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Aim: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. We previously showed that 18F-FLT uptake is a reliable imaging biomarker of tumor response in refractory NSCLC due to both mechanisms of resistance. Here we tested whether 18F-FDG PET/CT is able to detect the T790M- or MET-mediated resistance and to monitor the reversal of such resistance by EGFR T790M or MET inhibitors in tumor-bearing animals.Materials and Methods: Erlotinib-resistant NSCLC cell lines (H1975 and H1993) were treated with WZ4002, an EGFR T790M inhibitor, or the MET-inhibitor crizotinib depending on the mechanism of resistance. The levels and phosphorylation status of key proteins in the glycolytic cascade and oxidative phosphorylation were tested in response to treatment along with 18F-FDG uptake. Then nude mice bearing H1975 and H1993 xenografts were subjected to 18F-FDG PET/CT scan before and after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib or vehicle. Three-dimensional region of interest analysis was performed to determine the percent change of 18F-FDG uptake in response to treatment. At the end of imaging studies, tumors were removed, counted and analysed for glycolytic and mitochondrial proteins as well as signaling mediators. Results: H1975 cells showed a statistically significant reduction of 18F-FDG uptake in response to treatment with WZ4002 (-61%

Purpose: The present study aimed to assess bone mineral density (BMD) in a population of children and adolescents with cerebral palsy and mental retardation with or without epilepsy. Methods: One hundred thirteen patients (63 male and 50 female) were recruited for evaluation. Patients were divided in three groups: 40 patients (group 1) were affected by cerebral palsy and mental retardation; 47 (group 2) by cerebral palsy, mental retardation, and epilepsy; and 26 (group 3) by epilepsy. The control group consisted of 63 healthy children and adolescents. Patients underwent a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine (L1L4), and z-score was calculated for each patient; t-score was considered for patients 18 years of age and older. Key Findings: Abnormal BMD by DEXA was found in 17 patients (42.5%) in group 1, in 33 (70.2%) in group 2, and in 3 (11.5%) in group 3. In groups 1 and 2, tetraparesis and severe/profound mental retardation were related to a significantly abnormal BMD (p = 0.003). The multivariate analysis of independent factors on BMD (z-score) revealed a significant correlation between BMD (z-score) and age (p = 0.04), body mass index (BMI; p = 0.002), severe/profound mental retardation (p = 0.03), and epilepsy (p = 0.05). Significance: A significantly lower BMD z-score value was found in patients with cerebral palsy, mental retardation, and epilepsy compared with those without epilepsy. The epileptic disorder appears to be an aggravating factor on bone health when comorbid with cerebral palsy and mental retardation.

PURPOSE: The aim of this study was to assess bone mineral density (BMD) in a large population of children, adolescents, and young adults with epilepsy alone or in association with cerebral palsy and/or mental retardation. METHODS: Ninety-six patients were enrolled in the study. The group comprised 50 males and 46 females, aged between 3 and 25 years (mean age 11 years). The control group consisted of 63 healthy children and adolescents (23 males, 40 females), aged between 3 and 25 years (mean age 12.1 years). Patients underwent a dual-energy x-ray absorptiometry (DEXA) scan of the lumbar spine (L1-L4) and the z scores were calculated for each patient; the t score was considered for patients 18 years of age or older. RESULTS: Abnormal BMD was found in 56 patients (58.3%), with values documenting osteopenia in 42 (75%) and osteoporosis in 14 (25%). A significant difference emerged between epileptic patients and the control group in BMD, z score, and body mass index (BMI) (p =

To investigate how the glycolytic pathway is affected by the inhibition of EGFR signaling, we selected NSCLC cells that were resistant to erlotinib due to T790M mutation (H1975) or MET amplification (H1993) and treated them with erlotinib (negative control), third generation EGFR TKIs or MET inhibitors (positive controls) so that differential changes of glycolytic pathway could be observed in the same cellular context in response to the efficient inhibition of EGFR signaling. Materials and Methods. To this end H1975 cells were preliminarily tested for GLUT1, GLUT3, Hexokinase (HK) I and II, Pyruvate Kinase (PK) M1 and M2 expression before and after 48-72 h treatment with erlotinib (1?M) and WZ4002 (0.1?M and 1?M) by real time PCR and western blot analysis. In parallel experiments H1993 cells were treated with erlotinib (1?M) and PHA-665,752 (1?M). 18F-FDG uptake and glucose consumption were then determined in untreated and treated cells along with hexokinase activity and PKM2 phosphorylation status. Finally drug-induced changes of glycolytic pathway were compared to the levels of total and phosphorylated forms of EGFR signaling mediators. Results. Effective inhibition of EGFR signaling in H1975 cells treated with WZ4002 was associated with a dramatic reduction of HKII expression and activity, translocation of GLUT3 from membrane to cytosol and reduction of phosphorylated form of PKM2. Accordingly, a parallel decrease of 18FFDG uptake and glucose consumption was observed in response to effective treatment in those cells. No changes of glycolytic pathway were found in H1975 cells after treatment with erlotinib. Similarly, H1993 cells treated with PHA-665,752 showed a strong reduction of HKII expression, phosphorylated form of PKM2, glucose consumption and 18F-FDG uptake whereas only a slight decrease of phosphorylated form of PKM2 was observed after erlotinib treatment. Furthermore the strong reduction of HKII and phosphorylated form of PKM2 were associated with a decrease of P-EGFR or P-MET in treated H1975 and H1993 cells, respectively, along with a reduction of P-AKT, P-ERK and cyclin D1 in both cell lines. The slight reduction of phosphorylated form of PKM2 in erlotinib treated H1993 cells was associated with a decrease of P-EGFR without inhibition of downstream mediators. Conclusion. Early reduction of 18F-FDG uptake in response to efficient inhibition of EGFR signaling mainly occurs through changes in the expression and activity of HKII and phosphorylation status of PKM2.

Aim: The aim was to compare the imaging findings of 18F-fluorodeoxyglucose (18F-FDG) PET and integrated PET/CT in patients with primary, recurrent or metastatic ovarian cancer. Materials and methods. 21 women with ovarian cancer were evaluated. All patients had a integrated PET/CT scan. Localization, infiltration and uptake intensity of [18F]FDG were evaluated on PET and PET/CT. The certainty of localisation and characterisation was scored on a 3 point scale (L1 definite localisation; L2 probable localisation; L3 uncertain localisation; C1 benign; C2 equivocal; C3 malignant). Results. PET scored as L1 54 lesions (44%), as L2 51 (42%), and as L3 17 (14%). On the other hand, PET/CT scored as L1 120 lesions (98%), as L2 2 (2%), and none as L3. Thus PET/CT allowed a better localization in 54% of lesions. Moreover, PET scored as C1 25 lesions (20%), as C2 62 (51%), and as C3 35 (29%) . On the other hand, PET/CT scored as C1 57 lesions (47%), as C2 13 (11%), and as C3 52 (42%). Thus PET/CT allowed a sensible reduction in the number of equivocal lesions (40%). Even when patients were subgrouped on the basis of clinical stage of the disease, PET/CT was capable of better definition of the lesions either for localization and for characterization. Conclusions. In patients with ovarian cancer, PET/CT allows better anatomical localisation of pathologic uptake providing high accuracy for staging and restaging of ovarian cancer when compared with PET alone.

INTRODUCTION: The clinical applications of fluorine-18-deoxyglucose Positron Emission Tomography (FDG PET) have been proposed on account of experimental evidence of increased glucose metabolism in tumor cells. MATERIAL AND METHODS: We examined 98 lymphoma patients--33 with Hodgkin and 65 with non-Hodgkin disease--with FDG PET and compared its findings with those of clinical and conventional radiologic studies. FDG PET was also used to follow-up 32 patients and the results were once again compared with clinical and radiologic data. RESULTS: During staging, 138 lesions were found, 82 of them (59%) in nodal and 56 (41%) in extranodal locations. Extranodal tumor sites were found in 39 patients (40%), namely 4 with Hodgkin (12%) and 35 with non-Hodgkin (54%) disease. FDG PET findings were in agreement with clinical and radiologic results in all nodal and extranodal lesions, since all of them exhibited abnormally increased FDG uptake. PET detected new tumor sites in 6 patients. In the follow-up, agreement was observed in the majority (78%) of lesions, 30 of them in complete regression, 15 in partial regression and 17 in progression; however, the diagnostic results were in disagreement in the remaining (22%) tumor sites: no abnormal FDG uptake was found in 9 cases despite the persistence of radiologic abnormalities (post-treatment fibrosclerosis). Slightly increased FDG uptake (residual disease) was found in the other 8 lesions, where there was no clinical and/or radiologic evidence of disease. CONCLUSIONS: FDG PET is a functional imaging technique useful to diagnose lymphomas and providing metabolic characterization of cancer abnormalities. Whole body PET permits the simultaneous assessment of nodal and extranodal lymphoma localizations. During the follow-up, FDG PET permits better monitoring of treatment effects than clinical and radiologic examinations.

The multidrug-resistant phenotype is characterized by the reduced intracellular retention of several structurally and functionally unrelated cytotoxic compounds due to the energy-dependent pump activity of P-glycoprotein (Pgp). Because 99mTc-sestamibi is a suitable transport substrate of Pgp, we tested whether the time-dependent fractional retention of this tracer could be used as an index of Pgp expression in untreated breast carcinomas.Twenty-seven patients with histologically confirmed breast carcinoma were intravenously injected with 740 MBq (20 mCi) of 99mTc-sestamibi, and static planar images of the breast were obtained at 10, 60 and 240 min. The fractional retention of 99mTc-sestamibi was then calculated as the ratios between 60 and 10 min (R60/10) and between 240 and 10 min (R240/10) of decay-corrected counts/pixel registered in the region of interest drawn around the tumor. Surgically excised tumors were then obtained from each patient, and Pgp levels were determined using 125I-labeled MRK16 monoclonal antibody and in vitro quantitative autoradiography.The fractional retention of 99mTc-sestamibi at 60 and 240 min was significantly higher in tumors with low Pgp levels (Group I, n = 18) as compared to that measured in tumors with high Pgp expression (Group II, n = 9) (p0.001). In particular, R60/10 values were 0.86 and 0.59 in breast carcinomas of Groups I and II, respectively, whereas the values of R240/10 were 0.56 and 0.25 in low- and high-Pgp-expressing tumors, respectively.The determination of fractional retention of 99mTc-sestamibi may be used as a simple functional test for Pgp expression in untreated breast cancer. A preliminary estimate of the sensitivity and the specificity of the test indicates its potential use in clinical practice to identify patients with a high probability of developing multidrug resistance.

In this study, 15 patients (4 men and 11 women, mean age: 50 +/- 13 years) with unilateral adrenal masses detected on ultrasound (US), Computed Tomography (CT) and/or Magnetic Resonance (MR) studies were submitted to positron emission tomography (PET) with fluorine-18 deoxyglucose (FDG). Histology demonstrated 3 adenomas, 1 myelolipoma, 1 angiolipoma, 1 neurinoma, 1 cyst, 1 malignant pheochromocytoma, 4 carcinomas and 3 metastases. The patient population was divided into two groups. Group 1 (n = 7) consisted of benign adrenal lesions. Group 2 consisted of malignant adrenal tumors. Lesion measurements were performed on the basis of the results of US, CT and/or MR images. In Group 1, no FDG uptake was observed in adrenal masses. Conversely, in Group 2 adrenal lesions showed abnormally increased FDG uptake, suggesting high glucose tumor metabolism. No significant difference in lesion size was observed between Groups 1 and 2 (5.6 +/- 4.0 vs 6.3 +/- 3.0 cm). Furthermore, in 6 patients of Group 2, total body PET images showed abnormal FDG uptake in extra-adrenal locations, such as chest (n = 2) and abdominal (n = 5) lymph nodes, lungs (n = 6), liver (n = 5), pancreas (n = 1), bone (n = 1) and muscle (n = 1) tissues. In conclusion, the results of this study suggest that PET imaging with FDG can characterize adrenal masses. In particular, abnormally increased FDG uptake in adrenal malignancies allows to differentiate these abnormalities from benign lesions. Furthermore, total body imaging PET can identify extra-adrenal tumor sites in patients with malignant tumors.

In this study, 15 patients (4 men and 11 women, mean age: 50 +/- 13 years) with unilateral adrenal masses detected on ultrasound (US), Computed Tomography (CT) and/or Magnetic Resonance (MR) studies were submitted to positron emission tomography (PET) with fluorine-18 deoxyglucose (FDG). Histology demonstrated 3 adenomas, 1 myelolipoma, 1 angiolipoma, 1 neurinoma, 1 cyst, 1 malignant pheochromocytoma, 4 carcinomas and 3 metastases. The patient population was divided into two groups. Group 1 (n = 7) consisted of benign adrenal lesions. Group 2 consisted of malignant adrenal tumors. Lesion measurements were performed on the basis of the results of US, CT and/or MR images. In Group 1, no FDG uptake was observed in adrenal masses. Conversely, in Group 2 adrenal lesions showed abnormally increased FDG uptake, suggesting high glucose tumor metabolism. No significant difference in lesion size was observed between Groups 1 and 2 (5.6 +/- 4.0 vs 6.3 +/- 3.0 cm). Furthermore, in 6 patients of Group 2, total body PET images showed abnormal FDG uptake in extra-adrenal locations, such as chest (n = 2) and abdominal (n = 5) lymph nodes, lungs (n = 6), liver (n = 5), pancreas (n = 1), bone (n = 1) and muscle (n = 1) tissues. In conclusion, the results of this study suggest that PET imaging with FDG can characterize adrenal masses. In particular, abnormally increased FDG uptake in adrenal malignancies allows to differentiate these abnormalities from benign lesions. Furthermore, total body imaging PET can identify extra-adrenal tumor sites in patients with malignant tumors