Areas of Expertise

Nuclear Cardiology

Hybid Imaging (PET/CT and SPECT/CT)

Nuclear Cardiology

What is Nuclear Cardiology?
Nuclear cardiology is an established subspeciality that is based on the use of radiotracers to diagnose heart diseases and contribute to their management.  It has grown significantly in recent years because of developments in imaging hardware, software and tracers.

How are the studies performed?
Most nuclear cardiology studies are performed using a conventional gamma camera with a sodium iodide detector and single photon emission computed tomography (SPECT).  A new generation of cameras that use cadmium zinc telluride detectors is also now available and these have higher sensitivity and resolution (1).  Another option is to use positron emission computed tomography (PET).   Both SPECT and PET cameras have been combined with computed X-ray tomography (CT) and this offers not only more accurate attenuation correction but also makes possible evaluation of coronary calcification and coronary anatomy in the same sitting with myocardial perfusion (2). 

Which is the most common nuclear cardiology technique?
The most common test that is performed for diagnostic or management purposes is the myocardial perfusion scintigrpahy (MPS). Such studies are tomographic (SPECT) and can also be combined with ECG gating that allows assessment of global and regional ventricular function.       

What tracers are used for this?
Three tracers are available commercially for MPS:  thallium-201, technetium-99m-MIBI and technetium-99m tetrofosmin. 

Is it possible to assess myocardial perfusion with PET?
PET is another option for assessing myocardial perfusion. Rubidium-82, which is produced by a generator, is the most commonly used tracer, but the shorter lived perfusion tracers such as oxygen-15 water and nitrogen-13 ammonia are used in centres that have an on-site cyclotron.

For assessment of myocardial perfusion imaging studies, a stress test is required. What are the options?
The most commonly used technique for SPECT studies is dynamic exercise.  However, exercise may be difficult in those with limited mobility or it may be contraindicated in patients with left ventricular outflow tract obstruction or left main stem coronary disease.  Furthermore, certain conditions such as left bundle branch block (LBBB) and permanent pacing can be associated with stress-induced perfusion abnormalities at high heart rates in the absence of obstructive CAD (3).  For such patients, pharmacological manipulation of myocardial perfusion and oxygen demand is a valuable technique and it is the default method of stress for PET perfusion studies.   Pharmacological stress is accomplished with adenosine or dipyridamole and in case of contraindications to vasodilators, such as sinoatrial disease or persistent asthma, with dobutamine (3).  To avoid the side effects of vasodilator stress, agonists with a high selectivity for the adenosine A2A receptors responsible for the coronary vasodilator effect of adenosine have been developed recently (4).  It also is possible to combine stress techniques and the commonest pairing is dynamic exercise up to 75W with either adenosine or dipyridamole. This increases sensitivity for the detection of perfusion defects and their conspicuity but reduces also the side effects of the vasodilators. 

What do the images show?
The images show the tracer distribution in the myocardium.  Myocardial perfusion and hence tracer distribution is uniform in normal myocardium (figure 1).  A defect indicates either reduced perfusion in viable myocardium or a reduced amount of viable myocardium or a combination of both.  If a stress defect returns to normal in the resting images, this indicates the presence of an inducible perfusion abnormality.  Areas of infarction show a defect in both stress and rest images and the depth of the defect indicates the amount of myocardial loss (figure 2a, b, c).  Another important feature is left ventricular dilatation in the stress images that is less marked in the resting ones, since this implies extensive inducible ischaemia and is associated with an adverse prognosis. 

Which other nuclear cardiology techniques are used currently?
In previous decades, assessment of LV function was commonly performed by equilibrium radionuclide ventriculography (RNV) using technetium-99m labelled erythrocytes (5).  For biventricular functional assessment, a first pass technique based on the first passage of the tracer through the central circulation is well validated.  Both have now largely been replaced by either ECG gated SPECT of the perfusion images or echocardiography, but SPECT blood pool imaging has some advantages including the assessment of inter- and intra-ventricular synchrony from the phase image.  Currently, RNV is most commonly performed for monitoring LV function in patients receiving potentially cardiotoxicity chemotherapy such as doxorubicin and trastuzumab (5).  An emerging tool for clinical studies is iodine-123 meta-iodo-benzyl-guanidine (mIBG), a norepinephrine analogue, which allows imaging of sympathetic myocardial innervation and provides prognostic information in patients with heart failure independently of other risk predictors such as LVEF and BNP (6).  Regarding PET based imaging, assessment of myocardial metabolism in combination with myocardial perfusion is a relatively common examination in heart failure patients for identification of myocardial hibernation. Glucose metabolism is most easily imaged using 2-fluoro-2-deoxyglucose (FDG) labelled with fluorine-18 (7). 

Which are the most common clinical applications?

a) MPS:

International guidelines recommend imaging of coronary function using, among other tests, MPS in patients with a pre-test likelihood of disease between 30% and 60%.  When CAD is already known to be present, MPS may be considered in symptomatic patients and coronary angiography should follow if significant ischaemia is present (8).  All guidelines emphasise the accuracy of vasodilator stress with MPS in patients with LBBB, paced rhythm, resting ST-segment depression greater than 1 mm or pre-excitation.  Normal stress MPS indicates the absence of functionally significant CAD.  A recent meta-analysis showed sensitivity and specificity of 85-90% and 70-75% respectively for the detection of angiographically significant CAD, although in practice specificity is higher than this since some of the studies suffer from post-test referral bias (9).  Numerous studies have confirmed the excellent prognostic power of MPS and its important role in risk stratification and patient management as well as its cost effectiveness.  A normal scan is associated with a 0.7% annual risk of infarction and cardiac death, which is similar to the general population.  An abnormal scan confers around a 7-fold increase in annual coronary events and the likelihood of an event increases with the extent and severity of the inducible perfusion abnormalities (10).

For assessment of asymptomatic patients, international guidelines support MPS for individuals with a family history of premature CAD and patients with diabetes and abnormal resting ECG or increased calcium score (11).  MPS is also appropriate for assessment of asymptomatic patients undergoing elective intermediate to high risk non cardiac-surgery (12).  Regarding its role in the acute setting, the American Heart Association recommends MPS in patients with an intermediate likelihood of CAD presenting to the emergency room with chest pain in the absence of diagnostic ECG changes (13).  Normal MPS excludes infarction and so stress testing may then safely be considered to rule out inducible ischaemia. Conversely, an abnormal result has a high sensitivity for obstructive CAD leading to an acute coronary syndrome (ACS), particularly when associated with a regional wall motion abnormality.  In patients with ACS treated with coronary stenting, MPS is useful in the evaluation of the functional significance of non-culprit stenoses.  After ST elevation myocardial infarction (STEMI), stable patients who have not undergone coronary angiography can be evaluated further by MPS only 2 to 4 days after infarction, which contributes to risk stratification and further management plans. European and American guidelines also support the use of MPS for the detection of ischaemia in patients with NSTEMI who are not candidates for early intervention (14, 15). 

MPS has been used extensively in the evaluation of myocardial viability and hibernation. A large body of evidence supports current guidelines, which recommend viability assessment in patients with dyspnoea and chronic ischaemic LV dysfunction (16).  Uptake more than 50% of maximum after tracer injection under nitrate cover is accepted as a marker of viability, with a minimum of four viable segments (approximately 25% of the left ventricle) needed to predict improvement of LV function after revascularisation.  The most recent meta-analysis confirmed earlier data and showed that MPS is sensitive (83%-87%) but less specific (54%- 65%) compared with techniques that challenge myocardial contractile reserve, such as dobutamine echocardiography and CMR, for predicting recovery of regional function after revascularization (sensitivity 80% and 74%; and specificity 78% and 82%, respectively) (17).  For contrast-enhanced CMR, these values are 84% and 63%.  The usefulness of MPS in this setting has been challenged recently by the sub-study of the Surgical Treatment for Ischemic Heart Failure (STICH) trial (18).  According to this, the presence of viable myocardium was associated with an increased probability of survival but viability assessment failed to identity patients with a survival benefit from surgical revascularisation compared with medical therapy alone.  However, the results need to be interpreted with caution because the study definition of viability included myocardial segments that were viable but not necessarily dysfunctional and hence were not necessarily either hibernating of even ischaemic. In addition, viability assessment was performed in a non-randomised fashion in only 50% of patients leading to the potential for significant recruitment bias. 

b) Positron Emission Tomography

PET is another option for assessing myocardial perfusion and is considered to be the non-invasive gold standard for this indication because of its capacity to provide accurate and reproducible measures of perfusion in absolute terms (ml/g/min) both at rest and stress. Its clinical utility, however, is constrained by high cost and low availability compared with SPECT.   PET has also been used for risk stratification and its overall prognostic value has been demonstrated in several studies. In particular, measurement of coronary flow reserve offers additional prognostic information over qualitative analysis and SPECT MPS (19).   PET has also been considered for many years as the ‘’gold-standard’’ for assessment of myocardial viability and hibernation using metabolic tracers.  Dysfunctional myocardial segments with higher FDG uptake compared with that of ammonia or rubidium-82 (mismatch between and perfusion and metabolism) represent hibernating myocardium, while reduction of both perfusion and metabolism corresponds with myocardial scar (figure 3).  In cases of myocardial stunning, perfusion is normal or almost normal while FDG uptake is variable.  PET is the only modality for which at present, there is good quality information from a randomised study (PARR-2) demonstrating that patients with severe LV dysfunction whose therapy was guided by FDG PET had better outcome compared with standard care (20). 

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Key Messages

• A normal stress MPS indicates the absence of functionally significant CAD.
• Sensitivity and specificity values of MPS at least 80-90% for angiographically significant CAD.
• MPS for the assessment of myocardial ischaemia and scarring is an integral part of clinical guidelines and appropriateness criteria in many clinical settings
• A normal MPS indicates a 0.7% annual risk of infarction and cardiac death, which is similar to the general population.  An abnormal MPS study confers approximately a seven-fold increase in annual coronary events and the likelihood of an event increases with the extent and severity of the inducible perfusion abnormalities.
• Observational studies suggest that if >10% of the myocardium is ischaemic by MPS, clinical outcome is better with revascularisation than with medical therapy.  Conversely, if <10% is ischaemic, outcome with medical therapy is better. 
• PET is an accurate standard for quantitative myocardial perfusion and viability.
• PET is the only modality for which randomised data exist demonstrating that patients with severe LV dysfunction whose therapy was guided by FDG PET had better outcome compared with standard care.

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References

1. Bocher M, Blevis IM, Tuskerman L, et al. A fast cardiac gamma camera with dynamic SPECT capabilities: design, system validation and future potential. Eur J Nucl Med Mol Imaging 2010;37:1887-1902. 
2. Blankstein R, Di Carli MF. Integration of coronary anatomy and myocardial perfusion imaging. Nat Rev Cardiol 2010;7:226-36.
3. Hesse B, Tagil K, Cuocolo A, Anagnostopoulos C, Bardies M, Bax J et al. EANM/ESC procedural guidelines for myocardial perfusion imaging in nuclear cardiology. Eur J Nucl Med Mol Imaging 2005; 32(7):855-897.
4. Thomas GS, Tammelin BR, Schiffman GL et al.  Safety of regadenoson, a selective adenosine A2Aagonist, in patients with chronic obstructive pulmonary disease: a randomized, double-blind, placebo-controlled trial (RegCOPD trial), J Nucl Cardiol 2008;15:319-328.
5. Hesse B, Lindhardt TB, Acampa W, Anagnostopoulos C, Ballinger J, Bax JJ, Edenbrandt L, Flotats A, Germano G, Stopar TG, Franken P, Kelion A, Kjaer A, Le Guludec D, Ljungberg M, Maenhout AF, Marcassa C, Marving J, McKiddie F, Schaefer WM, Stegger L, Underwood R. EANM/ESC guidelines for radionuclide imaging of cardiac function. Eur J Nucl Med Mol Imaging. 2008;35(4):851-85.
6. Perrone-Filardi P, Paolillo S, Dellegrottaglie S, Gargiulo P, Savarese G, Marciano C, Casaretti L, Cecere M, Musella F, Pirozzi E, Parente A, Cuocolo A.  Assessment of cardiac sympathetic activity by MIBG imaging in patients with heart failure: a clinical appraisal. Heart. 2011; 97(22):1828-33.
7. Shellbert HR and Prior JO. Positron Emission Tomography. In V. Fuster et al, ed.  Hurst’s, The Heart. New York, NY: McGraw-Hill Companies Inc; 2004.p.557-693.
8. National Institute for Health and Clinical Excellence. Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin (clinical guideline 95). 2010.  
9. C Y Loong and C.Anagnostopoulos.  The Diagnosis of Coronary Artery Disease By Radionuclide Myocardial Perfusion Imaging  HEART Suppl V. 90, (2004), V2-9.
10. Shaw LJ, Narula J. Risk assessment and predictive value of coronary artery disease testing. J Nucl Med. 2009;50(8):1296-306.
11. Greenland P, Alpert JS, Beller GA, et al. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. Circulation 2010;122:e584-636.
12. Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. Circulation 2009;120:e169-276.
13. Amsterdam EA, Kirk JD, Bluemke DA, et al. American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology, Council on Cardiovascular Nursing, and Interdisciplinary Council on Quality of Care and Outcomes Research. Testing of low-risk patients presenting to the emergency department with chest pain: a scientific statement from the American Heart Association. Circulation 2010;122:1756-76.
14. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction).
15. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology Eur Heart J 2007;28:1598-660.
16. Guidelines on myocardial revascularization The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010;31:2501-55.
17. Schinkel AF, Bax JJ, Poldermans D, et al.  Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol 2007;32:375-410.
18. Bonow RO, Maurer G, Lee KL, et al. Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction. N Engl J Med 2011;364:1617-25.
19. Ghosh N, Rimoldi OE, Beanlands RS, Camici PG. Assessment of myocardial ischaemia and viability: role of positron emission tomography. Eur Heart J. 2010;31(24):2984-95.
20. D'Egidio G, Nichol G, Williams KA, Guo A, Garrard L, deKemp R, Ruddy TD, DaSilva J, Humen D, Gulenchyn KY, Freeman M, Racine N, Benard F, Hendry P, Beanlands RS; PARR-2 Investigators. Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial. JACC Cardiovasc Imaging. 2009;2(9):1060-8.

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Figure 1.  Normal MPS using thallium-201 with three selected short axis slices and central horizontal and vertical long axis slices after stress (left) and rest (centre).  All parts of the left ventricular myocardium having high tracer uptake, shown in orange and white.  The polar plots on the right show all parts of the left ventricular myocardium in a single circular image.  These can be compared with normal databases to assess the depth and extent of abnormalities and the overall ischaemic burden.

Figure 2. Patterns of myocardial perfusion shown from central vertical long axis slices. (a) Inducible perfusion abnormality without myocardial scarring.  There is reduced tracer uptake on stress imaging (arrows), severe at the apex and mild in the anterior wall, which returns to normal at rest. (b) Myocardial infarction. There is absent uptake at the apex on stress images which remains unchanged on rest imaging (arrows). (c) Partial thickness myocardial infarction with superimposed inducible ischaemia. There is moderate reduction of tracer uptake in the apex and apical anterior and inferior walls (arrows) on stress imaging. Images acquired at rest show improvement in these areas but the anterior wall and apex fails to return to normal, indicating partial thickness myocardial damage (arrowheads).

Figure 3. PET study with 13N-Ammonia (upper row) and 18F FDG  (lower row) for assessment of myocardial viability/hibernation. The study shows a large mismatch between perfusion and metabolism laterally compatible with hibernating myocardium.

Adapted from: Anagnostopoulos C, Underwood R.Nuclear cardiology. Clin Med. 2012;12(4):373-7

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Hybid Imaging (PET/CT and SPECT/CT)

Common applications of PET/CT in Oncology

FDG-PET has been incorporated in a number of international guidelines covering diagnosis and management of a broad range of malignancies. Below are discussed the most common indications and clinical scenarios for which PET is useful:

FDG-PET is an accurate technique for the evaluation of solitary pulmonary nodules. It has a sensitivity above 95% for detecting and characterizing malignant lung nodules greater than 1 cm and an overall specificity of 77%. In addition, it is more accurate than conventional methods for nodal staging and for detecting distant metastases of patients with known non small cell lung cancer (NSCLC) and also for the evaluation of selected patients with small cell cancer.  It is a cost-effective technique that has been incorporated into management guidelines, as there is strong evidence that addition of FDG-PET to conventional workup results in a change of stage in 10–40% of cases, especially upstaging by detecting additional lesions and up to 50% reduction in futile thoracotomy.  Regarding treatment response, FDG-PET can help to stratify patients by probability of progression free and overall survival. PET is also indicated for detecting recurrent NSCLC and restaging.  It is an ideal technique for distinguishing between recurrent or residual tumor from post therapy changes that can-not be done by conventional imaging. In addition, FDG-PET is helpful for delineating gross-tumor volume in patients planned to receive radiation therapy.

The main indication of FDG-PET in head and neck cancer is for detection of locoregional nodal disease and distant metastases. It is most commonly performed in patients with suspected local lymph node metastases in whom identification of additional contralateral or distant lymph node involvement needs to be assessed. FDG-PET can detect additional sites of disease compared to CT and result in a change of management in up to 35% of patients. PET can also provide information for directing biopsy for patients who present with a neck mass when the primary source has not been identified. Regarding treatment response in patients with squamous cell carcinoma, a negative FDG-PET study after radiotherapy with or without chemotherapy has a negative predictive value above 95% but a positive result should be interpreted cautiously as specificity is low, mainly due to false positive readings related to inflammation or post-treatment effects, if the study is performed less than 3 months from the end of the therapy.  If the study is performed after 10-12 weeks, PET/CT is a helpful tool for detecting recurrent or persistent disease in the neck.  FDG-PET is also recommended for detection of recurrent disease, when this is suspected clinically or by other imaging results. For thyroid cancer, FDG PET is indicated for restaging patients who have thyroglobulin-positive, iodine-negative disease. FDG PET is also helpful for assessment of disease extent in patients with poorly differentiated thyroid cancers and invasive Hurthle cell carcinomas.

In patients with oesophageal cancer, FDG-PET is a complementary technique to conventional imaging for initial staging.  It is particularly helpful for assessment of distant metastases, as it is superior to CT and it can lead to a change in treatment plan in up to 35% of patients. In patients with locally advanced disease, it seems to be effective in selecting those who have had a sufficient response to therapy to merit surgery. FDG-PET is also recommended for detection of recurrent disease and restaging as well as for delineation of gross-tumor volume in the setting radiotherapy planning.  In colorectal cancer, FDG-PET is indicated for preoperative evaluation of patients with potentially resectable metastatic disease. It is also indicated for detecting and restaging recurrent disease after initial therapy has been completed and there are increasing CEA levels but the CT is negative or inconclusive. FDG-PET is particularly helpful for detecting liver metastases and conversely, for ruling out distant disease in patients with proven liver metastases when surgery is planned.

FDG PET is useful in detecting metastatic melanoma in the initial evaluation of Stage II or greater, when disease is initially found in a lymph node or distant organ and the original site of the disease remains occult. PET may be considered to address specific signs and symptoms not explained by conventional imaging and it can also be performed for initial staging for orbital/ocular melanoma. In addition, it is helpful for confirmation of a suspected metastasis, to evaluate the extent of disease burden when there is relapse post-treatment and it can also be considered to screen for recurrent disease in patients with advanced disease at presentation.  In lymphoma, PET reveals metabolic status and allows differentiation between indolent and aggressive lymphomas. It is indicated for assessing treatment response (in selected histological types), both at an early stage (monitoring) and at the end of the treatment. FDG PET is more accurate than CT for assessing the presence of disease in residual masses post chemotherapy or radiotherapy.   A baseline study is helpful for establishing the full extent of disease and to perform a comparison when relapse is suspected, as the latter occurs most often in the region of previous disease.

In breast cancer, FDG PET is helpful in patients with locally advanced disease for detecting metastatic disease in those with equivocal results in other imaging tests.  It is also helpful for detecting recurrence when other studies are equivocal or suspicious.  For cervical cancer, FDG PET is indicated for staging as an adjunct to conventional imaging to determine extra¬pelvic spread. It is also indicated for restaging recurrent disease which may be potentially resectable/curable. In addition, data emerge suggesting that it can be used in radiation treatment planning to help define nodal volume of coverage. 

Beyond the above common indications for which there is good quality evidence to support the use of PET, the technique has also been found to be useful in a range of other clinical scenarios within the oncological setting. For instance, in patients with recurrent ovarian cancer, FDG PET can be helpful to identify individuals who are candidates for a secondary cytoreductive surgery, or in patients with elevated CA-125 or other relevant tumor markers, and/or changes in physical examination but normal conventional imaging.  In patients with prostate cancer, PET with18F-choline seems to be a useful examination both for initial staging and restaging recurrent disease.  PET with 18F-Fluride is superior compared to conventional bone scan for detection of metastatic disease. For renal cancer, FDG-PET is useful in detecting and restaging recurrent disease. In patients with testicular cancer, the only indication for which there is strong evidence for the use of FDG-PET is for restaging after chemotherapy if the CT demonstrates residual masses which need to be characterised for the presence (or the lack of it) of metabolically active disease.  In patients with GIST, FDG-PET can be performed as a baseline study prior to treatment of unresected disease and also within 4 weeks (after one or two cycles) from the start of tyrosine kinase inhibitor (TKI) therapy to assess treatment response. Further imaging with FDG-PET may also be considered to establish that complete response is documented, or that disease progression precludes further TK therapy.   In patients with pancreatic cancers who are candidates for resection by Whipple procedure, or subtotal pancreatectomy of pancreatic tail tumors, PET is useful to assess disease respectability. Regarding brain tumors, PET is used in patients with glioma. The radiopharmaceuticals that are typically used in such cases they do not currently exist in Greece, however, 18F-FLT or even FDG can be used to identify areas with the highest malignant differentiation in tumors which are histologically heterogeneous directing the clinician to the appropriate site(s) for biopsy (always in combination with the MRI data).  Dynamic PET imaging with 18F-FLT has also been found helpful for detecting residual disease or relapse after treatment.  PET has also been used in other malignancies, such those of the liver and the biliary system, as well as neuroendocrine tumors and sarcomas, however, its precise role in these entities is still under evaluation.

Suggestive Literature

Fletcher JW et al. Recommendations on the use of 18F-FDG PET in oncology.
J Nucl Med. 2008;49(3):480-508.

NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers V.2.2011.
(http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf)

NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V.2.2012.
(http://www.nccn.org/professionals/physician_gls/PDF/thy¬roid.pdf)

NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Carcinoma V.2.2012.
(http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf)

NCCN Clinical Practice Guidelines in Oncology. Esophageal Carcinoma V.2.2011.
(http://www.nccn.org/professionals/physician_gls/PDF/esoph¬ageal.pdf)

NCCN Clinical Practice Guidelines in Oncology. Colon Cancer V.3.2012; Rectal Cancer V.3.2012.
(http://www.nccn.org/professionals/physician_gls/PDF/colon. pdf;
http://www.nccn.org/professionals/physician_gls/PDF/ rectal.pdf)

NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer V.1.2012.
(http://www.nccn.org/professionals/physician_gls/PDF/cervi¬cal.pdf)

NCCN Clinical Practice Guidelines in Oncology. Melanoma V.3.2012.
(http://www.nccn.org/professionals/physician_gls/PDF/mela¬noma.pdf)

Cheson et al. International Harmonization revised response criteria. J Clin Oncol 2007;25:571-578.

la Fougère C et al.  Molecular imaging of gliomas with PET: opportunities and limitations.
Neuro Oncol. 2011 ;13(8):806-19.

Rioja J et al. Role of PET in urological oncology. BJU Int. 2010;106(11):1578-93.

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