DOTA-TATE),all of which demonstrate better sensitivity than111In-DTPA-octreo-tide for neuroendocrine tumors,and all have the addi-tional benefit of better resolution because they are imaged using PET.128Although all3radiotracers demonstrate variable affinity to somatostatin receptor subtypes,there is currently no evidence of a clinical impact from these dif-ferences;thus,there is no indication suggesting the prefer-ential use of one compound over the others.128

PET-CT Imaging in Cancer/Farwell et al

In addition,there are several cancer therapies that target a specific receptor or enzyme in tumor cells.Cur-rent examples of specific targets(and examples of treat-ments directed at them)include the estrogen receptor (tamoxifen and letrozole),HER2(trastuzumab),epider-mal growth factor receptor(gefitinib),and angiogenesis (bevacizumab).129Measuring the target expression at each site of disease is a task for which PET is well suited.PET imaging can determine whether the target is expressed at all disease sites and can quantify the level of target expres-sion at each site.Current examples of PET imaging to measure target expression include estrogen receptor imag-ing and androgen receptor imaging;HER2imaging; imaging angiogenesis nonspecifically by measuring blood flow and by imaging specific components expressed in neovasculature;and measuring novel targets,such as ma-trix metalloproteinases.130-135In all of these cases,PET imaging has the potential to provide prognostic informa-tion and can help predict the likelihood that a patient will respond to a targeted chemotherapeutic agent.One of the major imaging agents in this class is18F-fluoroestradiol (FES),which has exhibited the most promise in quantify-ing the functional estrogen receptor status of primary or metastatic breast cancer.136Studies by Mortimer et al have demonstrated that a high level of FES uptake in advanced breast cancer predicts a greater likelihood of response to tamoxifen.44More recent studies report simi-lar results for patients with recurrent or metastatic breast cancer who received a variety of hormonal agents.137 These preliminary results demonstrate the exciting poten-tial of PET imaging to help guide appropriate,individual-ized treatment for cancer,and they point the way for future clinical use.

Summary

PET is an established technique for cancer detection,and FDG continues to be the most widely used radiotracer for the staging and restaging of most tumors.However,many of the newer radiotracers described in this article will likely play a larger role in cancer care in the future and, along with FDG,will be used increasingly to determine a patient’s prognosis,make decisions regarding treatment planning,and evaluate treatment response.In addition, new radiotracers will continue to be developed as diagnos-tic agents for tumors with minimal FDG uptake,such as prostate cancer and neuroendocrine tumors.Unfortu-nately,several barriers to the development and use of new radiotracers exist;these include a costly FDA approval process,relatively small profit potential(and,thus,little interest by the pharmaceutical industry in sponsoring clinical trials),as well as uncertain reimbursement by the US Centers for Medicare and Medicaid Services and by private insurers.Thus,future applications of PET for can-cer imaging will need to rely on robust and reproducible quantitative data to validate the ability of PET to serve as an effective biomarker,and the passage of new radio-tracers through the FDA and Centers for Medicare and Medicaid Services approval processes must be supported. FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES Dr.Pryma reports personal fees from IBA Molecular and a grant from Siemens Medical.Dr.Mankoff reports grants and personal fees from Siemens Medical and Phillips Medical,and he serves on the GE Medical advisory board.

REFERENCES

1.IMV Medical Information Division.2012PET Imaging Market

Summary Report.Des Plaines,IL:IMV Medical Information Divi-sion;2012.

2.Eubank WB,Mankoff DA,Schmiedl UP,et al.Imaging of onco-

logic patients:benefit of combined CT and FDG-PET in the diag-nosis of malignancy.AJR Am J Roentgenol.1998;171:1103-1110. 3.Shim SS,Lee KS,Kim BT,et al.Non-small cell lung cancer:pro-

spective comparison of integrated FDG PET/CT and CT alone for preoperative staging.Radiology.2005;236:1011-1019.

4.Sokoloff L,Reivich M,Kennedy C,et al.The[14C]deoxyglucose

method for the measurement of local cerebral glucose utilization: theory,procedure,and normal values in the conscious and anesthe-tized albino rat.J Neurochem.1977;28:897-916.

5.Smith TA.Mammalian hexokinases and their abnormal expression

in cancer.Br J Biomed Sci.2000;57:170-178.

6.Phelps ME,Huang SC,Hoffman EJ,Selin C,Sokoloff L,Kuhl

DE.Tomographic measurement of local cerebral glucose metabolic rate in humans with(F-18)2-fluoro-2-deoxy-D-glucose:validation of method.Ann Neurol.1979;6:371-388.

7.Shankar LK,Hoffman JM,Bacharach S,et al.Consensus recom-

mendations for the use of18F-FDG-PET as an indicator of thera-peutic response in patients in National Cancer Institute Trials.

J Nucl Med.2006;47:1059-1066.

8.Huang SC.Anatomy of SUV.Standardized uptake value.Nucl Med

Biol.2000;27:643-646.

9.Krohn KA,Mankoff DA,Muzi M,Link JM,Spence AM.True

tracers:comparing FDG with glucose and FLT with thymidine.

Nucl Med Biol.2005;32:663-671.

10.Paquet N,Albert A,Foidart J,Hustinx R.Within-patient variabili-

ty of(18)F-FDG:standardized uptake values in normal tissues.

J Nucl Med.2004;45:784-788.

11.Weber WA,Ziegler SI,Thodtmann R,Hanauske AR,Schwaiger

M.Reproducibility of metabolic measurements in malignant tumors using FDG PET.J Nucl Med.1999;40:1771-1777.

12.Warburg O.Metabolism of Tumors.London,UK:Constable and

Company;1930.

13.Mathupala SP,Rempel A,Pedersen PL.Aberrant glycolytic metab-

olism of cancer cells:a remarkable coordination of genetic,tran-scriptional,post-translational,and mutational events that lead to a critical role for type II hexokinase.J Bioenerg Biomembr.1997;29: 339-343.

14.Szablewski L.Expression of glucose transporters in cancers.Biochim

Biophys Acta.2013;1835:164-169.

Review Article

15.Di Chiro G.Positron emission tomography using[18F]fluorodeox-

yglucose in brain tumors.A powerful diagnostic and prognostic tool.Invest Radiol.1987;22:360-371.

16.Hillner BE,Siegel BA,Hanna L,et al.Impact of18F-FDG PET

used after initial treatment of cancer:comparison of the National Oncologic PET Registry2006and2009cohorts.J Nucl Med.

2012;53:831-837.

17.Kelloff GJ,Hoffman JM,Johnson B,et al.Progress and promise

of FDG-PET imaging for cancer patient management and onco-logic drug development.Clin Cancer Res.2005;11:2785-2808. 18.Cuaron J,Dunphy M,Rimner A.Role of FDG-PET scans in stag-

ing,response assessment,and follow-up care for non-small cell lung cancer.Front Oncol.2012;2:208.

19.Eubank WB,Mankoff DA.Current and future uses of positron

emission tomography in breast cancer imaging.Semin Nucl Med.

2004;34:224-240.

20.Macapinlac HA.FDG PET and PET/CT imaging in lymphoma

and melanoma.Cancer J.2004;10:262-270.

21.Hoh CK,Seltzer MA,Franklin J,deKernion JB,Phelps ME,

Belldegrun A.Positron emission tomography in urological oncol-ogy.J Urol.1998;159:347-356.

22.Khan MA,Combs CS,Brunt EM,et al.Positron emission tomog-

raphy scanning in the evaluation of hepatocellular carcinoma.

J Hepatol.2000;32:792-797.

23.Bos R,van Der Hoeven JJ,van Der Wall E,et al.Biologic correlates

of(18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography.J Clin Oncol.2002;20:379-387.

24.Buerkle A,Weber WA.Imaging of tumor glucose utilization with posi-

tron emission tomography.Cancer Metastasis Rev.2008;27:545-554. 25.Morris MJ,Akhurst T,Osman I,et al.Fluorinated deoxyglucose

positron emission tomography imaging in progressive metastatic prostate cancer.Urology.2002;59:913-918.

26.Wang W,Larson SM,Tuttle RM,et al.Resistance of[18F]-fluoro-

deoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine.Thyroid.2001;11:1169-1175. 27.Minn H,Soini I.[18F]fluorodeoxyglucose scintigraphy in diagnosis

and follow up of treatment in advanced breast cancer.Eur J Nucl Med.1989;15:61-66.

28.Wahl RL,Zasadny K,Helvie M,Hutchins GD,Weber B,Cody

R.Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography:initial evaluation.J Clin Oncol.1993;11:2101-2111.

29.Krause BJ,Herrmann K,Wieder H,zum Buschenfelde CM.18F-

FDG PET and18F-FDG PET/CT for assessing response to therapy in esophageal cancer.J Nucl Med.2009;50(suppl1):89S-96S. 30.Hutchings M,Loft A,Hansen M,et al.FDG-PET after two cycles

of chemotherapy predicts treatment failure and progression-free sur-vival in Hodgkin lymphoma.Blood.2006;107:52-59.

31.Mankoff DA,Dunnwald LK,Gralow JR,et al.Changes in blood

flow and metabolism in locally advanced breast cancer treated with neoadjuvant chemotherapy.J Nucl Med.2003;44:1806-1814. 32.Hillner BE,Siegel BA,Shields AF,et al.The impact of positron

emission tomography(PET)on expected management during can-cer treatment:findings of the National Oncologic PET Registry.

Cancer.2009;115:410-418.

33.Ott K,Weber WA,Lordick F,et al.Metabolic imaging predicts

response,survival,and recurrence in adenocarcinomas of the esoph-agogastric junction.J Clin Oncol.2006;24:4692-4698.

34.Romer W,Hanauske AR,Ziegler S,et al.Positron emission to-

mography in non-Hodgkin’s lymphoma:assessment of chemother-apy with fluorodeoxyglucose.Blood.1998;91:4464-4471.

35.Smith IC,Welch AE,Hutcheon AW,et al.Positron emission to-

mography using[(18)F]-fluorodeoxy-D-glucose to predict the path-ologic response of breast cancer to primary chemotherapy.J Clin Oncol.2000;18:1676-1688.

36.Yamane T,Daimaru O,Ito S,Yoshiya K,Nagata T,Uchida H.

Decreased18F-FDG uptake1day after initiation of chemotherapy for malignant lymphomas.J Nucl Med.2004;45:1838-1842.

37.Cullinane C,Dorow DS,Kansara M,et al.An in vivo tumor

model exploiting metabolic response as a biomarker for targeted drug development.Cancer Res.2005;65:9633-9636.38.Shinto A,Nair N,Dutt A,Baghel NS.Early response assessment

in gastrointestinal stromal tumors with FDG PET scan24hours after a single dose of imatinib.Clin Nucl Med.2008;33:486-487.

39.Stroobants S,Goeminne J,Seegers M,et al.18FDG-Positron emis-

sion tomography for the early prediction of response in advanced soft tissue sarcoma treated with imatinib mesylate(Glivec).Eur J Cancer.2003;39:2012-2020.

40.Su H,Bodenstein C,Dumont RA,et al.Monitoring tumor glucose

utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors.Clin Cancer Res.2006;12:5659-5667.

41.Linden HM,Krohn KA,Livingston RB,Mankoff DA.Monitoring

targeted therapy:is fluorodeoxyglucose uptake a marker of early response?Clin Cancer Res.2006;12:5608-5610.

42.Demetri GD,Heinrich MC,Fletcher JA,et al.Molecular target

modulation,imaging,and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure.Clin Cancer Res.2009;15:5902-5909.

43.Van den Abbeele AD.The lessons of GIST—PET and PET/CT:a

new paradigm for imaging.Oncologist.2008;13(suppl2):8-13. 44.Mortimer JE,Dehdashti F,Siegel BA,Trinkaus K,

Katzenellenbogen JA,Welch MJ.Metabolic flare:indicator of hor-mone responsiveness in advanced breast cancer.J Clin Oncol.2001;

19:2797-2803.

45.Hicks RJ.The role of PET in monitoring therapy.Cancer Imaging.

2005;5:51-57.

46.Spence AM,Muzi M,Graham MM,et al.2-[(18)F]Fluoro-2-deox-

yglucose and glucose uptake in malignant gliomas before and after radiotherapy:correlation with outcome.Clin Cancer Res.2002;8: 971-979.

47.Young H,Baum R,Cremerius U,et al.Measurement of clinical

and subclinical tumour response using[18F]-fluorodeoxyglucose and positron emission tomography:review and1999EORTC rec-ommendations.European Organization for Research and Treat-ment of Cancer(EORTC)PET Study Group.Eur J Cancer.1999;

35:1773-1782.

48.Wahl RL,Jacene H,Kasamon Y,Lodge MA.From RECIST to

PERCIST:evolving considerations for PET response criteria in solid tumors.J Nucl Med.2009;50(suppl1):122S-150S.

49.Weber WA.Positron emission tomography as an imaging bio-

marker.J Clin Oncol.2006;24:3282-3292.

50.Kubota R,Yamada S,Kubota K,Ishiwata K,Tamahashi N,Ido T.

Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography.J Nucl Med.1992;33:1972-1980.

51.Buck AK,Halter G,Schirrmeister H,et al.Imaging proliferation

in lung tumors with PET:18F-FLT versus18F-FDG.J Nucl Med.

2003;44:1426-1431.

52.Eary JF,O’Sullivan F,Powitan Y,et al.Sarcoma tumor FDG

uptake measured by PET and patient outcome:a retrospective anal-ysis.Eur J Nucl Med Mol Imaging.2002;29:1149-1154.

53.Robbins RJ,Wan Q,Grewal RK,et al.Real-time prognosis for

metastatic thyroid carcinoma based on2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning.J Clin Endocrinol Metab.2006;91:498-505.

54.Fulham MJ,Melisi JW,Nishimiya J,Dwyer AJ,Di Chiro G.Neu-

roimaging of juvenile pilocytic astrocytomas:an enigma.Radiology.

1993;189:221-225.

55.Kole AC,Nieweg OE,Hoekstra HJ,van Horn JR,Koops HS,

Vaalburg W.Fluorine-18-fluorodeoxyglucose assessment of glucose metabolism in bone tumors.J Nucl Med.1998;39:810-815.

56.Uchida Y,Minoshima S,Kawata T,et al.Diagnostic value of

FDG PET and salivary gland scintigraphy for parotid tumors.Clin Nucl Med.2005;30:170-176.

57.Hanahan D,Weinberg RA.Hallmarks of cancer:the next genera-

tion.Cell.2011;144:646-674.

58.Weber WA.Monitoring tumor response to therapy with18F-FLT

PET.J Nucl Med.2010;51:841-844.

59.Troost EG,Bussink J,Hoffmann AL,Boerman OC,Oyen WJ,

Kaanders JH.18F-FLT PET/CT for early response monitoring and dose escalation in oropharyngeal tumors.J Nucl Med.2010;51:866-874.

PET-CT Imaging in Cancer/Farwell et al

60.Barwick T,Bencherif B,Mountz JM,Avril N.Molecular PET and

PET/CT imaging of tumour cell proliferation using F-18fluoro-L-thymidine:a comprehensive evaluation.Nucl Med Commun.2009;

30:908-917.

61.Mankoff DA,Shields AF,Krohn KA.PET imaging of cellular pro-

liferation.Radiol Clin North Am.2005;43:153-167.

62.Shields AF,Grierson JR,Dohmen BM,et al.Imaging proliferation

in vivo with[F-18]FLT and positron emission tomography.Nat Med.1998;4:1334-1336.

63.Grierson JR,Shields AF.Radiosynthesis of30-deoxy-30-[(18)F]fluo-

rothymidine:[(18)F]FLT for imaging of cellular proliferation in vivo.Nucl Med Biol.2000;27:143-156.

64.Paproski RJ,Ng AM,Yao SY,Graham K,Young JD,Cass CE.

The role of human nucleoside transporters in uptake of30-deoxy-30-fluorothymidine.Mol Pharmacol.2008;74:1372-1380.

65.Chalkidou A,Landau DB,Odell EW,Cornelius VR,O’Doherty

MJ,Marsden PK.Correlation between Ki-67immunohistochemistry and18F-fluorothymidine uptake in patients with cancer:a systematic review and meta-analysis.Eur J Cancer.2012;48:3499-3513.

66.Troost EG,Vogel WV,Merkx MA,et al.18F-FLT PET does not

discriminate between reactive and metastatic lymph nodes in pri-mary head and neck cancer patients.J Nucl Med.2007;48:726-735.

67.Mankoff D.Imaging studies in anticancer drug development.In:

Garrett-Mayer E,ed.Principles of Anticancer Drug Development: New York:Springer;2011:275-302.

68.Apisarnthanarax S,Alauddin MM,Mourtada F,et al.Early detec-

tion of chemoradioresponse in esophageal carcinoma by30-deoxy-30-3H-fluorothymidine using preclinical tumor models.Clin Cancer Res.2006;12:4590-4597.

69.Ullrich RT,Zander T,Neumaier B,et al.Early detection of erloti-

nib treatment response in NSCLC by30-deoxy-30-[18F]-fluoro-L-thymidine([18F]FLT)positron emission tomography(PET).PLoS One.2008;3:e3908.

70.Wardak M,Schiepers C,Dahlbom M,et al.Discriminant analysis

of(18)F-fluorothymidine kinetic parameters to predict survival in patients with recurrent high-grade glioma.Clin Cancer Res.2011;

17:6553-6562.

71.Kenny L,Coombes RC,Vigushin DM,Al-Nahhas A,Shousha S,

Aboagye EO.Imaging early changes in proliferation at1week post chemotherapy:a pilot study in breast cancer patients with30-deoxy-30-[18F]fluorothymidine positron emission tomography.Eur J Nucl Med Mol Imaging.2007;34:1339-1347.

72.Jolles PR,Kostakoglu L,Bear HD,et al.ACRIN6688phase II

study of fluorine-1830-deoxy-30fluorothymidine(FLT)in invasive breast cancer.J Clin Oncol.2011;29S.Abstract TPS125.

73.Sohn HJ,Yang YJ,Ryu JS,et al.[18F]Fluorothymidine positron

emission tomography before and7days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung.Clin Cancer Res.2008;14:7423-7429.

74.Herrmann K,Wieder HA,Buck AK,et al.Early response assess-

ment using30-deoxy-30-[18F]fluorothymidine-positron emission to-mography in high-grade non-Hodgkin’s lymphoma.Clin Cancer Res.2007;13:3552-3558.

75.Aarntzen EH,Srinivas M,De Wilt JH,et al.Early identification of

antigen-specific immune responses in vivo by[18F]-labeled30-fluoro-30-deoxy-thymidine([18F]FLT)PET imaging.Proc Natl Acad Sci U S A.2011;108:18396-18399.

76.Wieder HA,Geinitz H,Rosenberg R,et al.PET imaging with

[18F]30-deoxy-30-fluorothymidine for prediction of response to neo-adjuvant treatment in patients with rectal cancer.Eur J Nucl Med Mol Imaging.2007;34:878-883.

77.Everitt S,Hicks RJ,Ball D,et al.Imaging cellular proliferation dur-

ing chemo-radiotherapy:a pilot study of serial18F-FLT positron emission tomography/computed tomography imaging for non-small-cell lung cancer.Int J Radiat Oncol Biol Phys.2009;75:1098-1104.

78.Bading JR,Shields AF.Imaging of cell proliferation:status and

prospects.J Nucl Med.2008;49(suppl2):64S-80S.

79.Sun H,Sloan A,Mangner TJ,et al.Imaging DNA synthesis with

[18F]FMAU and positron emission tomography in patients with cancer.Eur J Nucl Med Mol Imaging.2005;32:15-22.

80.Nishii R,Volgin AY,Mawlawi O,et al.Evaluation of20-deoxy-20-

[18F]fluoro-5-methyl-1-beta-L-arabinofuranosyluracil([18F]-L-FMAU) as a PET imaging agent for cellular proliferation:comparison with [18F]-D-FMAU and[18F]FLT.Eur J Nucl Med Mol Imaging.2008;

35:990-998.

81.Sai KK,Jones LA,Mach RH.Development of(18)F-labeled PET

probes for imaging cell proliferation.Curr Top Med Chem.2013;

13:892-908.

82.Dehdashti F,Laforest R,Gao F,et al.Assessment of cellular prolif-

eration in tumors by PET using18F-ISO-1.J Nucl Med.2013;54: 350-357.

83.Vaupel P,Kallinowski F,Okunieff P.Blood flow,oxygen and nu-

trient supply,and metabolic microenvironment of human tumors:

a review.Cancer Res.1989;49:6449-6465.

84.Vaupel P,Mayer A.Hypoxia in cancer:significance and impact on

clinical outcome.Cancer Metastasis Rev.2007;26:225-239.

85.Sun X,Niu G,Chan N,Shen B,Chen X.Tumor hypoxia imag-

ing.Mol Imaging Biol.2011;13:399-410.

86.Matthews NE,Adams MA,Maxwell LR,Gofton TE,Graham

CH.Nitric oxide-mediated regulation of chemosensitivity in cancer cells.J Natl Cancer Inst.2001;93:1879-1885.

87.Nordsmark M,Bentzen SM,Rudat V,et al.Prognostic value of tu-

mor oxygenation in397head and neck tumors after primary radia-tion therapy.An international multi-center study.Radiother Oncol.

2005;77:18-24.

88.Rajendran JG,Krohn KA.Imaging hypoxia and angiogenesis in

tumors.Radiol Clin North Am.2005;43:169-187.

89.Dehdashti F,Grigsby PW,Lewis JS,Laforest R,Siegel BA,Welch

MJ.Assessing tumor hypoxia in cervical cancer by PET with60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone).J Nucl Med.

2008;49:201-205.

90.Rischin D,Hicks RJ,Fisher R,et al.Prognostic significance of

[18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine:a sub-study of Trans-Tasman Radiation Oncology Group Study98.02.

J Clin Oncol.2006;24:2098-2104.

91.Lee N,Nehmeh S,Schoder H,et al.Prospective trial incorporating

pre-/mid-treatment[18F]-misonidazole positron emission tomogra-phy for head-and-neck cancer patients undergoing concurrent che-moradiotherapy.Int J Radiat Oncol Biol Phys.2009;75:101-108. 92.Baskar R,Lee KA,Yeo R,Yeoh KW.Cancer and radiation ther-

apy:current advances and future directions.Int J Med Sci.2012;9: 193-199.

93.Buchholz TA,Davis DW,McConkey DJ,et al.Chemotherapy-

induced apoptosis and Bcl-2levels correlate with breast cancer response to chemotherapy.Cancer J.2003;9:33-41.

94.Kartachova M,van Zandwijk N,Burgers S,van Tinteren H,

Verheij M,Valdes Olmos RA.Prognostic significance of99m Tc Hynic-rh-annexin V scintigraphy during platinum-based chemo-therapy in advanced lung cancer.J Clin Oncol.2007;25:2534-2539.

95.Loose D,Vermeersch H,De Vos F,Deron P,Slegers G,Van de

Wiele C.Prognostic value of99m Tc-HYNIC annexin-V imaging in squamous cell carcinoma of the head and neck.Eur J Nucl Med Mol Imaging.2008;35:47-52.

96.Murakami Y,Takamatsu H,Taki J,et al.18F-labelled annexin V:a

PET tracer for apoptosis imaging.Eur J Nucl Med Mol Imaging.

2004;31:469-474.

97.Challapalli A,Kenny LM,Hallett WA,et al.18F-ICMT-11,a

caspase-3-specific PET tracer for apoptosis:biodistribution and radiation dosimetry.J Nucl Med.2013;54:1551-1556.

98.Doss M,Kolb HC,Walsh JC,et al.Biodistribution and radiation

dosimetry of18F-CP-18,a potential apoptosis imaging agent,as determined from PET/CT scans in healthy volunteers.J Nucl Med.

2013;54:2087-2092.

99.Allen AM,Ben-Ami M,Reshef A,et al.Assessment of response of

brain metastases to radiotherapy by PET imaging of apoptosis with

(18)F-ML-10.Eur J Nucl Med Mol Imaging.2012;39:1400-1408. 100.Neves AA,Brindle KM.Imaging cell death.J Nucl Med.2014;55: 1-4.

Review Article

101.Nguyen QD,Lavdas I,Gubbins J,et al.Temporal and spatial evo-lution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging.Clin Cancer Res.2013;19:3914-3924. 102.Mandl SJ,Mari C,Edinger M,et al.Multi-modality imaging iden-tifies key times for annexin V imaging as an early predictor of ther-apeutic outcome.Mol Imaging.2004;3:1-8.

103.Dolfi SC,Chan LL,Qiu J,et al.The metabolic demands of cancer cells are coupled to their size and protein synthesis rates.Cancer Metab.2013;1:20.

104.Yanagida O,Kanai Y,Chairoungdua A,et al.Human L-type amino acid transporter1(LAT1):characterization of function and expression in tumor cell lines.Biochim Biophys Acta.2001;1514: 291-302.

105.Singhal T,Narayanan TK,Jain V,Mukherjee J,Mantil J.11C-L-methionine positron emission tomography in the clinical manage-ment of cerebral gliomas.Mol Imaging Biol.2008;10:1-18.

https://www.wendangku.net/doc/f714188811.html,ngen K-J,Galldiks N.PET Imaging of Brain Tumors:Berlin;

Springer;2013.

107.Inoue T,Kim EE,Wong FC,et https://www.wendangku.net/doc/f714188811.html,parison of fluorine-18-fluorodeoxyglucose and carbon-11-methionine PET in detection of malignant tumors.J Nucl Med.1996;37:1472-1476.

108.Kubota R,Kubota K,Yamada S,et al.Methionine uptake by tu-mor tissue:a microautoradiographic comparison with FDG.J Nucl Med.1995;36:484-492.

109.Miyakubo M,Oriuchi N,Tsushima Y,et al.Diagnosis of maxillo-facial tumor with L-3-[18F]-fluoro-alpha-methyltyrosine(FMT) PET:a comparative study with FDG-PET.Ann Nucl Med.2007;

21:129-135.

110.Kaira K,Oriuchi N,Yanagitani N,et al.Assessment of therapy response in lung cancer with(18)F-alpha-methyl tyrosine PET.AJR Am J Roentgenol.2010;195:1204-1211.

111.Pauleit D,Stoffels G,Schaden W,et al.PET with O-(2-18F-fluo-roethyl)-L-tyrosine in peripheral tumors:first clinical results.J Nucl Med.2005;46:411-416.

112.Haerle SK,Fischer DR,Schmid DT,Ahmad N,Huber GF,Buck

A.18F-FET PET/CT in advanced head and neck squamous cell

carcinoma:an intra-individual comparison with18F-FDG PET/CT.

Mol Imaging Biol.2011;13:1036-1042.

113.Grosu AL,Astner ST,Riedel E,et al.An interindividual comparison of O-(2-[18F]fluoroethyl)-L-tyrosine(FET)-and L-[methyl-11C]me-thionine(MET)-PET in patients with brain gliomas and metastases.

Int J Radiat Oncol Biol Phys.2011;81:1049-1058.

114.Becherer A,Karanikas G,Szabo M,et al.Brain tumour imaging with PET:a comparison between[18F]fluorodopa and[11C]methi-onine.Eur J Nucl Med Mol Imaging.2003;30:1561-1567.

115.Schuster DM,Nieh PT,Jani AB,et al.Anti-3-[(18)F]FACBC posi-tron emission tomography-computerized tomography and(111)In-capromab pendetide single photon emission computerized tomography-computerized tomography in recurrent prostate carci-noma:results of a prospective clinical trial.J Urol.2014;191:1446-1453.

116.Nanni C,Schiavina R,Brunocilla E,et al.18F-FACBC compared with11C-choline PET/CT in patients with biochemical relapse af-ter radical prostatectomy:a prospective study in28patients.Clin Genitourin Cancer.2014;12:106-110.

117.Schuster DM,Nye JA,Nieh PT,et al.Initial experience with the radiotracer anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-[18F]FACBC)with PET in renal carcinoma.Mol Imaging Biol.2009;11:434-438.

118.Yoshimoto M,Waki A,Obata A,Furukawa T,Yonekura Y, Fujibayashi Y.Radiolabeled choline as a proliferation marker:com-parison with radiolabeled acetate.Nucl Med Biol.2004;31:859-865. 119.Tian M,Zhang H,Oriuchi N,Higuchi T,Endo https://www.wendangku.net/doc/f714188811.html,parison of 11C-choline PET and FDG PET for the differential diagnosis of ma-lignant tumors.Eur J Nucl Med Mol Imaging.2004;31:1064-1072.120.Scher B,Seitz M,Albinger W,et al.Value of11C-choline PET and PET/CT in patients with suspected prostate cancer.Eur J Nucl Med Mol Imaging.2007;34:45-53.

121.Ceci F,Castellucci P,Mamede M,et al.(11)C-Choline PET/CT in patients with hormone-resistant prostate cancer showing bio-chemical relapse after radical prostatectomy.Eur J Nucl Med Mol Imaging.2013;40:149-155.

122.Mamede M,Ceci F,Castellucci P,et al.The role of11C-choline PET imaging in the early detection of recurrence in surgically treated prostate cancer patients with very low PSA level<0.5ng/ mL.Clin Nucl Med.2013;38:e342-e345.

123.Contractor K,Challapalli A,Barwick T,et https://www.wendangku.net/doc/f714188811.html,e of[11C]choline PET-CT as a noninvasive method for detecting pelvic lymph node status from prostate cancer and relationship with choline kinase expression.Clin Cancer Res.2011;17:7673-7683.

124.Marzola MC,Chondrogiannis S,Ferretti A,et al.Role of18F-choline PET/CT in biochemically relapsed prostate cancer after radical prostatectomy:correlation with trigger PSA,PSA velocity, PSA doubling time,and metastatic distribution.Clin Nucl Med.

2013;38:e26-e32.

125.Afshar-Oromieh A,Malcher A,Eder M,et al.PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer:biodistribution in humans and first evaluation of tumour lesions.Eur J Nucl Med Mol Imaging.2013;40:486-495.

126.Cho SY,Gage KL,Mease RC,et al.Biodistribution,tumor detec-tion,and radiation dosimetry of18F-DCFBC,a low-molecular-weight inhibitor of prostate-specific membrane antigen,in patients with metastatic prostate cancer.J Nucl Med.2012;53:1883-1891. 127.Afshar-Oromieh A,Zechmann CM,Malcher A,et https://www.wendangku.net/doc/f714188811.html,parison of PET imaging with a(68)Ga-labelled PSMA ligand and(18)F-choline-based PET/CT for the diagnosis of recurrent prostate can-cer.Eur J Nucl Med Mol Imaging.2014;41:11-20.

128.Ambrosini V,Campana D,Tomassetti P,Fanti S.(68)Ga-labelled peptides for diagnosis of gastroenteropancreatic NET.Eur J Nucl Med Mol Imaging.2012;39(suppl1):S52-S60.

129.Kaklamani V,O’Regan RM.New targeted therapies in breast can-cer.Semin Oncol.2004;31:20-25.

130.Dehdashti F,Mortimer JE,Siegel BA,et al.Positron tomographic assessment of estrogen receptors in breast cancer:comparison with FDG-PET and in vitro receptor assays.J Nucl Med.1995;36:1766-1774.

https://www.wendangku.net/doc/f714188811.html,rson SM,Morris M,Gunther I,et al.Tumor localization of 16beta-18F-fluoro-5alpha-dihydrotestosterone versus18F-FDG in patients with progressive,metastatic prostate cancer.J Nucl Med.

2004;45:366-373.

132.Dijkers EC,Oude Munnink TH,Kosterink JG,et al.Biodistribu-tion of89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer.Clin Pharmacol Ther.2010;87:586-592.

133.Mankoff DA,Dunnwald LK,Gralow JR,et al.Blood flow and metabolism in locally advanced breast cancer:relationship to response to therapy.J Nucl Med.2002;43:500-509.

134.Beer AJ,Haubner R,Sarbia M,et al.Positron emission tomography using[18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man.Clin Cancer Res.2006;12:3942-3949.

135.Matusiak N,van Waarde A,Bischoff R,et al.Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT.Curr Pharm Des.2013;19:4647-4672.

136.Katzenellenbogen JA,Welch MJ,Dehdashti F.The development of estrogen and progestin radiopharmaceuticals for imaging breast can-cer.Anticancer Res.1997;17:1573-1576.

137.Linden HM,Stekhova SA,Link JM,et al.Quantitative fluoroestra-diol positron emission tomography imaging predicts response to en-docrine treatment in breast cancer.J Clin Oncol.2006;24:2793-2799.

PET-CT Imaging in Cancer/Farwell et al

心情不好说说发朋友圈,适合心情不好发的朋友圈

心情不好说说发朋友圈,适合心情不好发的朋友圈 1、如果一个人真的爱你，距离不是一个问题，它只会成为一种滋长爱情的力量。 2、曾经以为，伤心是会流很多眼泪的，原来，真正的伤心，是流不出一滴眼泪。什么事情都会过去，我就是这样活过来的。 3、人人都是自顾不暇的泥菩萨，别指望谁能帮你度过现实这条河。 4、你可能也不爱我，只是刚好遇见我。 5、烟灭酒半杯，往后日子多笑少流泪。 6、再也不幻想，再也不乱想，再也不会想，再也不用想。 7、听到你的消息还是会心头一震，不过这些都不重要了，孤独至少比爱你舒服。 8、所有回不去的良辰美景，都是举世无双的好时光。感谢过去，珍惜现在，憧憬未来。哭给自己听，笑给别人看，这就是所谓的人生。 9、我一直走一直走，直到走到回忆的尽头，才发现时光与你，都没有等我。 10、付出和接受都是种债都无法还清。

11、自以为是刻骨铭心的回忆，别人早已已经忘记了。 12、成熟就是自己吞下苦难、眼泪、委屈、转脸还能给别人一个笑容。 13、我也经常觉得冷可我不会随便抱别人。 14、这世上真的没有感同身受只能冷暖自知。 15、心情不好就少听悲伤的歌。 16、有的时候连自己都不知道自己心里想什么，只知道自己心好累。 17、心情不好的时候，音乐必须大声，这样才听不到心碎的声音。 18、我们就像仙人掌，防备了别人，孤单了自己。 19、不要在流眼泪的时候做任何决定，情绪负面的时候说话越少越好。 20、说出口的伤痛都已平复，绝口不提的才触及心底。 21、不该看的东西就别去看，很多时候我们心情不好是因为我们手贱。 22、说什么待我长发及腰，心情不好全剪了，叫他想一辈子去吧。 23、心情不好的时候，做什么事都那么力不从心。 24、很多人，因为寂寞而错爱了一人，但更多的人，因为错爱一

疲劳驾驶预警系统

DSD行车安全电脑（四合一版本） 产品介绍 DSD行车安全电脑是结合车载智能电脑 和车辆辅助驾驶安全电脑功能的全新一代创新 产品，其包括疲劳检测与防瞌睡系统、视频行 车记录仪、GPS定位导航以及全面的车载3G 平板电脑的功能。 DSD行车安全电脑的防瞌睡检测系统，利 用面部生物特征模式检测技术，通过对驾驶人 员视频图像的获取、跟踪和分析，对驾驶过程 中常见的注意力涣散、驾驶姿态异常、驾驶反应迟钝、疲劳瞌睡等非正常工作状态进行提示告警和记录;不仅如此，同步结合产品的视频行驶记录、GPS定位导航服务、3G实时信息推送等功能，DSD行车安全电脑可为行车安全提供最全面有效的保护。 DSD行车安全电脑将智能视频分析技术、生物模式识别技术与无线通讯及信息传递技术相结合，可全面应用于车辆主动安全驾驶及行车监察管理等关键环节，最终为行车安全提供功能完善、简便实用、可靠安全、能够全天候实时运行的创新科技产品。 产品功能 1、驾驶疲劳及防瞌睡预警 ■完成驾驶员的状态及姿态等异常驾驶状态 预警； ■完成驾驶员的多级疲劳检测及防瞌睡告警； ■完成驾驶员各类异常驾驶事件的主动分析 和记录； 2、GPS定位导航 ■正版GPS导航3D软件； ■全面的更新及扩展能力； DSD行车安全电脑提供功能全面的GPS定位导航服务，不仅如此，结合产品本身完善的处理能力和3G通讯能力，相应的导航软件可以做到实时更新，并为车辆加入更完善的车辆在线导航服务，预留了设备功能接口的链接扩展能力。 3、行车记录黑匣子 ■无论何时何地，DSD为你的合法权益提供行车保障。 DSD行车安全电脑提供完善的行车视频记录仪功能，通过广角视频获取和超大容量的自动存储，行车过程的全视频信息，可以在DSD设备中实时重现和清晰记录，并且叠加时间标签，为你的事后过程查询、责任

心情不好的时候怎么发朋友圈 形容心情不好的句子

1.手掌就那么大，握不住的东西太多了。 2.怎么可以对淋在雨里的小孩说要乖 3.还以为你不一样呢。 4.再大大咧咧的人也会觉得难过啊，就像下了很大的雨，别人在等伞，而我在等雨停。 5.不等了，也等不到了。 6.哭，是解决不了问题的。可是，就是解决不了才哭啊。 7.我也曾对你心动过，只是赶路要紧，我忘了说 8.都会走的，无一例外 9.我可以恢复出厂设置吗？ 10.我也不想一个人，但是我就擅长一个人待着。

11.要离开的人，你不妨推他一把。 12.一哄就好的人活该受尽委屈。 13.我表达不满的方式是晚一点回消息。 14.今天天气很好，好像也就一般。 15.连不开心都要暗示，你就应该知道他不在意。 16.我不会怪你，但我不会忘记每一次难过的原因。 17.我还以为这次我真能好好谈一个恋爱了呢 18.这场自救的仗我不想打了 19.生活中的糟糕小事都在消磨我对世界的兴趣。 20.心情不好说话就喜欢加句号。

21.下雨了，我说的不是天气。 22.成为遗憾，或许会被记住的久一点。 23.去吹吹风吧，能醒的话，感冒也没关系。 24.不管你承不承认，人确实是经历了一些事情后，就偷偷 换了一种性格。 25.今天还好吗，被人左右情绪了吗。 26.庆幸的是我一直很理性的看待所有的事情，我可悲的是 我是个很感性的人，所以所有的情绪我一样都没有逃过去。 27.不用考虑我，我没有感受，不用对不起，反正下次还是 会对不起。 28.我又把头发剪短了，好像变温柔了，好像过得比以前好，好像又不怎么样，我不清楚。 29.你剥开一个很酸的橘子，而感到后悔了，可对于橘子来说，那是它的一切。 30.这不就是你梦寐以求的长大吗，你怎么不笑了。

司机疲劳驾驶检测系统设计

司机疲劳驾驶检测系统设计

司机疲劳驾驶检测系统设计 摘要：随着社会经济的发展，商用长途运输车越来越多，司机为了追求经济效益，经常罔顾交通法的规定疲劳驾驶，而一些私家车也因为各种各样的原因经常铤而走险疲劳驾驶，酿成很多人间惨剧。为了减少减轻司机的精神压力并对疲劳及时提示预警，本论文以计算机视觉技术为主体，设计实用操作简单的疲劳驾驶检测系统，辅助驾驶员安全驾驶。 司机疲劳驾驶实时检测系统在实际应用中有很重要的意义。设计了一个利用图像分析的方法，通过测量PERCLOS指标值来进行疲劳判断的该类系统。系统首先对图像进行预处理，然后采用基于YCbCr颜色空间肤色模型进行人脸粗定位，根据人脸特征，逐次进行人眼区域缩小；最后通过对边缘信息进行先验知识结合积分投影的方法进行人眼定位和闭合度测量。考虑到视频图像序列帧与帧之间的相关性，采用线性运动预测的方法对人眼进行跟踪，减少了系统的运算量。实验结果表明系统能实时、准确地反映司机的疲劳状态。 关键词：疲劳驾驶人脸检测肤色检测交通安全疲劳判断

目录 摘要 Abstract 1.疲劳驾驶检测系统研究背景与意义............................ 2.疲劳驾驶检测系统研究与实现 2.1国内外疲劳驾驶检测系统研究现状 2.1.1国外疲劳驾驶检测系统的研究成果...................... 2.1.2国内疲劳驾驶检测系统的研究现状...................... 2.2疲劳驾驶检测系统浅析............................................. 2.3驾驶员疲劳检测系统的研究..................................... 2.3.1人脸检测 2.3.2人眼定位 2.3.3疲劳程度的综合判定........................................................................................... 3.基于人脸特征的列车司机疲劳驾驶检测与识 别系统研究....................................................................... 3.1研究内容及目标......................................................... 3.1.1基于人脸特征的疲劳驾驶检测与识别算法 开发................................................................................... 3.1.2疲劳驾驶检测与识别算法OSP移植 3.2基于Adaboost算法的人脸检测

心情不好适合发的句子,心情不好朋友圈句子

心情不好适合发的句子,心情不好朋友圈句子 1、难过的时候别说话，因为一张口眼泪就停不下。 2、原来除了记忆外，什么也不能永久。 3、虽然知道自己是个普通人但还是会希望在特别的人心里能有特别的存在。 4、放开彼此的手，当爱已经无法挽留，终于看透幸福的背后，是一道道伤口。 5、从有你真好到没你也行，这中间的心酸与艰难，你怎么会知道。 6、在最后的时光里我决定不再哭泣，在剩下的路里我也决定放弃。 7、深夜总是那么多无奈。挣不脱从前，怕极了以后。 8、心情不好的时候删东西就有一种快感。 9、有时候，莫名的心情不好，不想和任何人说话，只想一个人静静的发呆。有时候，想一个人躲起来脆弱，不愿别人看到自己的伤口。 10、心情不好，微微抬起头，看看湛蓝的天，看看悠悠的云，也是一种舒心的幸福。 11、某些人，某些事，久而久之就忘了，久而久之就不那么在意了。 12、有人总说：已经晚了。实际上，现在就是最好的时光。对于一个真正有所追求的人来说，生命的每个时期都是年轻的、及时的。13、被特别在乎的人忽略，会很难过，而更难过的是你还要装作你不在乎。 14、你伤我如此之深，我心里却全是你的甜言蜜语。

15、我心情不好没关系，你开心就好。 16、我承认我在发脾气的时候最喜欢说很极端的话。 17、再深的记忆，也有淡忘的一天。 18、这几天我心情不好阿！全世界都烦死人，只有你是死烦人。 19、从相遇到离开，我欠自己良多，不欠你分毫。 20、太多心酸无处诉说，太多难过如何洒脱。 21、曾经无话不说，如今的无话可说。 22、当初我们那么不甘心，最后还不是成了陌生人。 23、人老的唯一好处就是：能失去的东西越来越少了。 24、你看的，你听的，你都相信。我用心说的话你却从不相信。 25、我的难过无人知晓，我的心情无人过问。 26、任何瞬间的心动都不容易，不要怠慢了它。 27、在一瞬间曾经所有的梦都幻灭，剩下回忆湿了我的眼。 28、悉数记忆的流沙，那些逝去的年华，洗尽了我的尘沙。 29、我心情不好的时候你不在你知道我多想你安慰我吗？ 30、时间不是让人忘了痛，它只是让人习惯痛。 31、一个人吃饭也没什么不好，不过是空出来一个座，邀请了寂寞。 32、心情不好的时候，看看大海，大海那么大，足以包容你的一切。没有大海就望望天空吧，望着望着心就不痛了，脖子就会痛了。 33、嗯!生理性心情不好谢谢大哥没打死我。 34、以前觉得，人只要一天不洗澡就会长蛆。。。昨天心情不好没有洗澡就睡了，今天发现也没夸张到长蛆。。。

心情不好时发朋友圈的伤感心情说说100句

心情不好时发朋友圈的伤感心情说说100句 1、爱上等于哀伤。 2、离网络越近，离现实越远。 3、你不安定，注定我不安宁。 4、幻光留不住时光的时间。 5、你说的坚强，始终都学不会。 6、我爱你，爱了整整一个曾经。 7、有心则会累，无心者无所谓。 8、你的心不是能读懂我眼神的料。 9、他说爱你又没说只爱你一个。 10、一切都已结束，一切都将开始。 11、害怕背叛，所以不敢为爱承诺。 12、如果坦白是伤害，情愿选择谎言。 13、相爱的人，刚分开，却又心生思念。 14、女人从来不争气，男人从来不珍惜。 15、听你说他的一举一动我心如刀割。 16、不在恋爱中失败，就在恋爱中变态。 17、我就只有这么一颗心，你看着伤吧。 18、格式化我们的过去，一切重新开始。 19、有时爱情一眨眼，就把回忆当留言。 20、你说的太少或太多，都会让人很惶恐。 21、也许只有可悲，才能填补寂寞的空位。

22、不知道什么时候开始，变得如此狼狈。 23、如果说，你的忧伤是我最痛的伤口。 24、丢失的曼陀罗，我知道，不会太远。 25、我希望有个人懂我，即使我什么也不说。 26、明明说忘记，却总是不经意的想起。 27、我们都只是孩子，何必什么都懂。 28、我们在原地转了无数次，无法解脱。 29、有那么一瞬间，我以为我们会一辈子。 30、曾经的那些勇气，全都变成了回忆。 31、未知的下一秒才更容易让人刻骨铭心。 32、我尽量减少了难过，过平静的生活。 33、心不知下落，我早己找不回单纯的我。 34、宁可高傲的发霉，也不低调的凑合。 35、伤痛复合不了叻，心里永远有伤疤。 36、我捂着心脏，傻傻的痛到撕心裂肺。 37、习惯了伤感，竟然忘了什么是幸福? 38、只希望你能聆听我的世界，仅此而已。 39、看起来百毒不侵，其实早已百毒侵心。 40、给你自由的爱，冻结我们美好的回忆。 41、那种华丽旳颓废，有种令人心惊旳美丽。 42、我假装坚强，只是不想告诉自己我想哭。 43、没有人值得你放弃自己的卑微去讨好。 44、你的笑容，是我今生无法忘记的眷念。 45、明知是陌路，却还追逐，缠绵一生的毒。

司机疲劳驾驶检测系统设计

司机疲劳驾驶检测系统设计 摘要：随着社会经济的发展，商用长途运输车越来越多，司机为了追求经济效益，经常罔顾交通法的规定疲劳驾驶，而一些私家车也因为各种各样的原因经常铤而走险疲劳驾驶，酿成很多人间惨剧。为了减少减轻司机的精神压力并对疲劳及时提示预警，本论文以计算机视觉技术为主体，设计实用操作简单的疲劳驾驶检测系统，辅助驾驶员安全驾驶。 司机疲劳驾驶实时检测系统在实际应用中有很重要的意义。设计了一个利用图像分析的方法，通过测量PERCLOS指标值来进行疲劳判断的该类系统。系统首先对图像进行预处理，然后采用基于YCbCr颜色空间肤色模型进行人脸粗定位，根据人脸特征，逐次进行人眼区域缩小；最后通过对边缘信息进行先验知识结合积分投影的方法进行人眼定位和闭合度测量。考虑到视频图像序列帧与帧之间的相关性，采用线性运动预测的方法对人眼进行跟踪，减少了系统的运算量。实验结果表明系统能实时、准确地反映司机的疲劳状态。 关键词：疲劳驾驶人脸检测肤色检测交通安全疲劳判断

目录 摘要 Abstract 1.疲劳驾驶检测系统研究背景与意义............................................................................................................... 2.疲劳驾驶检测系统研究与实现 2.1国内外疲劳驾驶检测系统研究现状 2.1.1国外疲劳驾驶检测系统的研究成果......................................................................................................... 2.1.2国内疲劳驾驶检测系统的研究现状......................................................................................................... 2.2疲劳驾驶检测系统浅析................................................................................................................................ 2.3驾驶员疲劳检测系统的研究........................................................................................................................ 2.3.1人脸检测 2.3.2人眼定位 2.3.3疲劳程度的综合判定 ............................................................................................................................................................................. 3.基于人脸特征的列车司机疲劳驾驶检测与识别系统研究........................................................................... 3.1研究内容及目标............................................................................................................................................ 3.1.1基于人脸特征的疲劳驾驶检测与识别算法开发..................................................................................... 3.1.2疲劳驾驶检测与识别算法OSP移植 3.2基于Adaboost算法的人脸检测 3.2.1人脸检测技术概述 3.2.2Adaboost人脸检测算法 3.3基于Adaboost算法的人脸检测软件实现 3.3.1.样本训练过程 3.3.2人脸检测程序 3.4人眼检测与人眼状态分析算法 3.4.1基于Adaboost的人眼检测算法 3.4.2人眼级联分类器效果分析 3.4.3人眼状态分析算法 4.基于贝叶斯网络的驾驶疲劳程度识别模型 4.1基于贝叶斯网络模型的驾驶疲劳程度识别 4.2驾驶疲劳程度识别模型 4.2.1驾驶疲劳贝叶斯网络结构 4.2.2贝叶斯网络条件概率表的确定 4.2.3驾驶疲劳程度贝叶斯网络识别模型 4.3模型有效性验证 5.基于FPGA的疲劳驾驶检测系统设计 5.1疲劳驾驶检测系统总体设计方案 5.1.1系统红外光源原理 5.1.2系统总体设计 5.2系统硬件设计与实现 5.2.1系统硬件总体架构 5.2.2图像采集电路设计

精品-心情特烦想发个朋友圈_心情不好发朋友圈的句子短句

心情特烦想发个朋友圈_心情不好发朋友圈的句 子短句 心情不好发朋友圈的句子短句 1、突如其来的委屈，连笑都带着僵硬。 2、没有值不值得，只有愿不愿意。 3、一个人最伤心的事情无过于良心的死灭。 4、偶尔被需要，从来不重要。 5、走完同一条街，回到两个世界。 6、青春的抛物线，把将来始于相遇的地点。 7、别在没我的地方哭，我怕没人给你擦眼泪。 8、撕心裂肺的挽留，不过是心有不甘的表现。 9、我还是那么没出息，处处留意你的消息。 10、他依旧是我的软肋，却不再是我的盔甲。 11、我今天只做了两件事，呼吸和想你! 12、曾以为他生性冷淡，直到他对另一个人嘘寒问暖。 13、向日葵也知道，该面向太阳那头的希望。 14、决口不提不是因为忘记，而是因为铭记。

15、能动手尽量别吵吵，能整死尽量别留活口。 16、别对我笑，我怕以后得不到，还忘不掉。 17、有没有这样一个人，无论多么想念，却不曾再见面。 18、自古多情空余恨，此恨绵绵无绝期。 19、人生，是一场盛大的遇见。若你懂得，就请珍惜。 20、我的心好冷，等着你来疼。 21、过去的不再回来，回来的不再完美。 22、从现在起，我将不再期待，只珍惜我所拥有的。 23、是否在你们的生命划过，留下清晰可见的痕迹。 24、我在你眼里找不到出路，我倒在回忆里脱不开身。 25、我的倔强就是，宁愿笑着流泪，也不愿哭着说后悔。 26、你给我一滴眼泪，我就看到了你心中全部的海洋。 27、没有你，就算把世界给我，我还是一无所有。 28、这个不知所措的年龄，似乎一切都不尽人意。 29、最难过的喜欢，就是分开后的喜欢。 30、有时候突然不说话，回过神来才知道，自己在想他。 31、我想给他看最好看的我，可最好看的我却已经死了。 32、有一种单身，只是为了等待一个人。 33、你不会懂我的沉默，又怎么会懂我的难过。

司机疲劳驾驶检测系统设计

司机疲劳驾驶检测系统 设计 LG GROUP system office room 【LGA16H-LGYY-LGUA8Q8-LGA162】

司机疲劳驾驶检测系统设计 摘要：随着社会经济的发展，商用长途运输车越来越多，司机为了追求经济效益，经常罔顾交通法的规定疲劳驾驶，而一些私家车也因为各种各样的原因经常铤而走险疲劳驾驶，酿成很多人间惨剧。为了减少减轻司机的精神压力并对疲劳及时提示预警，本论文以计算机视觉技术为主体，设计实用操作简单的疲劳驾驶检测系统，辅助驾驶员安全驾驶。 司机疲劳驾驶实时检测系统在实际应用中有很重要的意义。设计了一个利用图像分析的方法，通过测量PERCLOS指标值来进行疲劳判断的该类系统。系统首先对图像进行预处理，然后采用基于YCbCr颜色空间肤色模型进行人脸粗定位，根据人脸特征，逐次进行人眼区域缩小；最后通过对边缘信息进行先验知识结合积分投影的方法进行人眼定位和闭合度测量。考虑到视频图像序列帧与帧之间的相关性，采用线性运动预测的方法对人眼进行跟踪，减少了系统的运算量。实验结果表明系统能实时、准确地反映司机的疲劳状态。 关键词：疲劳驾驶

目录 摘要 Abstract 3. 预警系统的组成及工作原理 典型的疲劳驾驶预警系统 疲劳驾驶预警系统比较 发展趋势 8.新型多功能驾驶员状态监测系统设计 无线脑电信号采集和分析 酒精监测 9.多源信息融合在驾驶疲劳检测中的应用 驾驶疲劳特征 模糊神经网络疲劳识别 智能控制技术在汽车疲劳驾驶监控中的应用研究 1.研究背景与意义 驾驶疲劳川是指驾驶员由于睡眠不足或长时间持续驾驶造成的反应能力下降，这种下降表现在驾驶员困倦、打磕睡、驾驶操作失误或完全丧失驾驶能力。美国印第安那大学对交通事故原因的调查研究发现85%的事故与驾驶员有关，车辆和环境因素只占15%。驾驶员在事故发生前一瞬间的行为和故障直接导致了事故的发生，这些行为包括知觉的延迟、对环境的决策错误、对危险情况的处理不当等。在所有的驾驶员错误中，最常见的是知觉延迟和决策错误，这些错误会产生注意力不集中、反映迟钝、操作不当等，产生这些错误的根本原因就是驾驶疲劳。 随着我国生活水平的提高，人们的衣食住行等方面有了很大的改善，在交通方面更是有了质的飞跃。四通八达的道路、便捷的交通工具大大地缩短了人与人的距离，其中汽车保有量更是与日俱增，一个家庭拥有两辆以上的小车已经不是什么新鲜的事

心情不好发朋友圈的说说 内心压抑憋屈的心情短语

心情不好发朋友圈的说说内心压抑憋屈的心情短语 1.与你无关的事，别问，别想，别多嘴。 2.多少事，从来急;天地转，光阴迫。一万年太久，只争朝夕。 3.有些事藏在心里是莫大的委屈，话到嘴边又觉得无足挂齿不值一提。 4.最怕的不是说出秘密，而是两个人的秘密，你却在第三个人那里听见。 5.放弃并不是心血来潮，各种失望累积在一起，最终在沉默中爆发。没有声音，没有吵闹，就这么静悄悄的放弃了。 6.人都会有心情不好的时候，说不上来的失落，道不明白的难过，理不清楚的交错。 7.活得累是因为心里装了多余的东西，跟吃饱了撑的是一个道理。 8.不要在人前哭，也不要在深夜做任何决定。 9.突如其来的脾气大概是积攒了很久的委屈。 10.这世界上根本不存在“不会做”这回事，当你失去了所有的依靠的时候，自然就什么都会了。 11.无论你活成什么样子，背地里都会有人对你说三道四。一笑了之，给自己一个灿烂的阳光，一片自由的海洋，让自己不断变强，其实就是最好的蔑视。 12.不卑不亢，落落大方，但行好事，莫问前程。 13.想得开，也就那么一回事。想不开，什么都是事。

14.我心里一直有你，只是比例变了而已。 15.爱到收不住，才是真的输。 16.要没点自我安慰的本事，还真活不到现在。 17.去找一个像太阳一样的人，帮你晒晒所有不值一提的迷茫。 18.奉劝各位：除了灾难、病痛，时时刻刻要快乐。 19.幸福如人饮水，冷暖自知，你的幸福，不在别人眼里，而在自己心里。 20.我是一个经常笑的人，可我不是经常开心的人 21.生活没那么多剧情，靠谱的人花样不多却能陪你过平淡生活。 22.有时候，明明心如刀割，却要灿烂的微笑，明明很脆弱，却表现的如此坚强，眼泪在眼里打转，却告诉每个人我很好。 23.世界再大还是遇见你，世界再小还是丢了你。 24.有些人，有些事，该忘就忘了吧，人家从没把你放心里过，你又何必自作多情。 25.有些事，现在看来不过如此，但在当时，真的就是一个人一秒一秒熬过来的。 26.愿我们，都有能力爱自己，有余力爱别人。 27.你真的很奇怪，烟对你不好你喜欢，酒对你不好你喜欢，我对你这么好，你却不喜欢。在我青春岁月里，唯有你最深得我意，也只有你最不识抬举。

关于发在朋友圈表示心情抑郁,很不开心,心情压抑的伤感说说100句

关于发在朋友圈表示心情抑郁，很不开心，心情压抑的伤感说说100句 寂寞的人总是会用心的记住他生命中出现过的每一个人，于是我总是意犹未尽地想起你在每个星光陨落的晚上一遍一遍数我的寂寞。这份关于心情抑郁，很不开心，心情压抑的伤感说说希望大家会喜欢。 1、我总是躲在梦与季节的深处，听花与黑夜唱尽梦魇，唱尽繁华，唱断所有记忆的来路。 2、逃避，不一定躲得过;面对，不一定最难过。孤独，不一定不快乐;得到，不一定能长久。失去不一定不再拥有，可能因为某个理由而伤心难过。 3、足够真心的人经得起等待，随口说说的人转身就牵了别人的手。 4、后来我才知道，那些真正要走的人，吝啬得连说再见都觉得是浪费时间。 5、曾经，我想和你分享我的所有秘密，但现在，你成了我心底的秘密。 6、想你的滋味，就象喝了一杯冰冷的水，然后凝成了滴滴热泪。 7、这世上没有真正的公主!除非你老爸家资亿万，能引来一帮图你油水的男生女生常绕在左右虚意奉承，否则，你别指望全世界的人都能宠你若宝!

8、我忘记了哪年哪月的哪一天，我在哪面墙上刻下了一张微笑着，忧伤着，凝望着我的脸。 9、想你的时候有些幸福，幸福得有些难过。幸福对我说，你还太小。 10、人，不怕渺小，只怕卑微;人，可以无傲气，但不可无傲骨，无论别人怎样看你，你要自己看得起自己。 11、在这个城市里，我不断地迷路，不断地坐错车，并一再下错车，常常不知道自己在哪里，要去什么地方。 12、总有一些文字，触动心灵。总有一段心语，痛彻心扉。总有一些句子，你看着看着就哭了。 13、我耗尽了热情，丢失了自己，伤痛处还含着淡淡的甜蜜，原来只是场奇迹。 14、有些歌，深入人心，有时候我不知道我是在听歌，还是在听自己? 15、如果时间不可以令你忘记那些不该记住的人，我们失去的岁月又有什么意义。 16、有些话，说与不说都是伤害;有些人，留与不留都会离开。 17、遗忘是我们不可更改的宿命，所有的一切都像是没有对齐的图纸，从前的一切回不到过去就这样慢慢延伸一点一点的错开来。也许错开了的东西我们真的应该遗忘了。 18、绾青丝，挽情思，任风雨飘摇，人生不惧。浮生一梦醉眼看，海如波，心如皓月，雪如天赐。你自妖娆，我自伴。 19、我不是真的想踩着你的头往上爬，我也没有办法，他踩我，我踩你，踩来踩去大家也就习惯了。真高兴往上爬的人是我，

心情不好发朋友圈的说说,心情不好时发的朋友圈

心情不好发朋友圈的说说,心情不好时发的朋友圈 1、心情不好，也不想好。 2、你可能也不爱我，只是刚好遇见我。 3、其实我很难过，只是骄傲不让我哭，宁愿坚强转身，也不委屈留下。 4、唯你最深得我心，也只有你最不识抬举。 5、起码我不后悔爱过你，永远也不会忘记你。 6、怀孕时要担心心情不好哭泣会影响宝宝发育，坐月子了还要担心心情不好分泌乳汁对宝贝不好，为什么我总要担心这样的破问题…… 7、心情不好的时候，我只想一个人安安安静的待着。 8、明明不是陌生人，却装旳比陌生人还陌生。 9、有些事情好像在冥冥中早已注定，譬如遇见，比如感觉，比如离开。 10、最近吃的都很少，虽然吃的少会心情不好，不过无所谓啦，少吃起码还能瘦一瘦，毕竟吃的多了心情也没好过。 11、莫名其妙心情不好。差不多见到谁都想打一架。

12、不开心就不要想，对自己好些，因为没有谁会真的在乎你。 13、寂静的夜里，难以入眠。有一种情不自禁的感觉在撩拨着我的心弦。 14、有时候，没有下一次，没有机会重来，没有暂停继续。有时候，错过了现在，就永远永远的没机会了。 15、走过每个场景，都是回忆，你要我怎么忘记。 16、是否你也像我一样，用言不由衷的话语，逼走最爱的人，然后独自心痛。 17、以朋友的名义爱着一个人，连吃醋的资格都没有，有多喜欢，就有多心酸。 18、其实我还好，只是突然回首，看到了个陌生的自己和一条回不去的路。 19、我想我的思念是种病，久久不能痊愈。 20、没有回应，再深的感情也得憋回去。 21、我在努力的变成你喜欢的样子，可是你却告诉我你爱的是她。 22、世界上最残忍的事，不是没遇到爱的人，而是遇到了却是最终错过。 23、你本来很爱一个人，可是，当所有的失望累积到了一个临界

朋友圈说说心情不好短语,心情不好的说说发朋友

朋友圈说说心情不好短语,心情不好的说说发朋友 1、最荒芜的不是这个世界，而是人心。 2、不要轻易说爱，许下的承诺就是欠下的债！ 3、时间不是让人忘了痛，它只是让人习惯痛。 4、我的硬伤不过是你的名字而已。总是一千次的忘记你，但又一千零一次的想起你。 5、天空下起了绵绵细雨，不知是否太过悲伤，连上帝也忍不住哭泣。 6、终于你只是一个名字而不是一段往事。 7、我们似乎都忘了那段感情，我忘得刻意，你忘得随意。 8、寂寞是听见某个熟悉名字，不小心想起某些故事；孤独是路过我身边的影子，笑着对我说似曾相识。 9、头发越剪越短，穿的越来越简单，睡的也越来越早，在乎的越来越少。 10、我会莫名其妙的心情不好，然后不惜得罪任何人。 11、有时候，没有下一次，没有机会重来，没有暂停继续。有时候，错过了现在，就永远永远的没机会了。

12、我没有朋友又怎样，这之后让我变得更加坚强。 13、一个人自以为刻骨铭心的回忆。别人也许早已经忘记了。 14、一停下来就迷失了方向，心情不好就是自己在这里坐坐，不管什么情绪都不会有人看见！想哭就哭吧！ 15、我说我喜欢猫，可到现在为止，我也没拥有过猫。 16、懂我的人知道我一发笑脸就是心情不好。 17、当初我们那么不甘心，最后还不是成了陌生人。 18、看不见的时候以为忘记了，重逢时只需一眼还是会溃不成军。 19、你的长相，影响了我滴健康成长，我看到你，心情比上坟还要纠结。 20、真正疼的要命的哭泣。不是有太多的情绪。而是面无表情的留下一滴一滴的苦泪。 21、一个人值不值得你穷极一生去喜欢，不是看他能对你有多好，而是看他心情不好的时候能对你有多差。 22、不需要有谁能够看穿我的笑容，因为我知道，那里面藏着一个真实的自己。 23、我想我的思念是种病，久久不能痊愈。 24、每次看到你的背影，我都拼命去追。

疲劳驾驶检测系统创业计划书

融合车辆CANBUS数据和计算机视觉方法的疲劳驾 驶检测系统创业计划书 目录

1．执行纲要 (4) 1.1公司简介 (4) 1.2市场描述 (5) 1.3组织与人力资源 (6) 1.4企业发展战略 (6) 2．项目背景 (6) 2.1产业背景 (6) 2.2公司产品 (7) 2.2.1 产品简介 (7) 2.2.2产品优点 (7) 2.2.3产品前景 (8) 3．市场调查和分析 (8) 3.1目标客户 (8) 有车一族 (8) 3.2市场前景调查 (8) 3.3竞争分析 (11) 3.3.1 竞争因素分析 (11) 3.3.2 竞争优势分析 (12) 3.4市场发展走势分析 (12) 4．公司战略 (13) 4.1公司总体战略 (13)

4.2发展战略 (13) 4.2.1 近期发展目标（1-2年） (13) 4.2.2 中期发展计划（3-5年） (14) 4.2.3 中期发展计划（5-10年） (14) 5．生产技术管理 (16) 5.1工厂建设 (16) 5.2原材料的采购与管理 (16) 5.3产品质量管理 (17) 5.3.1. 技术研发管理 (17) 5.3.2 原材料采购管理 (17) 5.3.3生产流程管理 (17) 在生产阶段，实行“三检查”方式。具体如下： (17) 6．市场营销 (19) 6.1营销计划 (19) 6.1.1 市场进入和开发阶段（1-2年） (19) 6.1.2 市场成长阶段（3-5年） (21) 6.1.3 市场成熟阶段（5-10年） (23) 6.2 定价战略 (25) 7. 风险分析与规避 (26) 7.1技术风险分析与规避 (26) 7.2市场风险分析与规避 (26) 7.3管理风险分析与规避 (27)

发朋友圈心情不好的句子,心情不好发的句子

发朋友圈心情不好的句子,心情不好发的句子 1、多希望你能看穿我的不安心和难过可是你没有。 2、不合适就是，我不能逗你笑，你也只会让我哭。 3、有些事情，只有经历了，才有穿透心扉的体验。 4、也许你会爱很多人，会拥抱很多人，但你皑皑老去的时候，只会有一个人，十年如一日的让你清晰的怀念或痛。 5、有一个很长很长的故事，我长话短说，我有个爱人，他不爱我了。 6、总在一次次的失落和沮丧中，找到了自我，那是一种多么真实的疼痛。 7、坐月子每天连半只鸡都吃不完，心情不好也跟奶水有关系啊，大家都不用那么......唉!会挺过去的 8、每当我心情不好的时候，我就去照镜子。 9、以后我们桥归桥路归路老死不相往来。 10、原谅我爱你好深，却一声不吭。 11、每个人都有一段悲伤，想隐藏却欲盖弥彰。 12、两个人的回忆那么多，可是看客却只剩下我一个。

13、我爱你，你却没有同样的想法。 14、用力的爱过，被狠狠的伤害过，撕心裂肺的哭过，最后全都一笑而过。 15、人生就像蒲公英，看似自由，却身不由己。有些事，不是不在意，而是在意了又能怎样。 16、如果不爱我，伤我的时候别太轻，要狠，要绝，我怕忘不了，更怕自己死不了心。 17、人人都是自顾不暇的泥菩萨，别指望谁能帮你度过现实这条河。 18、当心情不好时，就选择沉默，孤独者的表现。 19、当我不再执着时，你却说你爱上了我。那凋零了半世纪的树梢，现在已经变得光秃，没有了一片落叶。 20、就算全世界都抛弃了我。那又如何？我不放弃自己就好。 21、难过了，不要告诉别人，自己知道就好。 22、爱一个人可以一见钟情，可是忘掉一个人我不知道还要煎熬多少个日夜。 23、既然还不能学会放下，就不要拿起来。 24、成熟就是自己吞下苦难、眼泪、委屈、转脸还能给别人一个

疲劳驾驶预警系统

疲劳驾驶预警系统 疲劳驾驶预警系统作为一个新兴的汽车安全辅助驾驶产品，国际和国内刚处于起步研究状态，还没有完全成熟的产品。西安邦威电子科技有限公司历经3年多时间的集智攻关，突破了一系列技术难题，掌握了疲劳状态检测的核心技术，总体性能达到了国际先进水平。 西安邦威电子科技有限公司研制的SS600疲劳驾驶预警系统是基于车联网应用 的解决驾驶员疲劳驾驶安全隐患的智能检测设备，针对疲劳驾驶行为进行检测、预警和干预，以提高行车安全性。本系统应用公司自主研发的人脸检测算法（AD_FACE算法），依据对驾驶人员视频图像的获取，通过面部生物特征模式技术的检测、分析和判别，对常见的驾驶注意力不集中、反应迟钝、疲劳瞌睡、低头玩手机、接打电话和抽烟等非正常驾驶状态进行提示告警，具体包括：对驾驶员状态进行检测；对驾驶员活跃度、姿态、注意力进行评估；对驾驶疲劳和瞌睡进行告警。产品简便实用、可靠性高，能够全天候、实时非接触式进行驾驶员疲劳状态监测，为安全行车提供有效的汽车主动安全保障。 产品介绍 SS600疲劳驾驶预警系统采用本公司自主研发的人脸检测算法（AD_FACE算法），依据对驾驶人员视频图像的获取，通过面部生物特征模式技术的检测、分析和判别，对常见的驾驶注意力不集中、反应迟钝、疲劳瞌睡、低头玩手机、接打电话和抽烟等非正常驾驶状态进行提示告警，具体包括：对驾驶员状态进行检测；对驾驶员活跃度、姿态、注意力进行评估；对驾驶疲劳和瞌睡进行告警。产品简便实用、可靠性高，能够全天候、实时非接触式进行驾驶员疲劳状态监测，为安全行车提供有效的汽车主动安全保障。 SS600疲劳驾驶预警系统具有如下性能 非接触性：不影响驾驶习惯及驾驶环境。

心情不好适合发朋友圈的说说,心情不爽说说

心情不好适合发朋友圈的说说,心情不爽说说 1、当我心情不好的时候，我总是想做一些不一样的事来告诉别人，我很不好，可是很少有人会发现，而要我装没事像平常一样，我又做不到。 2、我没说话，不意味着我心情差。有时候，我就是想安静点。 3、据说，一个男孩喜欢你，他会一直不叫你的名字。 4、你知道那种感觉吗，明明那个人还在，可以打电话，可以发信息，但你没有任何立场，他永远不再是你的了，那种感觉真的特别难过。 5、我过得不好，我不想撒谎。 6、我知道，即便我挽留你千千万万遍，你也不会为我而驻足。 7、忧虑就是浪费时间，它不会改变任何事，只能搅乱你的脑袋，偷走你的快乐。 8、别用一个人的过去来揭人家的伤口，你听到的你看到的终究不是本质，谁还没有个过去，何必抓着不放。 9、如果你爱一个人，对方没有感觉，那说明对方不爱你，千万不要试着去感动对方，那不是爱，是任性，放过他，也是放过自己。 10、每一个矜持淡定的现在，都有一个很傻很天真的曾经。 11、不需要有谁能够看穿我的笑容，因为我知道，那里面藏着一个真实的自己。 12、不管是美好还是残酷的，不管是伤痛还是幸福的，只要伤痛着有你拥抱着，有你的温度就值得了。

13、真希望自己变回小孩，因为，摔破的膝盖总比破碎的心要容易修补。 14、明明心事重重却一副若无其事的样子，不是不想找人说，只是怕没人懂。 15、分手后的悔恨、不爱后的关怀、高高在上的自尊心、低智商的善良，这是感情世界里最没用的四种东西。 16、假如有一天我们不在一起了，也要像在一起一样。 17、宁愿做过了后悔，也不要错过了后悔。人生就像蒲公英，看似自由，却身不由己。有些话，你不经意的说出口，我却很认真的难过。 18、爱的如此心痛，如果早知如此，何必当初苦苦的追寻。 19、不要在心情糟烂差的时候，用决绝的话伤害爱你的人。 20、好像所有的悲剧都发生在雨天，所以注定人们总在阴雨天感到失落。 21、我们无法忘记一个人，往往不是因为对方有多么难忘，而是因为我们有多么依恋和执着。 22、经常莫名的心情不好，你说这是不是天气的缘故。 23、什么天长地久全部都是假话和废话。 24、我会莫名其妙的心情不好，然后不惜得罪任何人。 25、我知道，忘记是件轻松的事情，只要不看着，不想着，不记着，就忘记了，就像，烟火过后的天。 26、不悲伤不代表不认真，不痛苦不代表不投入，不流泪不代表不感动，不爱不代表没有爱。

心情不好怎么发朋友圈,心情不好的朋友圈说说

心情不好怎么发朋友圈,心情不好的朋友圈说说 1、那名叫岁月的苦茶，不好喝，依然吞下它。 2、这个城市没有草长莺飞的传说，它永远活在现实里面，快速的鼓点，匆忙的身影，麻木的眼神，虚假的笑容，而我正在被同化。 3、就算心情在不好也不应该把脾气洒在对自己好的人的身上。 4、承诺算个屁呀，你说你会和我一直走下去，可现在呢，还不是各奔东西。 5、既然无法言说，不如一笑而过；既然无法释怀，不如昂然自若。 6、当我不再执着时，你却说你爱上了我。那凋零了半世纪的树梢，现在已经变得光秃，没有了一片落叶。 7、淡淡的日子，淡淡的心情，淡淡的阳光，淡淡的风，凡事淡淡的，就好。 8、如果心情不好就吃顿好的。 9、在空气里感觉到你，来不及吸入与呼出，就静放在心里想你。 10、大家都是情不知所起，一往而深，我不一样，我是钱不知所去，一贫如洗。

11、很多事不是我想，就能做到的。很多东西，不是我要，就能得到的。很多人，不是我留，就能留住的。 12、没用的东西，再便宜也不要买;不爱的人，再寂寞也不要依赖! 13、我们总喜欢幻想未来应当如何，未来如何完美，可到最后我们总会发现现实和理想相差太多。 14、我的硬伤不过是你的名字而已。总是一千次的忘记你，但又一千零一次的想起你。 15、每个故事都是合理的。主角演完完整的故事，配角在片段里充当过客。 16、没有过不去的事情，只有过不去的心情。只要把心情变一变、世界就完全不一样了。 17、心情不好导致这么晚了却还是毫无困意心里莫名的不开心难过到想哭却哭不出。 18、如果没有感觉，就不要给我错觉。 19、我会莫名其妙的心情不好，然后不惜得罪任何人。 20、有些事情好像在冥冥中早已注定，譬如遇见，比如感觉，比如离开。

关于一个人心情不好的句子 心情低落说说发朋友圈

关于一个人心情不好的句子心情低落说说发朋友圈 4、可怕的不是爱错人、而是不敢再用真心爱人。 5、你做对一件事没人说你好、你做错一件事全世界都在指责你。 6、有一种孤独、不是做一些事没有人陪伴、而是做一些事没有人理解。 7、真的不必把太多人请进生命里、太过热情总是不被珍惜。 8、每个单身的人背后至少藏着一个让人心碎的秘密。 9、当你很努力的想要挽留一个人的感情、那种瞬间变得卑微了的感觉真恶心。 10、当眼泪流下来、才知道、分开也是另一种明白。 11、为了一个你、和多少人淡了关系、结果你走了、他们也没了。

12、任何一颗心灵的成熟、都必须经过寂寞的洗礼和孤独的磨炼。 13、错过的过错是孤单、想念的念想是离别、看这反反复复的无奈、可怜的结局总会等待。 14、我嫉妒你身边每一个无关紧要的人、他们就那样轻而易举、见到我朝思暮想的你。 15、难不难过都是自己过、伤不伤心都是一颗心、我们都喜欢逞强、都喜欢流着眼泪笑着说没事。 16、活着活着、活成了讨厌的样子。笑着笑着、笑成了可笑的角色。走着走着走丢了、只剩影子和我。 17、当时间消磨掉了你的热情、你便会发现、那些曾令你歇斯底里的去执着的人、现已变得可有可无。 18、假如人生不曾相遇、我还是我、你依然是你、只是错过了人生最绚丽的奇遇!

19、记住了并不代表是永恒、忘却了也不等于没发生。 20、到最后、只是我们与旧时光相遇。一见如故、再见陌路。 21、有时候、亲密并不一定和爱有关、而疏离并不代表不喜欢 22、我不后悔爱过你、只是如果可以回到从前、我会选择不认识你。 23、和好容易、如初太难、你是我喉咙里的刺、拔出来会痛、咽下去会死。 24、只是一起走过一段路而已、何必把怀念弄的比经过还长。 25、你之所以感到孤独、并不是没有人关心你、而是你在乎的那个人没有关心你。 26、最深的绝望、是你明知道自我渴望、却得对它装聋作哑。 27、这次没有争吵、没有拉黑、但我们都懂、从此再无交集、这应该可以算是最好的离开方式。

发朋友圈的句子心情不好,心情不好的朋友圈句子

发朋友圈的句子心情不好,心情不好的朋友圈句子 1、每次心情不好的时候都想去看看张云雷，他真的是我又丧又糟的时间里，唯一的精神慰藉了。 2、淡淡的日子，淡淡的心情，淡淡的阳光，淡淡的风，凡事淡淡的，就好。 3、每个人都用文字来诉说自我的悲伤，不料却越写越伤。 4、情人最后难免沦为朋友，可是，我们连朋友都做不成。 5、神马鸟人，老婆坐月子，老公打牌打到现在还没回!是当老婆的太纵容，还是当老公的太不当回事!!要抑制住，不能心情不好! 6、每次看到你的背影，我都拼命去追。 7、爱的如此心痛，如果早知如此，何必当初苦苦的追寻。 8、有些事情，我们不得不承认，即使拼命的去挽回，故事的结尾还是遍体鳞伤。 9、痛过之后就不会觉得痛了，有的只会是一颗冷漠的心。 10、道理我们都懂只是有时故事太撩人情绪在作祟。 11、坐月子哭对身体不好，本来奶水就不够心情不好还会回奶，这些道理我都懂。可是我就是止不住的难过。

12、心无定数，自然迷茫，心无定所，自然孤独。 13、那么多爱，那么多痛，那么多爱你，最后却终究是分离。 14、坐月子中，想着为孩子好，反正是烧什么吃什么，TM吃的跟猪一样的，冒火心情不好! 15、有的人，该忘就忘了吧，人家不在乎你，又何必委屈自己呢？再怎么痛，再怎么难过，人家也看不到，也不会心疼你，你难过给谁看？ 16、别让不好的事物影响了自己的心情，你是为自己而活。 17、表象只能骗得了别人的眼睛，但骗不了自己内心。 18、睡不着的时候，往事就一件件浮上来，特别是那些值得后悔的事，就像撕得失败的标签，再怎么抠仍然黏有半块在心上。 19、招惹你的是我，舍不得的是我，感动你的是我，放不下的也是我，我一个人包揽了所有的剧，你累了不想演了，不肯剧终的是我。 20、愿你比别人更不怕一个人独处，愿日后想起时你会被自己感动。 21、最感叹的莫过于一见如故，最悲伤的莫过于再见陌路。 22、我不是淑女，心情不好的时候，我也想优雅地，骂个脏话。 23、曾经深爱过，毫不留余地的伤过，现在默然了，不是不爱了，