Automated detection and classification of tumor histotypes on dynamic PET imaging data through machine-learning driven voxel classification.

2-deoxy-2-fluorine-(18F)fluoro-d-glucose Positron Emission Tomography/Computed Tomography (18F-FDG-PET/CT) is widely used in oncology mainly for diagnosis and staging of various cancer types, including lung cancer, which is the most common cancer worldwide. Since histopathologic subtypes of lung cancer show different degree of 18F-FDG uptake, to date there are some diagnostic limits and uncertainties, hindering an 18F-FDG-PET-driven classification of histologic subtypes of lung cancers. On the other hand, since activated macrophages, neutrophils, fibroblasts and granulation tissues also show an increased 18F-FDG activity, infectious and/or inflammatory processes and post-surgical and post-radiation changes may cause false-positive results, especially for lymph-nodes assessment. Here we propose a model-free, machine-learning based algorithm for the automated classification of adenocarcinoma, the most common type of lung cancer, and other types of tumors. Input for the algorithm are dynamic acquisitions of PET data (dPET), providing for a spatially and temporally resolved characterization of the uptake kinetic. The algorithm consists in a trained Random Forest classifier which, relying contextually on several spatial and temporal features of 18F-FDG uptake, generates as an outcome probability maps allowing to distinguish adenocarcinoma from other lung histotype and to identify metastatic lymph-nodes, ultimately increasing the specificity of the technique. Its performance, evaluated on a dPET dataset of 19 patients affected by primary lung cancer, provides a probability 0.943 ± 0.090 for the detection of adenocarcinoma. The use of this algorithm will guarantee an automatic and more accurate localization and discrimination of tumors, also providing a powerful tool for detecting at which extent tumor has spread beyond a primary tumor into lymphatic system.

Correction to: Comparison of three-parameter kinetic model analysis to standard Patlak's analysis in 18F-FDG PET imaging of lung cancer patients.

Following publication of the original article [1], the authors flagged that the author affiliations detailed in the article are incorrect for the authors M. L. Calcagni and A. Giordano.

Comparison of three-parameter kinetic model analysis to standard Patlak's analysis in 18F-FDG PET imaging of lung cancer patients.

BACKGROUND: Patlak's graphical analysis can provide tracer net influx constant (Ki) with limitation of assuming irreversible tracer trapping, that is, release rate constant (kb) set to zero. We compared linear Patlak's analysis to non-linear three-compartment three-parameter kinetic model analysis (3P-KMA) providing Ki, kb, and fraction of free 18F-FDG in blood and interstitial volume (Vb). METHODS: Dynamic PET data of 21 lung cancer patients were retrospectively analyzed, yielding for each patient an 18F-FDG input function (IF) and a tissue time-activity curve. The former was fitted with a three-exponentially decreasing function, and the latter was fitted with an analytical formula involving the fitted IF data (11 data points, ranging 7.5-57.5 min post-injection). Bland-Altman analysis was used for Ki comparison between Patlak's analysis and 3P-KMA. Additionally, a three-compartment five-parameter KMA (5P-KMA) was implemented for comparison with Patlak's analysis and 3P-KMA. RESULTS: We found that 3P-KMA Ki was significantly greater than Patlak's Ki over the whole patient series, + 6.0% on average, with limits of agreement of ± 17.1% (95% confidence). Excluding 8 out of 21 patients with kb > 0 deleted this difference. A strong correlation was found between Ki ratio (=3P-KMA/Patlak) and kb (R = 0.801; P < 0.001). No significant difference in Ki was found between 3P-KMA versus 5P-KMA, and between 5P-KMA versus Patlak's analysis, with limits of agreement of ± 23.0 and ± 31.7% (95% confidence), respectively. CONCLUSIONS: Comparison between 3P-KMA and Patlak's analysis significantly showed that the latter underestimates Ki because it arbitrarily set kb to zero: the greater the kb value, the greater the Ki underestimation. This underestimation was not revealed when comparing 5P-KMA and Patlak's analysis. We suggest that further studies are warranted to investigate the 3P-KMA efficiency in various tissues showing greater 18F-FDG trapping reversibility than lung cancer lesions.

Clinical significance of incidental focal colorectal (18)F-fluorodeoxyglucose uptake: our experience and a review of the literature.

AIM: The aims of the present study were: (i) to evaluate the focal incidental colorectal uptake of (18)F-fluorodeoxyglucose ([(18)F]FDG) and to correlate it with colonoscopy and histological findings; (ii) to evaluate the relationship between the presence/absence of neoplastic disease and clinical data and the anatomical site of [(18)F]FDG uptake; and (iii) to compare our results with those reported for incidental colorectal uptake of [(18)F]FDG in the literature and those obtained from various screening programmes for colorectal cancer. METHOD: The database of 6000 patients referred for [(18)F]FDG positron emission tomography/computed tomography (PET-CT) to our centre was retrospectively reviewed for incidental colorectal uptake of [(18)F]FDG. Patients with focal uptake were selected and the aetiology of PET findings was verified with a subsequent colonoscopy and histopathological analysis when available. RESULTS: Incidental colorectal uptake of [(18)F]FDG was seen in 144 (2.4%) patients, of whom 64 (1.1%) had focal uptake; 48 out of these 64 patients underwent colonoscopy, which showed malignant tumours in 12 (25%), premalignant lesions in 19 (40%), non-neoplastic lesions in six (12%) and lesions not confirmed by colonoscopy in 11 (23%). Our data agreed with previously published data. Statistical analysis did not show any significant relationship between the presence/absence of neoplastic disease and patient sex or age, type of primary disease and anatomical site of [(18)F]FDG uptake. Comparing our data with various screening programmes, a significant difference was found only with series in which colonoscopy was performed in patients at high risk for colorectal cancer. CONCLUSION: Focal incidental colorectal uptake of [(18)F]FDG is observed in about 1% of PET/CT studies and carries a high risk of neoplastic disease. A PET-CT report should suggest colonoscopy when abnormal findings are reported.

Role of PET in medullary thyroid carcinoma.

In the diagnostic assessment of medullary thyroid carcinoma (MTC), nuclear medicine imaging provides its contribution mainly in the postoperative work-up to detect residual or recurrent tumor. With respect to scintigraphy with gamma-emitter radiopharmaceuticals, positron emission tomography (PET) offers interesting perspectives owing to its higher image quality, spatial resolution and speed. Moreover, the recent developments of hybrid machines allow to obtain images that simultaneously hold both anatomic (computed tomography) and functional (PET) information with great impact on diagnostic efficacy. (18)F-fluoro-deoxyglucose ((18)F-FDG) is the most frequently used PET tracer in oncology. Preliminary reports of FDG-PET in MTC patients show encouraging results with a higher sensitivity in detecting local recurrent and metastatic disease when compared with single photon emission tracers. However, (18)F-FDG uptake depends on lesion size and to some extent on the grade of differentiation and biologic aggressiveness of the tumor; so FDG-PET seems useful mainly in patients with very high calcitonin levels and high progression rate. Like other neuroendocrine tumors, MTC is characterized by the presence of amine uptake mechanism and/or peptide receptors at the cell membrane allowing the clinical use of specific radiopharmaceuticals that reflect the different metabolic pathways of MTC, and in particular the synthesis, storage and release of hormones ((18)F-dihydroxyphenilalanine, (18)F-DOPA and (18)F-fluorodopamine, (18)F-FDA) and the expression of receptors ((68)Ga-labeled somatostatin analogs). These tracers are currently under investigation and will further improve the diagnostic approach of MTC.

Middle cerebral artery dolichoectasia in a young woman with a previous stroke.

We observed a 32-year-old female who had suffered from a left hemisphere ischemic stroke with right hemiparesis at the age of seven. At that time, a CT scan demonstrated a left ischemic lesion in nucleo-capsular region and a cerebral angiogram documented a complete occlusion of the supraclinoid segment of the internal carotid artery. When we observed the patient neurological examination demonstrated a moderate right brachio-crural hemiparesis. A brain MRI showed an old ischemic lesion involving the left nucleo-capsular and 'flow voids' suggestive for a vascular malformation in the left sylvian region. A cerebral rotational angiogram with 3-D reconstructions demonstrated a dolichoectatic left middle cerebral artery with an unusual 'corkscrew' aspect. Middle cerebral artery dolichoectasia is a rare pathological condition that may manifest with a stroke. The patients with intracranial arterial dolichoectasia (IADE) are most often hypertensive elderly men, and, to the best of our knowledge, an ischemic stroke associated with IADE has never been reported in children.

SPECT myocardial perfusion imaging: long-term prognostic value in diabetic patients with and without coronary artery disease.

AIM: To determine the long-term prognostic value of SPECT myocardial perfusion imaging (MPI) for the occurrence of cardiovascular events in diabetic patients. PATIENTS, METHODS: SPECT MPI of 210 consecutive Caucasian diabetic patients were analysed using Kaplan-Meier event-free survival curves and independent predictors were determined by Cox multivariate analyses. RESULTS: Follow-up was complete in 200 (95%) patients with a median period of 3.0 years (0.8-5.0). The population was composed of 114 (57%) men, age 65 +/- 10 years, 181 (90.5%) type 2 diabetes mellitus, 50 (25%) with a history of coronary artery disease (CAD) and 98 (49%) presenting chest pain prior to MPI. The prevalence of abnormal MPI was 58%. Patients with a normal MPI had neither cardiac death, nor myocardial infarction, independently of a history of coronary artery disease or chest pain. Among the independent predictors of cardiac death and myocardial infarction, the strongest was abnormal MPI (p < 0.0001), followed by history of CAD (Hazard Ratio (HR) = 15.9; p = 0.0001), diabetic retinopathy (HR = 10.0; p = 0.001) and inability to exercise (HR = 7.7; p = 0.02). Patients with normal MPI had a low revascularisation rate of 2.4% during the follow-up period. Compared to normal MPI, cardiovascular events increased 5.2 fold for reversible defects, 8.5 fold for fixed defects and 20.1 fold for the association of both defects. CONCLUSION: Diabetic patients with normal MPI had an excellent prognosis independently of history of CAD. On the opposite, an abnormal MPI led to a >5-fold increase in cardiovascular events. This emphasizes the value of SPECT MPI in predicting and risk-stratifying cardiovascular events in diabetic patients.

[New perspectives in diagnosis and therapy of endocrine gastroenteropancreatic (GEP) tumors with somatostatin analogues]. / Nuove prospettive nella diagnosi e terapia dei tumori endocrini gastroenteropancreatici (GEP) con analoghi della somatostatina.

In the last decade important progresses have been obtained in the diagnosis and therapy of endocrine gastroenteropancreatic (GEP) tumors, mainly derived from the somatostatin receptors characterization and the introduction of long acting somatostatin analogues. Receptorial scintigraphy with radio-labeled analogues (Octreoscan) is the first choice investigation for staging and follow-up of endocrine GEP tumors, thanks to the high sensitivity in revealing the primary tumor and metastases, and for its capability to reveal lesions that are not identified by other imaging methods. Moreover, somatostatin analogues uptake by tumors allow us to use radiopharmaceutical compounds for advanced disease treatment. Between the radio-labeled drugs until now studied, interesting results have been obtained by DOTA-lanreotide (MAURITIUS), DOTA0 Tyr3-octreotide (DOTATOC) and DOTA0 Tyr3-octreotate, bound to beta-emitting radio-isotope suitable for therapeutic use. In the field of the pharmacological therapy of GEP tumors, the clinical trials show that somatostatin analogues reduce the symptoms related to functionally active tumors and stabilize or slow tumor growth improving the patient quality of life. Although somatostatin analogues alone could not be able to cure GEP tumors, their early utilization in association with surgical debulking of primary tumor and metastases, embolization or chemoembolization, and interferon, chemotherapy and radio-metabolic therapy (mainly directed to the destruction of micrometastases), increases the possibility of a radical therapeutic intervention. The continuous evolution of pharmacological research provides always new analogues (octreotide LAR, lanreotide, vapreotide, BIM-23244, BN 81644, PTR-3173, BIM-23A387, SOM-230, etc.) with different pharmacokinetic and receptorial properties and acting with more effectiveness in the different individual clinical situations. In this context there have been recently introduced also the "chimeric" analogues. On the other hand, the widespread utilization of molecular biology and immunohistochemical methods can allow, in perspective, to better define the receptorial pattern of individual endocrine tumors, after their surgical removal. The necessity to integrate endocrinological, nuclear medicine, surgical, oncologic and laboratory competencies behaves a multidisciplinary approach based on the utilization of diagnostic-therapeutic protocols supplying comparable results. It does not appear unjustified to expect, in the future, a scenery of more "individual" and more effective therapies for patients affected by GEP tumours.

123I-MIBG radioaerosol lung clearance in COPD patients with fixed and partially reversible obstruction to evaluate the functional status of pulmonary adrenergic innervation.

In order to test the hypothesis that a greater sympathetic activity underlies partial reversibility of the bronchial obstruction in selected patients with chronic obstructive pulmonary disease (COPD), we assessed the pulmonary clearance of inhaled I-meta-iodobenzylguanidine ( I-MIBG) radioaerosol in 10 patients with fixed and nine with reversible obstruction. The clearance of inhaled I-MIBG is known to be inversely related to I-MIBG uptake by adrenergic terminals. Groups were matched for age and judged free from confounding comorbidity. The penetration index did not distinguish between the groups (fixed obstruction, 97.39+/-14.59%; reversible obstruction, 89.09+/-19.95%; P=0.659); this excludes the possibility that the inequality of tracer penetration could affect I-MIBG clearance. The I-MIBG clearance was 140.92+/-7.67 min in patients with fixed obstruction and 151.08+/-31.54 min in patients with reversible obstruction ( P=0.604). In conclusion, COPD patients with fixed and reversible obstruction show comparable binding of the tracer to adrenergic pulmonary receptors. Thus, a greater receptor responsiveness or post-receptor mechanism probably underlies the partial reversibility of bronchial obstruction.

Clinical role of positron emission tomography (PET) in endocrine tumours.

Positron emission tomography (PET) is considered one of the most effective nuclear medicine imaging modality in oncology. In many types of malignant tumours PET has proven to be high sensitive in detecting both primary neoplasm and metastatic disease both before therapy for staging purposes and after surgery, radiotherapy and chemotherapy during follow-up. In particular, PET showed high accuracy in differentiating post-treatment scar from viable tumoural tissue and high sensitivity in visualising very small metastatic foci as those in normal-sized (less than 1 cm in diameter) lymph nodes. A large variety of positron emitter tracers have been produced for PET imaging: the most widely used tracer in clinical oncology is 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Deoxy-glucose (DG) is a glucose analog that enters the cell using specific transmenbrane carrier proteins (especially GLUT-1). Once within the cytoplasm, DG is phosphorylated to FG-6-phosphate but does not appear to be further metabolised. In most malignant tumours there is an increase of the glycolityc metabolism which accounts for an increase of the FDG uptake. However, the metabolic cellular activity can be only slightly increased or even normal in well differentiated and slow growing tumours as some endocrine neoplasms. In the present review, the clinical usefulness and limits of PET imaging are discussed in the management of patients with endocrine tumors.

Correlation of Tc-99m-red blood cell phleboscintigraphy with clinical severity of chronic venous disease.

Equilibrium red blood cell phleboscintigraphy of the lower limbs for the diagnostic management of chronic venous disease has been proposed. The aim of this study was to verify the correlation of the phleboscintigraphic assessment of chronic venous disease with the clinical grading of the severity of the disease, since other diagnostic modalities have been recently demonstrated a poor and only partial correlation. Equilibrium Tc-99m-red blood cell phleboscintigraphy was performed in 27 patients with chronic venous disease. Scintigraphic images of 52 limbs were classified according to a four-class qualitative grading of the severity of the venous disease, and a quantitative scintigraphic index (saphena /femoral ratio) was assigned to each limb. The scintigraphic qualitative grading showed a highly significant correlation with the clinical grading (Rs=0.82, p<0.01), a good interobserver and intraobserver agreement (86.5% and 92.3%, respectively) and more than 90% sensitivity and specificity to identify the categories "minimal or no chronic venous disease" or "more significant disease" (assessed according to the Bayes theorem). Sensitivity and specificity results for the quantitative assessment were not as good. Phleboscintigraphy correlates well with the clinical grading of the severity of chronic venous disease of the lower limbs and may have potential as a valuable diagnostic tool for the noninvasive assessment of chronic venous disease.

Brain perfusion abnormalities in Alzheimer's disease: comparison between patients with focal temporal lobe dysfunction and patients with diffuse cognitive impairment.

OBJECTIVES: Patients with Alzheimer's disease (AD) showing a selective impairment of episodic and semantic memory have recently been classified as affected by focal temporal lobe dysfunction (FTLD) and considered as a distinct subgroup of patients affected by a particular form of AD. The aim was to compare the cerebral perfusion of patients with AD with FTLD and patients with AD with the more typical profile of diffuse cognitive impairment (dAD). METHODS: Ten patients with AD with FTLD, 14 patients with AD with dAD, and 12 normal controls were studied. All the 24 patients with AD underwent a complete neuropsychological assessment. SPECT examination with [(99m)Tc]-HMPAO, using a four head brain dedicated tomograph, was performed in patients and controls. Tracer uptake was quantified in 27 regions of interest (ROIs), including lateral and mesial temporal areas. Mean counts in the 27 ROIs of controls, patients with FTLD and those with dAD were compared using an ANOVA for repeated measures with Bonferroni's correction. A logistic regression analysis, followed by a receiver operating characteristic (ROC) analysis, was also applied to select SPECT patterns which significantly differentiated patients with FTLD and those with dAD. RESULTS: Two scintigraphic patterns of abnormalities, shaping a double dissociation between the FTLD and dAD groups, emerged: a bilateral mesial temporal hypoperfusion, characteristic of FTLD and a posterior parietal (and temporal parietal) hypoperfusion characteristic of patients with dAD. CONCLUSIONS: These scintigraphic findings provide further support to the hypothesis that FTLD is not a mere stage but a distinct anatomoclinical form of AD. The combination of neuropsychological tests and [(99m)Tc]-HMPAO SPECT may be very useful in identifying patients with FTLD from the wider group of patients with dAD. This issue is particularly worthwhile, as there is increasing evidence that patients with FTLD have a slower rate of cognitive decline.

Relationship between myocardial 123I-metaiodobenzylguanidine scintigraphic uptake and heart rate variability in patients with syndrome X.

BACKGROUND: We have recently demonstrated a striking impairment in cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) in most patients with syndrome X. In this study we investigated the relationship between cardiac MIBG defects and cardiac autonomic activity in these patients. METHODS: MIBG myocardial scintigraphy and time-domain and frequency-domain heart rate variability (HRV) were compared in 11 syndrome X patients and 10 healthy controls. Cardiac MIBG uptake was assessed by the heart/mediastinum ratio and a cardiac MIBG uptake defect score (higher values = lower uptake). RESULTS: The heart/mediastinum ratio was lower (1.71 +/- 0.6 vs 2.19 +/- 0.3, p = 0.03) and MIBG uptake score higher (37.1 +/- 32 vs 4.0 +/- 2.5, p = 0.005) in syndrome X patients, whereas average HRV values did not differ between the two groups. However, while there were no correlations between MIBG uptake and HRV in controls, in syndrome X patients both the heart/mediastinum ratio and MIBG uptake score correlated significantly with two HRV parameters, specific for vagal activity: the square root of the mean squared differences of consecutive RR intervals (r = 0.73, p = 0.01, and r = -0.67, p = 0.02, respectively), and high frequency (r = 0.64, p = 0.03, and r = -0.74, p = 0.009, respectively). CONCLUSIONS; In patients with syndrome X, the impairment in cardiac MIBG uptake was associated with a reduction in HRV indexes mainly reflecting vagal modulation of sinus node, thus suggesting that a predominance of cardiac adrenergic activity may be present in those with abnormal cardiac MIBG scintigraphy.

Rhinoscintigraphy: a simple radioisotope technique to study the mucociliary system.

PURPOSE: This was a radioisotope study of nasal mucociliary clearance of total and subtotal nasal obstruction. METHODS: Rhinoscintigraphy was performed by insufflating 1.85 MBq (69 mCi) Tc-99m MAA in 20 patients. Six cases were regarded as the control group, because the presence of small spurs does not affect nasal patency. The remaining 14 patients had various rhinopathic conditions. Two regions of interest were selected, one in the nasal cavity and one in the pharynx. Mucociliary transport speed was calculated. RESULTS: This parameter appeared to be a sensitive index for the assessment of the degree of mucociliary alteration. It showed that polyposis impairs mucociliary transport most severely, thus confirming the results of other published studies. CONCLUSIONS: Rhinoscintigraphy proved to be a reliable, easily reproducible, and harmless method, so it may be used for follow-up examinations in patients who have had surgery of the nose and paranasal sinuses, and for drug therapy of rhinopathic conditions.

Assessment of sympathetic innervation of the heart in diabetes mellitus using 123I-MIBG.

Radio-labeled metaiodobenzylguanidine (MIBG) is considered an established sympathetic neuron imaging agent capable of scintigraphically visualizing the organs richly innervated by the sympathetic nervous system. Its clinical applications now include cardiac and pulmonary adrenergic imaging. The quantitative determination of global and/or regional abnormalities of MIBG heart uptake has been demonstrated to be very useful in several clinical settings representing one of the major determinants of adverse prognosis. The presence and the severity of autonomic neuropathy are known as important prognostic factors in patients with diabetes. MIBG scintigraphy is able to non-invasively assess and characterize the adrenergic abnormalities of the cardiac innervation also in these patients. In order to evaluate whether 123I-MIBG is able to reveal abnormalities of myocardial adrenergic function in different groups of diabetic patients, we performed 123I-MIBG scintigraphy in control subjects and in normotensive Type 1 diabetic patients with and without autonomic neuropathy (N+ and N- patients), selected according to results of cardiovascular reflex tests. Regional abnormalities of adrenergic innervation were revealed in 10% of control subjects, in 70% of N- patients and in 100% of N+ patients. The finding of a higher than expected prevalence of MIBG regional abnormalities in patients without signs or symptoms of autonomic neuropathy allows to hypothesize that cardiac autonomic nervous damage occurs earlier than previously known in diabetic patients whose cardiovascular tests are still completely normal.

Quantitative comparison of technetium-99m tetrofosmin and thallium-201 images of the thyroid and abnormal parathyroid glands.

The aim of the study was to quantitatively compare the scintigraphic images of the thyroid and abnormal parathyroid glands obtained with technetium-99m tetrofosmin and thallium-201 in patients with hyperparathyroidism. Forty-six patients with hyperparathyroidism underwent (201)Tl (74 MBq), (99m)Tc-pertechnetate (74 MBq) and (99m)Tc-tetrofosmin (555-740 MBq) scintigraphy in a single session. Image analysis included the computation of the thyroid/background ratio in the whole study population and the parathyroid/background ratio, parathyroid/thyroid ratio and diagnostic sensitivity in 17 patients who underwent parathyroid surgery. The pertechnetate subtraction technique was used. (201)Tl and (99m)Tc-tetrofosmin showed a similar thyroid/background ratio (1.79+/-0.41 and 1.81+/-0. 47, respectively, P=NS); however, (99m)Tc-tetrofosmin showed a higher parathyroid/background ratio than (201)Tl (2.06+/-0.54 vs 1. 79+/- 0.50, P=0.007). Despite the superior quality of (99m)Tc-tetrofosmin images, both tracers showed identical sensitivity in detecting enlarged parathyroid glands in patients with primary hyperparathyroidism (89%) and in those with secondary hyperparathyroidism (50%).