COVID-19 pandemic: Implications for radionuclide therapy in Nuclear Medicine departments.

The global COVID-19 health and economic crisis has forced people to adopt challenging rules of social distancing and self-isolation. Health care staff has been advised to change working routines to keep themselves and their patients safe. Radionuclide therapy has had an increasing role in clinical practice. Most therapeutic radionuclide procedures have applications in oncology. Cancer patients are an especially fragile and vulnerable population with higher risk due to co morbidities and immunosuppression. COVID-19 is another risk that must be considered in treatment planning. Therapeutic, prophylactic, and supportive interventions may require changes for these patients. The most common radionuclide therapies involve patients with differentiated thyroid cancer (DTC) who need radioiodine therapy (RAI), patients with neuroendocrine tumours (NETs) who need peptide receptor radionuclide therapy (PRRT), patients with hepatocellular carcinoma (HCC) who need therapy with radiolabelled microspheres, and patients with prostate cancer and bone metastasis who need radionuclide palliative therapy. If infected, cancer patients could be at a higher risk for serious COVID-19 disease. Treatment decisions for thyroid cancer and NETs are challenging in this environment. Any decision to postpone therapy must be carefully considered, balancing risks and benefits. A risk of worsened prognosis due to delayed or suboptimal cancer treatment must be weighed against the risk of severe COVID-19 illness.

Pleuropericardial Cyst Mimicking a Metastasis of Differentiated Thyroid Carcinoma on Whole-Body Iodine-131 Scan: a Case Report.

Post-therapeutic whole-body scan (WBS) with I-131 has been widely used for the follow-up of patients with well-differentiated thyroid cancer (DTC). Although the sensitivity of WBS with I-131 in detection of functioning thyroid tissues is high, its specificity is low. So, a further evaluation is required in cases of unexpected findings. The purpose of the study was to demonstrate that awareness of the potential pitfalls of WBS in DTC, knowledge of physiology and characteristics of radioiodine uptake, and correlation with other imaging modalities are needed to avoid incorrect management of patients with DTC. This is a case report of a 49-year-old woman with an unexpected area of increased I-131 uptake in the posterior lower chest, which was finally diagnosed as a pleuropericardial cyst. Due to the false-positive uptake of I-131 in the chest, an accurate interpretation of the scintigraphic findings should be made.

Brain SPECT and perfusion MRI: do they provide complementary information about the tumour lesion and its grading?

AIM: To evaluate the relative and combined utility of 99mTc-tetrofosmin (99mTc-TF) brain single-photon-emission computed tomography (SPECT) and dynamic susceptibility contrast (DSC) perfusion magnetic resonance imaging (MRI) in grading brain gliomas. MATERIALS AND METHODS: Thirty-six patients with clinically suspected brain tumours were assessed by 99mTc-TF SPECT and DSC-MRI. Brain tumour malignancy was confirmed in all patients at histopathology. On both techniques brain lesions were evaluated via visual and semi-quantitative analysis methods (deriving tetrofosmin index [T-index] and relative cerebral blood volume [rCBV] ratios, respectively). RESULTS: 99mTc-TF SPECT showed abnormally elevated tracer uptake in 31/36 patients whereas MRI detected the brain tumour in all patients. Optimal cut-off values of each index for discriminating between low- and high-grade gliomas were obtained through receiver operating characteristic (ROC) analyses. A T-index cut-off of 6.35 ensured 82% sensitivity and 71% specificity for discriminating between high- and low-grade gliomas, whereas a relative rCBV ratio cut-off of 1.80 achieved 91% sensitivity and 100% specificity. Requiring a positive result on either technique to characterise a high-grade glioma was associated with similar specificity and slightly increased sensitivity. CONCLUSION: Both imaging techniques, 99mTF SPECT and DSC MRI, may provide complementary indices of tumour grade and have an independent diagnostic value for high-risk tumours.

Isolated cardiac amyloidosis. Utility of bone seeking tracers scintigraphy in differentiating the subtype of amyloid: A case report.

BACKGROUND: Three types of amyloid are responsible for cardiac amyloidosis. Differentiation of the subtype is critical for the disease progression and the therapeutic decision. RESULTS: Myocardial scintigraphy using Tc-PYP is able to differentiate the cardiac amyloid subtype with high sensitivity and specificity. The myocardial uptake of PYP is higher in patients with TTR amyloidosis. CONCLUSION: Non-invasive tests for the detection of cardiac amyloidosis, like myocardial scintigraphy with bone seeking tracers, can play a major role in the diagnosis progression and therapeutic management of patients with cardiac amyloidosis.

Hybrid cardiac imaging: insights in the dilemma of the appropriate clinical management of patients with suspected coronary artery disease.

AIM: To evaluate the potential of SPECT myocardial perfusion imaging (MPI)-computed tomography coronary angiography (CTCA) hybrid fusion imaging to improve the diagnostic performance of cardiac SPECT/MPI and CTCA alone in order to act as more accurate gate keeper to further investigation invasive or not. METHODS AND RESULTS: Twenty-five patients were subjected to SPECT/MPI and CTCA within a period of 1 month without any medical treatment modification. A fusion software package was used for cardiac SPECT-CTCA image fusion. Semiquantitative analysis was performed for cardiac SPECT, CTCA and SPECT/MPI-CTCA fusion images. Patients were classified in 2 groups according to the clinical decision for further investigation (group A), or not (group B). Statistically significant differences were observed when SPECT/MPI-CTCA fusion images were used instead of cardiac SPECT alone (p<0.05). No statistically significant differences were observed comparing CTCA alone to SPECT/MPI-CTCA fusion images (p=0.25). A mid-term follow-up (mean 3.58 ± 0.24 years) showed that all patients classified in group A based on the interpretation of SPECT MPI-CTCA fused images underwent conventional coronary angiography with further necessity for PTCA or CABG whereas absence of major or minor cardiac events was revealed for all patients of group B. CONCLUSION: In patients suspected for coronary artery disease, cardiac SPECT/MPI-CTCA fusion imaging was found to considerably alter the clinical decision for referral to further investigation derived from SPECT/MPI.

Pseudomonas aeruginosa urinary tract infection in children: risk factors and outcomes.

PURPOSE: Pseudomonas aeruginosa is an unusual uropathogen that is mostly responsible for nosocomial or catheter associated urinary tract infections in adults. Data about P. aeruginosa urinary tract infections in children are scarce. We investigated P. aeruginosa urinary tract infections in children in a well-defined area. MATERIALS AND METHODS: Clinical, laboratory and radiological characteristics of all children with P. aeruginosa urinary tract infections were compared to those of gender matched children with community acquired Escherichia coli urinary tract infections during a 12-year period. RESULTS: A total of 35 children with 43 P. aeruginosa urinary tract infection episodes representing 6.7% of total urinary tract infection cases during the study period were compared to 70 children with E. coli urinary tract infections. Children with P. aeruginosa more often presented with a history of at least 1 previous urinary tract infection episode (p <0.0001), hospitalization (p = 0.0001), use of antibiotics (p = 0.0001), malformations predisposing to urinary tract infections (p = 0.004), vesicoureteral reflux (p <0.0001), abnormal dimercapto-succinic acid scan (p = 0.0003), longer hospitalization and surgery. Use of antibiotics either as prophylaxis or as treatment within the preceding 2 months was demonstrated by multivariate logistic regression analysis as the single independent risk factor for P. aeruginosa urinary tract infections (odds ratio 21.6, 95% CI 4.65-100, p = 0.0001). P. aeruginosa isolates were often resistant to gentamicin (27.9%) and ceftazidime (13.9%) but remained sensitive to carbapenems and ciprofloxacin. CONCLUSIONS: P. aeruginosa urinary tract infection is associated with distinct risk factors and outcomes, and should be considered in predisposed children with symptoms of urinary tract infection who are on prophylaxis or have a history of a recent course of antibiotics.

Overview of positron emission tomography chemistry: clinical and technical considerations and combination with computed tomography.

The concept of emission and transmission tomography was introduced by David Kuhl and Roy Edwards in the late 1950s. Their work later led to the design and construction of several tomographic instruments at the University of Pennsylvania. Tomographic imaging techniques were further developed by Michel Ter-Pogossian, Michael E. Phelps and others at the Washington University School of Medicine. Positron emission tomography (PET) is a nuclear medicine imaging technique which produces a 3-dimensional image or map of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. Images of tracer concentration in 3-dimensional space within the body are then reconstructed by computer analysis. In modern scanners, this reconstruction is often accomplished with the aid of a CT X-ray scan performed on the patient during the same session, in the same machine. If the biologically active molecule chosen for PET is 18F-fluorodeoxyglucose (FDG), an analogue of glucose, the concentrations of tracer imaged give tissue metabolic activity in terms of regional glucose uptake. Although use of this tracer results in the most common type of PET scan, other tracer molecules are used in PET to image the tissue concentration of many other types of molecules of interest. The main role of this article was to analyse the available types of radiopharmaceuticals used in PET-CT along with the principles of its clinical and technical considerations.

Effect of angiotensin-converting enzyme inhibitors on systemic inflammation and myocardial sympathetic innervation in normotensive patients with type 2 diabetes mellitus.

Diabetes mellitus (DM) may cause an increase in the inflammatory status and oxidative stress as well as sympathetic nervous system overactivity, even in the absence of any other organic heart disease. We investigated the effect of perindopril, an angiotensin-converting enzyme inhibitor (ACE-i), on indexes of systemic inflammation and oxidative stress in normotensive patients with type 2 DM. We also examined the effect of the drug on the disturbances of left ventricular myocardial adrenergic innervation that may be seen in these patients. We studied 62 normotensive patients with type 2 DM, who were randomized to receive perindopril (n=32) or placebo (n=30). At the start of the study and after 6 months' therapy blood samples were taken to evaluate total peroxides (TP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), and the patients underwent a (123)I-metaiodobenzylguanidine myocardial scintigraphy study. ACE-i caused a significant reduction in levels of cytokines and TP (P<0.001 for IL-6 and TNF-alpha, P=0.001 for TP). There was also a reduction in total defect score (P<0.001) and the heart to mediastinum ratio at 10 min and 4 h was improved (P<0.001 for both). No significant alterations were observed in the placebo group. Our data indicate that the addition of ACE-i to the medication of normotensive diabetic type 2 patients may improve the disturbed myocardial adrenergic innervation, the systemic inflammatory status and oxidative stress. Our findings indicate the cardioprotective action of ACE-i and suggest that earlier treatment might be appropriate in those patients.

Contribution of 99mTc-anti-carcinoembryonic antigen antibody and 99mTc-sestamibi scintimammography in the evaluation of high risk palpable breast lesions.

Mammography is the screening test of choice for breast cancer. Its low specificity leads to a large number of unnecessary biopsies. Scintimammography, with either Tc-sestamibi (MIBI) or Tc-anti-carcinoembryonic antigen (CEA) Fab', has been proposed as a non-invasive test to lower the high false positive rate of mammography in certain patients. The two agents have not been compared, nor has their combined application been evaluated. We performed a prospective, non-randomized, open-label, single-centre study of 32 women with clinically and mammographically suspected breast cancer [Breast Imaging Reporting and Data System (BI-RADS, American College of Radiology) 4 or 5]. All patients underwent Tc-MIBI and Tc-anti-CEA Fab' scintimammography, and the results were correlated with histopathology. Overall, the accuracies for MIBI and CEA scans were 90.3% (28/31) and 77.4% (24/31), respectively. The probability of disease after mammography was 0.939+/-0.081 (95% confidence interval, CI). The post-mammography probabilities after positive MIBI or CEA scan were 0.965 and 0.960, respectively, and after negative MIBI or CEA scan 0.750 and 0.875, respectively. None of the above differences is significant. The post-test probability when both scans were positive (irrespective of which was performed first) was 0.977. It can be concluded that there are indications that scintimammography with Tc-MIBI is superior to that with Tc-anti-CEA Fab' when these tests are used as screening tests for breast cancer. However, mammography remains the screening test of choice for highly suspicious clinically palpable breast lesions. In this group of patients, the application of scintimammography with either Tc-MIBI or Tc-anti-CEA Fab' (alone or in combination) offers no additional advantage.

Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: relationship to regional wall motion and myocardial perfusion abnormalities.

BACKGROUND: Iodine 123-labeled metaiodobenzylguanidine (MIBG) has been used to study cardiac adrenergic nerve activity. Cardiac MIBG uptake is diminished in patients with heart failure. However, it is not known how this reduction is related to regional abnormalities of myocardial wall motion or perfusion. METHODS AND RESULTS: We studied 24 patients with idiopathic dilated cardiomyopathy (ejection fraction <45%) and 15 healthy control subjects using I-123 MIBG cardiac imaging, echocardiographic assessment of wall motion abnormalities, technetium 99m sestamibi perfusion scintigraphy, and hemodynamic assessment. Cardiac MIBG was significantly correlated with ejection fraction (r = 0.67), cardiac index (r = 0.57), left ventricular wall motion score index (r = -0.68), and systolic wall stress (r = -0.61). MIBG was lower in patients than in control subjects (1.43 +/- 0.19 vs 2.05 +/- 0.02; P <.01), whereas the washout rate was higher (P <.01). Moreover, a significant correlation was found between the reduction in MIBG uptake and the severity of echocardiographic wall motion abnormalities in the anterior wall (r = 0.543), apex (r = 0.530), and septum (r = 0.675), as well as with the severity of decrease in resting myocardial perfusion in the anterior wall (r = 0.480) and septum (r = 0.580). CONCLUSIONS: Patients with idiopathic dilated cardiomyopathy show not only global but also regional abnormalities of cardiac sympathetic innervation. The severity of these changes is partially correlated with abnormalities of regional wall motion and myocardial perfusion.

The role of 99m Tc-sestamibi scintimammography and colour Doppler ultrasonography in the evaluation of breast lesions.

In the present study we evaluated comparatively the diagnostic value of mammography, of 99mTc-sestamibi scintimammography (sestamibi-SC) and of colour Doppler ultrasonography (CD-US) in 116 breast lesions. Diagnosis was based on histopathological examination. Overall, out of 86 malignant tumours, 80 (93%) and 75 (87%) had a positive sestamibi-SC and positive CD-US, respectively. Out of 30 benign lesions, 25 (83%) and 26 (87%) had a negative sestamibi-SC and negative CD-US respectively. The true positive results were similar in palpable and in non-palpable lesions for both methods. Out of 19 non-palpable malignant tumours, mammography confirmed malignancy in only one case (5%), which was significantly lower than the results obtained by sestamibi-SC (89%; Px0.0001) and by CD-US (74%; P=0.0001). In palpable malignant tumours, by using mamography, true positive results were obtained in 54/67 (80.5%) patients, which was significantly lower than the results obtained by sestamibi-SC (94%; P=0.03) and marginally different to the results obtained by CD-US (91%; P=0.13). It is concluded that sestamibi-SC and CD-US are useful tools in clarifying the nature of breast lesions in cases with doubtful mammography. The clinical value of these diagnostic procedures in guiding subsequent therapeutic interventions requires further investigation.

Value of Tc-99m sestamibi scintigraphy in the detection of bone lesions in multiple myeloma: comparison with Tc-99m methylene diphosphonate.

Technetium 99m-2-methoxyisobutylisonitrile (Tc-99m MIBI) is a lipophilic agent that accumulates preferentially within living malignant cells due to the higher transmembrane electrical potential as a consequence of the higher metabolic rate than in the surrounding normal cells. It has been effectively used to detect malignant tumors at diagnosis and follow-up and has been reported to be useful in detecting disease lesions in multiple myeloma. We studied 28 consecutive patients with multiple myeloma at diagnosis to determine the value of Tc-99m MIBI in comparison with Tc-99m methylene diphosphonate (MDP), conventional X-rays, computed tomography (CT) scan, and magnetic resonance imaging (MRI). We found 26 patients with obvious osteolytic lesions in X-rays, 22 patients with positive Tc-99m MIBI scans, and 15 patients with positive Tc-99m MDP scans. There was no coincidence of the positive lesions in the two scans, while in two patients the osteolytic areas were positive in the Tc-99m MDP scans, and in one case the osteolytic area was positive in the Tc-99m MIBI scan. The intensity of Tc-99m MIBI scans correlated with disease activity as determined by lactate dehydrogenase (LDH) (p<0.05), C-reactive protein (CRP) (p<0.01), beta2-microglobulin (p<0.05), and serum ferritin (p<0.01). We believe that Tc-99m MIBI scintigraphy can detect bone marrow lesions in myeloma patients that cannot be detected by other imaging methods and that it can be useful especially in solitary myeloma to exclude other involved sites. In addition, it could be a prognostic factor related to disease activity and multidrug resistance. We believe that a multicenter study is needed to evaluate the usefulness of this agent.

Effects of asynchronous ventricular activation on myocardial adrenergic innervation in patients with permanent dual-chamber pacemakers; an I(123)-metaiodobenzylguanidine cardiac scintigraphic study.

AIMS: To evaluate myocardial sympathetic innervation abnormalities in patients with DDD pacemakers for complete heart block. METHODS: We studied 39 patients, chronically paced in DDD mode because of complete atrioventricular block. Twenty-three healthy individuals served as a control group. All patients underwent planar and single-photon emission computed tomography (SPECT) myocardial imaging 4 h after intravenous infusion of 185 MBq I(123)-MIBG. The heart to mediastinum ratio was calculated to quantify cardiac I(123)-MIBG accumulation, while the SPECT study was performed to investigate the regional distribution of adrenergic innervation. All patients underwent a SPECT thallium(201)myocardial study during the same week as the I(123)-MIBG study. RESULTS: The heart to mediastinum ratio was significantly smaller in paced patients than in the controls (P<0.001). 89.7% of paced patients had regional abnormalities of I(123)-MIBG uptake, mainly in the inferior (92.3%) and apical (38.5%) wall. 46.2% of paced patients had regional perfusion defects, also mainly in the inferior (46.2%) and apical (10.3%) wall. Neither the I(123)-MIBG abnormalities nor the perfusion defects were related to the duration of pacing. CONCLUSIONS: Stimulation from the apex of the right ventricle leads to regional disturbances of the adrenergic innervation of the left ventricular myocardium, as assessed by I(123)-MIBG activity.

Myocardial perfusion in patients with permanent ventricular pacing and normal coronary arteries.

OBJECTIVES: The purposes of this study were to test the specificity of dipyridamole myocardial perfusion scintigraphy in patients with permanent ventricular pacing (PVP) and to evaluate coronary blood flow and reserve in these patients. BACKGROUND: Permanent ventricular pacing is associated with exercise perfusion defects on myocardial scintigraphy in the absence of coronary artery disease (CAD). On the basis of studies in patients with left bundle brunch block, coronary vasodilation with dipyridamole has been proposed as an alternative to exercise testing for detecting CAD in paced patients, but this approach has never been tested. METHODS: Fourteen patients with a PVP and normal coronary arteries underwent stress thallium-201 scintigraphy and cardiac catheterization. In these patients and in eight control subjects, coronary flow velocities were measured in the left anterior descending coronary artery (LAD) and in the dominant coronary artery before and after adenosine administration. RESULTS: In the paced patients, coronary flow velocities in the LAD and in the dominant coronary artery were significantly lower than those in the control subjects. In addition, seven patients showed perfusion defects on dipyridamole thallium-201 single-photon emission computed tomography, with a specificity of 50% for this test. The defect-related artery in these patients had lower coronary flow reserve (2.6 +/- 0.5) as compared with those without perfusion defects (3.9 +/- 1.0, p < 0.05) or the control group (3.5 +/- 0.5, p < 0.05). CONCLUSIONS: Permanent ventricular pacing is associated with alterations in regional myocardial perfusion. Furthermore, abnormalities of microvascular flow, as indicated by reduced coronary flow reserve in the defect-related artery, are at least partially responsible for the uncertain specificity of dipyridamole myocardial perfusion scintigraphy.

High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours.

The blood-brain barrier is a major obstacle for the chemotherapeutic drugs to effectively reach primary or secondary brain tumours. Stealth liposomal drugs are highly accumulated in tumoural tissues. In the present study we investigated the relative accumulation of(99m)Tc-DTPA radiolabelled stealth liposomal doxorubicin (Caelyx) in 10 patients with metastatic brain tumours and five patients with brain glioblastoma undergoing radiotherapy. Patients with metastatic brain lesions were treated with 10 consecutive fractions of radiotherapy (whole brain, 3 Gy/fraction, day 1-12) followed by a booster dose of 9 Gy (3 Gy/fraction, day 21-23). Caelyx, at a dose of 25 mg mg(-2)was given on day 1 and on day 21. Radiolabelled Caelyx accumulation was 13-19 times higher in the glioblastomas and 7-13 times higher in the metastatic lesions, as compared to the normal brain. The drug accumulation in the tumoural areas was 40-60% of the accumulation in the bone marrow of the skull bones. The normal brain radioactivity was <4% of the bone marrow, confirming an important shielding effect of the blood-brain barrier in the normal but not in the tumoural tissue. Four of 10 patients with metastatic lesions showed a complete response in CT-scan performed 2 months following therapy. There was no severe toxicity related to radiotherapy or to chemotherapy noted. It is concluded that stealth liposomal drugs selectively overcome the blood-brain barrier in the tumoural areas. The clinical importance of this observation is now under investigation.

High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas--rationale for combination with radiotherapy.

Sarcomas are radioresistant tumors, the only curative therapy being radical surgical resection. Stealth liposomal doxorubicin (Caelyx) is a novel drug formulation that allows prolonged circulation and high intratumoral concentration. This study investigates the concurrent use of radiotherapy with Caelyx in a cohort of 7 patients with locally advanced or recurrent sarcoma. Radiotherapy was given as a standard fractionation regimen to a total dose of 70 Gy. Caelyx was given as a 30-min infusion at a dose of 25 mg/m2 every 2 weeks. Scintigraphic imaging with Caelyx-99mTc-DTPA showed an increased (2.8 +/- 0.9 times higher) intratumoral drug accumulation compared to the surrounding healthy tissue. The regimen was well tolerated without any severe hematological or systemic toxicity. 'In field' radiation toxicity was not increased. Complete response was observed in 4/7 cases. It is concluded that combined chemo-radiotherapy with stealth liposomal doxorubicin for locally advanced sarcomas is feasible and promising, the benefit expected from the unique ability of the stealth liposomes to accumulate selectively in the tumoral tissue.

Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer.

PURPOSE: Stealth (ALZA Corporation, Palo Alto, CA) liposomal drug formulation allows a higher intratumoral accumulation and a prolonged plasma half-life of the encapsulated drugs. In the study presented here, we evaluated the feasibility of Stealth liposomal doxorubicin (Caelyx; ALZA Corporation) administered concurrently with conventionally fractionated radiotherapy in the treatment of non-small-cell lung cancer (NSCLC) and head and neck cancer (HNC). PATIENTS AND METHODS: Fifteen patients with NSCLC and 15 with squamous-cell HNC were recruited in two phase I dose-escalation trials. The starting dose of Caelyx was 10 mg/m(2) every 2 weeks (for three cycles during radiotherapy) and was increased by 5 mg/m(2) dose increments for every three patients. RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m(2) for HNC and 25 mg/m(2) in NSCLC patients. Oral/pharyngeal mucositis was the dose-limiting toxicity for HNC patients. "In field" radiation skin toxicity was slightly increased. Hematologic toxicity was minimal. Single photon emission computed tomographic evaluation of Caelyx distribution, using technetium-99m-diethylenetriamine pentaacetic acid labeling, revealed a high intratumoral accumulation of the drug. The tumor to thoracic vessel area count ratio in the NSCLC cases ranged from 0.6 to 1.6 (mean +/- SD, 1.01 +/- 0.29), whereas this ratio was higher (0.8 to 1.85; mean +/- SD, 1.35 +/- 0.39) in HNC cases (P =.049). The complete response rate was 21% in the NSCLC cases and 75% in the HNC cases. NSCLC cases with higher Caelyx tumor accumulation responded better to the regimen. The tumor microvessel density assessed with the anti-CD31 monoclonal antibody directly correlated with the degree of the Caelyx accumulation (P =.007; r =. 92). CONCLUSION: We conclude that combination of radiotherapy with Stealth liposomal doxorubicin is feasible. The potential role of such a regimen in the treatment of highly angiogenic tumors requires further investigation.