Decreased FDG Uptake Research Articles

Phase 2 Study of Ponatinib in Patients (Pts) with Advanced Gastrointestinal Stromal Tumors (Gist) After Failure of Tyrosine Kinase Inhibitor (Tki) Therapy: Early Results

ABSTRACT Aim: Ponatinib is an oral multi-targeted TKI with potent preclinical activity against mutant oncoproteins KIT and PDGFRa, including a broad range of clinically-relevant primary (especially KIT exon 11) and secondary (including KIT exon 17) resistance mutants. This in vitro activity suggests it may be effective in GIST pts with failure of prior TKI therapies. Methods: This phase 2 single arm trial evaluated efficacy and safety of ponatinib at 45 mg qd in advanced GIST pts after failure of prior TKI therapies. Pts were enrolled in Cohorts based on the presence (A) or absence (B) of KIT exon 11 mutations. Primary end point: clinical benefit rate (CBR=CR+PR+SD at 16 wks) by modified RECIST 1.1 in Cohort A. Secondary end points: CBR in Cohort B and total; ORR, PFS, OS, safety/tolerability in each cohort and total. New pt enrollment was held due to safety observations in other ponatinib trials; enrollment criteria are being revised to include only pts with failure of all 3 GIST-approved TKI. NCT01874665. Results: From Jun to Oct 2013, 35 pts were enrolled (Cohorts A: 24, B: 11). Median age: 58 yrs; 46% had 2 prior approved TKIs, 46% had 3 prior approved TKIs. 74% pts had ≥4 prior cancer regimens. Median time since diagnosis: 6 yrs. Median follow-up as of Apr 7 2014: Cohorts A: 7 mos, B: 4 mos. 14 pts on study, 21 discontinued: 10 PD, 7 AE, 4 other. Cohort A CBR: 50% (11/22 pts); ORR: 9% (2/22); Best Response: 2 PR and 14 SD. All 5 Cohort A pts with matched PET scans (BL v. C1) had decreased FDG uptake in active lesions, 3 remain on study with SD or better. Cohort B CBR: 27% (3/11); ORR: 0%. Most common (≥30%) treatment-emergent AE (TEAE): rash (57%), fatigue (49%), myalgia (46%), dry skin (43%), headache (43%), constipation (40%), abdominal pain (37%), hypertension (34%) and increased serum alkaline phosphatase (31%). Serious TEAE (≥2 pts): abdominal pain (11%), nausea (6%), vomiting (6%), and fatigue (6%). One pt had myocardial ischemia and 1 pt had right ventricular dysfunction. There was 1 death (pneumonia) that was possibly ponatinib-related. Conclusions: Initial analysis of this ongoing trial suggests that ponatinib has clinical activity in advanced GIST pts after failure of prior TKI therapies. Disclosure: M.C. Heinrich: Compensated consultant and/or advisor for Novartis, ARIAD, Pfizer, MolecularMD. Stock or other ownership interests in MolecularMD. I received honoraria directly from Novartis, Pfizer and Onyx. Conducted research funded by ARIAD; M. von Mehren: I am a compensated consultant and/or advisor for Novartis, ARIAD and GSK I have received honoraria directly from Novartis; G.D. Demetri: Compensated consultant/advisor for ARIAD, Novartis, Pfizer, Bayer & Blueprint Medicines, stock /other ownership in Blueprint Medcine. Received research funding from Novartis, Bayer and Pfizer; provided compensated expert testimony for ARIAD and Bayer; J. Fletcher: I am a compensated consultant and/or advisor for ARIAD, and received honoraria directly from Novartis; J. Sun: I have an employment /leadership role with ARIAD Pharmaceuticals – Senior Biostatistician. I have stock or other ownership interest in ARIAD Pharmaceuticals; J.G. Hodgson: I have an employment/leadership role with ARIAD Pharmaceuticals: Associate Director. I have stock or other ownership interest in ARIAD Pharmaceuticals; V.M. Rivera: I have an employment/leadership role with ARIAD Pharmaceuticals - Vice President, Preclinical and Translational Research. I have stock or other ownership interest in ARIAD Pharmaceuticals; C.D. Turner: I have an employment /leadership role with ARIAD Pharmaceuticals – Senior Medical Director. I have stock or other ownership interest in ARIAD Pharmaceuticals; S. George: I am a compensated consultant and/or advisor for Novartis, Bayer, Pfizer, ARIAD. I have received honoraria directly from Novartis. I have conducted research funded by Bayer, Novartis, and ARIAD

Effectiveness of pazopanib for postoperative recurrence of granulocyte colony-stimulating factor-producing primary hepatic angiosarcoma

A 38-year-old Japanese woman was referred to our hospital with complaints of fever, general fatigue, and upper abdominal discomfort. Computed tomography revealed a massive tumor in the right lobe of the liver, and laboratory data demonstrated increased white blood cell (WBC) count and serum granulocyte colony-stimulating factor (G-CSF) level. An extended right hepatectomy was performed, and pathological examination revealed spindle-shape tumor cells that formed vessel-like structures that were compatible with hepatic angiosarcoma. As a rapid recurrence occurred after surgery, S-1 was administered as a first-line chemotherapy, and weekly paclitaxel was administered as the second-line chemotherapy. However, patient eventually became resistant to these therapies. Therefore, pazopanib, a multitargeted tyrosine kinase inhibitor, was administered, after which both the WBC count and G-CSF level rapidly decreased. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed decreased FDG uptake. This is the first report on the administration of pazopanib as a third-line chemotherapeutic agent for treating G-CSF-producing primary hepatic angiosarcoma. The efficacy of this therapy was demonstrated with FDG-PET.

A Dual-Radioisotope Hybrid Whole-Body Micro-Positron Emission Tomography/Computed Tomography System Reveals Functional Heterogeneity and Early Local and Systemic Changes Following Targeted Radiation to the Murine Caudal Skeleton

The purpose of this study was to develop a longitudinal non-invasive functional imaging method using a dual-radioisotope hybrid micro-positron emission tomography/computed tomography (PET/CT) scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p < 0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation, which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p < 0.0001) decreased FDG uptake but increased NaF uptake (p = 0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p < 0.01). Non-invasive longitudinal imaging with dual-radioisotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function at local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer-term studies to clarify the effects of radiation on marrow and bone.

Correlation between standardized uptake value in pre- and post-neoadjuvant chemoradiotherapy and tumor regression grade in patients with locally advanced esophageal cancer.

150 Background: A multimodality approach with neoadjuvant chemotherapy and radiation is the standard of care in the United States in the treatment of patients with locally advanced esophageal cancer. It is well established that neoadjuvant chemoradiotherapy (CRT) in these patients can facilitate downstaging, correlating with pathologic response, and improving overall survival. Our clinical practice involves the use of positron emission tomography (PET) to assist with staging in patients prior to undergoing neoadjuvant CRT and surgery. While there has been evidence showing correlation between tumor regression grade (TRG) and increased overall survival in these patients, the relationship between standardized uptake values on PET scans and TRG has not been discerned. The purpose of this study was to determine whether pre and post-chemoradiotherapy SUV on PET scans correlate with TRG in esophageal cancer patients receiving neoadjuvant chemoradiotherapy. Methods: A retrospective review of 56 patients with stage II-III esophageal cancer treated with neo-adjuvant CRT followed by surgery was performed. Pre- and post- treatment PET scans were reviewed. Maximum SUV at the site of the primary tumor was recorded. Upon completion of surgery, tumor regression grade was determined by a specialized pathologist. Spearman correlation was used to compare pre, post, and change in max SUV, to the 4 level TRG variables. Results: The median follow-up was 24 months. No significant correlation was found between pre-treatment or post treatment SUV and TRG with p value of 0.73 and 0.94 respectively. There was no significant correlation between decreased FDG uptake following CRT and TRG with p value of 0.82. Consistent with previous data, TRG predicted the therapeutic efficacy and prognosis for patients with locally advanced esophageal carcinoma treated by neoadjuvant chemotherapy. Conclusions: Our results are preliminary and retrospective in nature. A larger sample is needed to confirm these findings. Decreased FDG uptake in sequential PET scans strongly correlates with tumor response, but is not accurate enough to predict pathological response.

Monitoring tumour response during chemo-radiotherapy: a parametric method using FDG-PET/CT images in patients with oesophageal cancer

BackgroundThe objective of this study is to investigate the feasibility and the additional interest of a parametric imaging (PI) method to monitor the early tumour metabolic response in a prospective series of oesophageal cancer patients who underwent positron emission tomography with fluoro-2-deoxy-d-glucose (FDG-PET/CT) before and during curative-intent chemo-radiotherapy.MethodsFifty-seven patients with squamous cell carcinoma (SCC) of the oesophagus prospectively underwent FDG-PET/CT before chemo-radiotherapy (CRT) (PET1) and at 21 ± 3 days after the beginning of CRT (PET2). The outcome was assessed at 3 months and 1 year after the completion of CRT (clinical examination, CT scan or FDG-PET/CT, biopsy). For each patient, PET1 and PET2 were registered using CT images. The 2 PET image sets were subtracted, so the voxels with significant changes in FDG uptake were identified. A model-based analysis of this graph was used to identify the tumour voxels in which significant changes occurred between the two scans and yielded indices characterising these changes (green and red clusters). Quantitative parameters were compared with clinical outcome at 3 months and at 1 year.ResultsThe baseline tumour FDG uptake decreased significantly at PET2 (p < 0.0001). The tumour volume significantly decreased between PET1 and PET2 (p < 0.02). The initial functional volume of the lesion (TV1) was significantly lower (p < 0.02) in patients in clinical response (CR) at 3 months and 1 year. The volume of the lesion during the treatment (TV2) was significantly lower in patients identified as in CR at 3 months (p < 0.03), but did not predict the outcome at 1 year. Multivariate analyses of outcome at 3 months showed that the risk of failure/death increased with younger age (p = 0.001), larger metabolic volume on PET1 (p = 0.009) and larger volume with decreased FDG uptake (p = 0.047). As for outcome at 1 year, the risk of failure/death increased with younger age (p = 0.006), nodal involvement (p = 0.08) and larger volumes with increased uptake (p = 0.03).ConclusionA parametric method to assess tumour response on serial FDG-PET performed during chemo-radiotherapy was evaluated. Early metabolic changes, i.e. variations in FDG uptake, provided additional prognostic information in multivariate analyses ClinicalTrials.gov NCT 00934505.Trial registrationCurrent Controlled Trials ISRCTN7824458

Single hind limb burn injury to mice alters nuclear factor-κB expression and [¹⁸F] 2-fluoro-2-deoxy-D-glucose uptake.

Burn trauma to the extremities can produce marked systemic effects in mice. Burn injury to the dorsal surface of mice is also associated with changes in glucose metabolism ([18F] 2-fluoro-2-deoxy-D-glucose [18FDG] uptake) by brown adipose tissue (BAT) and nuclear factor (NF)-κB activity in several tissues including skeletal muscle. This study examined the effect of a single hind limb burn in mice on 18FDG uptake by NF-κB activity in vivo, and blood flow was determined by laser Doppler techniques. Male NF-κB luciferase reporter mice (28-30 g) were anesthetized, both legs were shaven, and the right leg was subjected to scald injury by immersion in 90°C water for 5 seconds. Sham-treated animals were used as controls. Each burned and sham mouse was resuscitated with saline (2 mL, i.p.). The individual animals were placed in wire bottom cages with no food and free access to water. After 24 hours, the animals were imaged with laser Doppler for measuring blood flow in the hind limb. The animals were then unanesthetized with 50 μCi of FDG or luciferin (1.0 mg, i.v.) via tail vein. Five minutes after luciferin injection, NF-κB mice were studied by bioluminescence imaging with a charge-coupled device camera. One hour after 18FDG injection, the animals were killed with carbon dioxide overdose, and 18FDG biodistribution was measured. Tissues were also analyzed for NF-κB luciferase activity. The scalding procedure used here produced a full-thickness burn injury to the leg with sharp margins. 18FDG uptake by the burned leg was lower than that in the contralateral limb. Similarly, luciferase activity and blood flow in the burned leg were lower than those in the contralateral leg. 18FDG uptake by BAT and heart increased, whereas that by brain decreased. In conclusion, the present study suggests that burn injury to a single leg decreased FDG uptake by skeletal muscle but increased 18FDG uptake by BAT. The injury to the leg reduced NF-κB expression compared with the contralateral leg and the uninjured skeletal muscle of the sham but activated NF-κB expression in a number of other organs. These findings are consistent with the hypothesis that burn trauma to the extremities can produce marked systemic effects, including activation of NF-κB expression and activation of 18FDG uptake by BAT.

18F-FDG PET/CT Findings Preceded Elevation of Serum Proteinase 3 Antineutrophil Cytoplasmic Antibodies in Wegener Granulomatosis

A 67-year-old woman underwent F-FDG PET/CT after developing a fever of unknown origin. PET/CT revealed intensive FDG uptake at the nasal and lung lesions. On the laboratory data, serum myeloperoxidase antineutrophil cytoplasmic antibodies (ANCA) titer was elevated, although serum directed against proteinase 3 (PR3) ANCA titer was within normal limits. One month after treatment, follow-up PET/CT revealed decreased FDG uptake at the lesions. One year later, serum PR3-ANCA titer elevated, which finally led to a diagnosis of Wegener granulomatosis (WG). WG lesions may be detected earlier by FDG PET/CT than by serum PR3-ANCA titers.

Significant Activity Of The mTOR Inhibitor Sirolimus and HDAC Inhibitor Vorinostat In Heavily Pretreated Refractory Hodgkin Lymphoma Patients

BackgroundPreclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC. MethodsWe designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints. ResultsA total of 16 patients (men, n=8; women, n=8), median age 33 years, median of 6.5 prior therapies (including autologous SCT [n=15], autologous and allogeneic SCT [n=4]) were enrolled in dose escalation (n=1) or RP2D (n=15) cohorts. At the median follow-up of 3.2 months, 15 (94%) patients demonstrated decreased FDG uptake including 2 CRs (13%) and 5 PRs (31%) using CHESON criteria, with a total CR+PR rate of 44%. The median reduction of tumor was -27% (-100% to +20%, Figure). The estimated median time-to-treatment failure has not been reached and 63% of the patients continued on therapy with further improvement in their level of disease response. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (4 patients, 25%), grade 4 thrombocytopenia (6, 38%), grade 3 anemia (1, 6%), febrile neutropenia (1, 6%) and led to treatment interruptions and/or dose modifications in 10 (63%) patients. Five (31%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR. This patient has had a continuing response to therapy (-56%) for 8.4+ months. PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis continue. ConclusionThe combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Enrollment continues. [Display omitted] Disclosures:Off Label Use: sirolimus - mTOR inhibitor vorinostat - HDAC inhibitor.

Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan contributes to the diagnosis and management of brucellar spondylodiskitis

BackgroundLimited data suggest that fluorine-18 fluoro-2-deoxy-D-glucose (F-18 FDG) positron emission tomography combined with computed tomography (PET/CT) scan may be useful for diagnosing infections of the spine. Brucellar spondylodiskitis might be devastating and current imaging techniques lack sensitivity and specificity. The aim of this prospective study was to determine the role of F-18 FDG PET/CT scan in the diagnosis of brucellar spondylodiskitis and in monitoring the efficacy of its treatment.MethodsTen consecutive patients with brucellar spondylitis were prospectively evaluated with PET/CT. Baseline evaluation included also magnetic resonance imaging (MRI) of the affected spine, indices of inflammation, the slide agglutination test (SAT), and the standard hematology and biochemistry. All cases were treated with suitable antibiotics until resolution or significant improvement of clinical and radiological (MRI) findings. Upon completion of treatment, they were re-evaluated with follow-up PET/CT scan. The maximum standardized uptake values (SUV) were measured and compared with SAT.ResultsIn all patients there was an increased F-18 FDG activity in the infected spine region detected by the initial MRI. F-18 FDG PET/CT provided additional information, compared to MRI, in 4 (40%) patients. More specifically it revealed additional spine lesions (in 3 patients), lymphadenitis, arthritis, organomegaly, as well as new paravertebral soft tissue involvement and epidural masses. This additional information had an impact on the duration of treatment in these patients. At the end of treatment all patients had a complete clinical response; 5 patients had positive serology, 6 patients had residual MRI findings, while 9 had a positive PET/CT but with significantly decreased FDG uptake compared to baseline (median 2.6, range 1.4 – 4.4 vs. median 5.5, range 2.8 – 9.4, p = 0.005). During the follow up period (median 12.5 months) no relapses have been observed. No significant association was observed between the SUV and SAT.ConclusionsOur study suggests that in patients with brucellar spondylodiskitis F-18 FDG PET/CT scan can provide additional information on the spread of the infection, compared to MRI. Successful treatment is associated with a significant decrease in SUVmax values; thus, PET/CT scan may be a complementary method for determining the efficacy of treatment.

MRI and FDG PET/CT Findings of Hepatic Epithelioid Hemangioendothelioma

The aim of this study was to evaluate retrospectively magnetic resonance imaging (MRI) and (18)F fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) findings of hepatic epithelioid hemangioendothelioma (HEH). MRI and FDG PET/CT findings were reviewed in 6 patients with HEH confirmed by pathology. All patients underwent magnetic resonance (MR) examination. Early PET/CT scans were performed 1 hour after FDG injection in all 6 patients. After an interval of 1 hour, delayed PET/CT scans were performed in 4 patients. A total of 60 lesions were detected in all 6 patients. MRI features of HEH included multifocal hepatic disease, predominantly subcapsular location, coalescence of lesions, and capsular retraction. T2-weighted MR images frequently showed a target-like configuration of the lesions. Contrast-enhanced MR images showed variable degrees of peripheral rim enhancement with delayed central enhancement. Forty lesions (67%) with increased FDG uptake and 20 lesions (33%) with FDG uptake similar to the surrounding liver parenchyma were found in all 6 patients. The mean maximum standardized uptake value (SUV(max)) of all lesions was 3.6 ± 1.1, with a low variability of SUV(max) among lesions ranging from 1.7 to 6.6. There was no relationship between lesion sizes and corresponding SUV(max). Some larger lesions demonstrated a hypermetabolic peripheral rim reflecting hypercellular tumor regions and a relatively hypometabolic central area corresponding to hypocellular stroma. Eleven lesions with increased FDG uptake on the delayed PET/CT images were found in 3 patients, and 19 lesions with decreased FDG uptake were found in all 4 patients with total 32 lesions. MRI demonstrated morphological features of HEH and FDG PET/CT reflected the histopathological composition of the tumors. FDG uptake of HEH may be related to tumor cellularity, but not the tumor size. Dual-time-point imaging may be not useful for differentiating benign lesions from HEH. Familiarity with the morphological and functional imaging findings of HEH is useful for recognition of this rare hepatic tumor.

Posterior parietooccipital hypometabolism may differentiate mild cognitive impairment from dementia in Parkinson’s disease

Patients with Parkinson's disease (PD) may have normal cognition, mild cognitive impairment (MCI) or dementia. We investigated differences in cerebral metabolism associated with these three cognitive states and the relationship between metabolism and cognitive dysfunction. FDG PET and a battery of neuropsychological tests were used to study PD patients with dementia (n = 19), MCI (n = 28) and normal cognition (n = 21), and control subjects (n = 20). Regional glucose metabolism in patients and controls was analysed using statistical parametric mapping (SPM8) corrected for age, motor severity and depression. Correlations between the mini-mental state examination score and Z-score values of the different cognitive domains with respect to cerebral FDG uptake were assessed using SPM8. PD patients with MCI (PD-MCI patients) exhibited decreased FDG uptake in the frontal lobe, and to a lesser extent in parietal areas compared with cognitively normal patients. Patients with dementia showed reduced metabolism in the parietal, occipital and temporal areas and a less extensive reduction in the frontal lobe compared with PD-MCI patients, while widespread hypometabolism was seen in comparison with patients with normal cognition. PD-MCI patients exhibited reduced FDG uptake in the parietal and occipital lobes and in localized areas of the frontal and temporal lobes compared with controls, whereas patients with dementia showed a widespread reduction of cortical metabolism. Mini-mental state examination score correlated positively with metabolism in several lobes, executive function with metabolism in the parietooccipitotemporal junction and frontal lobe, memory with temporoparietal metabolism, visuospatial function with occipitoparietal and temporal metabolism, and language with frontal metabolism. PD patients with MCI exhibited hypometabolism in several cortical regions compared with controls, and in the frontal and parietal regions compared with cognitively normal patients. Hypometabolism was higher in patients with dementia than in those with MCI, mainly in the posterior cortical areas where it was correlated with visuospatial, memory and executive functions.

Comparison of diffusion-weighted MRI with 18F-fluorodeoxyglucose-positron emission tomography/CT and electroencephalography in sporadic Creutzfeldt–Jakob disease

18F-fluorodeoxyglucose-positron emission tomography/CT (18F-FDG PET/CT) scanning may be a useful tool for early diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD), as it may reveal lowered cellular glucose transport and metabolism in the cortex, cerebellum and basal ganglia. The aim of the present study was to compare the findings from PET/CT, MRI and electroencephalography (EEG) for patients with sCJD, to explore whether typical sites or reliable patterns of regional metabolic change could be found and to evaluate the results of diagnostic imaging in the light of clinical symptomatology. Five patients with biopsy-confirmed sCJD and nine with probable sCJD (aged 36–68years) were evaluated using PET/CT, diffusion-weighted (DW)-MRI and EEG. In 13 of the 14 patients (92.86%), PET/CT imaging detected extra regions with abnormalities in addition to the hyperintense areas shown with DW-MRI. Two patients with no abnormal DW-MRI findings in the basal ganglia had bilateral extrapyramidal signs accompanied by basal ganglia hypometabolism on PET. Eight patients (57.14%) had decreased FDG uptake in the thalamic nuclei on PET scans; however, DW-MRI did not identify corresponding hyperintense changes in the thalamic nuclei. In 11 patients (78.57%), DW-MRI revealed more regions with abnormalities than EEG, and 10 patients (71.43%) had DW-MRI abnormalities in the thalamic nuclei and basal ganglia that EEG was unable to detect. There was a high level of correspondence among the PET/CT, DW-MRI and EEG results, with PET revealing more abnormal regions than the other imaging modalities. In the absence of neuropathological findings, FDG-PET could improve the accuracy of sCJD diagnosis when combined with DW-MRI and EEG, particularly for differentiating sCJD from paraneoplastic syndromes. Our results suggest that PET/CT is able to detect sCJD at an earlier stage and with greater sensitivity than DW-MRI.

Abstract 1280: Preclinical and Clinical Evidence for MEK Pathway Inhibition by GDC-0973 using FDG-PET

Abstract Inhibitors of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) can cause potent growth arrest leading to tumor stasis or even regression, especially in BRAF mutant tumors. Seeking a pharmacodynamic marker of drug action, the effect of MEK inhibition on FDG PET signals was studied in rodent xenograft models using responsive and non-responsive cell lines. Colo205, HCT116, and A375 tumors showed substantial (30-50 %) signal (FDG flux, Ki, measured by a Patlak analysis) decreases within 72 h of beginning MEK inhibition and a rebound to baseline signal within 72 h of discontinuing treatment. BT474 tumors showed no effect. In MEK responsive tumors immunohistochemistry showed that glucose transporter GLUT1 redistributes away from the plasma membrane during treatment, which may explain the FDG PET findings. Fluorothymidine (FLT) uptake is also modulated by MEK inhibition, but the relative availability of clinical FDG PET centers and the robust preclinical results suggested the use of FDG PET, and not FLT PET, in clinic. FDG PET was implemented at all 4 Phase 1 study sites according to a standardized scanning charter. Scans were acquired at screening, at days 10-14 of cycle 1 (steady state drug concentration) and at days 26-28 of cycle 1 (trough drug concentration). Patients with RAS or RAF mutant tumors were treated at GDC-0973 MTD on the 21/7 and 14/14 dosing schedules. CT scans were acquired just prior to cycle 3 (∼ day 56) for response assessment. PET images were collected and read centrally. Up to 5 hypermetabolic lesions were assessed for mean and maximum standardized uptake value (SUV). A decrease of more than 20% in mean (across lesions) percentage change-from-baseline in SUVmax was considered a partial metabolic response (PMR). Compliance with the scanning guidelines across sites was generally good. Out of a total of 23 patients from both cohorts with PET scans read to date, 7 patients appeared to show a temporal profile of decreased FDG uptake at steady state with a rebound towards baseline at trough, mirroring the preclinical findings. Of 17 patients in the 21/7 MTD cohort whose PET scans were measured, 9 patients (∼53%) demonstrated a PMR at least one timepoint during cycle 1. Two of these patients demonstrated a PR per CT at 2 months (first tumor assessment) and also showed a robust PET response at both timepoints (Patient 1: -55% and -61% respectively; Patient 2: -63% and -53%). In addition, 2 other patients with a PMR at one or both timepoints had stable disease for at least 5 months. Of 6 patients in the 14/14 MTD cohort with PET scans read, 5 patients (83%) demonstrated a PMR at least one timepoint. Taken together, the preclinical PET evidence for a mechanistic effect of MEK inhibition on tumor glucose metabolism combined with the significant proportion of patients demonstrating PMR in this phase 1 study are consistent with hypothesis that GDC-0973 is achieving pathway modulation when given as single agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2011-1280

Hashimoto’s encephalopathy mimicking spinocerebellar ataxia

A 39-year-old man was admitted for complaints of worsening gait difficulty, weakness and dysarthria. His symptoms had developed 17 months earlier with unsteadiness of gait. Subsequently, he gradually developed difficulties in handwriting, weakness and dysarthria. His symptoms were considered as spinocerebellar ataxia in a local hospital and treated with CoQ10, and vitamins B1 and B12. No improvement was observed. His disability accelerated 2 weeks prior to admission. There is no family history of cerebellar symptoms. Physical examination revealed palpable thyroid gland. Neurological examination showed normal mental status, right central facial weakness, lingual fasciculations, brisk jaw jerk, hyperactive gag reflex and scanning dysarthria. Strength of left upper and right limbs was 4/5 with bilateral palmomental reflexes and right Babinski signs. Focal dystonia was observed in the right hand. He was only able to walk several steps, with broad-based, ataxic gait. Marked slowing and dysmetria of rapid alternating movements were noted. Pinprick and position sensations were preserved. There was no orthostatic hypotension. Magnetic resonance imaging (MRI) of the brain disclosed slight atrophy of the cerebellum without gadolinium enhancement (Fig. 1a). The electroencephalogram, Montreal Cognitive Assessment test and electromyography were normal. Cerebrospinal fluid (CSF) showed 126 mg/dl protein (normal 15–45 mg/dl) and normal IgG index. There were no oligoclonal bands (OB). Anti-GM1, GQ1b and GD1b antibodies were negative in both serum and CSF. Screenings of connective tissue disease, heavy metal and antibodies against viruses were negative. Angiotensin converting enzyme, vitamin B12, vitamin E, folate and rapid plasma reagin tests were unremarkable. Paraneoplastic antibodies were not detected in the serum. The chest CT was normal. Positron emission tomography (PET) only demonstrated a slightly decreased FDG uptake in the right thalamus (Fig. 1b). Genetic testing of SCA1-7, SCA12, SCA17 and DRPLA was negative. The patient was euthyroid with increased thyroglobulin antibody (TG-Ab) and thyroperoxidase antibody (TPO-Ab) concentrations at 83.2 U/ml (normal 0–60 U/ml) and [1,300 U/ml (normal 0–60 U/ml), respectively. Both TGAb and TPO-Ab were present in the CSF at 17.4 and 87.5 U/ml respectively. Thyroid ultrasound and scan revealed slightly enlarged thyroid gland with several hypoechoic areas and normal tracer uptake. Although antigliadin antibodies were not tested, neurological manifestations of gluten sensitivity are mainly ataxia, peripheral neuropathy, epilepsy and headache [6], which are not typical in this case. We diagnosed the condition as Hashimoto’s encephalopathy (HE) and initiated intravenous methylprednisolone 1 g/day for 5 days followed by oral prednisone tapering. Y. Tang and C. Chu contributed equally to this work.

Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma

To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)-targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging. EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using (64)Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with (90)Y-DOTA-cetuximab. EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher (64)Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to (90)Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody. Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles.

A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC)

e16056 Background: Everolimus, a mTOR inhibitor and Sorafenib, a Raf kinase inhibitor had shown their efficacy in RCC, as single agents. Combining these two active agents could have potential additive or synergistic effects. We conducted a phase I study to evaluate the maximum tolerated dose (MTD) of this combination in patients with progressive mRCC. Methods: Patients predominantly had clear cell RCC, and progressive measurable diseases on prior treatments including immunotherapy, TKI and/or Everolimus. Patients were evaluated weekly for toxicities and every 8 weeks for radiological response, including at least both PET/CT and CT scans at baseline and 1st staging. Patients received daily Everolimus and twice daily sorafenib both orally at escalating dose levels of 2.5mg/400mg (dose level 0), 5mg/400mg (+1), and 10mg/400mg (+2). Results: 18 patients with mRCC were enrolled and 15 patients were evaluable. 6 patients were treated on dose level 0, dose- limited toxicity (DLT) was found in 2/6 patients, one with thrombocytopenia/leukopenia, the other with pneumonitis; 6 patients were treated on dose level +1, DLT of pulmonary embolism was found in 1/6 patient; and 3 patients were treated on dose level +2, without DLT. The most common side effect was grade 1/2 hand-foot syndrome (4/15, 27%). The MTD was dose level +2. Overall response by RECIST was 27% (4/15 patients): pathological complete response (CR) was 6% (1/15); radiographic CR was 6% (1/5); surgical CR after resection was 6% (1/15). 47% (7/15) of the patients had stable disease. Decreased FDG uptake was found in 67% (10/15) of the patients. The median PFS was 5.53 months (range, 1.4–14.7), and OS was 7.9 months (range, 2.3–23). Conclusions: The MTD of combining daily Everolimus 10mg and twice daily sorafenib 400mg are safe and effective for progressive metastatic RCC. The phase II trial is planned to start in early 2009. [Table: see text]

PLX4032, a highly selective V600EBRAF kinase inhibitor: Clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial

9021 Background: PLX4032 is an oral, highly selective inhibitor of oncogenic V600EBRAF kinase currently in phase I trial. V600EBRAF mutation activates Raf/MEK/ERK pathway in multiple tumor types. We evaluated the relationship between PK, PD (pERK, Ki67, FDG-PET), tumor histology and clinical activity following PLX4032 administration in a phase I trial. Methods: In the phase I trial, 6 melanoma pts with V600EBRAF were treated with PLX4032 daily at several dose levels and tumor biopsies (baseline vs. day 15) were assessed histologically and by semi-quantitative IHC analysis (modified H-score) for pERK and Ki67. The first 4 pts received a crystalline formulation of PLX4032; the last 2 pts received a formulation with increased bioavailability. Plasma PK parameters were collected at frequent time points on Days 1, 8 and 15. FDG-PET was performed on Days 1 and 15 on last 2 pts. Results: In the first 4 pts, no histological changes were observed with treatment and all developed disease progression. All had decreased percentage of Ki67 positive nuclei (pre-Rx, range 20–60%, median 45%; post-Rx, range 5–25%, median 12.5%) and 3 of the 4 had decreased pERK levels (pre-Rx, range 50–100, median 60; post-Rx, range 10–40, median 11). Mean PLX4032 AUC0–24h ∼ 126 μM*h was in the range for preclinical tumor stasis but below the threshold for shrinkage. In the last 2 pts, striking tumor necrosis and tumor melanosis was observed in the post-Rx samples. One pt remains on study with a confirmed PR, the other showed a clinical response before disease progression occurred in cycle 2. The percentage of Ki67 positive nuclei declined substantially (pre-Rx, 30% and 50% to post-Rx, 5% and 3%), as did the levels of pERK in the pt with PR (pre-Rx: 70 to post-Rx: 2). Mean PLX4032 AUC0–24h was well above the preclinical threshold in the range of 500 - 1000 μM*h. Both pts had decreased FDG uptake on D15. Conclusions: Clinical activity of PLX4032 treatment correlates with drug exposure levels as measured by AUC0–24h and was associated with histological changes in V600EBRAF positive melanomas on Day 15. Reduction of pERK, along with evidence of reduced proliferation and FDG uptake was observed. Further analysis of PD markers with additional pts at the MTD is planned. [Table: see text]

Association between FDG uptake, CSF biomarkers and cognitive performance in patients with probable Alzheimer’s disease

Brain imaging of FDG uptake and cerebrospinal fluid (CSF) concentration of amyloid-beta 1-42 (Abeta(1-42)) or tau proteins are promising biomarkers in the diagnosis of Alzheimer's disease (AD). There is still uncertainty regarding any association between decreased FDG uptake and alterations in CSF markers. The relationship between FDG uptake, CSF Abeta(1-42) and total tau (T-tau), as well as the Mini-Mental State Examination (MMSE) score was investigated in 34 subjects with probable AD using step-wise linear regression. FDG uptake was scaled to the pons. Scaled FDG uptake was significantly reduced in the probable AD subjects compared to 17 controls bilaterally in the precuneus/posterior cingulate area, angular gyrus/inferior parietal cortex, inferior temporal/midtemporal cortex, midfrontal cortex, and left caudate. Voxel-based single-subject analysis of the probable AD subjects at p < 0.001 (uncorrected) revealed a total volume of significant hypometabolism ranging from 0 to 452 ml (median 70 ml). The total hypometabolic volume was negatively correlated with the MMSE score, but it was not correlated with the CSF measures. VOI-based step-wise linear regression revealed that scaled FDG uptake in the precuneus/posterior cingulate was negatively correlated with CSF Abeta(1-42). Scaled FDG uptake in the caudate was positively correlated with CSF T-tau. The extent and local severity of the reduction in FDG uptake in probable AD subjects are associated with cognitive impairment. In addition, there appears to be a relationship between local FDG uptake and CSF biomarkers which differs between different brain regions.

The Future of Cardiovascular Imaging in the Diagnosis and Management of Heart Failure, Part 1

Radiographic, ultrasound, nuclear, and magnetic resonance methods have become indispensable in the management of heart failure (HF). Imaging is widely used in decision making in HF, not only in relation to left ventricular (LV) systolic and diastolic function but also in the selection of medical, device, and surgical therapy in HF and valvular heart disease. Future developments in the care of advanced heart disease, including stem cell therapy, device therapy to control remodeling, and percutaneous valve interventions, as well as the need to identify subclinical heart disease, are likely to expand this use. Moreover, the epidemic of diabesity (diabetes and obesity) will augment the existing epidemic of HF just when it appeared to have peaked.1 Large numbers of patients will need information from imaging to guide clinical decision making (Table 1). The sources of this information will need to be expeditious, inexpensive, and preferably objective and quantitative.2 View this table: Table 1. Established HF: What the Clinician Needs Although some of the measurements in HF patients are structural (LV mass and geometry), the main components of an imaging assessment in HF will continue to be primarily functional (LV ejection fraction, size, filling pressures, filling characteristics, and right ventricular [RV] function). A number of new technologies will enhance the future accuracy and reliability of these measures. ### LV Volumes and Ejection Fraction Routine techniques (contrast ventriculography, 2D echocardiography) provide real-time imaging in standard imaging planes. The only traditional method that has escaped this limitation has been radionuclide ventriculography, in which the ejection fraction is calculated from scintigraphic counts, but this introduces the separate potential problems of attenuation and overlying chambers. #### Limitations of 2D Imaging Two-dimensional imaging approaches require expert acquisition and observers and have limited reliability in obtaining appropriate cut planes in sequential studies. The limitation of requiring imaging planes in the correct axis is particularly an issue for 2D echocardiography, which …

Specificity of the anti-glycolytic activity of 3-bromopyruvate confirmed by FDG uptake in a rat model of breast cancer

To evaluate the anti-glycolytic effects of 3-BrPA on rats bearing RMT mammary tumors, by determining FDG uptake after intravenous administration of the therapeutic dose. Sixteen rats bearing RMT tumors were treated either with 15 mM 3-BrPA in 2.5 ml of PBS or with 2.5 ml of PBS. After treatment, all rats received FDG and were sacrificed 1 h later. 3-BrPA treatment significantly decreased FDG uptake in tumors by 77% (p = 0.002). FDG uptake did not significantly decrease in normal tissues after treatment. Our study showed that 3-BrPA exhibits a strong anti-glycolytic effect on RMT cells implanted in rats.